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Bacterial accumulation in intestinal folds induced by physical and biological factors

The gut microbiota, vital for host health, influences metabolism, immune function, and development. Understanding the dynamic processes of bacterial accumulation within the gut is crucial, as it is closely rel...

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Insights for disease modeling from single-cell transcriptomics of iPSC-derived Ngn2-induced neurons and astrocytes across differentiation time and co-culture

Trans-differentiation of human-induced pluripotent stem cells into neurons via Ngn2-induction (hiPSC-N) has become an efficient system to quickly generate neurons a likely significant advance for disease model...

Molecular control of cellulosic fin morphogenesis in ascidians

The tunicates form a group of filter-feeding marine animals closely related to vertebrates. They share with them a number of features such as a notochord and a dorsal neural tube in the tadpole larvae of ascid...

Cue-driven microbial cooperation and communication: evolving quorum sensing with honest signaling

Quorum sensing (QS) is the ability of microorganisms to assess local clonal density by measuring the extracellular concentration of signal molecules that they produce and excrete. QS is also the only known way...

Publisher Correction: Female behavior drives the formation of distinct social structures in C57BL/6J versus wild-derived outbred mice in field enclosures

The original article was published in BMC Biology 2024 22 :35

MAPK-dependent control of mitotic progression in S. pombe

Mitogen-activated protein kinases (MAPKs) preserve cell homeostasis by transducing physicochemical fluctuations of the environment into multiple adaptive responses. These responses involve transcriptional rewi...

Phylogenomics resolves the higher-level phylogeny of herbivorous eriophyoid mites (Acariformes: Eriophyoidea)

Eriophyoid mites (Eriophyoidea) are among the largest groups in the Acariformes; they are strictly phytophagous. The higher-level phylogeny of eriophyoid mites, however, remains unresolved due to the limited n...

Single-cell RNA sequencing integrated with bulk RNA sequencing analysis identifies a tumor immune microenvironment-related lncRNA signature in lung adenocarcinoma

Recently, long non-coding RNAs (lncRNAs) have been demonstrated as essential roles in tumor immune microenvironments (TIME). Nevertheless, researches on the clinical significance of TIME-related lncRNAs are li...

OsmiR319-OsPCF5 modulate resistance to brown planthopper in rice through association with MYB proteins

The brown planthopper (BPH) is a kind of piercing-sucking insect specific to rice, with the damage tops the list of pathogens and insects in recent years. microRNAs (miRNAs) are pivotal regulators of plant–env...

Evolution of compound eye morphology underlies differences in vision between closely related Drosophila species

Insects have evolved complex visual systems and display an astonishing range of adaptations for diverse ecological niches. Species of Drosophila melanogaster subgroup exhibit extensive intra- and interspecific di...

Modeling antibody drug conjugate potential using a granzyme B antibody fusion protein

Antibody drug conjugates (ADCs) constitute a promising class of targeted anti-tumor therapeutics that harness the selectivity of monoclonal antibodies with the potency of cytotoxic drugs. ADC development is be...

DNA methylation haplotype block signatures responding to Staphylococcus aureus subclinical mastitis and association with production and health traits

DNA methylation has been documented to play vital roles in diseases and biological processes. In bovine, little is known about the regulatory roles of DNA methylation alterations on production and health trait...

Cytoplasmic genome contributions to domestication and improvement of modern maize

Studies on maize evolution and domestication are largely limited to the nuclear genomes, and the contribution of cytoplasmic genomes to selection and domestication of modern maize remains elusive. Maize cytopl...

The pharyngeal taste organ of a blood-feeding insect functions in food recognition

Obligate blood-feeding insects obtain the nutrients and water necessary to ensure survival from the vertebrate blood. The internal taste sensilla, situated in the pharynx, evaluate the suitability of the inges...

The fitness trade-off between growth and stress resistance determines the phenotypic landscape

A central challenge in biology is to discover a principle that determines individual phenotypic differences within a species. The growth rate is particularly important for a unicellular organism, and the growt...

An odorant receptor mediates the avoidance of Plutella xylostella against parasitoid

Ecosystems are brimming with myriad compounds, including some at very low concentrations that are indispensable for insect survival and reproduction. Screening strategies for identifying active compounds are t...

Mitochondrial perturbation in immune cells enhances cell-mediated innate immunity in Drosophila

Mitochondria participate in various cellular processes including energy metabolism, apoptosis, autophagy, production of reactive oxygen species, stress responses, inflammation and immunity. However, the role o...

Reconstructing the ancestral gene pool to uncover the origins and genetic links of Hmong–Mien speakers

Hmong–Mien (HM) speakers are linguistically related and live primarily in China, but little is known about their ancestral origins or the evolutionary mechanism shaping their genomic diversity. In particular, ...

Differentiation is accompanied by a progressive loss in transcriptional memory

Cell differentiation requires the integration of two opposite processes, a stabilizing cellular memory, especially at the transcriptional scale, and a burst of gene expression variability which follows the dif...

Author Correction: Genomics insights into flowering and floral pattern formation: regional duplication and seasonal pattern of gene expression in Camellia

The original article was published in BMC Biology 2024 22 :50

Introgressions lead to reference bias in wheat RNA-seq analysis

RNA-seq is a fundamental technique in genomics, yet reference bias, where transcripts derived from non-reference alleles are quantified less accurately, can undermine the accuracy of RNA-seq quantification and...

Differentiated adaptative genetic architecture and language-related demographical history in South China inferred from 619 genomes from 56 populations

The underrepresentation of human genomic resources from Southern Chinese populations limited their health equality in the precision medicine era and complete understanding of their genetic formation, admixture...

A CTL − Lys immune function maintains insect metamorphosis by preventing gut bacterial dysbiosis and limiting opportunistic infections

Gut bacteria are beneficial to the host, many of which must be passed on to host offspring. During metamorphosis, the midgut of holometabolous insects undergoes histolysis and remodeling, and thus risks losing...

Integrative systems biology of wheat susceptibility to Fusarium graminearum uncovers a conserved gene regulatory network and identifies master regulators targeted by fungal core effectors

Plant diseases are driven by an intricate set of defense mechanisms counterbalanced by the expression of host susceptibility factors promoted through the action of pathogen effectors. In spite of their central...

Origin and diversity of Capsella bursa-pastoris from the genomic point of view

Capsella bursa-pastoris , a cosmopolitan weed of hybrid origin, is an emerging model object for the study of early consequences of polyploidy, being a fast growing annual and a close relative of Arabidopsis thalia...

The cytoskeleton adaptor protein Sorbs1 controls the development of lymphatic and venous vessels in zebrafish

Lymphangiogenesis, the formation of lymphatic vessels, is tightly linked to the development of the venous vasculature, both at the cellular and molecular levels. Here, we identify a novel role for Sorbs1, the ...

Genomics insights into flowering and floral pattern formation: regional duplication and seasonal pattern of gene expression in Camellia

The formation and domestication of ornamental traits are influenced by various aspects, such as the recognition of esthetic values and cultural traditions. Camellia japonica is widely appreciated and domesticated...

The Author Correction to this article has been published in BMC Biology 2024 22 :57

Gene flow and an anomaly zone complicate phylogenomic inference in a rapidly radiated avian family (Prunellidae)

Resolving the phylogeny of rapidly radiating lineages presents a challenge when building the Tree of Life. An Old World avian family Prunellidae (Accentors) comprises twelve species that rapidly diversified at...

Primary cilia promote the differentiation of human neurons through the WNT signaling pathway

Primary cilia emanate from most human cell types, including neurons. Cilia are important for communicating with the cell’s immediate environment: signal reception and transduction to/from the ciliated cell. De...

Evolution of ancient satellite DNAs in extant alligators and caimans (Crocodylia, Reptilia)

Crocodilians are one of the oldest extant vertebrate lineages, exhibiting a combination of evolutionary success and morphological resilience that has persisted throughout the history of life on Earth. This abi...

Membranes are functionalized by a proteolipid code

Membranes are protein and lipid structures that surround cells and other biological compartments. We present a conceptual model wherein all membranes are organized into structural and functional zones. The ass...

Functional characterization of NBS-LRR genes reveals an NBS-LRR gene that mediates resistance against Fusarium wilt

Most disease resistance (R) genes in plants encode proteins that contain leucine-rich-repeat (LRR) and nucleotide-binding site (NBS) domains, which belong to the NBS-LRR family. The sequenced genomes of Fusarium ...

CircRNA identification and feature interpretability analysis

Circular RNAs (circRNAs) can regulate microRNA activity and are related to various diseases, such as cancer. Functional research on circRNAs is the focus of scientific research. Accurate identification of circ...

Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine

High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic t...

Population genomics of Agrotis segetum provide insights into the local adaptive evolution of agricultural pests

The adaptive mechanisms of agricultural pests are the key to understanding the evolution of the pests and to developing new control strategies. However, there are few studies on the genetic basis of adaptation...

Weathered granites and soils harbour microbes with lanthanide-dependent methylotrophic enzymes

Prior to soil formation, phosphate liberated by rock weathering is often sequestered into highly insoluble lanthanide phosphate minerals. Dissolution of these minerals releases phosphate and lanthanides to the...

Predicting thresholds for population replacement gene drives

Threshold-dependent gene drives (TDGDs) could be used to spread desirable traits through a population, and are likely to be less invasive and easier to control than threshold-independent gene drives. Engineere...

Genome-wide comparative methylation analysis reveals the fate of germ stem cells after surrogate production in teleost

Surrogate production by germline stem cell transplantation is a powerful method to produce donor-derived gametes via a host, a practice known as surrogacy. The gametes produced by surrogates are often analysed...

A combination of conserved and diverged responses underlies Theobroma cacao ’s defense response to Phytophthora palmivora

Plants have complex and dynamic immune systems that have evolved to resist pathogens. Humans have worked to enhance these defenses in crops through breeding. However, many crops harbor only a fraction of the g...

ADARs regulate cuticle collagen expression and promote survival to pathogen infection

In all organisms, the innate immune system defends against pathogens through basal expression of molecules that provide critical barriers to invasion and inducible expression of effectors that combat infection...

A human stomach cell type transcriptome atlas

The identification of cell type-specific genes and their modification under different conditions is central to our understanding of human health and disease. The stomach, a hollow organ in the upper gastrointe...

Female behavior drives the formation of distinct social structures in C57BL/6J versus wild-derived outbred mice in field enclosures

Social behavior and social organization have major influences on individual health and fitness. Yet, biomedical research focuses on studying a few genotypes under impoverished social conditions. Understanding ...

The Correction to this article has been published in BMC Biology 2024 22 :72

Convergent genomic signatures associated with vertebrate viviparity

Viviparity—live birth—is a complex and innovative mode of reproduction that has evolved repeatedly across the vertebrate Tree of Life. Viviparous species exhibit remarkable levels of reproductive diversity, bo...

Enolase of Streptococcus suis serotype 2 promotes biomolecular condensation of ribosomal protein SA for HBMECs apoptosis

Ribosomal protein SA (RPSA) of human brain microvascular endothelial cells (HBMECs) can transfer from the cytosol to the cell surface and act as a receptor for some pathogens, including Streptococcus suis serotyp...

Bright lights, big synapses: fluorescent proteins let neurons shine

The availability of fluorescent proteins to visualize neurons and synapses has revolutionized our understanding of these key structures in brains. Here, I will discuss the new insights gleaned from the use of ...

A new chromosome-scale duck genome shows a major histocompatibility complex with several expanded multigene families

The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. ...

Genome-wide methylome stability and parental effects in the worldwide distributed Lombardy poplar

Despite the increasing number of epigenomic studies in plants, little is known about the forces that shape the methylome in long-lived woody perennials. The Lombardy poplar offers an ideal opportunity to inves...

An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG

Cyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) cha...

The functional role of spatial anisotropies in ensemble perception

The human brain can rapidly represent sets of similar stimuli by their ensemble summary statistics, like the average orientation or size. Classic models assume that ensemble statistics are computed by integrat...

Fever-like temperature impacts on Staphylococcus aureus and Pseudomonas aeruginosa interaction, physiology, and virulence both in vitro and in vivo

Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) cause a wide variety of bacterial infections and coinfections, showing a complex interaction that involves the production of different metabolites and me...

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ISSN: 1756-0500

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• Published: 12 December 2023

Examining the role of community resilience and social capital on mental health in public health emergency and disaster response: a scoping review

• C. E. Hall 1 , 2 ,
• H. Wehling 1 ,
• J. Stansfield 3 ,
• J. South 3 ,
• S. K. Brooks 2 ,
• N. Greenberg 2 , 4 ,
• R. Amlôt 1 &
• D. Weston 1  

BMC Public Health volume  23 , Article number:  2482 ( 2023 ) Cite this article

1772 Accesses

21 Altmetric

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The ability of the public to remain psychologically resilient in the face of public health emergencies and disasters (such as the COVID-19 pandemic) is a key factor in the effectiveness of a national response to such events. Community resilience and social capital are often perceived as beneficial and ensuring that a community is socially and psychologically resilient may aid emergency response and recovery. This review presents a synthesis of literature which answers the following research questions: How are community resilience and social capital quantified in research?; What is the impact of community resilience on mental wellbeing?; What is the impact of infectious disease outbreaks, disasters and emergencies on community resilience and social capital?; and, What types of interventions enhance community resilience and social capital?

A scoping review procedure was followed. Searches were run across Medline, PsycInfo, and EMBASE, with search terms covering both community resilience and social capital, public health emergencies, and mental health. 26 papers met the inclusion criteria.

The majority of retained papers originated in the USA, used a survey methodology to collect data, and involved a natural disaster. There was no common method for measuring community resilience or social capital. The association between community resilience and social capital with mental health was regarded as positive in most cases. However, we found that community resilience, and social capital, were initially negatively impacted by public health emergencies and enhanced by social group activities.

Several key recommendations are proposed based on the outcomes from the review, which include: the need for a standardised and validated approach to measuring both community resilience and social capital; that there should be enhanced effort to improve preparedness to public health emergencies in communities by gauging current levels of community resilience and social capital; that community resilience and social capital should be bolstered if areas are at risk of disasters or public health emergencies; the need to ensure that suitable short-term support is provided to communities with high resilience in the immediate aftermath of a public health emergency or disaster; the importance of conducting robust evaluation of community resilience initiatives deployed during the COVID-19 pandemic.

Peer Review reports

For the general population, public health emergencies and disasters (e.g., natural disasters; infectious disease outbreaks; Chemical, Biological, Radiological or Nuclear incidents) can give rise to a plethora of negative outcomes relating to both health (e.g. increased mental health problems [ 1 , 2 , 3 , 4 ]) and the economy (e.g., increased unemployment and decreased levels of tourism [ 4 , 5 , 6 ]). COVID-19 is a current, and ongoing, example of a public health emergency which has affected over 421 million individuals worldwide [ 7 ]. The long term implications of COVID-19 are not yet known, but there are likely to be repercussions for physical health, mental health, and other non-health related outcomes for a substantial time to come [ 8 , 9 ]. As a result, it is critical to establish methods which may inform approaches to alleviate the longer-term negative consequences that are likely to emerge in the aftermath of both COVID-19 and any future public health emergency.

The definition of resilience often differs within the literature, but ultimately resilience is considered a dynamic process of adaptation. It is related to processes and capabilities at the individual, community and system level that result in good health and social outcomes, in spite of negative events, serious threats and hazards [ 10 ]. Furthermore, Ziglio [ 10 ] refers to four key types of resilience capacity: adaptive, the ability to withstand and adjust to unfavourable conditions and shocks; absorptive, the ability to withstand but also to recover and manage using available assets and skills; anticipatory, the ability to predict and minimize vulnerability; and transformative, transformative change so that systems better cope with new conditions.

There is no one settled definition of community resilience (CR). However, it generally relates to the ability of a community to withstand, adapt and permit growth in adverse circumstances due to social structures, networks and interdependencies within the community [ 11 ]. Social capital (SC) is considered a major determinant of CR [ 12 , 13 ], and reflects strength of a social network, community reciprocity, and trust in people and institutions [ 14 ]. These aspects of community are usually conceptualised primarily as protective factors that enable communities to cope and adapt collectively to threats. SC is often broken down into further categories [ 15 ], for example: cognitive SC (i.e. perceptions of community relations, such as trust, mutual help and attachment) and structural SC (i.e. what actually happens within the community, such as participation, socialising) [ 16 ]; or, bonding SC (i.e. connections among individuals who are emotionally close, and result in bonds to a particular group [ 17 ]) and bridging SC (i.e. acquaintances or individuals loosely connected that span different social groups [ 18 ]). Generally, CR is perceived to be primarily beneficial for multiple reasons (e.g. increased social support [ 18 , 19 ], protection of mental health [ 20 , 21 ]), and strengthening community resilience is a stated health goal of the World Health Organisation [ 22 ] when aiming to alleviate health inequalities and protect wellbeing. This is also reflected by organisations such as Public Health England (now split into the UK Health Security Agency and the Office for Health Improvement and Disparities) [ 23 ] and more recently, CR has been targeted through the endorsement of Community Champions (who are volunteers trained to support and to help improve health and wellbeing. Community Champions also reflect their local communities in terms of population demographics for example age, ethnicity and gender) as part of the COVID-19 response in the UK (e.g. [ 24 , 25 ]).

Despite the vested interest in bolstering communities, the research base establishing: how to understand and measure CR and SC; the effect of CR and SC, both during and following a public health emergency (such as the COVID-19 pandemic); and which types of CR or SC are the most effective to engage, is relatively small. Given the importance of ensuring resilience against, and swift recovery from, public health emergencies, it is critically important to establish and understand the evidence base for these approaches. As a result, the current review sought to answer the following research questions: (1) How are CR and SC quantified in research?; (2) What is the impact of community resilience on mental wellbeing?; (3) What is the impact of infectious disease outbreaks, disasters and emergencies on community resilience and social capital?; and, (4) What types of interventions enhance community resilience and social capital?

By collating research in order to answer these research questions, the authors have been able to propose several key recommendations that could be used to both enhance and evaluate CR and SC effectively to facilitate the long-term recovery from COVID-19, and also to inform the use of CR and SC in any future public health disasters and emergencies.

A scoping review methodology was followed due to the ease of summarising literature on a given topic for policy makers and practitioners [ 26 ], and is detailed in the following sections.

Identification of relevant studies

An initial search strategy was developed by authors CH and DW and included terms which related to: CR and SC, given the absence of a consistent definition of CR, and the link between CR and SC, the review focuses on both CR and SC to identify as much relevant literature as possible (adapted for purpose from Annex 1: [ 27 ], as well as through consultation with review commissioners); public health emergencies and disasters [ 28 , 29 , 30 , 31 ], and psychological wellbeing and recovery (derived a priori from literature). To ensure a focus on both public health and psychological research, the final search was carried across Medline, PsycInfo, and EMBASE using OVID. The final search took place on the 18th of May 2020, the search strategy used for all three databases can be found in Supplementary file 1 .

Selection criteria

The inclusion and exclusion criteria were developed alongside the search strategy. Initially the criteria were relatively inclusive and were subject to iterative development to reflect the authors’ familiarisation with the literature. For example, the decision was taken to exclude research which focused exclusively on social support and did not mention communities as an initial title/abstract search suggested that the majority of this literature did not meet the requirements of our research question.

The full and final inclusion and exclusion criteria used can be found in Supplementary file 2 . In summary, authors decided to focus on the general population (i.e., non-specialist, e.g. non-healthcare worker or government official) to allow the review to remain community focused. The research must also have assessed the impact of CR and/or SC on mental health and wellbeing, resilience, and recovery during and following public health emergencies and infectious disease outbreaks which affect communities (to ensure the research is relevant to the review aims), have conducted primary research, and have a full text available or provided by the first author when contacted.

Charting the data

All papers were first title and abstract screened by CH or DW. Papers then were full text reviewed by CH to ensure each paper met the required eligibility criteria, if unsure about a paper it was also full text reviewed by DW. All papers that were retained post full-text review were subjected to a standardised data extraction procedure. A table was made for the purpose of extracting the following data: title, authors, origin, year of publication, study design, aim, disaster type, sample size and characteristics, variables examined, results, restrictions/limitations, and recommendations. Supplementary file 3 details the charting the data process.

Analytical method

Data was synthesised using a Framework approach [ 32 ], a common method for analysing qualitative research. This method was chosen as it was originally used for large-scale social policy research [ 33 ] as it seeks to identify: what works, for whom, in what conditions, and why [ 34 ]. This approach is also useful for identifying commonalities and differences in qualitative data and potential relationships between different parts of the data [ 33 ]. An a priori framework was established by CH and DW. Extracted data was synthesised in relation to each research question, and the process was iterative to ensure maximum saturation using the available data.

Study selection

The final search strategy yielded 3584 records. Following the removal of duplicates, 2191 records remained and were included in title and abstract screening. A PRISMA flow diagram is presented in Fig.  1 .

PRISMA flow diagram

At the title and abstract screening stage, the process became more iterative as the inclusion criteria were developed and refined. For the first iteration of screening, CH or DW sorted all records into ‘include,’ ‘exclude,’ and ‘unsure’. All ‘unsure’ papers were re-assessed by CH, and a random selection of ~ 20% of these were also assessed by DW. Where there was disagreement between authors the records were retained, and full text screened. The remaining papers were reviewed by CH, and all records were categorised into ‘include’ and ‘exclude’. Following full-text screening, 26 papers were retained for use in the review.

Study characteristics

This section of the review addresses study characteristics of those which met the inclusion criteria, which comprises: date of publication, country of origin, study design, study location, disaster, and variables examined.

Date of publication

Publication dates across the 26 papers spanned from 2008 to 2020 (see Fig.  2 ). The number of papers published was relatively low and consistent across this timescale (i.e. 1–2 per year, except 2010 and 2013 when none were published) up until 2017 where the number of papers peaked at 5. From 2017 to 2020 there were 15 papers published in total. The amount of papers published in recent years suggests a shift in research and interest towards CR and SC in a disaster/ public health emergency context.

Graph to show retained papers date of publication

Country of origin

The locations of the first authors’ institutes at the time of publication were extracted to provide a geographical spread of the retained papers. The majority originated from the USA [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ], followed by China [ 42 , 43 , 44 , 45 , 46 ], Japan [ 47 , 48 , 49 , 50 ], Australia [ 51 , 52 , 53 ], The Netherlands [ 54 , 55 ], New Zealand [ 56 ], Peru [ 57 ], Iran [ 58 ], Austria [ 59 ], and Croatia [ 60 ].

There were multiple methodological approaches carried out across retained papers. The most common formats included surveys or questionnaires [ 36 , 37 , 38 , 42 , 46 , 47 , 48 , 49 , 50 , 53 , 54 , 55 , 57 , 59 ], followed by interviews [ 39 , 40 , 43 , 51 , 52 , 60 ]. Four papers used both surveys and interviews [ 35 , 41 , 45 , 58 ], and two papers conducted data analysis (one using open access data from a Social Survey [ 44 ] and one using a Primary Health Organisations Register [ 56 ]).

Study location

The majority of the studies were carried out in Japan [ 36 , 42 , 44 , 47 , 48 , 49 , 50 ], followed by the USA [ 35 , 37 , 38 , 39 , 40 , 41 ], China [ 43 , 45 , 46 , 53 ], Australia [ 51 , 52 ], and the UK [ 54 , 55 ]. The remaining studies were carried out in Croatia [ 60 ], Peru [ 57 ], Austria [ 59 ], New Zealand [ 56 ] and Iran [ 58 ].

Multiple different types of disaster were researched across the retained papers. Earthquakes were the most common type of disaster examined [ 45 , 47 , 49 , 50 , 53 , 56 , 57 , 58 ], followed by research which assessed the impact of two disastrous events which had happened in the same area (e.g. Hurricane Katrina and the Deepwater Horizon oil spill in Mississippi, and the Great East Japan earthquake and Tsunami; [ 36 , 37 , 38 , 42 , 44 , 48 ]). Other disaster types included: flooding [ 51 , 54 , 55 , 59 , 60 ], hurricanes [ 35 , 39 , 41 ], infectious disease outbreaks [ 43 , 46 ], oil spillage [ 40 ], and drought [ 52 ].

Variables of interest examined

Across the 26 retained papers: eight referred to examining the impact of SC [ 35 , 37 , 39 , 41 , 46 , 49 , 55 , 60 ]; eight examined the impact of cognitive and structural SC as separate entities [ 40 , 42 , 45 , 48 , 50 , 54 , 57 , 59 ]; one examined bridging and bonding SC as separate entities [ 58 ]; two examined the impact of CR [ 38 , 56 ]; and two employed a qualitative methodology but drew findings in relation to bonding and bridging SC, and SC generally [ 51 , 52 ]. Additionally, five papers examined the impact of the following variables: ‘community social cohesion’ [ 36 ], ‘neighbourhood connectedness’ [ 44 ], ‘social support at the community level’ [ 47 ], ‘community connectedness’ [ 43 ] and ‘sense of community’ [ 53 ]. Table  1 provides additional details on this.

How is CR and SC measured or quantified in research?

The measures used to examine CR and SC are presented Table  1 . It is apparent that there is no uniformity in how SC or CR is measured across the research. Multiple measures are used throughout the retained studies, and nearly all are unique. Additionally, SC was examined at multiple different levels (e.g. cognitive and structural, bonding and bridging), and in multiple different forms (e.g. community connectedness, community cohesion).

What is the association between CR and SC on mental wellbeing?

To best compare research, the following section reports on CR, and facets of SC separately. Please see Supplementary file 4  for additional information on retained papers methods of measuring mental wellbeing.

• Community resilience

CR relates to the ability of a community to withstand, adapt and permit growth in adverse circumstances due to social structures, networks and interdependencies within the community [ 11 ].

The impact of CR on mental wellbeing was consistently positive. For example, research indicated that there was a positive association between CR and number of common mental health (i.e. anxiety and mood) treatments post-disaster [ 56 ]. Similarly, other research suggests that CR is positively related to psychological resilience, which is inversely related to depressive symptoms) [ 37 ]. The same research also concluded that CR is protective of psychological resilience and is therefore protective of depressive symptoms [ 37 ].

• Social capital

SC reflects the strength of a social network, community reciprocity, and trust in people and institutions [ 14 ]. These aspects of community are usually conceptualised primarily as protective factors that enable communities to cope and adapt collectively to threats.

There were inconsistencies across research which examined the impact of abstract SC (i.e. not refined into bonding/bridging or structural/cognitive) on mental wellbeing. However, for the majority of cases, research deems SC to be beneficial. For example, research has concluded that, SC is protective against post-traumatic stress disorder [ 55 ], anxiety [ 46 ], psychological distress [ 50 ], and stress [ 46 ]. Additionally, SC has been found to facilitate post-traumatic growth [ 38 ], and also to be useful to be drawn upon in times of stress [ 52 ], both of which could be protective of mental health. Similarly, research has also found that emotional recovery following a disaster is more difficult for those who report to have low levels of SC [ 51 ].

Conversely, however, research has also concluded that when other situational factors (e.g. personal resources) were controlled for, a positive relationship between community resources and life satisfaction was no longer significant [ 60 ]. Furthermore, some research has concluded that a high level of SC can result in a community facing greater stress immediately post disaster. Indeed, one retained paper found that high levels of SC correlate with higher levels of post-traumatic stress immediately following a disaster [ 39 ]. However, in the later stages following a disaster, this relationship can reverse, with SC subsequently providing an aid to recovery [ 41 ]. By way of explanation, some researchers have suggested that communities with stronger SC carry the greatest load in terms of helping others (i.e. family, friends and neighbours) as well as themselves immediately following the disaster, but then as time passes the communities recover at a faster rate as they are able to rely on their social networks for support [ 41 ].

Cognitive and structural social capital

Cognitive SC refers to perceptions of community relations, such as trust, mutual help and attachment, and structural SC refers to what actually happens within the community, such as participation, socialising [ 16 ].

Cognitive SC has been found to be protective [ 49 ] against PTSD [ 54 , 57 ], depression [ 40 , 54 ]) mild mood disorder; [ 48 ]), anxiety [ 48 , 54 ] and increase self-efficacy [ 59 ].

For structural SC, research is again inconsistent. On the one hand, structural SC has been found to: increase perceived self-efficacy, be protective of depression [ 40 ], buffer the impact of housing damage on cognitive decline [ 42 ] and provide support during disasters and over the recovery period [ 59 ]. However, on the other hand, it has been found to have no association with PTSD [ 54 , 57 ] or depression, and is also associated with a higher prevalence of anxiety [ 54 ]. Similarly, it is also suggested by additional research that structural SC can harm women’s mental health, either due to the pressure of expectations to help and support others or feelings of isolation [ 49 ].

Bonding and bridging social capital

Bonding SC refers to connections among individuals who are emotionally close, and result in bonds to a particular group [ 17 ], and bridging SC refers to acquaintances or individuals loosely connected that span different social groups [ 18 ].

One research study concluded that both bonding and bridging SC were protective against post-traumatic stress disorder symptoms [ 58 ]. Bridging capital was deemed to be around twice as effective in buffering against post-traumatic stress disorder than bonding SC [ 58 ].

Other community variables

Community social cohesion was significantly associated with a lower risk of post-traumatic stress disorder symptom development [ 35 ], and this was apparent even whilst controlling for depressive symptoms at baseline and disaster impact variables (e.g. loss of family member or housing damage) [ 36 ]. Similarly, sense of community, community connectedness, social support at the community level and neighbourhood connectedness all provided protective benefits for a range of mental health, wellbeing and recovery variables, including: depression [ 53 ], subjective wellbeing (in older adults only) [ 43 ], psychological distress [ 47 ], happiness [ 44 ] and life satisfaction [ 53 ].

Research has also concluded that community level social support is protective against mild mood and anxiety disorder, but only for individuals who have had no previous disaster experience [ 48 ]. Additionally, a study which separated SC into social cohesion and social participation concluded that at a community level, social cohesion is protective against depression [ 49 ] whereas social participation at community level is associated with an increased risk of depression amongst women [ 49 ].

What is the impact of Infectious disease outbreaks / disasters and emergencies on community resilience?

From a cross-sectional perspective, research has indicated that disasters and emergencies can have a negative effect on certain types of SC. Specifically, cognitive SC has been found to be impacted by disaster impact, whereas structural SC has gone unaffected [ 45 ]. Disaster impact has also been shown to have a negative effect on community relationships more generally [ 52 ].

Additionally, of the eight studies which collected data at multiple time points [ 35 , 36 , 41 , 42 , 47 , 49 , 56 , 60 ], three reported the effect of a disaster on the level of SC within a community [ 40 , 42 , 49 ]. All three of these studies concluded that disasters may have a negative impact on the levels of SC within a community. The first study found that the Deepwater Horizon oil spill had a negative effect on SC and social support, and this in turn explained an overall increase in the levels of depression within the community [ 40 ]. A possible explanation for the negative effect lays in ‘corrosive communities’, known for increased social conflict and reduced social support, that are sometimes created following oil spills [ 40 ]. It is proposed that corrosive communities often emerge due to a loss of natural resources that bring social groups together (e.g., for recreational activities), as well as social disparity (e.g., due to unequal distribution of economic impact) becoming apparent in the community following disaster [ 40 ]. The second study found that SC (in the form of social cohesion, informal socialising and social participation) decreased after the 2011 earthquake and tsunami in Japan; it was suggested that this change correlated with incidence of cognitive decline [ 42 ]. However, the third study reported more mixed effects based on physical circumstances of the communities’ natural environment: Following an earthquake, those who lived in mountainous areas with an initial high level of pre-community SC saw a decrease in SC post disaster [ 49 ]. However, communities in flat areas (which were home to younger residents and had a higher population density) saw an increase in SC [ 49 ]. It was proposed that this difference could be due to the need for those who lived in mountainous areas to seek prolonged refuge due to subsequent landslides [ 49 ].

What types of intervention enhance CR and SC and protect survivors?

There were mixed effects across the 26 retained papers when examining the effect of CR and SC on mental wellbeing. However, there is evidence that an increase in SC [ 56 , 57 ], with a focus on cognitive SC [ 57 ], namely by: building social networks [ 45 , 51 , 53 ], enhancing feelings of social cohesion [ 35 , 36 ] and promoting a sense of community [ 53 ], can result in an increase in CR and potentially protect survivors’ wellbeing and mental health following a disaster. An increase in SC may also aid in decreasing the need for individual psychological interventions in the aftermath of a disaster [ 55 ]. As a result, recommendations and suggested methods to bolster CR and SC from the retained papers have been extracted and separated into general methods, preparedness and policy level implementation.

General methods

Suggested methods to build SC included organising recreational activity-based groups [ 44 ] to broaden [ 51 , 53 ] and preserve current social networks [ 42 ], introducing initiatives to increase social cohesion and trust [ 51 ], and volunteering to increase the number of social ties between residents [ 59 ]. Research also notes that it is important to take a ‘no one left behind approach’ when organising recreational and social community events, as failure to do so could induce feelings of isolation for some members of the community [ 49 ]. Furthermore, gender differences should also be considered as research indicates that males and females may react differently to community level SC (as evidence suggests males are instead more impacted by individual level SC; in comparison to women who have larger and more diverse social networks [ 49 ]). Therefore, interventions which aim to raise community level social participation, with the aim of expanding social connections and gaining support, may be beneficial [ 42 , 47 ].

Preparedness

In order to prepare for disasters, it may be beneficial to introduce community-targeted methods or interventions to increase levels of SC and CR as these may aid in ameliorating the consequences of a public health emergency or disaster [ 57 ]. To indicate which communities have low levels of SC, one study suggests implementing a 3-item scale of social cohesion to map areas and target interventions [ 42 ].

It is important to consider that communities with a high level of SC may have a lower level of risk perception, due to the established connections and supportive network they have with those around them [ 61 ]. However, for the purpose of preparedness, this is not ideal as perception of risk is a key factor when seeking to encourage behavioural adherence. This could be overcome by introducing communication strategies which emphasise the necessity of social support, but also highlights the need for additional measures to reduce residual risk [ 59 ]. Furthermore, support in the form of financial assistance to foster current community initiatives may prove beneficial to rural areas, for example through the use of an asset-based community development framework [ 52 ].

Policy level

At a policy level, the included papers suggest a range of ways that CR and SC could be bolstered and used. These include: providing financial support for community initiatives and collective coping strategies, (e.g. using asset-based community development [ 52 ]); ensuring policies for long-term recovery focus on community sustainable development (e.g. community festival and community centre activities) [ 44 ]; and development of a network amongst cooperative corporations formed for reconstruction and to organise self-help recovery sessions among residents of adjacent areas [ 58 ].

This scoping review sought to synthesise literature concerning the role of SC and CR during public health emergencies and disasters. Specifically, in this review we have examined: the methods used to measure CR and SC; the impact of CR and SC on mental wellbeing during disasters and emergencies; the impact of disasters and emergencies on CR and SC; and the types of interventions which can be used to enhance CR. To do this, data was extracted from 26 peer-reviewed journal articles. From this synthesis, several key themes have been identified, which can be used to develop guidelines and recommendations for deploying CR and SC in a public health emergency or disaster context. These key themes and resulting recommendations are summarised below.

Firstly, this review established that there is no consistent or standardised approach to measuring CR or SC within the general population. This finding is consistent with a review conducted by the World Health Organization which concludes that despite there being a number of frameworks that contain indicators across different determinants of health, there is a lack of consensus on priority areas for measurement and no widely accepted indicator [ 27 ]. As a result, there are many measures of CR and SC apparent within the literature (e.g., [ 62 , 63 ]), an example of a developed and validated measure is provided by Sherrieb, Norris and Galea [ 64 ]. Similarly, the definitions of CR and SC differ widely between researchers, which created a barrier to comparing and summarising information. Therefore, future research could seek to compare various interpretations of CR and to identify any overlapping concepts. However, a previous systemic review conducted by Patel et al. (2017) concludes that there are nine core elements of CR (local knowledge, community networks and relationships, communication, health, governance and leadership, resources, economic investment, preparedness, and mental outlook), with 19 further sub-elements therein [ 30 ]. Therefore, as CR is a multi-dimensional construct, the implications from the findings are that multiple aspects of social infrastructure may need to be considered.

Secondly, our synthesis of research concerning the role of CR and SC for ensuring mental health and wellbeing during, or following, a public health emergency or disaster revealed mixed effects. Much of the research indicates either a generally protective effect on mental health and wellbeing, or no effect; however, the literature demonstrates some potential for a high level of CR/SC to backfire and result in a negative effect for populations during, or following, a public health emergency or disaster. Considered together, our synthesis indicates that cognitive SC is the only facet of SC which was perceived as universally protective across all retained papers. This is consistent with a systematic review which also concludes that: (a) community level cognitive SC is associated with a lower risk of common mental disorders, while; (b) community level structural SC had inconsistent effects [ 65 ].

Further examination of additional data extracted from studies which found that CR/SC had a negative effect on mental health and wellbeing revealed no commonalities that might explain these effects (Please see Supplementary file 5 for additional information)

One potential explanation may come from a retained paper which found that high levels of SC result in an increase in stress level immediately post disaster [ 41 ]. This was suggested to be due to individuals having greater burdens due to wishing to help and support their wide networks as well as themselves. However, as time passes the levels of SC allow the community to come together and recover at a faster rate [ 41 ]. As this was the only retained paper which produced this finding, it would be beneficial for future research to examine boundary conditions for the positive effects of CR/SC; that is, to explore circumstances under which CR/SC may be more likely to put communities at greater risk. This further research should also include additional longitudinal research to validate the conclusions drawn by [ 41 ] as resilience is a dynamic process of adaption.

Thirdly, disasters and emergencies were generally found to have a negative effect on levels of SC. One retained paper found a mixed effect of SC in relation to an earthquake, however this paper separated participants by area in which they lived (i.e., mountainous vs. flat), which explains this inconsistent effect [ 49 ]. Dangerous areas (i.e. mountainous) saw a decrease in community SC in comparison to safer areas following the earthquake (an effect the authors attributed to the need to seek prolonged refuge), whereas participants from the safer areas (which are home to younger residents with a higher population density) saw an increase in SC [ 49 ]. This is consistent with the idea that being able to participate socially is a key element of SC [ 12 ]. Overall, however, this was the only retained paper which produced a variable finding in relation to the effect of disaster on levels of CR/SC.

Finally, research identified through our synthesis promotes the idea of bolstering SC (particularly cognitive SC) and cohesion in communities likely to be affected by disaster to improve levels of CR. This finding provides further understanding of the relationship between CR and SC; an association that has been reported in various articles seeking to provide conceptual frameworks (e.g., [ 66 , 67 ]) as well as indicator/measurement frameworks [ 27 ]. Therefore, this could be done by creating and promoting initiatives which foster SC and create bonds within the community. Papers included in the current review suggest that recreational-based activity groups and volunteering are potential methods for fostering SC and creating community bonds [ 44 , 51 , 59 ]. Similarly, further research demonstrates that feelings of social cohesion are enhanced by general social activities (e.g. fairs and parades [ 18 ]). Also, actively encouraging activities, programs and interventions which enhance connectedness and SC have been reported to be desirable to increase CR [ 68 ]. This suggestion is supported by a recent scoping review of literature [ 67 ] examined community champion approaches for the COVID-19 pandemic response and recovery and established that creating and promoting SC focused initiatives within the community during pandemic response is highly beneficial [ 67 ]. In terms of preparedness, research states that it may be beneficial for levels of SC and CR in communities at risk to be assessed, to allow targeted interventions where the population may be at most risk following an incident [ 42 , 44 ]. Additionally, from a more critical perspective, we acknowledge that ‘resilience’ can often be perceived as a focus on individual capacity to adapt to adversity rather than changing or mitigating the causes of adverse conditions [ 69 , 70 ]. Therefore, CR requires an integrated system approach across individual, community and structural levels [ 17 ]. Also, it is important that community members are engaged in defining and agreeing how community resilience is measured [ 27 ] rather than it being imposed by system leads or decision-makers.

In the aftermath of the pandemic, is it expected that there will be long-term repercussions both from an economic [ 8 ] and a mental health perspective [ 71 ]. Furthermore, the findings from this review suggest that although those in areas with high levels of SC may be negatively affected in the acute stage, as time passes, they have potential to rebound at a faster rate than those with lower levels of SC. Ongoing evaluation of the effectiveness of current initiatives as the COVID-19 pandemic progresses into a recovery phase will be invaluable for supplementing the evidence base identified through this review.

• Recommendations

As a result of this review, a number of recommendations are suggested for policy and practice during public health emergencies and recovery.

Future research should seek to establish a standardised and validated approach to measuring and defining CR and SC within communities. There are ongoing efforts in this area, for example [ 72 ]. Additionally, community members should be involved in the process of defining how CR is measured.

There should be an enhanced effort to improve preparedness for public health emergencies and disasters in local communities by gauging current levels of SC and CR within communities using a standardised measure. This approach could support specific targeting of populations with low levels of CR/SC in case of a disaster or public health emergency, whilst also allowing for consideration of support for those with high levels of CR (as these populations can be heavily impacted initially following a disaster). By distinguishing levels of SC and CR, tailored community-centred approaches could be implemented, such as those listed in a guide released by PHE in 2015 [ 73 ].

CR and SC (specifically cognitive SC) should be bolstered if communities are at risk of experiencing a disaster or public health emergency. This can be achieved by using interventions which aim to increase a sense of community and create new social ties (e.g., recreational group activities, volunteering). Additionally, when aiming to achieve this, it is important to be mindful of the risk of increased levels of CR/SC to backfire, as well as seeking to advocate an integrated system approach across individual, community and structural levels.

It is necessary to be aware that although communities with high existing levels of resilience / SC may experience short-term negative consequences following a disaster, over time these communities might be able to recover at a faster rate. It is therefore important to ensure that suitable short-term support is provided to these communities in the immediate aftermath of a public health emergency or disaster.

Robust evaluation of the community resilience initiatives deployed during the COVID-19 pandemic response is essential to inform the evidence base concerning the effectiveness of CR/ SC. These evaluations should continue through the response phase and into the recovery phase to help develop our understanding of the long-term consequences of such interventions.

Limitations

Despite this review being the first in this specific topic area, there are limitations that must be considered. Firstly, it is necessary to note that communities are generally highly diverse and the term ‘community’ in academic literature is a subject of much debate (see: [ 74 ]), therefore this must be considered when comparing and collating research involving communities. Additionally, the measures of CR and SC differ substantially across research, including across the 26 retained papers used in the current review. This makes the act of comparing and collating research findings very difficult. This issue is highlighted as a key outcome from this review, and suggestions for how to overcome this in future research are provided. Additionally, we acknowledge that there will be a relationship between CR & SC even where studies measure only at individual or community level. A review [ 75 ] on articulating a hypothesis of the link to health inequalities suggests that wider structural determinants of health need to be accounted for. Secondly, despite the final search strategy encompassing terms for both CR and SC, only one retained paper directly measured CR; thus, making the research findings more relevant to SC. Future research could seek to focus on CR to allow for a comparison of findings. Thirdly, the review was conducted early in the COVID-19 pandemic and so does not include more recent publications focusing on resilience specifically in the context of COVID-19. Regardless of this fact, the synthesis of, and recommendations drawn from, the reviewed studies are agnostic to time and specific incident and contain critical elements necessary to address as the pandemic moves from response to recovery. Further research should review the effectiveness of specific interventions during the COVID-19 pandemic for collation in a subsequent update to this current paper. Fourthly, the current review synthesises findings from countries with individualistic and collectivistic cultures, which may account for some variation in the findings. Lastly, despite choosing a scoping review method for ease of synthesising a wide literature base for use by public health emergency researchers in a relatively tight timeframe, there are disadvantages of a scoping review approach to consider: (1) quality appraisal of retained studies was not carried out; (2) due to the broad nature of a scoping review, more refined and targeted reviews of literature (e.g., systematic reviews) may be able to provide more detailed research outcomes. Therefore, future research should seek to use alternative methods (e.g., empirical research, systematic reviews of literature) to add to the evidence base on CR and SC impact and use in public health practice.

This review sought to establish: (1) How CR and SC are quantified in research?; (2) The impact of community resilience on mental wellbeing?; (3) The impact of infectious disease outbreaks, disasters and emergencies on community resilience and social capital?; and, (4) What types of interventions enhance community resilience and social capital?. The chosen search strategy yielded 26 relevant papers from which we were able extract information relating to the aims of this review.

Results from the review revealed that CR and SC are not measured consistently across research. The impact of CR / SC on mental health and wellbeing during emergencies and disasters is mixed (with some potential for backlash), however the literature does identify cognitive SC as particularly protective. Although only a small number of papers compared CR or SC before and after a disaster, the findings were relatively consistent: SC or CR is negatively impacted by a disaster. Methods suggested to bolster SC in communities were centred around social activities, such as recreational group activities and volunteering. Recommendations for both research and practice (with a particular focus on the ongoing COVID-19 pandemic) are also presented.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Social Capital

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This study was supported by the National Institute for Health Research Research Unit (NIHR HPRU) in Emergency Preparedness and Response, a partnership between Public Health England, King’s College London and the University of East Anglia. The views expressed are those of the author(s) and not necessarily those of the NIHR, Public Health England, the UK Health Security Agency or the Department of Health and Social Care [Grant number: NIHR20008900]. Part of this work has been funded by the Office for Health Improvement and Disparities, Department of Health and Social Care, as part of a Collaborative Agreement with Leeds Beckett University.

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Hall, C.E., Wehling, H., Stansfield, J. et al. Examining the role of community resilience and social capital on mental health in public health emergency and disaster response: a scoping review. BMC Public Health 23 , 2482 (2023). https://doi.org/10.1186/s12889-023-17242-x

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DOI : https://doi.org/10.1186/s12889-023-17242-x

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A scoping review to identify and organize literature trends of bias research within medical student and resident education

• Brianne E. Lewis 1 &
• Akshata R. Naik 2  

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Physician bias refers to the unconscious negative perceptions that physicians have of patients or their conditions. Medical schools and residency programs often incorporate training to reduce biases among their trainees. In order to assess trends and organize available literature, we conducted a scoping review with a goal to categorize different biases that are studied within medical student (MS), resident (Res) and mixed populations (MS and Res). We also characterized these studies based on their research goal as either documenting evidence of bias (EOB), bias intervention (BI) or both. These findings will provide data which can be used to identify gaps and inform future work across these criteria.

Online databases (PubMed, PsycINFO, WebofScience) were searched for articles published between 1980 and 2021. All references were imported into Covidence for independent screening against inclusion criteria. Conflicts were resolved by deliberation. Studies were sorted by goal: ‘evidence of bias’ and/or ‘bias intervention’, and by population (MS or Res or mixed) andinto descriptive categories of bias.

Of the initial 806 unique papers identified, a total of 139 articles fit the inclusion criteria for data extraction. The included studies were sorted into 11 categories of bias and showed that bias against race/ethnicity, specific diseases/conditions, and weight were the most researched topics. Of the studies included, there was a higher ratio of EOB:BI studies at the MS level. While at the Res level, a lower ratio of EOB:BI was found.

Conclusions

This study will be of interest to institutions, program directors and medical educators who wish to specifically address a category of bias and identify where there is a dearth of research. This study also underscores the need to introduce bias interventions at the MS level.

Peer Review reports

Physician bias ultimately impacts patient care by eroding the physician–patient relationship [ 1 , 2 , 3 , 4 ]. To overcome this issue, certain states require physicians to report a varying number of hours of implicit bias training as part of their recurring licensing requirement [ 5 , 6 ]. Research efforts on the influence of implicit bias on clinical decision-making gained traction after the “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care” report published in 2003 [ 7 ]. This report sparked a conversation about the impact of bias against women, people of color, and other marginalized groups within healthcare. Bias from a healthcare provider has been shown to affect provider-patient communication and may also influence treatment decisions [ 8 , 9 ]. Nevertheless, opportunities within medical education curriculum are created to evaluate biases at an earlier stage of physician-training and provide instruction to intervene them [ 10 , 11 , 12 ]. We aimed to identify trends and organize literature on bias training provided during medical school and residency programs since the meaning of ‘bias’ is broad and encompasses several types of attitudes and predispositions [ 13 ].

Several reviews, narrative or systematic in nature, have been published in the field of bias research in medicine and healthcare [ 14 , 15 , 16 ]. Many of these reviews have a broad focus on implicit bias and they often fail to define the patient’s specific attributes- such as age, weight, disease, or condition against which physicians hold their biases. However, two recently published reviews categorized implicit biases into various descriptive characteristics albeit with research goals different than this study [ 17 , 18 ]. The study by Fitzgerald et al. reviewed literature focused on bias among physicians and nurses to highlight its role in healthcare disparities [ 17 ]. While the study by Gonzalez et al. focused on bias curricular interventions across professions related to social determinants of health such as education, law, medicine and social work [ 18 ]. Our research goal was to identify the various bias characteristics that are studied within medical student and/or resident populations and categorize them. Further, we were interested in whether biases were merely identified or if they were intervened. To address these deficits in the field and provide clarity, we utilized a scoping review approach to categorize the literature based on a) the bias addressed and b) the study goal within medical students (MS), residents (Res) and a mixed population (MS and Res).

To date no literature review has organized bias research by specific categories held solely by medical trainees (medical students and/or residents) and quantified intervention studies. We did not perform a quality assessment or outcome evaluation of the bias intervention strategies, as it was not the goal of this work and is standard with a scoping review methodology [ 19 , 20 ]. By generating a comprehensive list of bias categories researched among medical trainee population, we highlight areas of opportunity for future implicit bias research specifically within the undergraduate and graduate medical education curriculum. We anticipate that the results from this scoping review will be useful for educators, administrators, and stakeholders seeking to implement active programs or workshops that intervene specific biases in pre-clinical medical education and prepare physicians-in-training for patient encounters. Additionally, behavioral scientists who seek to support clinicians, and develop debiasing theories [ 21 ] and models may also find our results informative.

We conducted an exhaustive and focused scoping review and followed the methodological framework for scoping reviews as previously described in the literature [ 20 , 22 ]. This study aligned with the four goals of a scoping review [ 20 ]. We followed the first five out of the six steps outlined by Arksey and O’Malley’s to ensure our review’s validity 1) identifying the research question 2) identifying relevant studies 3) selecting the studies 4) charting the data and 5) collating, summarizing and reporting the results [ 22 ]. We did not follow the optional sixth step of undertaking consultation with key stakeholders as it was not needed to address our research question it [ 23 ]. Furthermore, we used Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) that aided in managing steps 2–5 presented above.

Research question, search strategy and inclusion criteria

The purpose of this study was to identify trends in bias research at the medical school and residency level. Prior to conducting our literature search we developed our research question and detailed the inclusion criteria, and generated the search syntax with the assistance from a medical librarian. Search syntax was adjusted to the requirements of the database. We searched PubMed, Web of Science, and PsycINFO using MeSH terms shown below.

Bias* [ti] OR prejudice*[ti] OR racism[ti] OR homophobia[ti] OR mistreatment[ti] OR sexism[ti] OR ageism[ti]) AND (prejudice [mh] OR "Bias"[Mesh:NoExp]) AND (Education, Medical [mh] OR Schools, Medical [mh] OR students, medical [mh] OR Internship and Residency [mh] OR “undergraduate medical education” OR “graduate medical education” OR “medical resident” OR “medical residents” OR “medical residency” OR “medical residencies” OR “medical schools” OR “medical school” OR “medical students” OR “medical student”) AND (curriculum [mh] OR program evaluation [mh] OR program development [mh] OR language* OR teaching OR material* OR instruction* OR train* OR program* OR curricul* OR workshop*

Our inclusion criteria incorporated studies which were either original research articles, or review articles that synthesized new data. We excluded publications that were not peer-reviewed or supported with data such as narrative reviews, opinion pieces, editorials, perspectives and commentaries. We included studies outside of the U.S. since the purpose of this work was to generate a comprehensive list of biases. Physicians, regardless of their country of origin, can hold biases against specific patient attributes [ 17 ]. Furthermore, physicians may practice in a different country than where they trained [ 24 ]. Manuscripts were included if they were published in the English language for which full-texts were available. Since the goal of this scoping review was to assess trends, we accepted studies published from 1980–2021.

Our inclusion criteria also considered the goal and the population of the study. We defined the study goal as either that documented evidence of bias or a program directed bias intervention. Evidence of bias (EOB) had to originate from the medical trainee regarding a patient attribute. Bias intervention (BI) studies involved strategies to counter biases such as activities, workshops, seminars or curricular innovations. The population studied had to include medical students (MS) or residents (Res) or mixed. We defined the study population as ‘mixed’ when it consisted of both MS and Res. Studies conducted on other healthcare professionals were included if MS or Res were also studied. Our search criteria excluded studies that documented bias against medical professionals (students, residents and clinicians) either by patients, medical schools, healthcare administrators or others, and was focused on studies where the biases were solely held by medical trainees (MS and Res).

Data extraction and analysis

Following the initial database search, references were downloaded and bulk uploaded into Covidence and duplicates were removed. After the initial screening of title and abstracts, full-texts were reviewed. Authors independently completed title and abstract screening, and full text reviews. Any conflicts at the stage of abstract screening were moved to full-text screening. Conflicts during full-text screening were resolved by deliberation and referring to the inclusion and exclusion criteria detailed in the research protocol. The level of agreement between the two authors for full text reviews as measured by inter-rater reliability was 0.72 (Cohen’s Kappa).

A data extraction template was created in Covidence to extract data from included full texts. Data extraction template included the following variables; country in which the study was conducted, year of publication, goal of the study (EOB, BI or both), population of the study (MS, Res or mixed) and the type of bias studied. Final data was exported to Microsoft Excel for quantification. For charting our data and categorizing the included studies, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews(PRISMA-ScR) guidelines [ 25 ]. Results from this scoping review study are meant to provide a visual synthesis of existing bias research and identify gaps in knowledge.

Study selection

Our search strategy yielded a total of 892 unique abstracts which were imported into ‘Covidence’ for screening. A total of 86 duplicate references were removed. Then, 806 titles and abstracts were screened for relevance independently by the authors and 519 studies were excluded at this stage. Any conflicts among the reviewers at this stage were resolved by discussion and referring to the inclusion and exclusion criteria. Then a full text review of the remaining 287 papers was completed by the authors against the inclusion criteria for eligibility. Full text review was also conducted independently by the authors and any conflicts were resolved upon discussion. Finally, we included 139 studies which were used for data extraction (Fig.  1 ).

PRISMA diagram of the study selection process used in our scoping review to identify the bias categories that have been reported within medical education literature. Study took place from 2021–2022. Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Publication trends in bias research

First, we charted the studies to demonstrate the timeline of research focused on bias within the study population of our interest (MS or Res or mixed). Our analysis revealed an increase in publications with respect to time (Fig.  2 ). Of the 139 included studies, fewer studies were published prior to 2001, with a total of only eight papers being published from the years 1985–2000. A substantial increase in publications occurred after 2004, with 2019 being the peak year where most of the studies pertaining to bias were published (Fig.  2 ).

Studies matching inclusion criteria mapped by year of publication. Search criteria included studies addressing bias from 1980–2021 within medical students (MS) or residents (Res) or mixed (MS + Res) populations. * Publication in 2022 was published online ahead of print

Overview of included studies

We present a descriptive analysis of the 139 included studies in Table 1 based on the following parameters: study location, goal of the study, population of the study and the category of bias studied. All of the above parameters except the category of bias included a denominator of 139 studies. Several studies addressed more than one bias characteristic; therefore, we documented 163 biases sorted in 11 categories over the 139 papers. The bias categories that we generated and their respective occurrences are listed in Table 1 . Of the 139 studies that were included, most studies originated in the United States ( n  = 89/139, 64%) and Europe ( n  = 20/139, 20%).

Sorting of included research by bias category

We grouped the 139 included studies depending on the patient attribute or the descriptive characteristic against which the bias was studied (Table 1 ). By sorting the studies into different bias categories, we aimed to not only quantitate the amount of research addressing a particular topic of bias, but also reveal the biases that are understudied.

Through our analysis, we generated 11 descriptive categories against which bias was studied: Age, physical disability, education level, biological sex, disease or condition, LGBTQ + , non-specified, race/ethnicity, rural/urban, socio-economic status, and weight (Table 1 ). “Age” and “weight” categories included papers that studied bias against older population and higher weight individuals, respectively. The categories “education level” and “socio-economic status” included papers that studied bias against individuals with low education level and individuals belonging to low socioeconomic status, respectively. Within the bias category named ‘biological sex’, we included papers that studied bias against individuals perceived as women/females. Papers that studied bias against gender-identity or sexual orientation were included in its own category named, ‘LGBTQ + ’. The bias category, ‘disease or condition’ was broad and included research on bias against any patient with a specific disease, condition or lifestyle. Studies included in this category researched bias against any physical illnesses, mental illnesses, or sexually transmitted infections. It also included studies that addressed bias against a treatment such as transplant or pain management. It was not significant to report these as individual categories but rather as a whole with a common underlying theme. Rural/urban bias referred to bias that was held against a person based on their place of residence. Studies grouped together in the ‘non-specified bias’ category explored bias without specifying any descriptive characteristic in their methods. These studies did not address any specific bias characteristic in particular but consisted of a study population of our interest (MS or Res or mixed). Based on our analysis, the top five most studied bias categories in our included population within medical education literature were: racial or ethnic bias ( n  = 39/163, 24%), disease or condition bias ( n  = 29/163, 18%), weight bias ( n  = 22/163, 13%), LGBTQ + bias ( n  = 21/163, 13%), and age bias ( n  = 16/163, 10%) which are presented in Table 1 .

Sorting of included research by population

In order to understand the distribution of bias research based on their populations examined, we sorted the included studies in one of the following: medical students (MS), residents (Res) or mixed (Table 1 ). The following distributions were observed: medical students only ( n  = 105/139, 76%), residents only ( n  = 19/139, 14%) or mixed which consisted of both medical students and residents ( n  = 15/139, 11%). In combination, these results demonstrate that medical educators have focused bias research efforts primarily on medical student populations.

Sorting of included research by goal

A critical component of this scoping review was to quantify the research goal of the included studies within each of the bias categories. We defined the research goal as either to document evidence of bias (EOB) or to evaluate a bias intervention (BI) (see Fig.  1 for inclusion criteria). Some of the included studies focused on both, documenting evidence in addition to intervening biases and those studies were grouped separately. The analysis revealed that 69/139 (50%) of the included studies focused exclusively on documenting evidence of bias (EOB). There were fewer studies ( n  = 51/139, 37%) which solely focused on bias interventions such as programs, seminars or curricular innovations. A small minority of the included studies were more comprehensive in that they documented EOB followed by an intervention strategy ( n  = 19/139, 11%). These results demonstrate that most bias research is dedicated to documenting evidence of bias among these groups rather than evaluating a bias intervention strategy.

Research goal distribution

Our next objective was to calculate the distribution of studies with respect to the study goal (EOB, BI or both), within the 163 biases studied across the 139 papers as calculated in Table 1 . In general, the goal of the studies favors documenting evidence of bias with the exception of race/ethnic bias which is more focused on bias intervention (Fig.  3 ). Fewer studies were aimed at both, documenting evidence then providing an intervention, across all bias categories.

Sorting of total biases ( n  = 163) within medical students or residents or a mixed population based on the bias category . Dark grey indicates studies with a dual goal, to document evidence of bias and to intervene bias. Medium grey bars indicate studies which focused on documenting evidence of bias. Light grey bars indicate studies focused on bias intervention within these populations. Numbers inside the bars indicate the total number of biases for the respective study goal. * Non-specified bias includes studies which focused on implicit bias but did not mention the type of bias investigated

Furthermore, we also calculated the ratio of EOB, BI and both (EOB + BI) within each of our population of interest (MS; n  = 122, Res; n  = 26 and mixed; n  = 15) for the 163 biases observed in our included studies. Over half ( n  = 64/122, 52%) of the total bias occurrences in MS were focused on documenting EOB (Fig.  4 ). Contrastingly, a shift was observed within resident populations where most biases addressed were aimed at intervention ( n  = 12/26, 41%) rather than EOB ( n  = 4/26, 14%) (Fig.  4 ). Studies which included both MS and Res (mixed) were primarily focused on documenting EOB ( n  = 9/15, 60%), with 33% ( n  = 5/15) aimed at bias intervention and 7% ( n  = 1/15) which did both (Fig.  4 ). Although far fewer studies were documented in the Res population it is important to highlight that most of these studies were focused on bias intervention when compared to MS population where we documented a majority of studies focused on evidence of bias.

A ratio of the study goal for the total biases ( n  = 163) mapped within each of the study population (MS, Res and Mixed). A study goal with a) documenting evidence of bias (EOB) is depicted in dotted grey, b) bias intervention (BI) in medium grey, and c) a dual focus (EOB + BI) is depicted in dark grey. * N  = 122 for medical student studies. b N  = 26 for residents. c N  = 15 for mixed

Addressing biases at an earlier stage of medical career is critical for future physicians engaging with diverse patients, since it is established that bias negatively influences provider-patient interactions [ 171 ], clinical decision-making [ 172 ] and reduces favorable treatment outcomes [ 2 ]. We set out with an intention to explore how bias is addressed within the medical curriculum. Our research question was: how has the trend in bias research changed over time, more specifically a) what is the timeline of papers published? b) what bias characteristics have been studied in the physician-trainee population and c) how are these biases addressed? With the introduction of ‘standards of diversity’ by the Liaison Committee on Medical Education, along with the Association of American Medical Colleges (AAMC) and the American Medical Association (AMA) [ 173 , 174 ], we certainly expected and observed a sustained uptick in research pertaining to bias. As shown here, research addressing bias in the target population (MS and Res) is on the rise, however only 139 papers fit our inclusion criteria. Of these studies, nearly 90% have been published since 2005 after the “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care” report was published in 2003 [ 7 ]. However, given the well documented effects of physician held bias, we anticipated significantly more number of studies focused on bias at the medical student or resident level.

A key component from this study was that we generated descriptive categories of biases. Sorting the biases into descriptive categories helps to identify a more targeted approach for a specific bias intervention, rather than to broadly intervene bias as a whole. In fact, our analysis found a number of publications (labeled “non-specified bias” in Table 1 ) which studied implicit bias without specifying the patient attribute or the characteristic that the bias was against. In total, we generated 11 descriptive categories of bias from our scoping review which are shown in Table 1 and Fig.  3 . Furthermore, our bias descriptors grouped similar kinds of biases within a single category. For example, the category, “disease or condition” included papers that studied bias against any type of disease (Mental illness, HIV stigma, diabetes), condition (Pain management), or lifestyle. We neither performed a qualitative assessment of the studies nor did we test the efficacy of the bias intervention studies and consider it a future direction of this work.

Evidence suggests that medical educators and healthcare professionals are struggling to find the appropriate approach to intervene biases [ 175 , 176 , 177 ] So far, bias reduction, bias reflection and bias management approaches have been proposed [ 26 , 27 , 178 ]. Previous implicit bias intervention strategies have been shown to be ineffective when biased attitudes of participants were assessed after a lag [ 179 ]. Understanding the descriptive categories of bias and previous existing research efforts, as we present here is only a fraction of the challenge. The theory of “cognitive bias” [ 180 ] and related branches of research [ 13 , 181 , 182 , 183 , 184 ] have been studied in the field of psychology for over three decades. It is only recently that cognitive bias theory has been applied to the field of medical education medicine, to explain its negative influence on clinical decision-making pertaining only to racial minorities [ 1 , 2 , 15 , 16 , 17 , 185 ]. In order to elicit meaningful changes with respect to targeted bias intervention, it is necessary to understand the psychological underpinnings (attitudes) leading to a certain descriptive category of bias (behaviors). The questions which medical educators need to ask are: a) Can these descriptive biases be identified under certain type/s of cognitive errors that elicits the bias and vice versa b) Are we working towards an attitude change which can elicit a sustained positive behavior change among healthcare professionals? And most importantly, c) are we creating a culture where participants voluntarily enroll themselves in bias interventions as opposed to being mandated to participate? Cognitive psychologists and behavioral scientists are well-positioned to help us find answers to these questions as they understand human behavior. Therefore, an interdisciplinary approach, a marriage between cognitive psychologists and medical educators, is key in targeting biases held by medical students, residents, and ultimately future physicians. This review may also be of interest to behavioral psychologists, keen on providing targeted intervening strategies to clinicians depending on the characteristics (age, weight, sex or race) the portrayed bias is against. Further, instead of an individualized approach, we need to strive for systemic changes and evidence-based strategies to intervene biases.

The next element in change is directing intervention strategies at the right stage in clinical education. Our study demonstrated that most of the research collected at the medical student level was focused on documenting evidence of bias. Although the overall number of studies at the resident level were fewer than at the medical student level, the ratio of research in favor of bias intervention was higher at the resident level (see Fig.  3 ). However, it could be helpful to focus on bias intervention earlier in learning, rather than at a later stage [ 186 ]. Additionally, educational resources such as textbooks, preparatory materials, and educators themselves are potential sources of propagating biases and therefore need constant evaluation against best practices [ 187 , 188 ].

This study has limitations. First, the list of the descriptive bias categories that we generated was not grounded in any particular theory so assigning a category was subjective. Additionally, there were studies that were categorized as “nonspecified” bias as the studies themselves did not mention the specific type of bias that they were addressing. Moreover, we had to exclude numerous publications solely because they were not evidence-based and were either perspectives, commentaries or opinion pieces. Finally, there were overall fewer studies focused on the resident population, so the calculated ratio of MS:Res studies did not compare similar sample sizes.

Future directions of our study include working with behavioral scientists to categorize these bias characteristics (Table 1 ) into cognitive error types [ 189 ]. Additionally, we aim to assess the effectiveness of the intervention strategies and categorize the approach of the intervention strategies.

The primary goal of our review was to organize, compare and quantify literature pertaining to bias within medical school curricula and residency programs. We neither performed a qualitative assessment of the studies nor did we test the efficacy of studies that were sorted into “bias intervention” as is typical of scoping reviews [ 22 ]. In summary, our research identified 11 descriptive categories of biases studied within medical students and resident populations with “race and ethnicity”, “disease or condition”, “weight”, “LGBTQ + ” and “age” being the top five most studied biases. Additionally, we found a greater number of studies conducted in medical students (105/139) when compared to residents (19/139). However, most of the studies in the resident population focused on bias intervention. The results from our review highlight the following gaps: a) bias categories where more research is needed, b) biases that are studied within medical school versus in residency programs and c) study focus in terms of demonstrating the presence of bias or working towards bias intervention.

This review provides a visual analysis of the known categories of bias addressed within the medical school curriculum and in residency programs in addition to providing a comparison of studies with respect to the study goal within medical education literature. The results from our review should be of interest to community organizations, institutions, program directors and medical educators interested in knowing and understanding the types of bias existing within healthcare populations. It might be of special interest to researchers who wish to explore other types of biases that have been understudied within medical school and resident populations, thus filling the gaps existing in bias research.

Despite the number of studies designed to provide bias intervention for MS and Res populations, and an overall cultural shift to be aware of one’s own biases, biases held by both medical students and residents still persist. Further, psychologists have recently demonstrated the ineffectiveness of some bias intervention efforts [ 179 , 190 ]. Therefore, it is perhaps unrealistic to expect these biases to be eliminated altogether. However, effective intervention strategies grounded in cognitive psychology should be implemented earlier on in medical training. Our focus should be on providing evidence-based approaches and safe spaces for an attitude and culture change, so as to induce actionable behavioral changes.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

• Medical student

Evidence of bias

• Bias intervention

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Acknowledgements

The authors would like to thank Dr. Misa Mi, Professor and Medical Librarian at the Oakland University William Beaumont School of Medicine (OWUB) for her assistance with selection of databases and construction of literature search strategies for the scoping review. The authors also wish to thank Dr. Changiz Mohiyeddini, Professor in Behavioral Medicine and Psychopathology at Oakland University William Beaumont School of Medicine (OUWB) for his expertise and constructive feedback on our manuscript.

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A.R.N and B.E.L were equally involved in study conception, design, collecting data and analyzing the data. B.E.L and A.R.N both contributed towards writing the manuscript. A.R.N and B.E.L are both senior authors on this paper. All authors reviewed the manuscript.

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Lewis, B.E., Naik, A.R. A scoping review to identify and organize literature trends of bias research within medical student and resident education. BMC Med Educ 23 , 919 (2023). https://doi.org/10.1186/s12909-023-04829-6

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Sustainable Development Goal (SDG) 3.7 aims to ensure universal access to sexual and reproductive healthcare services, where antenatal care (ANC) is a core component. This study aimed to examine the influence ...

A service mapping exercise of four health and social care staff mental health and wellbeing services, Resilience Hubs, to describe health service provision and interventions

NHS England funded 40 Mental Health and Wellbeing Hubs to support health and social care staff affected by the COVID-19 pandemic. We aimed to document variations in how national guidance was adapted to the loc...

Equitable access to quality injury care; Equi-Injury project protocol for prioritizing interventions in four low- or middle-income countries: a mixed method study

Equitable access to quality care after injury is an essential step for improved health outcomes in low- and middle-income countries (LMICs). We introduce the Equi-Injury project, in which we will use integrate...

Understanding health system resilience in responding to COVID-19 pandemic: experiences and lessons from an evolving context of federalization in Nepal

The COVID-19 pandemic has tested the resilience capacities of health systems worldwide and highlighted the need to understand the concept, pathways, and elements of resilience in different country contexts. In...

Adaptation and qualitative evaluation of the BETTER intervention for chronic disease prevention and screening by public health nurses in low income neighbourhoods: views of community residents

The BETTER intervention is an effective comprehensive evidence-based program for chronic disease prevention and screening (CDPS) delivered by trained prevention practitioners (PPs), a new role in primary care....

Advance directives in the emergency department–a systematic review of the status quo

Providing individualised healthcare in line with patient wishes is a particular challenge for emergency healthcare professionals. Documentation of patient wishes (DPW), e.g. as advance directives, can guide cl...

A cross-sectional study on turnover intention of nurses in eastern China

This study aimed to investigate the turnover intention among nurses in eastern China and explore the association between turnover intention and personal characteristics, family factors, and work-related factors.

Awareness of standard precautions, circumstances of occurrence and management of occupational exposures to body fluids among healthcare workers in a regional level referral hospital (Bertoua, Cameroon)

Healthcare workers (HCW) are exposed to infectious agents within biological materials including blood, tissues, other body fluids and on medical supplies, contaminated surfaces within the care delivery environ...

Early age at menarche and history of sexually transmitted infections significantly predict cervical cancer screening uptake among women aged 25–49 years: evidence from the 2021 Côte d’Ivoire demographic and health survey

Cervical cancer is the second dominant type of cancer among Ivorian women with an estimated age-standardised incidence and mortality rate of 31.2 cases and 22.8 deaths per 100,000 women in 2020, respectively. ...

Health workforce incentives and dis-incentives during the COVID-19 pandemic: experiences from Democratic Republic of Congo, Nigeria, Senegal, and Uganda

The COVID-19 pandemic presented a myriad of challenges for the health workforce around the world due to its escalating demand on service delivery. A motivated health workforce is critical to effectual emergenc...

Transition of care from post-acute services for the older adults in Quebec: a pilot impact evaluation

Early discharge of frail older adults from post-acute care service may result in individuals’ reduced functional ability to carry out activities of daily living, and social, emotional, and psychological distre...

Capturing artificial intelligence applications’ value proposition in healthcare – a qualitative research study

Artificial intelligence (AI) applications pave the way for innovations in the healthcare (HC) industry. However, their adoption in HC organizations is still nascent as organizations often face a fragmented and...

Is it possible to make ‘living’ guidelines? An evaluation of the Australian Living Stroke Guidelines

Keeping best practice guidelines up-to-date with rapidly emerging research evidence is challenging. ‘Living guidelines’ approaches enable continual incorporation of new research, assisting healthcare professio...

Co-development of a training programme on disability for healthcare workers in Uganda

Approximately 1.3 billion people worldwide face barriers in accessing inclusive healthcare due to disabilities, leading to worse health outcomes, particularly in low and middle-income countries (LMIC). However...

Cost-effectiveness of intraoperative radiation therapy versus intensity-modulated radiation therapy for the treatment of early breast cancer: a disinvestment analysis

Adjuvant radiotherapy represents a key component in curative-intent treatment for early-stage breast cancer patients. In recent years, two accelerated partial breast irradiation (APBI) techniques are preferred...

Patterns and determinants of healthcare utilization and medication use before and during the COVID-19 crisis in Afghanistan, Bangladesh, and India

COVID-19 rapidly spread through South Asian countries and overwhelmed the health systems that were unprepared for such an outbreak. Evidence from high-income countries showed that COVID-19 impacted healthcare ...

Trends in antidiabetic drug use and expenditure in public hospitals in Northwest China, 2012-21: a case study of Gansu Province

Since the twenty-first century, the prevalence of diabetes has risen globally year by year. In Gansu Province, an economically underdeveloped province in northwest China, the cost of drugs for diabetes patient...

Empowerment of individuals in Iranian health systems: a qualitative study using the Z-cognitive map approach

The empowerment of people is considered as one of the most effective approaches in national healthcare systems. Identifying the effective criteria for this empowerment approach can be useful for planning enhan...

Correction: A mixed methods analysis of the medication review intervention centered around the use of the ‘Systematic Tool to Reduce Inappropriate Prescribing’ Assistant (STRIPA) in Swiss primary care practices

The original article was published in BMC Health Services Research 2024 24 :350

The trend of dental check-up and prevalence of dental complications following the use of bone modifying agents in patients with metastatic breast and prostate cancer: analysis of data from the Korean National Health Insurance Service

Bone-modifying agents (BMA) are key components in the management of cancer patients with bone metastasis. Despite their clinical benefits, the use of BMA is associated with dental adverse events (AEs) includin...

Implementing digital sexual and reproductive health care services in youth clinics: a qualitative study on perceived barriers and facilitators among midwives in Stockholm, Sweden

Digital health care services have the potential to improve access to sexual and reproductive health care for youth but require substantial implementation efforts to translate into individual and public health ...

The use of medical health applications by primary care physicians in Israel: a cross-sectional study

The use of medical health applications (mHealth apps) by patients, caregivers, and physicians is widespread. mHealth apps are often employed by physicians to quickly access professional knowledge, guide treatm...

Geographical distribution of emergency obstetric and neonatal care signal functions in Ethiopian health facilities: 2021–2022 Ethiopian service Provision Assessment (SPA)

The maternal mortality ratio in Ethiopia is still high, with an estimate of 412 deaths per 100,000 live births in 2016. Signal functions for emergency obstetric and neonatal care must be accessible and usable ...

Building resilience: analysis of health care leaders’ perspectives on the Covid-19 response in Region Stockholm

The Covid-19 pandemic has tested health care organizations worldwide. Responses have demonstrated great variation and Sweden has been an outlier in terms of both strategy and how it was enacted, making it an i...

Linkage to HIV care and early retention in HIV care among men in the ‘universal test-and-treat’ era in a high HIV-burdened district, KwaZulu-Natal, South Africa

Despite the numerous efforts and initiatives, males with HIV are still less likely than women to receive HIV treatment. Across Sub-Saharan Africa, men are tested, linked, and retained in HIV care at lower rate...

Workforce strategies during the first wave of the COVID-19 pandemic: a retrospective online survey at intensive care units in Germany

As the COVID-19 pandemic swept across the globe at the beginning of 2020, healthcare systems were forced to rapidly adapt and expand to meet the sudden surge in demand for intensive care services. This study i...

“They seemed to be like cogs working in different directions”: a longitudinal qualitative study on Long COVID healthcare services in the United Kingdom from a person-centred lens

The COVID-19 pandemic has presented significant challenges to the already over-stretched healthcare system in the United Kingdom (UK). These challenges are particularly pronounced for people living with the no...

Strategies to implement evidence-informed decision making at the organizational level: a rapid systematic review

Achievement of evidence-informed decision making (EIDM) requires the integration of evidence into all practice decisions by identifying and synthesizing evidence, then developing and executing plans to impleme...

Barriers and facilitators to implementing a multilevel, multicomponent intervention promoting colorectal cancer screening in health centers: a qualitative study of key informant perspectives

Colorectal cancer (CRC) continues to be a major cause of death in the U.S. despite the availability of effective screening tools. U.S. Latinos have lower rates of CRC screening and higher rates of death due to...

Is the national health insurance scheme a pathway to sustained access to medicines in Nigeria?

The debate surrounding access to medicines in Nigeria has become increasingly necessary due to the high cost of essential medicine drugs and the prevalence of counterfeit medicines in the country. The Nigerian...

Turnover intention of foreign trained physicians in German rehabilitation facilities—a quantitative study

Germany’s medical specialist shortage is an acute challenge, especially in the rehabilitation segment. One countermeasure is to recruit foreign trained physicians (FTP), but the high turnover of FTP is a burde...

Co-creation process of an intervention to implement a multiparameter point-of-care testing device in a primary healthcare setting for non-communicable diseases in Peru

Point-of-care testing (POCT) devices are diagnostic tools that can provide quick and accurate results within minutes, making them suitable for diagnosing non-communicable diseases (NCDs). However, these device...

Factors influencing the length of stay in forensic psychiatric settings: a systematic review

Forensic psychiatry is often associated with long admissions and has a high cost of care. There is little known about factors influencing length of stay (LOS), and no previous systematic review has synthesised...

Rural-urban differences in use of health services before and after dementia diagnosis: a retrospective cohort study

Rural-urban differences in health service use among persons with prevalent dementia are known. However, the extent of geographic differences in health service use over a long observation period, and prior to d...

Evaluation of heroin-assisted treatment in Norway: protocol for a mixed methods study

Opioid agonist treatment (OAT) for patients with opioid use disorder (OUD) has a convincing evidence base, although variable retention rates suggest that it may not be beneficial for all. One of the options to...

A comprehensive value-based method for new nuclear medical service pricing: with case study of radium [223 Ra ] bone metastases treatment

Innovative nuclear medicine services offer substantial clinical value to patients. However, these advancements often come with high costs. Traditional payment strategies do not incentivize medical institutes t...

“These are just finishing our medicines”: older persons’ perceptions and experiences of access to healthcare in public and private health facilities in Uganda

There is limited research on the experiences of access to medicines for non-communicable diseases (NCDs) in health facilities among older persons in Uganda. This paper explores the perspectives of older person...

A collaborative endeavour to integrate leadership and person-centred ethics: a focus group study on experiences from developing and realising an educational programme to support the transition towards person-centred care

Ensuring the transition towards person-centred care is a growing focus in health and social care systems globally. Presented as an ethical framework for health and social care professionals, such a transition ...

Access to continuous professional development for capacity building among nurses and midwives providing emergency obstetric and neonatal care in Rwanda

Nurses and midwives are at the forefront of the provision of Emergency Obstetric and Neonatal Care (EmONC) and Continuous Professional Development (CPD) is crucial to provide them with competencies they need t...

Improving acute myocardial infarction care in northern Tanzania: barrier identification and implementation strategy mapping

Evidence-based care for acute myocardial infarction (AMI) reduces morbidity and mortality. Prior studies in Tanzania identified substantial gaps in the uptake of evidence-based AMI care. Implementation science...

Group Health & Wellness Coaching: development and validation of the required competencies

As the popularity and demonstrated effectiveness of Health and Wellness Coaching (HWC) continue to grow to address chronic disease prevalence worldwide, delivery of this approach in a group format is gaining t...

The association between midwifery staffing and reported harmful incidents: a cross-sectional analysis of routinely collected data

Independent inquiries have identified that appropriate staffing in maternity units is key to enabling quality care and minimising harm, but optimal staffing levels can be difficult to achieve when there is a s...

Using the consolidated Framework for Implementation Research to integrate innovation recipients’ perspectives into the implementation of a digital version of the spinal cord injury health maintenance tool: a qualitative analysis

Despite advances in managing secondary health complications after spinal cord injury (SCI), challenges remain in developing targeted community health strategies. In response, the SCI Health Maintenance Tool (S...

Cost-effectiveness analysis of CTZ/TAZ for the treatment of ventilated hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in Japan

Resistant bacterial infections, particularly those caused by gram-negative pathogens, are associated with high mortality and economic burdens. Ceftolozane/tazobactam demonstrated efficacy comparable to meropen...

Benchmark findings from a veteran electronic patient-reported outcomes evaluation from a chronic pain management telehealth program

Chronic pain is a leading cause of disability and negatively impacts biological/physical, psychological, and social aspects of life resulting in significant pain interference or disability. This project was pa...

Exploring healthcare provider retention in a rural and frontier community in Northern Idaho

A shortage of healthcare providers, particularly in primary care and mental health, exists in the predominately rural state of Idaho. There are also barriers to retaining healthcare providers to work in rural ...

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Authors: Zoe S. Oftring, Doortje M. Mehrtens, Julian Mollin, Eckard Hamelmann and Sebastian Gaus

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Authors: Catalina Morales-Betancourt, Diego Fontiveros-Escalona, Adriana Montealegre-Pomar, Tania Carbayo-Jiménez, María Palomares-Eraso, Concepción de Alba-Romero, Elena Bergón-Sendín, Maria Teresa Moral Pumarega and Carmen Pallás-Alonso

Growth and endocrinopathies among children with β-Thalassemia major treated at Dubai Thalassemia centre

Authors: Rabah Almahmoud, Amal Hussein, Fatheya Al Khaja, Ahmed Farrag Soliman, Hany Dewedar, Zainab Al Shareef and Sarah Mathai

Cholangiocarcinoma identified in perforated choledochal cyst in a 3-year-old boy

Authors: Lun Yu, Wenli Xiu, Aimei Yue, Xiwei Hao, Zhong Jiang, Jie Wu and Qian Dong

Epidermolysis Bullosa: Two rare case reports of COL7A1 and EBS-GEN SEV KRT14 variants with review of literature

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Sex-related change in BMI of 15- to 16-year-old Norwegian girls in cross-sectional studies in 2002 and 2017

Authors: Asborg A. Bjertnaes, Jacob H. Grundt, Petur B. Juliusson, Trond J. Markestad, Tor A. Strand and Mads N. Holten-Andersen

A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format

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A 'snip' in time: what is the best age to circumcise?

Authors: Brian J Morris, Jake H Waskett, Joya Banerjee, Richard G Wamai, Aaron AR Tobian, Ronald H Gray, Stefan A Bailis, Robert C Bailey, Jeffrey D Klausner, Robin J Willcourt, Daniel T Halperin, Thomas E Wiswell and Adrian Mindel

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Communicating with parents about vaccination: a framework for health professionals

Authors: Julie Leask, Paul Kinnersley, Cath Jackson, Francine Cheater, Helen Bedford and Greg Rowles

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Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy

• Pauline Hulo 1 , 2 ,
• Sophie Deshayes 1 ,
• Judith Fresquet 1 ,
• Anne-Laure Chéné 1 , 3 ,
• Stéphanie Blandin 4 ,
• Nicolas Boisgerault 1 ,
• Jean-François Fonteneau 1 ,
• Lucas Treps 1 ,
• Marc G Denis 1 , 5 ,
• Jaafar Bennouna 1 , 2 ,
• Delphine Fradin 1 ,
• Elvire Pons-Tostivint 1 , 2   na1 &
• Christophe Blanquart 1   na1  

Respiratory Research volume  25 , Article number:  156 ( 2024 ) Cite this article

12 Accesses

Metrics details

Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies.

To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3’RNA sequencing, real-time PCR, flow cytometry and confocal microscopy.

We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level.

Conclusions

This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.

Lung cancer is the main cause of cancer-related deaths worldwide. Non-small cell lung cancer/carcinoma (NSCLC) is the main pathological subtype of lung cancers, accounting for about 80–85% of them [ 1 ], and most of the patients are diagnosed at an advanced stage. Immune checkpoint inhibitors (ICIs) are a revolutionary milestone in the field of thoracic oncology, mostly represented by anti-PD-1 (programmed death-1) and anti-PD-L1 (programmed death - ligand 1, also called B7-H1 or CD274) molecules. Over the last decade, ICIs alone or in combination with chemotherapy have been the new standard of care in advanced, unresectable NSCLC with no oncogene drivers, regardless histologic subtypes [ 1 , 2 ]. Several ICIs such as p embrolizumab, cemiplimab, or atezolizumab improved overall survival (OS) compared to chemotherapy in untreated NSCLC patients. However, their efficacy was restricted to patients with high PD-L1 expression on tumor cells (tumor proportion score) ≥ 50% [ 2 ]. Afterwards, several trials showed that a combination of platinum-based chemotherapy plus ICIs was superior to chemotherapy alone, regardless of PD-L1 expression [ 3 , 4 , 5 , 6 ]. More recently, it has been demonstrated that ICIs in combination with platinum-based chemotherapy improve event-free-survival over chemotherapy alone (OS data were still immature but seemed in favor of the combination arm) [ 7 , 8 ] in patients with localized NSCLC treated in the neoadjuvant setting. Thus, platinum-based chemotherapy remains the backbone of NSCLC treatment, in localized or advanced stage with no targetable oncogenic alterations.

Cytotoxic chemotherapies change tumors biological characteristics. Nevertheless, the way chemotherapy might affect tumor cells, microenvironment cells or both, and the way it might also sensitize them to ICIs remains unclear. A good understanding of therapies consequences on cancer cells should help to improve current first line treatment efficiency, and also to propose more adapted second line therapies. Indeed, at relapse, docetaxel or pemetrexed (for non-squamous histology) as single agents are preferred therapeutic options if not administered at frontline, regardless resistance mechanisms [ 2 ]. The reason is that the study of resistance mechanisms in patients is very challenging, because it would require a new biopsy from the recurrence site. To overcome these limitations, preclinical models that help to assess the molecular impact of systemic therapies on tumor cells are highly required. Indeed, the usual 2D cell culture lacks the structural architecture and tumor microenvironment (TME). Interestingly, cell culture in three dimensions (3D) notably reproduces biological barriers that greatly hinder drug delivery and cell to cell interactions that might affect the epithelial to mesenchymal transition state of cells. These models are nowadays mainly used to assess therapies efficacy and they represent a growing field of development, in particular those including TME cells [ 9 ].

In this work, we used multicellular tumor spheroid (MCTS) models constituted of NSCLC tumor cells, with or without microenvironment, fibroblasts and monocytes, so as to study the impact of platinum-based chemotherapies, carboplatin-paclitaxel or carboplatin-gemcitabine. We also assessed the impact of this treatment using 3’RNA sequencing, flow cytometry and real-time PCR.

Human monocytes were freshly isolated by magnetic sorting from Peripheral Blood Mononuclear Cell (PBMC) of healthy volunteers following the manufacturer’s protocol (classical monocyte isolation kit, Miltenyi Biotec). Lung cancer cell line ADCA117 was established from the pleural fluid of a NSCLC cancer patient [ 10 ]. ADCA117 cell line belongs to a biocollection of samples from patients at Nantes University Hospital, collected in accordance with the standards established by the Declaration of Helsinki. Recruited patients had received no prior anticancer therapies and provided signed informed consent. All the collected samples and the associated clinical information were registered in a database (DC-2017-2987) validated by the French Ministry of Research. This study was approved by a local ethical committee (CPP Ouest-IV-Nantes). The other NSCLC cell lines (H1975 and H1437) as well as Human Foreskin Fibroblast-2 (HFF-2) cell line were all purchased from ATCC (LGC Standards). The characteristics of lung cancer cell lines used are summarized in table S1 . ADCA117 GFP and HFF-2 ruby were obtained by transduction using lentiviral particles and were selected using puromycin at 5 µg/ml (Sigma-Aldrich). These cell lines were cultured in complete RPMI-1640 or DMEM 4.5 g/l Glucose media (Gibco) supplemented with 2mM L-glutamine, 100IU/mL penicillin, 0.1 mg/mL streptomycin (Gibco) and 10% heat-inactivated fetal calf serum (FCS) (Gibco), respectively, at 37 °C and 5% CO2 atmosphere.

Multicellular tumor spheroids (MCTS) formation

Tumor cells were mixed with or without monocytes from healthy donors and HFF-2 (MCTS complex) at a ratio of 2:0.5:0.5 (2 × 10 4 total cells) in 96-well U bottom plates NUNCLON SPHERA (Thermo Fisher Scientific) and in a volume of 180 µL of complete culture medium. The plates were centrifuged 2 min at 800×g and incubated at 37 °C in a 5% CO2 atmosphere for 3 days.

Carboplatin, paclitaxel and gemcitabine were obtained from Nantes University Hospital’s drugstore.

Viability measurement

After treatments, MCTS were collected and cell viability was measured using CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer’s recommendations using a luminometer (Mithras LB 940, Berthold Technologies).

MCTS were treated with both carboplatin 50µM and paclitaxel 150nM or carboplatin 50µM and gemcitabine 100nM at day 3, and after by paclitaxel 150nM or gemcitabine 100nM alone at days 6 and 8. At day 10, MCTS were collected and mRNA were extracted using Nucleospin RNA kit (Macherey-Nagel). The mRNA quality was analyzed using Agilent 20,100 Bioanalyzer (Agilent) in RNA Nanochips (Agilent).

Regarding gene analysis, 3′ sequencing RNA profiling was performed by the GenoBird plateform (IRS-UN, Nantes, France) using a NovaSeq 6000 (Illumina Inc.) and NovaSeq 6000 SP Reagent Kit 100 cycles (Illumina Inc.) according to the manufacturer’s protocol (NovaSeq 6000 Sequencing System Guide Document #1000000019358v11 Material #20,023,471, Illumina). The full procedure is described in Charpentier et al., Protocol exchange ( https://doi.org/10.21203/rs.3.pex-1336/v1 ). The raw sequence reads were filtered based on quality using FastQC. Adapted sequences were trimmed off the raw sequence reads using Cutadapt. Reads were then aligned to the reference genome using BWA. Moreover, differential expressions were detected with DESeq2 Bioconductor package.

Flow cytometry

MCTS were treated with carboplatin 50µM and paclitaxel 150nM or gemcitabine 100nM at day 3 and with paclitaxel 150nM or gemcitabine 100nM at days 6 and 8. At day 10, MCTS were collected and treated with TrypLE express (Gibco) for 10 to 120 min at 37°c. Dissociated cells were incubated with an anti-PD-L1 coupled to phycoerythrin (PE) (557,924, BD), an anti-CD14 coupled to allophycocyanin (APC) (301,808, Biolegend), an anti-CD163 coupled to BV421 (333,611, Biolegend) or corresponding control isotypes. After two washes with Phosphate Buffered Saline (PBS), cells were analyzed using FACSymphony™ A5 flow cytometer (BD Biosciences) and DIVA 8 software (BD Biosciences).

Real time PCR

mRNA were extracted using Nucleospin RNA kit (Macherey-Nagel). 0.5 µg of total RNA were reverse transcribed using MMLV reverse transcriptase (Invitrogen). PCR reactions were performed using QuantiTect Primer Assays (Qiagen) and RT 2 Real-time SYBR-Green/ROX PCR mastermix (Qiagen) and carried out using QuantStudio™ Real-Time PCR system 3 (ThermoFisher). RPLP0 gene expression was used as internal standard.

Confocal microscopy

MCTS made with fluorescent cells were collected, washed once in PBS and fixed in 4% paraformaldehyde (Electron Microscopy Sciences) for 48 h at RT. MCTS were washed once with PBS and permeabilized for 24 h with PBS containing 2% Triton X-100 at RT. This solution was removed and afterwards MCTS were incubated with a solution of PBS containing 1% BSA, 0.2% Triton X-100 and Hoescht 5 µg/mL (Sigma-Aldrich) for 48 h at 4 °C. Two washing steps were performed with PBS containing 3% NaCl and 0.2% Triton X-100 for 2 h at RT. Finally, MCTS were resuspended in a RapiClear solution (SunJin Lab) and observed with a confocal microscope (Nikon A1R Si).

Statistical analysis

Control and treated groups were compared with Mann-Whitney nonparametric t-test. Error bars represent standard errors of mean (SEM). The symbols correspond to a P -value inferior to *0.05, **0.01, ***0.001, ****0.0001. All statistical analyses were performed using GraphPad Prism Software (version 8.0).

Determination of chemotherapy optimal doses

In order to identify treatment conditions inducing 20–30% of cell death in our experiments, we first determined the sensitivity of ADAC117 cells cultured as MCTS to carboplatin, paclitaxel and gemcitabine by performing dose response experiments using molecules as monotherapy and measuring cell viability after 72 h of incubation. ADCA117 MCTS were most sensitive to paclitaxel (IC 50  = 0.0020 mM, 95% CI = 0.0014 to 0.0029) (Fig.  1 A) and to gemcitabine (IC 50  = 0.0013 mM, 95% CI = 0.0010 to 0.0018) (Fig.  1 B) compared to carboplatin (IC 50  = 0.133 mM, 95% CI = 0.094 to 0.188) (Fig.  1 C). As observed in clinical practice, chemotherapy schedule consisted in an initial combination of carboplatin-paclitaxel (CaPa) or carboplatin-gemcitabine (CaGe) followed by repeated infusion of paclitaxel or gemcitabine as illustrated in Fig.  1 D. Individual doses of molecules were chosen in order to induce a decrease of about 20–30% in cell viability after 72 h of treatment according to Fig.  1 A, B and C. As observed in Fig.  1 E and F, treatments affected MCTS structure and decreased cell viability of approximately 60% and 80% for CaPa and CaGe, respectively.

Determination of the optimal doses of carboplatin, paclitaxel and gemcitabine. Lung cancer cells, ADCA117, were grown as MCTS. MCTS were then incubated for 72 h with increasing concentrations of paclitaxel ( A ), gemcitabine ( B ) or carboplatin ( C , D ) Treatment sequence of MCTS. ( E , F ) MCTS were treated with a combination of carboplatin 50µM and paclitaxel 150nM (CaPa) or gemcitabine 100nM (CaGe) repeated 3 times. ( E ) MCTS were observed using an optical microscopy (upper panel) or histology using hematoxylin, phloxin, safran staining (lower panel) and ( F ) cell viability was measured. Results are expressed as the mean +/- SEM of three independent experiments. ***, p  < 0.001 (Mann-Whitney t-test)

With the objective to identify transcriptomic modifications following CaPa or CaGe in lung cancer cells, we performed a 3’RNA sequencing analysis. Two hundred and seventy one genes were up-regulated (padj < 0.01 and Log2 fold change > 1) and 364 genes were down-regulated (padj < 0.01 and Log2 fold change < -1) in cells exposed to CaPa compared to non-exposed ones (Fig.  2 A and table S2 ). Regarding CaGe, 286 genes were up-regulated (padj < 0.01 and Log2 fold change > 1) and 417 genes were down-regulated (padj < 0.01 and Log2 fold change < -1) in MCTS cells (Fig.  2 B and Table S3 ).

mRNA expression changes in ADCA117 MCTS after exposure to carboplatin-paclitaxel or carboplatin-gemcitabine combinations. ADCA117 MCTS were non-treated ( n  = 13) or treated with a combination of carboplatin (50µM)-paclitaxel (150nM) (CaPa) ( n  = 5) or gemcitabine (100 nM) (CaGe) ( n  = 5) repeated 3 times. mRNA were extracted and analyzed using 3’RNA sequencing. ( A , B ) Volcano-plot of the differentially expressed mRNAs after CaPa ( A ) or CaGe ( B ) exposure. Red: significant regulation, Green: non-significant regulation, Blue: significant regulation but under fold-change (FC) cutoff. FC cutoff ≥ 1 or ≤-1

The lists containing the 10 most significantly regulated genes following CaPa or CaGe are presented in Tables  1 and 2 , respectively. Pathway enrichment analyses showed that pathways involved in cell stress were up-regulated (Fig.  3 , left panels) whereas those involved in cell functions such as cell cycle and DNA repair were down-regulated (Fig.  3 , right panels), regardless the type of chemotherapy. Analysis of the genes affected by both CaPa and CaGe showed that 202 genes were co-upregulated and 285 genes co-downregulated (Figure S1 ).

Pathway analysis on the effect of carboplatin-paclitaxel or carboplatin-gemcitabine combinations exposure in ADCA117 MCTS. ADCA117 MCTS were treated with a combination of carboplatin (50µM)-paclitaxel (150nM) (CaPa) or gemcitabine (100 nM) (CaGe) repeated 3 times. mRNA were extracted and analyzed using 3’RNA sequencing. ( A , B ) KEGG pathways enrichment of CaPa ( A ) or CaGe ( B )-dysregulated mRNAs

Impact of CaPa and CaGe on immune status of lung cancer cells

Immune check point inhibitors (ICI) have strongly modified therapeutic strategies in NSCLC patients, and are currently a standard of care, alone or in combination with chemotherapy. Thus, we have analyzed the effect of CaPa and CaGe treatments on the expression of a panel of genes considered as hallmarks of response/resistance to immune check point inhibitors [ 11 ] from data obtained through 3’RNA sequencing. Among this panel, mRNA expression of 3 genes were upregulated after CaPa, CD274 , coding for PD-L1, NECTIN4 , and NT5E , coding for 5’ Nucleotidase (Fig.  4 A) (Table  3 ). Expression of four genes decreased after CaPa, TNFSF18 , coding for GITRL, HMGB1 , TNFSF4 , coding for OX-40 L and HLA-A , all involved in the positive regulation of anti-tumor immune response (Fig.  4 A)(Table  3 ). The genes most significantly deregulated with CaGe were common with CaPa and included NECTIN4 , CD274 , HMGB1 , TNFSF18 and TNFSF4 (Fig.  4 B; Table  4 ).

PD-L1 is a major target in the current strategy of immunotherapy based on the use of check point inhibitors. We therefore focused our work on this protein expressed at the surface of cells and involved in the inhibition of immunologic anti-tumor response. Using flow cytometry, we confirmed the induction of CD274 gene expression at the protein level in ADCA117 cells that do not express PD-L1 in control conditions (Fig.  4 C and D). This induction was not observed in all cells. We observed that treatments strongly affect MCTS, after hematoxylin, phloxin, safran (HPS) staining, and also induce PD-L1 expression, but only at MCTS periphery where cells are in direct contact with chemotherapies (Figure S2 A).

PD-L1 ( CD274 ) expression is induced following carboplatin-paclitaxel and carboplatin-gemcitabine exposure. ( A , B ) Changes in the expression of genes involved in immunogenicity and check point inhibitor resistance in ADCA117 MCTS after CaPa ( A ) or CaGe ( B ) treatment using 3’RNASeq data. ( C , D ) PD-L1 expression was measured following CaPa ( C ) or CaGe ( D ) treatment using flow cytometry after MCTS dissociation

Impact of CaPa and CaGe on PDL-1 expression in MCTS constituted of tumor cells, fibroblasts and macrophages

In order to get closer to malignant tissues complexity, we have included fibroblasts and macrophages, two major components of TME, with ADCA 117 cells to build complex MCTS. CaPa or CaGe treatments altered MCTS structure (Fig.  5 A) and significantly decreased global viability by approximately 50% and 80%, respectively (Fig.  5 B). Using confocal microscopy, we observed a MCTS size reduction after treatment (Fig.  5 C), whereas CaPa seemed not to affect tumor cells at MCTS core, CaGe particularly affected lung cancer cells at MCTS core as illustrated by a loss of GFP fluorescence and the presence of highly compact nuclei in this area (Fig.  5 C). Fibroblasts did not appear to be affected by chemotherapy. The fact of adding monocytes into MCTS led to macrophages formation expressing CD14 and CD163 as showed using flow cytometry (Fig.  5 D) and real-time PCR (Fig.  5 E).

Impact of carboplatin-paclitaxel treatment on complex MCTS viability and structure. Lung cancer cells, ADCA117, fibroblasts (HFF-2) and monocytes were cultured as MCTS. MCTS were treated with a combination of carboplatin 50µM and paclitaxel 150nM (CaPa) or gemcitabine 100nM (CaGe) repeated 3 times. ( A ) MCTS were observed using optical microscopy (upper panel) or histology using hematoxylin, phloxin, safran staining (lower panel) and ( B ) cell viability was measured. Results are expressed as the mean +/- SEM of three independent experiments. ***, p  < 0.001 (Mann-Whitney t-test). ( C ) MCTS were observed using confocal microscopy. Blue: nuclei, green: ADCA117-GFP and red: HFF-2 ruby. ( D ) MCTS were dissociated and analyzed using flow cytometry. Dot plot shows CD14 and CD163 expression on HLA-DR + and CD14 + cells. ( E ) mRNA were extracted and both CD14 and CD163 expressions were measured using real-time PCR. Results are expressed as the mean +/- SEM of the three independent experiments

After CaPa or CaGe, both CD14 and CD163 expressions were strongly reduced suggesting macrophages elimination by chemotherapy. MCTS treatment with CaPa or CaGe induced PD-L1 expression at both mRNA (Fig.  6 A) and protein level (Fig.  6 B). Using flow cytometry, we observed that PD-L1 expression was specifically induced at the surface of cancer cells (Fig.  6 B). Indeed, PD-L1 expression was not detected at the surface of fibroblasts and macrophages after CaPa or CaGe (Figure S3 ). As previously observed using immunohistology, PD-L1 was only expressed at the periphery of treated MCTS (Figure S2 B).

PD-L1 (CD274) expression is induced following CaPa or CaGe exposure in complex MCTS. Lung cancer cells, ADCA117, fibroblasts (HFF-2) and monocytes were grown as MCTS. MCTS were treated with a combination of carboplatin 50µM and paclitaxel 150nM (CaPa) or gemcitabine 100nM (CaGe) repeated 3 times. ( A ) mRNA were extracted and CD274 expression was measured using RT-PCR. Results are expressed as the mean +/- SEM of at least three independent experiments. *, p  < 0,05 (Mann-Whitney t-test). ( B ) PD-L1 expression was measured using flow cytometry after dissociation of MCTS. Left: CaPa; right: CaGe

To extend our work to additional models of lung cancer MCTS including fibroblasts and macrophages, we selected a cell line expressing a similar level of CD274 than ADCA117, H1437, as well as a cell line expressing higher level of CD274 compared to ADCA117, H1975 (Figure S4 ). We observed heterogeneity in lung cancer cells sensitivity cultured as MCTS to CaPa and to a lesser extend to CaGe. Indeed, ADCA117 MCTS were highly sensitive to CaPa (approximately 55% of cell death) (Fig.  5 B) whereas H1975 MCTS were weakly sensitive (approximately 25% of cell death) and H1437 MCTS were resistant (Fig.  7 A). Figure  7 B shows that CaPa induces CD274 expression in H1437 but did not modify CD274 expression in H1975 MCTS already presenting high expression of this protein. Moreover, CaGe induced a significant cell viability decrease in ADCA117 (Fig.  5 B, approximately 80% of cell death), H1975 (approximately 45% of cell death) and H1437 (approximately 55% of cell death) MCTS (Fig.  7 A) and increased CD274 expression in H1437 once again but not in H1975 MCTS (Fig.  7 B).

CaPa and CaGe treatment effect on complex MCTS. Lung cancer cells, H1975 or H1437, fibroblasts (HFF-2) and monocytes were grown as MCTS. MCTS were treated with a combination of carboplatin 50µM and paclitaxel 150nM (CaPa) or gemcitabine 100nM (CaGe) repeated 3 times. ( A ) Cells viability was measured. ( B ) mRNA from cells were extracted and CD274 expression was measured using real-time PCR. Results are expressed as the mean +/- SEM. n  = 5. *, p  < 0.05 (Mann-Whitney t-test)

In ADCA117 MCTS, we previously observed that NECTIN4 , HMGB1 and TNFSF18 expression was modified after CaPa or CaGe. We studied the impact of treatments on these genes expression (Fig.  8 ) using H1437 and H1975 complex MCTS. In H1975 complex MCTS, no modifications were observed for NECTIN4 and HMGB1 expression (Fig.  8 A). A non-significant increase in TNFSF18 was observed. However, as for NECTIN4 in ADCA117 MCTS, basal expression was very low compared to ADCA117 (Figure S4 ). In H1437 complex MCTS, NECTIN4 expression remained the same after treatments whereas both HMGB1 (tendency with CaPa)) and TNFSF18 expressions increased (Fig.  8 B).

CaPa and CaGe treatment effect on NECTIN4 , HMGB1 and TNFSF18 expressions in complex MCTS. Lung cancer cells, H1975 ( A ) or H1437 ( B ), fibroblasts (HFF-2) and monocytes were grown as MCTS. MCTS were treated with a combination of carboplatin 50µM and paclitaxel 150nM (CaPa) or gemcitabine 100nM (CaGe) repeated 3 times. mRNA from cells were extracted and genes expression was measured using real-time PCR. Results are expressed as the mean +/- SEM. n  = 5. *, p  < 0.05; **, p  < 0.01

ICIs development has deeply changed NSCLC therapeutic care of patients over the last decade, by demonstrating survival improvement. Importantly, platinum-based chemotherapy remained the backbone of treatment, in combination with ICIs, regardless tumor stage and histology. However, most patients will finally relapse, and rebiopsies are often difficult to obtain. Chemotherapies impact tumor cells and their microenvironment. However, molecular modifications remain largely unknown due to the challenging access to tumor tissues before and after systemic therapies. In order to overcome this limitation, the objective of our study is to develop and characterize 3D models of lung cancer, including or not TME cells. Indeed, the number of models with TME cells is limited particularly regarding the presence of macrophages. Moreover, to evaluate the impact of chemotherapies, we used a protocol based on chemotherapy cycles administrated in the clinic and not only a treatment during 72 h as it was usually the case in in vitro studies. Thus, we have developed Multicellular Tumor Spheroids (MCTS) models containing NSCLC cells, with or without fibroblasts and monocytes. First, we treated MCTS constituted of tumor cells alone with a combination of chemotherapeutic agents, carboplatin-paclitaxel (CaPa) or carboplatin-gemcitabine (CaGe), according to the treatment schedule used in patients (Fig.  1 D). These treatments decreased cell viability and induced strong transcriptomic modifications. In particular, several genes involved in tumor cell immunogenicity [ 11 ] were deregulated, such as CD274 coding for PD-L1, which was induced. CD274 induction was confirmed at the protein level using flow cytometry and immunohistology. These experiments showed that PD-L1 induction was restricted to a fraction of cells localized at MCTS periphery, those in direct contact with chemotherapies. Then, chemotherapies impact was studied using complex MCTS constituted of NSCLC tumor cells, fibroblasts and monocytes. These treatments reduced cell viability depending on the cancer cell line used to form MCTS. Some MCTS being resistant to treatments, reduced the number of macrophages but had no impact on fibroblasts. A cell immunogenicity modification was also observed. Furthermore, CD274 gene expression increased, as previously observed, in NSCLC cells with low basal expression, but remained the same in NSCLC cells with a high basal CD274 expression. Herein, this PD-L1 induction was not either related to the treatment used nor to the presence or not of fibroblasts and macrophages. However, other genes regulation involved in anti-tumor immune response and resistance to immunotherapies, NECTIN4 , HMGB1 , TNFSF18 , by CaPa or CaGe seem to be dependent on the cell line used and thus to be more heterogeneous.

Paclitaxel and gemcitabine belong respectively to taxane, a family of drugs interfering with microtubule during cell division, and nucleoside, a family of metabolic inhibitors. In regards of their different action mode, numbers of genes are differentially regulated when using CaPa or CaGe combinations. CaPa induced specifically genes expression involved in inflammatory pathways such as TNFα signaling, inflammatory response and interferon-γ response, and specifically reduced pathways involved in cell division such as E2F targets, G2M checkpoint and mitotic spindle (Figure S1 B and Table S4 ). CaGe specifically induced genes expression involved in pathways such as DNA damages with P53 and UV response, and reduced, therefore, pathways involved in inflammation such as interferon-γ and interferon-α responses (Figure S1 C and Table S5 ). Nevertheless, most of deregulated genes are common to the two combinations and suggests a strong impact of carboplatin, a platin salt. Mainly, genes induced are involved in pathways regulating inflammation and DNA damages like TNFα signaling and inflammatory response, as well as P53 and apoptosis respectively (Figure S1 D and Table S6 ). At the level of immunogenicity, CaGe and CaPa had a similar impact on the hallmark genes of resistance/sensitivity to immune checkpoint inhibitors in ADACA 117. However, in H1437 and H1975, the effect seemed to depend on cells sensitivity to treatments. Indeed, CaGe induced a stronger decrease in cell viability compared to CaPa as well as a higher regulation of CD274 and TNFSF18 expression. Therefore, depending on cells, CaGe and CaPa effect might be different on immunogenicity. This illustrates the complexity and heterogeneity of the response to treatments observed in clinical practice [ 12 , 13 ].

PD-L1, expressed on various solid tumor and immune cells, plays a crucial role in developing cancer immunoresistance by binding PD-1 expressed at the surface of T-lymphocytes, resulting in the inhibition of T-lymphocytes migration, proliferation and secretion of cytotoxic mediators [ 14 ]. Thus, PD-L1 is a major target in immunotherapy strategy. We observed that CaPa and CaGe combinations increased PD-L1 expression suggesting a possible conversion of negative/low PD-L1 cells to positive/high PD-L1 cells after chemotherapy. This PD-L1 induction had already been observed in a heterogeneous way in NSCLC tumors using immunohistochemistry and this seemed to depend on the type of chemotherapy used [ 15 , 16 , 17 , 18 ]. Interestingly, this PD-L1 induction following chemotherapies could explain, at least partially, the superiority of chemotherapy/immunotherapy compared to chemotherapy alone even in patients with a PD-L1 score < 1% in tumor [ 3 , 5 , 12 , 19 , 20 ]. Likewise, in patients with resectable NSCLC, a neoadjuvant combination of chemotherapy (carboplatin/cisplatin with paclitaxel) plus ICI showed a better efficacy than chemotherapy alone regardless of PDL-1 status suggesting a possible sensitization of tumors to ICIs by inducing PD-L1 expression. In addition, several studies showed a trend to an increase in PD-L1 level at relapse, after a cytotoxic chemotherapy in adjuvant or advanced stage [ 12 , 13 ]. The reproduction of this chemotherapy effect on PD-L1 expression in MCTS suggests that this 3D model could be an interesting alternative to tumor samples to study treatments impact on tumor cells.

TME cells, including fibroblasts and macrophages, play a major role in the tumors development. Thus, we added these cells in our MCTS to take into account the interactions with tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) as well as physical properties of the three-dimensional cell culture [ 21 , 22 ]. Monocytes differentiated into TAMs expressing CD14 and CD163 markers, usually tend to associate with immunosuppressive M2-like phenotype [ 23 , 24 ]. We also observed that macrophages were highly sensitive to treatments whereas fibroblasts were not. Several studies have shown a depleting effect of gemcitabine on myeloid derived suppressive cells in NSCLC [ 25 ]. This effect was also observed in other types of cancers with chemotherapeutic agents including platinum derivatives, anthracyclines and taxane [ 25 ]. This suggests that after chemotherapy, residual tumours could be infiltrated by new monocytes in a new environment, with different phenotypes. It is difficult to generate data in order to confirm TME modification in tumours due to the difficult access to samples before and after treatments. Furthermore, CAFs are a major TME component that contribute to tumor growth, supporting resistance to treatments, migration and invasion [ 26 ]. As for monocytes, the presence of fibroblasts did not modify the induction of CD274 expression following treatments. As opposed to monocytes/macrophages, fibroblasts seemed less sensitive to chemotherapies suggesting a stability of fibroblast populations during tumors development and after treatments [ 27 , 28 , 29 ].

In conclusion, our study suggests that the use of 3D models is of great interest to assess the impact of first line chemotherapy and thus to identify new and more efficient strategies for second line therapies. However, to get closer to physiopathological situation, 3D models improvement remains necessary such as the introduction of other immune cells beside monocytes as well as endothelial compartments among others.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request. 3’RNAseq data are registered under GSE243934 reference in NCBI’s Gene Expression Omnibus (GEO) database.

Abbreviations

Two dimension

Three dimension

Allophycocyanin

American type culture collection

Cancer-associated fibroblasts

Carboplatin-gemcitabine

Carbolatin-paclitaxel

deoxyribonucleic acid

Fetal calf serum

Green fluorescent protein

Human Foreskin Fibroblasts-2

Hematoxylin, phloxin, safran

Immune checkpoint inhibitors

Multicellular tumor spheroids

Non-Small Cell Lung Cancer

Overall survival

Peripheral Blood Mononuclear Cell

Phosphate buffered saline

Polymerase Chain Reaction

Programmed death-1

Programmed death - ligand 1

Standard errors of mean

Tumor-associated macrophages

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Acknowledgements

The authors thank the cluster LUNG innOvatiOn (LUNG O2) for logistic support, the National Research Agency under the Programme d’Investissements d’Avenir (ANR-16-IDEX-0007), the Cytometry Facility « CytoCell » from Nantes, the IBISA MicroPICell facility (Biogenouest) and the member of the national infrastructure France-Bioimaging supported by the French National Research Agency (ANR-10-INBS-04) for technical support, for their expert technical assistance. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest) for its technical support.

This work was supported by INSERM, CNRS, the Institut de Recherche en Santé Respiratoire des Pays de la Loire, Intergroupe Francophone de Cancérologie Thoracique (IFCT) and the Ligue contre le Cancer Grand-Ouest.

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Elvire Pons-Tostivint and Christophe Blanquart have equally contributed to this work as co-senior authors.

Authors and Affiliations

Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d’Angers, Nantes, CRCI2NA, F- 44000, France

Pauline Hulo, Sophie Deshayes, Judith Fresquet, Anne-Laure Chéné, Nicolas Boisgerault, Jean-François Fonteneau, Lucas Treps, Marc G Denis, Jaafar Bennouna, Delphine Fradin, Elvire Pons-Tostivint & Christophe Blanquart

Medical oncology, Nantes Université, CHU Nantes, Nantes, F-44000, France

Pauline Hulo, Jaafar Bennouna & Elvire Pons-Tostivint

Service de pneumologie, L’institut du thorax, Hôpital Guillaume et René Laennec, CHU Nantes, Nantes, France

Anne-Laure Chéné

Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, US16, SFR Bonamy, Nantes, F-44000, France

Stéphanie Blandin

Department of Biochemistry, Nantes Université, CHU Nantes, Nantes, F-44000, France

Marc G Denis

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Contributions

PH, SD, JF and SB performed experiments; ALC provided samples from patients and provided critical review; PH, NB, JFF, MD and JB interpreted the study and provided critical review; LT and DF performed bioinformatics analysis and provided critical review; EPT and CB conceived, designed, supervised, analyzed and interpreted the study and provided critical review. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Elvire Pons-Tostivint or Christophe Blanquart .

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ADCA117 lung cancer cell line was established from the pleural fluid of a NSCLC cancer patient. ADCA117 cell line belongs to a biocollection of samples, from patients from Nantes University Hospital, collected in accordance with the standards established by the Declaration of Helsinki. Recruited patients had received no prior anticancer therapies and gave signed informed consent. All the collected samples and the associated clinical information were registered in a database (DC-2017-2987) validated by the French Ministry of Research. Our study was approved by local independent ethical committee (CPP Ouest-IV-Nantes).

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Supplementary Figure S1:

Number of genes regulated specifically and in common by CaPa and CaGe treatments. A) Left, vendiagramm showing the number of genes upregulated in common or specifically after CaPa or CaGe treatment. A) Right, vendiagramm showing the number of genes downregulated in common or specifically after CaPa or CaGe treatment. B-D) Hallmark gene sets pathways enrichment of genes specifically regulated by CaPa (B), by CaGe (C) and in common between CaPa and CaGe (D) (GSEA, Human MSigDB v2023.2.Hs updated October 2023)(Subramanian, Tamayo, et al. (2005, PNAS).

Supplementary Figure S2:

PD-L1 (CD274) expression is induced following carboplatin-paclitaxel exposure in complex MCTS. Lung cancer cells, ADCA117, alone (A) or with fibroblasts (HFF-2) and monocytes (B) were grown as MCTS. MCTS were treated with a combination of carboplatin 50µM and paclitaxel 150nM (CaPa) repeated 3 times. Then, MCTS were analyzed using Immunohistology. Right panel: PD-L1 labelling in MCTS. MCTS were fixed with 4% paraformaldehyde (Electron Microscopy Sciences) for 24 h at room temperature (RT). After one PBS wash, MCTS were included in HistoGel (Microtech, Thermo Fisher Scientific). Then, an immunohistochemical analysis was performed using standard techniques with the Cellular and Tissue Imaging Core Facility of Nantes University (Micro-PICell). Left panel: hematoxylin, phloxin, safran (HPS) MCTS staining. Right panel: antigen retrieval was performed using Impath Retrieval Solution pH 6.0 (Impath, ref: 44,998) at 101 °C for 20 min. Slides were incubated with hydrogen peroxyde blocking solution (Thermo scientific, ref: TA-125-HP) for 10 min then, incubated with rabbit serum 1.5% (Vector Laboratories, ref: S-5000) for 20 min at room temperature. PD-L1 antibody (R&D systems, AF156) was used at 0.5 µg/ml for 1 h then, biotinylated rabbit anti-goat secondary antibody was used at 3.75 µg/ml (Vector Laboratories, ref BA-5000) for 30 min. Revelation was performed using Large Volume Streptavidin peroxidase (Thermo Scientific, ref: TS-125-HR) for 30 min and DAB (3,3′-Diaminobenzidine). Pictures were obtained using a NanoZoomer 2.0HT (Hamamatsu).

Supplementary Figure S3:

PD-L1 (CD274) expression is not induced in fibroblasts and macrophages following treatment. Lung cancer cells, ADCA117 (GFP +), fibroblasts (HFF-2) and monocytes were grown as MCTS. MCTS were treated with a combination of carboplatin 50µM and carboplatine 150 nM (CaPa) or gemcitabine 100nM (CaGe) repeated 3 times. PD-L1 expression was measured using flow cytometry after MCTS dissociation. PD-L1 expression analysis was performed on GFP – cells.

Supplementary Figure S4:

CD274 , NECTIN4 , HMGB1 and TNFSF18 genes expression in ADCA117, H1437 and H1975 cells. mRNA of lung cancer cells, ADCA117, H1437 and H1975 were extracted and genes expression was measured using real-time PCR. Results are expressed as the mean +/− SEM of three independent experiments.

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Hulo, P., Deshayes, S., Fresquet, J. et al. Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy. Respir Res 25 , 156 (2024). https://doi.org/10.1186/s12931-024-02791-5

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DOI : https://doi.org/10.1186/s12931-024-02791-5

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Goat flock abortion: a retrospective study at Abergelle Agricultural Research Center, Tigray, Ethiopia

• Guash Abay Assefa 1 ,
• Teshale Teklue 2 ,
• Mebrahtom Hagazi 1 ,
• Gebretnsae Mezgebe 1 ,
• Weldegebrial G. Aregawi 3 &
• Adehanom Baraki Tesfaye 2  

BMC Veterinary Research volume  20 , Article number:  132 ( 2024 ) Cite this article

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Small ruminants are the principal component of livestock production in Tigray region, Ethiopia. But their productivity is affected by various factors. According to farmers and expert observation, goat abortion is among the leading causes of production losses in Tanqua-Abergelle district. However, study findings that examine the extent of distribution and economic impact of abortion cases in goats in the district are scarce. This retrospective study investigated the occurrence of abortion and its associated risk factors in three goat breed types at Abergelle Agricultural Research Center goat breeding site over a seven year period. The study included a total of does above one year old, and data were collected from a casebook that was specifically prepared for abortion cases. A thorough follow up was conducted to identify abortion cases. Additionally, a community survey was conducted in selected villages where the research center is located.

The overall abortion proportion was 29.8% in the goat farm. Begait goat breeds had the highest abortion proportion (50.9%, CI 0.36–0.64) in 2015/16. Multivariate logistic regression analysis identified year, season, age and breed as major risk factors of abortion occurrence at flock level. Accordingly, the likelihood of goats experiencing abortion during the dry season (proportion = 34) was 1.87 times higher compared to those in the wet season (proportion = 22.8). Begait breeds had a higher incidence of abortion (proportion 37.5%, OR 4.87, CI 2.49–10.35) compared to other breeds. Age was negatively associated with abortion, suggesting that older goats (OR = 0.67) had a higher relative risk than younger goats (OR = 0.57). Moreover, the study noted a high incidence of abortion during the years 2014/15 to 2016/17 (proportion = 35.7–39.7). Within-breed analysis revealed that age and season were significant risk factors for Abergelle and Begait breeds, respectively by using a multivariate logistic regression analysis. A community survey indicated that 89.7% households responded their goats experienced abortion.

Conclusions

This study highlighted the high prevalence of goat abortion at Abergelle and identifies important risk factors associated with its occurrence. The findings can inform targeted interventions to reduce abortion rates and improve goat productivity in the district.

Peer Review reports

Small ruminants, sheep and goats, play a vital role in the livelihood of smallholder farmers in Tigray, Ethiopia. The rolling hills of Tigray, carpeted with vibrant bushes and shrubs, offer the perfect grazing ground for sheep and goats to thrive. They are the primary source of meat, milk, manure and savings contributing significantly to the food security [ 1 , 2 ]. Additionally, small ruminants are the main source of raw skin for the local leather industry (Sheba Leather Industry PLC) that processes and exports skin products of small ruminants in the region, and provide employment opportunity in the region. The local leather industry exports finished leather and leather products such as leather clothes, footwear (shoes, boots and sandals), bags and other leather products from Tigray. According to a Central Statistics Authority of Ethiopia survey [ 3 ]; Tigray region possesses 2,097,619 sheep, and 4,838,969 goats. Goats are mainly reared in the lowlands of the Tigray region, such as in Tanqua Abergelle district. Tanqua Abergelle district is known for its prime goat production and is a central hub for goat rearing, with an estimated population of 154,330. Despite their abundance, goat productivity and production in the district fall short of their potential, posing challenges for both the local economy and the wider Tigray region [ 1 , 4 ].

One of the major constraints to goat production in Tanqua Aberegelle district is high occurrence of abortion cases [ 5 ]. Farmers and experts have consistently reported a significant number of abortions annually, raising concerns about the underlying factors contributing to this issue. Only few studies have highlighted the occurrence of abortion in Tigray [ 6 , 7 ] and in the district [ 5 ] respectively. Abortion, defined as the termination of pregnancy before fetal viability [ 8 ], can result from various causes, including infectious agents, environmental factors, and management practices. Previous studies in Tigray have identified brucella species as a potential cause of abortion in small ruminants [ 7 ], while other research suggests that infectious diseases, extreme weather conditions, feed shortage, physical traumas, and plant poisoning are common causes of abortion in small ruminants of Ethiopia [ 9 ].

Infectious agents, such as Chlamydia psittaci and Coxiella burnetii , have been implicated as major causes of abortion in goats, along with mineral deficiencies, fetal anomalies, and leukoencephalomalacia [ 10 ]. Bovine viral diarrhea virus has also been identified as a potential cause, particularly in goats housed with persistently infected cattle [ 11 ]. These findings highlight the multi-factorial nature of goat abortion, with infectious agents, environmental factors, and management practices all playing a role. Abortion in small ruminants not only leads to reproductive losses [ 12 , 13 ] but also poses zoonotic risks, as some causative agents can transmit to humans [ 14 , 15 , 16 , 17 ].

The Abergelle Agricultural Research Center, established by the Tigray Agricultural Research Institute, is primarily known for its goat breeding and conservation programs. Since 2011, Abergelle, Begait, and their crossbreeds (Abergelle x Begait) have been monitored for performance evaluation. During this period, the flocks were also monitored for susceptibility to different diseases including abortion. Records of abortions within the goat flocks were collected from various evaluation groups. In this report, we present estimates of abortion proportions and their associated risk factors within and among the breeds during the study periods.

Study area description

This study was conducted in Abergelle Agricultural Research Center goat conservation and breeding site called Ariqa site and near community located in Tanqua Abergelle district of Tigray region, Ethiopia. The district is bordered on the south by Amhara region, by Tekeze River from the west, on the north by Kola Tembien, on the east by Degua-Tembien, and on the southeast by the Southeastern zone of Tigray region (Fig.  1 ). The total area of Tanqua Abergelle district is 1445.63 square kilometers. It extends 13˚ 13.371̍ north latitude and E38˚ 58.856̍ east longitudes. The study districts are categorized as hot to warm sub-moist lowlands of sub-agro ecological zone with an altitude of 1300–1600 m above sea level, and the mean annual rainfall ranges from 400 to 600 mm, which is characterized by low, erratic and variable rainfall. The annual temperature ranges from 28 to 42 0 C. The estimated numbers of livestock population in the woreda are to be 69,285 cattle, 154,330 goat, and 83,042 sheep [4]. The dominant goat breed kept is known to be “Abergelle” and are small in size and low milk potential [ 18 ]. The production management system is extensive, which is mixed crop farming system. The “Begait” goats are known for their high-quality meat and milk and have bigger size and are originally to be found in the western part of Tigray region [ 19 , 20 ].

The study animals were three types of goat breeds, namely Abergelle, Begiat and their crosses. All does above and equal to one year old were included in this study regardless of their breeds. These does assigned to breeding activity based on their breeding status, body condition and health status. The sample sizes differed every year based on the number of does give birth, maturity, and culling of the goats. To all breeds, a semi-intensive management system is practiced at the center with the flock grazing and browsing outdoors during the day (7:30 − 5:30 AM and 2:00–5:30 PM) and housed in pens (with half concrete building walls with mesh wire and corrugated metal sheet roofs) at night. Hay and water are freely available to the goats but additional supplementary feed (inclusive of wheat bran, “nug” cake (type of pulse), molasses, lime and salt) also provided depending on the age and physiological status of the animal.

Cross-breeding program is an alternative genetic improvement tool, applied using two different breeds of high (Begait) and low (Abergelle) genetic potentials. Bucks are selected based on their general health status and presence of abnormalities. Accordingly, Bucks with good general health and no visible abnormalities (such as small testes or hocked joints) are selected and then randomly assigned to doe groups. Mating groups are assigned twice a year (June and December) and 15 to 20 does were assigned to a single buck and usually lasts for about 42 days (minimum of two oestrous cycles) and controlled single sire mating is practiced.

Administrative map of Tanqua Abergelle district, Tigray region, Ethiopia

Data collection

A seven-year abortion data set, recorded from September 2006 to August 2012 Ethiopian Calendar (2013/14-2019/2020 Gregorian Calendar), was used for the analysis. The Ethiopian year starts in September and ends in August. Every case of abortion was recorded in a separate casebook each year by an employed enumerator. For each animal that aborted, data on age, parity, season, date of abortion, breed, and stage of abortion were promptly recorded. Every year, this data was transferred from the case book to a computer and then used for this study.

Seasons were categorized as dry and wet based on local weather observations. Age was categorized as young (≤ 2 years old) and adult (> 2 years old). The study included all does that were at least one year old and exposed to breeding every year. Bucks were assigned to breeding groups of does based on the breeding activity’s objective. In this case, the breeding farm aims to conserve pure Abergelle breeds and improve their milk and meat production capacity by crossbreeding them with Begait goats. There were three breed categories at the research center: pure Abergelle, pure Begait, and their crosses (Abergelle x Begait). Parity was categorized as nullparous/primiparous (≤ 1 parity) and multiparous (> 1 parity) according to Ullah et al. [ 21 ].

A community-level random field survey was conducted through interviews to assess the situation of goat abortion in Tanqua Abergelle districts in 2017/18. A total of 29 farmers participated in the interview.

Data analysis

A descriptive statistical analysis was used to assess the state of goat abortion in the community and the abortion proportion on the farm. Abortion proportion was calculated by dividing the number of positive animals (numerator) by the total number of animals at risk (denominator) at the end of the study year according to [ 9 ]. Goats included in the denominator were those in the above-one-year age range assigned for breeding.

Factors such as breed, parity, age, season, and study year were considered independent variables, while abortion proportion was the dependent variable.

The association between risk factors and the dependent variable (abortion proportion) was analyzed using the chi-square test in R software. The level of significance was set at 5% and the confidence level at 95%.

The second part of the statistical analysis employed univariable and multivariable logistic regression analysis in R software. The univariable analysis was conducted for breed-related and animal-level variables, where each variable was tested one by one using the “glm” function from the “lme4” package. Variables that differed significantly in the univariable analysis ( P  < 0.05) were included in the multivariable analysis. Multicollinearity and confounding factors were also checked by determining the variance inflation factor using the “vif” function from the “car” package. An individual VIF above 10 and/or an average VIF above 1 was considered indicative of significant multicollinearity. Based on this analysis, our independent variables were independent of each other. Model fitness was assessed using the Chi-square goodness of fit and deviance residuals. The backward stepwise approach is a statistical modeling method that involves the iterative removal of the least informative explanatory variable from an initial model containing all possible variables. The process continues until a final and optimal model is achieved [ 22 ].

Descriptive analysis of the overall abortion proportion and their associated risk factors

The abortion figures of goats for a seven-year period, from September 2013 to August 2020, are presented in Table  1 . The estimated overall percentage of abortion during the study period was 29.8% (95% confidence interval [CI] 0.27–0.33). Descriptively, the overall percentage of abortion was highest for the Begait breed (37.5%; CI 0.32–0.43), followed by the Abergelle breed (27.3%; CI 0.24–0.31) and its crosses (13.2%; CI 0.06–0.23). The abortion proportions for all breeds were higher in the years 2014/15 to 2017/18 than in the other years. Figuratively, the overall abortion proportions during the study period were high. Seasonal changes showed a significant impact on the occurrence of abortions for each breed where abortion proportion during the dry season was estimated to be 34% as compared to the wet season (22.8%). Additionally, the percentage of abortion in goats less than or equal to two years of age and goats older than two years was estimated at 36.4% and 27.8%, respectively. A chi-square analysis identified a significant associations between abortion occurrence and the following factors: study year, season, breed ( P  ≤ 0.001), and age ( P  ≤ 0.05). Parity, however, was not significantly associated ( P  > 0.05).

Concerning to the stage of abortion, 52.7% (154/292) of goats experienced early abortion, while 47.3% (138/292) experienced late abortion.

The wide probability intervals provide poor support for the risk factors evaluated. Some of the predictors for breeds (considering crosses) had small sample sizes where further data and analysis may allow for better estimation in the future.

The predicted probabilities of the abortion proportions for the three breeds in the different study years were also estimated (Fig.  2 ). The predicted probabilities of abortion between breeds aligned in direction and magnitude across the study years except for the cross breeds. As indicated in the Fig.  2 , the proportions of abortion increased until 2016/17 and only started to dropdown at the end of 2019/20 compared to the previous years, similar to what is explained in the table above.

The predicted probabilities of abortion proportion for the three breeds across years

The abortion proportion between breeds and its associated risk factors

In the second part of statistical analysis (Table  2 ), using generalized linear model approach tested each variable one by one in each model, variables year ( P  ≤ 0.0001), season ( P  ≤ 0.0001), age ( P  < 0.05), and breed ( P  ≤ 0.001) were significantly associated with abortion occurrence. Conversely, parity was not significantly associated ( P  > 0.05).

Univariable logistic regression analysis revealed that goats in the dry season (OR 1.74, CI: 1.28–2.37, P  ≤ 0.0001) had a higher likelihood of experiencing abortion compared to those in the wet season (OR 0.29, CI 0.23–0.37). The likelihood of experiencing abortion increased each year when compared to the reference year (2013/14 G.C), with the highest proportions observed from 2014/15 to 2016/17, slight decrease from the years 2017/18 to 2019/20. Regarding breeds, Begait breed (OR 3.5, CI 1.85–7.23) followed by the Abergelle breed (OR 2.22, CI 1.2–4.55) exhibited higher abortion proportions compared to the cross breeds (reference group) (OR 0.17, CI 0.08–0.31). Additionally, goats that were two years old or younger had lower odds for experiencing abortion (OR = 0.57) than goats older than two years (OR = 0.67). Both coefficients being negative (-0.56 for ≤ 2 year and − 0.0.40 for > 2 year), indicating that increasing age is associated with a decreased risk of abortion.

A backward stepwise approach was used to assess model fitness based on the pearson chi-square test and the deviance table. Initially, the model included all available explanatory variables. However, parity was not statistically significant. Therefore, parity was removed from the model, which was then re-fitted. The resulting chi-square test was highly significant ( P  ≤ 0.0001), indicating that we should reject the null hypothesis that the standard model (without parity) is the correct model.

The multivariate logistic regression analysis presented in Table  3 identified year, season, age of abortion, and breed type as the relevant risk factors affecting the occurrence of abortion during the study periods. Compared to the univariate regression analysis, removing the variable parity resulted in a stronger significance level, odds proportion, and coefficients. As a result, the major findings are as follows: During the dry season, goats are1.87 times more likely to abort compared to the wet season. The odds of Begait and Abergelle breeds having an abortion are 4.87 and 2.68 higher, respectively, compared to the crossbreed. Concerning the age, goats aged over 2 years has approximately 43% reduced odds abortion compared those under the ages of less than or equal to 2 years. Concerning the year of abortion, goats in 2019/20, 2018/19, 2017/18, 2016/17, 2015/16, and 2014/15 were 1.64, 2.62, 3.15, 4.6, 4.14, and 3.78 times, respectively, were more likely to abort than those in 2013/14.

Within breed evaluation of abortion proportion and its associated risk factors

The chi-square analysis revealed that parity and season differed significantly ( P  < 0.05) whereas age and years were highly significantly associated ( P  ≤ 0.01) with the occurrence of abortion at animal level in Abergelle goat breeds. In Begait goat breeds, parity and age were not significantly associated ( P  > 0.05) whereas season ( P  ≤ 0.001) and year ( P  ≤ 0.01) were significantly differed to abortion proportion. For the Cross goat breeds; none of the estimated risk factors were significantly associated with the proportion of abortions ( P  > 0.05).

The univariable logistic regression analysis presented in Table  4 shows that the abortion proportion for Abergelle breeds, increased from 2013/14 to 2016/17 but gradually declined from 2017/18 to 2019/20. Goats were significantly more likely to abort during the dry season (OR 1.55, CI 1.023–2.46) compared to the wet season (OR 0.28, CI 0.20–0.38). A backward stepwise approach to assess model fitness identified age as the only statistically significant factor ( P  < 0.01) and it was retained in the alternative model. Interestingly, age is still negatively associated with the occurrence of abortion where both age groups had reduced odds of abortion by approximately 43%.

Similar to Abergelle goats, the proportion of abortion in Begait goat breeds (Table  5 ), increased over the years with the exception for a decrease in 2019/20. Additionally, goats were significantly more likely to abort during the dry season (OR 2.2, CI 1.38–3.57) compared to the wet season (OR 0.36, CI 0.24–0.52). A backward stepwise approach identified season as the only significant factor ( P  ≤ 0.001) for inclusion in the alternative model. Therefore, the multivariable regression analysis identified season as the most significant risk factor among those analyzed. Goats were 2.2 times more likely to abort during the dry season compared to the wet season.

For the cross breeds, none of the risk factors was significantly different.

Participatory interview

To support our findings from the breeding site, we conducted unstructured questionnaire survey at the community level (outside the research farm) (Table  6 ). Nearly 90% (26 out of 29) of the interviewed households reported goat abortions.

Importantly, 26 farmers reported multiple abortions: two or more goats aborted per household. Notably, one household reported a significant loss of 20 goat kids due to abortion. Heat stress and drought were reported as primary cause of abortion by most farmers with only seven mentioning physical trauma. The hot season emerged as the highest risk period, mentioned by 25 times respondents. Notably, the first trimester (44.8%) was identified as the most vulnerable pregnancy stage for abortion, followed by the third trimester (34.50%). Regarding the consequence on does, difficult birth and decrease milk production were reported most frequently (each 31.0%), followed by placental retention (17.20%). Interestingly, 65.50% of respondents believed goats experiencing their first pregnancy (first kidding) were at higher risk of abortion. Awareness of potential zoonotic risks from contact with aborted animals was remarkably low (86.2%), with only four household expressing concerns. Additionally, our corresponding author (Guash Abay) observations, along with reports from farmers and experts, suggest that a single abortion event, especially during the dry season, can affect multiple pregnant does within the same flock.

Animal health interventions are key to support the breed improvement through different reproductive technologies, such as cross breeding and selection in our case [ 23 ]. The Abergelle Agricultural Research Center goat breeding site evaluates the genetic performance of the three breeds (Pure Abergelle, Pure Begait, and their Crosses (Abergelle x Begait) (Fig.  3 )) to optimize the meat demand of the society as well as the country at large. Goat reproductive problems such as abortion were among the prioritized issues evaluated and monitored during the study periods.

A high proportion of abortion (29.8%) was observed in a goat breeding farm with a semi-intensive management system. Furthermore, a preliminary community survey revealed an even higher proportion of abortion (overall 89.7%) among goat flocks in the area employing an extensive (traditional) management system. These findings align with reports from other parts of Ethiopia: with [ 24 ] reported 57.5%, and [ 9 ] reported 58.68%. However, Alamerew et al. [ 25 ] observed a lower proportion of 19.5% in North Shoa, Central Ethiopia. Globally abortion storms have been reported in various countries as well. For example, in Morocco [ 26 ], 10.26% of does were reported to be affected, while in Algeria [ 27 ], the proportion reached 75.33% for both sheep and goats, and 34% caprine abortion in the Netherlands [ 16 ]. Notably, Abubakar et al. [ 28 ] identified a high proportion of abortions in goats infected with Peste des Petitis Ruminant (PPR). According to Menzies [ 29 ], abortion proportions exceeding 5%, especially when concentrated in a short time period or specific location, warrant immediate investigation.

A sustained 2–5% range might indicate endemic causes. Considering this, the high prevalence suggests the potential abortion factors within the farm and the surrounding community, demanding further investigation.

Our discussion with district veterinarians and farmers, focusing on abortion in small ruminants, confirmed the high frequency of occurrence and a strong desire for investigation from the farmers. Notably, farmers reported simultaneous abortions affecting multiple pregnant does within flocks, particularly during the dry season when feed and rainfall are limited. This led many to believe that these abortions are caused by “devil attacks,” a local belief that devils can harm people and animals during hot weather and nights.

Unfortunately, due to limited laboratory capacity both within the region and at our research institute, we were unable to investigate potential infectious or mineral deficiency causes further. Veterinary laboratories are centralized in Addis Ababa, the capital city of Ethiopia, which is 1000 km away from the study area. Furthermore, limited budgets, a shortage of veterinary personnel, and insufficient equipment and reagents for sample collection and transportation (e.g., transport mediums) in both organizations significantly hindered our efforts to transport samples to Addis Ababa for laboratory analysis.

Seasonal differences significantly impacted the occurrence of abortion in the goat farm. The district experiences a long dry season (Sep-May) with inconsistent rainfall during June to August leading to feed shortages and repeated droughts (Guash Abay, personal observation). Additionally, very high rates of abortions (abortion storms) were observed annually during specific months: September, and March to mid-June. September marks the beginning of the dry season, while March to mid-June are the hottest months of the year with scarce feed resources (Guash Abay, personal observation). Overall, proportion of abortions remained high during the study period, despite some variation between years. There was a slight reduction of abortion during the later three years (2017/18-2019/20) though it wasn’t a significant reduction. This could be attributed to gradual improvement in managemental practice such as feeding, husbandry and bio-security to pregnant goats, as well as culling of goats with poor health or productivity. Our findings aligned with [ 29 ] who reported increased goat abortions during the dry period. Additionally, several studies have linked climate changes, including rising temperatures and erratic rainfall patterns, to abortion outbreaks in goats, including in Ethiopia [ 9 ] and South Africa [ 30 ].

Breed difference significantly affected proportion of abortion occurrence. Begait breeds originally from different agro-ecology in western part of Tigray that were undergoing adaptation trial, exhibited a notably higher abortion proportion (37.5%) compared to other breeds. This suggests begait breeds might be more susceptible to abortion in the study environment. Similar breed-related differences in abortion susceptibility have been reported in goat farms elsewhere, including Namibia [ 31 ] and Mexico [ 32 ].

For Abergelle breeds, only age significant influenced abortion risk, while for Begait breeds, season was the key factor. Notably, previous studies on Abergelle studies focused on their niche environment, while Begait studies took place outside their usual habitat. These differences along with confounding factors, could explain the contrasting results observed in our study.

Despite the potential role of bacterial and viral zoonotic agents in abortion, a staggering 86.2% of the community lacked awareness about zoonotic diseases linked to animal abortion. This significant knowledge gap stems from limited public education and awareness programs in the district on zoonotic diseases. Researches in Ethiopia have confirmed the significant impact of zoonotic pathogens on small ruminant abortions. For instance, studied by [ 25 ] identified Q-fever and Toxoplasmosis as prevalent causes, while others like [ 33 ] and [ 34 ] found Chlamydia spp., Coxiella burnetii , and Toxoplasma gondii as infectious causes. Notably [ 7 ], even detected Brucella species in small ruminants in southern Tigray. Similar trends are observed globally. In the Netherlands, Q fever has been linked to goat farm outbreaks [ 16 , 35 ], while Caprine alphaherpesvirus 1 emerged as a major cause in Spain [ 36 ].

In the study district (community level), the risk of transmission of zoonotic infectious agents is high due to traditional farming systems. Goats and sheep are reared together in the same flocks, without separate management systems such as isolating sick animals or providing specific feeding and housing for pregnant does and kids. Additionally, the proximity of animal and human housing facilities increases the potential for disease transmission. Moreover, newly purchased animals are introduced to the flock without implementing preventive measures such as quarantine and vaccination.

Some figurative description of the type of breeds in the farm: A ) Abergelle goat breed type B ) Begait breed goat type

In conclusion, our study identified alarmingly high proportion of abortions among goats both on our farm and in the surrounding community. This explains to significant economic losses through kid mortality and reduced milk production. Breed and season were identified as the most likely factors influencing abortion occurrence within the farm, with Begait goats showing particular susceptibility. Additionally, limited awareness of zoonotic causes of abortion was observed among community members. While our study was limited by its retrospective nature and the absence of laboratory investigations or a representative community survey, it highlights the importance of abortion as a factor hindering small ruminant production and productivity in the region. We strongly recommend further investigation to identify the specific causative agents of abortion, quantify the associated economic losses, and inform the development of targeted intervention strategies.

Data availability

All data are available upon request from the authors.

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Acknowledgements

The authors would like to acknowledge for Abergelle Agricultural Research Center researchers who participated in the data collection. We sincerely thank to the community for their support to provide us the information.

This research work was financially supported by Tigray Agricultural Research Institute (TARI), Abergelle Agricultural Research Center.

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G.A.A and T.T led the research activity; data managed and analyzed, drafted the manuscript and prepared the manuscript for final publication. M.H, and G.M helped during data management (data collection, data entry), and follow up the research activity and preparing the manuscript for publication. W.A, and A.B.T helped during data analysis, and preparing the manuscript for final publication.

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Correspondence to Guash Abay Assefa .

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All study protocols for animal and human were approved by Mekelle University College of Veterinary Science Animal Ethics Committee (AEEC) and all the methods were conducted according to the “Guidelines on Care and Use of Animals for Scientific Purposes” available in www.mu.edu.et or www.afrohun.org . The study was conducted in compliance with the ARRIVE guidelines. All methods were carried out according to the ethical standards of the Declaration of Helsinki for the farmers’ interview. Before conducting the interview, the objectives, expected results and benefits of the study was explained to goat owners and written informed consent to participate was obtained from all participant farmers.

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Assefa, G.A., Teklue, T., Hagazi, M. et al. Goat flock abortion: a retrospective study at Abergelle Agricultural Research Center, Tigray, Ethiopia. BMC Vet Res 20 , 132 (2024). https://doi.org/10.1186/s12917-024-03986-0

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Received : 09 February 2023

Accepted : 21 March 2024

Published : 02 April 2024

DOI : https://doi.org/10.1186/s12917-024-03986-0

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