Reported antibiotic use among patients in the multicenter ANDEMIA infectious diseases surveillance study in sub-saharan Africa.

BACKGROUND: Exposure to antibiotics has been shown to be one of the drivers of antimicrobial resistance (AMR) and is critical to address when planning and implementing strategies for combatting AMR. However, data on antibiotic use in sub-Saharan Africa are still limited. Using hospital-based surveillance data from the African Network for Improved Diagnostics, Epidemiology and Management of Common Infectious Agents (ANDEMIA), we assessed self-reported antibiotic use in multiple sub-Saharan African countries. METHODS: ANDEMIA included 12 urban and rural health facilities in Côte d'Ivoire, Burkina Faso, Democratic Republic of the Congo, and Republic of South Africa. Patients with acute respiratory infection (RTI), acute gastrointestinal infection (GI) and acute febrile disease of unknown cause (AFDUC) were routinely enrolled, and clinical, demographic, socio-economic and behavioral data were collected using standardized questionnaires. An analysis of ANDEMIA data from February 2018 to May 2022 was conducted. Reported antibiotic use in the ten days prior to study enrolment were described by substance and by the WHO AWaRe classification ("Access", "Watch", "Reserve", and "Not recommended" antibiotics). Frequency of antibiotic use was stratified by location, disease syndrome and individual patient factors. RESULTS: Among 19,700 ANDEMIA patients, 7,258 (36.8%) reported antibiotic use. A total of 9,695 antibiotics were reported, including 54.7% (n = 5,299) from the WHO Access antibiotic group and 44.7% (n = 4,330) from the WHO Watch antibiotic group. The Watch antibiotic ceftriaxone was the most commonly reported antibiotic (n = 3,071, 31.7%). Watch antibiotic use ranged from 17.4% (56/322) among RTI patients in Côte d'Ivoire urban facilities to 73.7% (630/855) among AFDUC patients in Burkina Faso urban facilities. Reported antibiotic use included WHO Not recommended antibiotics but no Reserve antibiotics. CONCLUSIONS: Reported antibiotic use data from this multicenter study in sub-Saharan Africa revealed a high proportion of WHO Watch antibiotics. Differences in Watch antibiotic use were found by disease syndrome, country and health facility location, which calls for a more differentiated approach to antibiotic use interventions including further evaluation of accessibility and affordability of patient treatment.

Seroprevalence of anti-SARS-CoV-2 antibodies and risk of viral exposure among healthcare workers in the South Kivu province, eastern Democratic Republic of the Congo: a cross-sectional study.

OBJECTIVES: Healthcare workers (HCWs) are on the frontline of combating COVID-19, hence are at elevated risk of contracting an infection with SARS-CoV-2. The present study aims to measure the impact of SARS-CoV-2 on HCWs in central sub-Saharan Africa. SETTING: A cross-sectional serological study was conducted at six urban and five rural hospitals during the first pandemic wave in the South Kivu province, Democratic Republic of the Congo (DRC). PARTICIPANTS: Serum specimens from 1029 HCWs employed during the first pandemic wave were collected between August and October 2020, and data on demographics and work-related factors were recorded during structured interviews. PRIMARY AND SECONDARY OUTCOME MEASURES: The presence of IgG antibodies against SARS-CoV-2 was examined by ELISA. Positive specimens were further tested using a micro-neutralisation assay. Factors driving SARS-CoV-2 seropositivity were assessed by multivariable analysis. RESULTS: Overall SARS-CoV-2 seroprevalence was high among HCWs (33.1%), and significantly higher in urban (41.5%) compared with rural (19.8%) hospitals. Having had presented with COVID-19-like symptoms before was a strong predictor of seropositivity (31.5%). Personal protective equipment (PPE, 88.1% and 11.9%) and alcohol-based hand sanitizer (71.1% and 28.9%) were more often available, and hand hygiene was more often reported after patient contact (63.0% and 37.0%) in urban compared with rural hospitals, respectively. This may suggest that higher exposure during non-work times in high incidence urban areas counteracts higher work protection levels of HCWs. CONCLUSIONS: High SARS-CoV-2 seropositivity indicates widespread transmission of the virus in this region of DRC. Given the absence of publicly reported cases during the same time period at the rural sites, serological studies are very relevant in revealing infection dynamics especially in regions with low diagnostic capacities. This, and discrepancies in the application of PPE between urban and rural sites, should be considered in future pandemic response programmes.

West Nile Virus, an Underdiagnosed Cause of Acute Fever of Unknown Origin and Neurological Disease among Hospitalized Patients in South Africa.

West Nile virus (WNV), a mosquito-borne flavivirus, is endemic to South Africa. However, its contribution to acute febrile and neurological disease in hospitalized patients in South Africa is unknown. This study examined two patient cohorts for WNV using molecular testing and IgM serology with confirmation of serological results by viral neutralization tests (VNT) to address this knowledge gap. Univariate analysis was performed using collected demographic and clinical information to identify risk factors. In the first cohort, 219 cerebrospinal fluid (CSF) specimens from patients with acute neurological disease in Gauteng hospitals collected in January to June 2017 were tested for WNV. The study identified WNV in 8/219 (3.65%, 95.00% CI (1.59-7.07)) patients with unsolved neurological infections. The second cohort, from 2019 to 2021, included 441 patients enrolled between January and June with acute febrile or neurological disease from urban and rural sites in Gauteng and Mpumalanga provinces. West Nile virus was diagnosed in 40/441 (9.07%, 95.00% CI (6.73-12.12)) of patients, of which 29/40 (72.50%, 95.00% CI (56.11-85.40)) had neurological signs, including headaches, encephalitis, meningitis, and acute flaccid paralysis (AFP). Notably, most of the cases were identified in children although adolescents and senior adults had a significantly higher risk of testing WNV positive. This suggests a previously underestimated disease burden and that WNV might be underrecognized as a cause of febrile and neurological diseases in hospitalized patients in South Africa, especially in children. This emphasizes the importance of further research and awareness regarding arboviruses of public health concern.

Evolutionary Insight into the Association between New Jersey Polyomavirus and Humans.

Advances in viral discovery techniques have led to the identification of numerous novel viruses in human samples. However, the low prevalence of certain viruses in humans raises doubts about their association with our species. To ascertain the authenticity of a virus as a genuine human-infecting agent, it can be useful to investigate the diversification of its lineage within hominines, the group encompassing humans and African great apes. Building upon this rationale, we examined the case of the New Jersey polyomavirus (NJPyV; Alphapolyomavirus terdecihominis), which has only been detected in a single patient thus far. In this study, we obtained and analyzed sequences from closely related viruses infecting all African great ape species. We show that NJPyV nests within the diversity of these viruses and that its lineage placement is compatible with an ancient origin in humans, despite its apparent rarity in human populations.

Vertebrate environmental DNA from leaf swabs.

Terrestrial vertebrates are threatened by anthropogenic activities around the world. The rapid biodiversity loss that ensues is most intense in the tropics and affects ecosystem functions, such as seed dispersal, or may facilitate pathogen transmission1. Monitoring vertebrate distributions is essential for understanding changes in biodiversity and ecosystems and also for adaptive management strategies. Environmental DNA (eDNA) approaches have the potential to play a key role in such efforts. Here, we explore whether eDNA swabbed from terrestrial vegetation in a tropical biodiversity hotspot is a useful tool for vertebrate biomonitoring. By swabbing leaves, we collected eDNA from 24 swabs at three locations in Kibale National Park, Uganda and used two metabarcoding systems to catalog the vertebrate taxa in the samples. We detected 52 wild vertebrate genera, including 26 avian and 24 mammalian genera; 30 of these assignments could be refined to the species level. We detected an average of 7.6 genera per swab. This approach, with its inexpensive and simple collection and DNA extraction, opens the door for inexpensive large-scale vertebrate biomonitoring.

Subregional origins of emerging SARS-CoV-2 variants during the second pandemic wave in Côte d'Ivoire.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility, virulence and immune escape abilities have heavily altered the COVID-19 pandemic's course. Deciphering local and global transmission patterns of those variants is thus key in building a profound understanding of the virus' spread around the globe. In the present study, we investigate SARS-CoV-2 variant epidemiology in Côte d'Ivoire, Western sub-Saharan Africa. We therefore generated 234 full SARS-CoV-2 genomes stemming from Central and Northern Côte d'Ivoire. Covering the first and second pandemic wave the country had been facing, we identified 20 viral lineages and showed that in Côte d'Ivoire the second pandemic wave in 2021 was driven by the spread of the Alpha (B.1.1.7) and Eta (B.1.525) variant. Our analyses are consistent with a limited number of international introductions of Alpha and Eta into Côte d'Ivoire, and those introduction events mostly stemmed from within the West African subregion. This suggests that subregional travel to Côte d'Ivoire had more impact on local pandemic waves than direct intercontinental travel.

Brain structure and function: a multidisciplinary pipeline to study hominoid brain evolution.

To decipher the evolution of the hominoid brain and its functions, it is essential to conduct comparative studies in primates, including our closest living relatives. However, strong ethical concerns preclude in vivo neuroimaging of great apes. We propose a responsible and multidisciplinary alternative approach that links behavior to brain anatomy in non-human primates from diverse ecological backgrounds. The brains of primates observed in the wild or in captivity are extracted and fixed shortly after natural death, and then studied using advanced MRI neuroimaging and histology to reveal macro- and microstructures. By linking detailed neuroanatomy with observed behavior within and across primate species, our approach provides new perspectives on brain evolution. Combined with endocranial brain imprints extracted from computed tomographic scans of the skulls these data provide a framework for decoding evolutionary changes in hominin fossils. This approach is poised to become a key resource for investigating the evolution and functional differentiation of hominoid brains.

Kiwira Virus, a Newfound Hantavirus Discovered in Free-tailed Bats (Molossidae) in East and Central Africa.

A novel hantavirus, named Kiwira virus, was molecularly detected in six Angolan free-tailed bats (Mops condylurus, family Molossidae) captured in Tanzania and in one free-tailed bat in the Democratic Republic of Congo. Hantavirus RNA was found in different organs, with the highest loads in the spleen. Nucleotide sequences of large parts of the genomic S and L segments were determined by in-solution hybridisation capture and high throughput sequencing. Phylogenetic analyses placed Kiwira virus into the genus Mobatvirus of the family Hantaviridae, with the bat-infecting Quezon virus and Robina virus as closest relatives. The detection of several infected individuals in two African countries, including animals with systemic hantavirus infection, provides evidence of active replication and a stable circulation of Kiwira virus in M. condylurus bats and points to this species as a natural host. Since the M. condylurus home range covers large regions of Sub-Saharan Africa and the species is known to roost inside and around human dwellings, a potential spillover of the Kiwira virus to humans must be considered.

The cost of living in larger primate groups includes higher fly densities.

Flies are implicated in carrying and mechanically transmitting many primate pathogens. We investigated how fly associations vary across six monkey species (Cercopithecus ascanius, Cercopithecus mitis, Colobus guereza, Lophocebus albigena, Papio anubis, and Piliocolobus tephrosceles) and whether monkey group size impacts fly densities. Fly densities were generally higher inside groups than outside them, and considering data from these primate species together revealed that larger groups harbored more flies. Within species, this pattern was strongest for colobine monkeys, and we speculate this might be due to their smaller home ranges, suggesting that movement patterns may influence fly-primate associations. Fly associations increase with group sizes and may thus represent a cost to sociality.

Zoonotic origin of the human malaria parasite Plasmodium malariae from African apes.

The human parasite Plasmodium malariae has relatives infecting African apes (Plasmodium rodhaini) and New World monkeys (Plasmodium brasilianum), but its origins remain unknown. Using a novel approach to characterise P. malariae-related sequences in wild and captive African apes, we found that this group comprises three distinct lineages, one of which represents a previously unknown, highly divergent species infecting chimpanzees, bonobos and gorillas across central Africa. A second ape-derived lineage is much more closely related to the third, human-infective lineage P. malariae, but exhibits little evidence of genetic exchange with it, and so likely represents a separate species. Moreover, the levels and nature of genetic polymorphisms in P. malariae indicate that it resulted from the zoonotic transmission of an African ape parasite, reminiscent of the origin of P. falciparum. In contrast, P. brasilianum falls within the radiation of human P. malariae, and thus reflects a recent anthroponosis.

Non-invasive genomics of respiratory pathogens infecting wild great apes using hybridisation capture.

Human respiratory pathogens have repeatedly caused lethal outbreaks in wild great apes across Africa, leading to population declines. Nonetheless, our knowledge of potential genomic changes associated with pathogen introduction and spread at the human-great ape interface remains sparse. Here, we made use of target enrichment coupled with next generation sequencing to non-invasively investigate five outbreaks of human-introduced respiratory disease in wild chimpanzees living in Taï National Park, Ivory Coast. By retrieving 34 complete viral genomes and three distinct constellations of pneumococcal virulence factors, we provide genomic insights into these spillover events and describe a framework for non-invasive genomic surveillance in wildlife.

Evidence against Zika virus infection of pets and peri-domestic animals in Latin America and Africa.

Decades after its discovery in East Africa, Zika virus (ZIKV) emerged in Brazil in 2013 and infected millions of people during intense urban transmission. Whether vertebrates other than humans are involved in ZIKV transmission cycles remained unclear. Here, we investigate the role of different animals as ZIKV reservoirs by testing 1723 sera of pets, peri-domestic animals and African non-human primates (NHP) sampled during 2013-2018 in Brazil and 2006-2016 in Côte d'Ivoire. Exhaustive neutralization testing substantiated co-circulation of multiple flaviviruses and failed to confirm ZIKV infection in pets or peri-domestic animals in Côte d'Ivoire (n=259) and Brazil (n=1416). In contrast, ZIKV seroprevalence was 22.2% (2/9, 95% CI, 2.8-60.1) in West African chimpanzees (Pan troglodytes verus) and 11.1% (1/9, 95% CI, 0.3-48.3) in king colobus (Colobus polycomos). Our results indicate that while NHP may represent ZIKV reservoirs in Africa, pets or peri-domestic animals likely do not play a role in ZIKV transmission cycles.

High Prevalence of Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (Anti-SARS-CoV-2) Antibodies After the First Wave of Coronavirus Disease 2019 (COVID-19) in Kinshasa, Democratic Republic of the Congo: Results of a Cross-sectional Household-Based Survey.

BACKGROUND: In October 2020, after the first wave of coronavirus disease 2019 (COVID-19), only 8290 confirmed cases were reported in Kinshasa, Democratic Republic of the Congo, but the real prevalence remains unknown. To guide public health policies, we aimed to describe the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibodies in the general population in Kinshasa. METHODS: We conducted a cross-sectional, household-based serosurvey between 22 October 2020 and 8 November 2020. Participants were interviewed at home and tested for antibodies against SARS-CoV-2 spike and nucleocapsid proteins in a Luminex-based assay. A positive serology was defined as a sample that reacted with both SARS-CoV-2 proteins (100% sensitivity, 99.7% specificity). The overall weighted, age-standardized prevalence was estimated and the infection-to-case ratio was calculated to determine the proportion of undiagnosed SARS-CoV-2 infections. RESULTS: A total of 1233 participants from 292 households were included (mean age, 32.4 years; 764 [61.2%] women). The overall weighted, age-standardized SARS-CoV-2 seroprevalence was 16.6% (95% CI: 14.0-19.5%). The estimated infection-to-case ratio was 292:1. Prevalence was higher among participants ≥40 years than among those <18 years (21.2% vs 14.9%, respectively; P < .05). It was also higher in participants who reported hospitalization than among those who did not (29.8% vs 16.0%, respectively; P < .05). However, differences were not significant in the multivariate model (P = .1). CONCLUSIONS: The prevalence of SARS-CoV-2 is much higher than the number of COVID-19 cases reported. These results justify the organization of a sequential series of serosurveys by public health authorities to adapt response measures to the dynamics of the pandemic.

The Movement of Pathogen Carrying Flies at the Human-Wildlife Interface.

Flies form high-density associations with human settlements and groups of nonhuman primates and are implicated in transmitting pathogens. We investigate the movement of nonhuman primate-associated flies across landscapes surrounding Kibale National Park, Uganda, using a mark-recapture experiment. Flies were marked in nine nonhuman primate groups at the forest edge ([Formula: see text] = 929 flies per group), and we then attempted to recapture them in more anthropized areas (50 m, 200 m and 500 m from where marked; 2-21 days after marking). Flies marked in nonhuman primate groups were recaptured in human areas (19/28,615 recaptured). Metabarcoding of the flies in nonhuman primate groups revealed the DNA of multiple eukaryotic primate parasites. Taken together, these results demonstrate the potential of flies to serve as vectors between nonhuman primates, livestock and humans at this biodiverse interface.

Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions.

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers.

Leprosy in wild chimpanzees.

Humans are considered as the main host for Mycobacterium leprae1, the aetiological agent of leprosy, but spillover has occurred to other mammals that are now maintenance hosts, such as nine-banded armadillos and red squirrels2,3. Although naturally acquired leprosy has also been described in captive nonhuman primates4-7, the exact origins of infection remain unclear. Here we describe leprosy-like lesions in two wild populations of western chimpanzees (Pan troglodytes verus) in Cantanhez National Park, Guinea-Bissau and Taï National Park, Côte d'Ivoire, West Africa. Longitudinal monitoring of both populations revealed the progression of disease symptoms compatible with advanced leprosy. Screening of faecal and necropsy samples confirmed the presence of M. leprae as the causative agent at each site and phylogenomic comparisons with other strains from humans and other animals show that the chimpanzee strains belong to different and rare genotypes (4N/O and 2F). These findings suggest that M. leprae may be circulating in more wild animals than suspected, either as a result of exposure to humans or other unknown environmental sources.

A great ape perspective on the origins and evolution of human viruses.

Over the last two decades, the viromes of our closest relatives, the African great apes (AGA), have been intensively studied. Comparative approaches have unveiled diverse evolutionary patterns, highlighting both stable host-virus associations over extended evolutionary timescales and much more recent viral emergence events. In this chapter, we summarize these findings and outline how they have shed a new light on the origins and evolution of many human-infecting viruses. We also show how this knowledge can be used to better understand the evolution of human health in relation to viral infections.

Implementation of Automated Blood Culture With Quality Assurance in a Resource-Limited Setting.

Background: Blood cultures (BC) have a high clinical relevance and are a priority specimen for surveillance of antimicrobial resistance. Manual BC are still most frequently used in resource-limited settings. Data on automated BC performance in Africa are scarce. We implemented automated BC at a surveillance site of the African Network for improved Diagnostics, Epidemiology and Management of Common Infectious Agents (ANDEMIA). Methods: Between June 2017 and January 2018, pairs of automated BC (BacT/ALERT®FA Plus) and manual BC (brain-heart infusion broth) were compared at a University hospital in Bouaké, Côte d'Ivoire. BC were inoculated each with a target blood volume of 10 ml from the same venipuncture. Automated BC were incubated for up to 5 days, manual BC for up to 10 days. Terminal subcultures were performed for manual BC only. The two systems were compared regarding yield, contamination, and turnaround time. For quality assurance, isolates were retested in a German routine microbiological laboratory. Results: BC sampling was increased from on average 24 BC to 63 BC per month. A total of 337 matched pairs of BC were included. Automated BC was positive in 36.5%, manual BC in 24.0% (p-value < 0.01), proportion of contamination was 47.9 and 43.8%, respectively (p-value = 1.0). Turnaround time of positive BC was shortened by 2.5 days with automated compared to manual BC (p < 0.01). Most common detected pathogens in both systems were Klebsiella spp. (26.0%) and Staphylococcus aureus (18.2%). Most contaminants were members of the skin flora. Retesting of 162 isolates was concordant in 79.6% on family level. Conclusions: Implementing automated BC in a resource-limited setting is possible and improves microbiological diagnostic performance. Automated BC increased yield and shortened turnaround times. Regular training and mentorship of clinicians has to be intensified to increase number and quality of BC. Pre-analytical training to improve diagnostic stewardship is essential when implementing a new microbiological method. Retesting highlighted that manual identification and antimicrobial susceptibility testing can be of good quality and sustainable. The implementation of automated tools should be decided individually according to economic considerations, number of samples, stable supply chain of consumables, and technical sustainability.

The African Network for Improved Diagnostics, Epidemiology and Management of common infectious Agents.

BACKGROUND: In sub-Saharan Africa, acute respiratory infections (ARI), acute gastrointestinal infections (GI) and acute febrile disease of unknown cause (AFDUC) have a large disease burden, especially among children, while respective aetiologies often remain unresolved. The need for robust infectious disease surveillance to detect emerging pathogens along with common human pathogens has been highlighted by the ongoing novel coronavirus disease 2019 (COVID-19) pandemic. The African Network for Improved Diagnostics, Epidemiology and Management of Common Infectious Agents (ANDEMIA) is a sentinel surveillance study on the aetiology and clinical characteristics of ARI, GI and AFDUC in sub-Saharan Africa. METHODS: ANDEMIA includes 12 urban and rural health care facilities in four African countries (Côte d'Ivoire, Burkina Faso, Democratic Republic of the Congo and Republic of South Africa). It was piloted in 2018 in Côte d'Ivoire and the initial phase will run from 2019 to 2021. Case definitions for ARI, GI and AFDUC were established, as well as syndrome-specific sampling algorithms including the collection of blood, naso- and oropharyngeal swabs and stool. Samples are tested using comprehensive diagnostic protocols, ranging from classic bacteriology and antimicrobial resistance screening to multiplex real-time polymerase chain reaction (PCR) systems and High Throughput Sequencing. In March 2020, PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and analysis of full genomic information was included in the study. Standardised questionnaires collect relevant clinical, demographic, socio-economic and behavioural data for epidemiologic analyses. Controls are enrolled over a 12-month period for a nested case-control study. Data will be assessed descriptively and aetiologies will be evaluated using a latent class analysis among cases. Among cases and controls, an integrated analytic approach using logistic regression and Bayesian estimation will be employed to improve the assessment of aetiology and associated risk factors. DISCUSSION: ANDEMIA aims to expand our understanding of ARI, GI and AFDUC aetiologies in sub-Saharan Africa using a comprehensive laboratory diagnostics strategy. It will foster early detection of emerging threats and continued monitoring of important common pathogens. The network collaboration will be strengthened and site diagnostic capacities will be reinforced to improve quality management and patient care.

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

OBJECTIVE: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. DESIGN: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. RESULTS: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. CONCLUSION: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.