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RSV is divided into two antigenic subtypes, RSV A and RSV B, which is largely based on the variation in the G protein, while the fusion protein F is more conserved and a target for antibody-mediated neutralization. Here we evaluate the breadth of the protective immune responses across RSV A and RSV B subtypes, induced by vaccines based on the RSV A-based fusion protein, stabilized in the prefusion conformation (preF) in preclinical models. Immunization of naïve cotton rats with preF subunit or preF encoded by a replication incompetent Adenoviral 26, induced antibodies capable of neutralizing recent RSV A and RSV B clinical isolates, as well as protective efficacy against a challenge with RSV A and RSV B strains. Similarly, induction of cross-neutralizing antibodies was observed after immunization with Ad26-encoded preF, preF protein or a mix of both (Ad26/preF protein) in RSV pre-exposed mice and African Green Monkeys. Transfer of serum of human subjects immunized with Ad26/preF protein into cotton rats provide protection against challenges with both RSV A and RSV B, with complete protection against both strains observed in the lower respiratory tract. In contrast, almost no protection against RSV A and B infection was observed after the transfer of a human serum pool isolated pre-vaccination. These results collectively show that the RSV A-based monovalent Ad26/preF protein vaccine induced neutralizing antibodies, as well as protection against both RSV A and RSV B subtypes in animals, including by passive transfer of human antibodies alone, suggesting that clinical efficacy against both subtypes can be achieved.

Abstract Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

Abstract Background Togo's National Malaria Control Programme has initiated an active home-based malaria management model for all age groups in rural areas of Bassar Health District. This report describes the model, reports its main results, and determines the factors associated with positive rapid diagnostic test results. Methods From 2014 to 2017, in three peripheral care units of Bassar Health District (Binaparba, Nangbani, and Baghan), community health workers visited residents' homes weekly to identify patients with malaria symptoms, perform rapid diagnostic tests in symptomatic patients, and give medication to positive cases. Univariate and multivariate logistic regression models were used to determine the factors associated with positive tests. Results The study covered 11,337 people (817 in 2014, 1804 in 2015, 2638 in 2016, and 6078 in 2017). The overall mean age was 18 years (95% CI 5–29; min–max: 0–112 years). The median age was 10 years (SD: 16.9). The proportions of people tested positive were 75.3% in Binaparba, 77.4% in Nangbani, and 56.6% in Baghan. The 5–10 age group was the most affected category (24.2% positive tests). Positive tests were more frequent during the rainy than during the dry season (62 vs. 38%) and the probability of positive test was 1.76 times higher during the rainy than during the dry season (adjusted OR = 1.74; 95% CI 1.60–1.90). A fever (37.5 °C or higher) increased significantly the probability of positive test (adjusted OR = 2.19; 95% CI 1.89–2.54). The risk of positive test was 1.89 times higher in passive than in active malaria detection (adjusted OR = 1.89; 95% CI 1.73–2.0). Conclusions This novel experimental community and home-based malaria management in Togo suggested that active detection of malaria cases is feasible within 24 h, which allows rapid treatments before progression to often-fatal complications. This PECADOM + program will help Togo's National Malaria Control Programme reduce malaria morbidity and mortality in remote and hard-to-reach communities.

Abstract Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel approaches are required to improve patient outcomes. We have evaluated patient-derived explants (PDEs) as a novel preclinical platform for breast cancer (BC) and implemented cutting-edge digital pathology and multi-immunofluorescent approaches for investigating biomarker changes in both tumour and stromal areas at endpoint. Short-term culture of intact fragments of BCs as PDEs retained an intact immune microenvironment, and tumour architecture was augmented by the inclusion of autologous serum in the culture media. Cell death/proliferation responses to FET chemotherapy in BC-PDEs correlated significantly with BC patient progression-free survival (p = 0.012 and p = 0.0041, respectively) and cell death responses to the HER2 antibody therapy trastuzumab correlated significantly with HER2 status (p = 0.018). These studies show that the PDE platform combined with digital pathology is a robust preclinical approach for informing clinical responses to chemotherapy and antibody-directed therapies in breast cancer. Furthermore, since BC-PDEs retain an intact tumour architecture over the short-term, they facilitate the preclinical testing of anti-cancer agents targeting the tumour microenvironment.

Background Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. Objectives To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Design A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Setting Nineteen UK oncology centres. Participants Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for

Objectives Integrating malaria prediction models into malaria control strategies can help to anticipate the response to seasonal epidemics. This study aimed to explore the possibility of using routine malaria data and satellite-derived climate data to forecast malaria cases in Togo.Methods Generalised additive (mixed) models were developed to forecast the monthly number of malaria cases in 40 health districts and three target groups. Routinely collected malaria data from 2013 to 2016 and meteorological and vegetation data with a time lag of 1 or 2 months were used for model training, while the year 2017 was used for model testing. Two methods for selecting lagged meteorological and environmental variables were compared: a first method based on statistical approach (‘SA’) and a second method based on biological reasoning (‘BR’). Both methods were applied to obtain a model per target group and health district and a mixed model per target group and health region with the health district as a random effect. The predictive skills of the four models were compared for each health district and target group.Results The most selected predictors in the models per district for the ‘SA’ method were the normalised difference vegetation index, minimum temperature and mean temperature. The ‘SA’ method provided the most accurate models for the training period, except for some health districts in children ≥5 years old and adults and in pregnant women. The most accurate models for the testing period varied by health district and target group, provided either by the ‘SA’ method or the ‘BR’ method. Despite the development of models with four different approaches, the number of malaria cases was inaccurately forecasted.Conclusions These models cannot be used as such in malaria control activities in Togo. The use of finer spatial and temporal scales and non-environmental data could improve malaria prediction.

BackgroundIncarcerated youth commonly present with emotion dysregulation, aggression, and comorbid psychiatric disorders, yet often do not receive necessary mental health treatment while confined. It is therefore crucial to expand the evidence base regarding empirically supported mental health interventions which are feasible to implement in secure settings to address incarcerated youth's mental health needs. Through a community-academic partnership, the current pilot study evaluated a comprehensive dialectical behavior therapy program implemented in a juvenile correctional treatment center.MethodsYouth participants (N = 113) were on average 15.37 years old (SD = 1.10, range = 13–17), 68.1% boys, and identified as 69.0% Latinx, 22.1% Black, 8.0% White, and 0.9% Native American. Youth received comprehensive dialectical behavior therapy for adolescents (DBT-A), including individual therapy, skills training groups, family therapy, multi-family skills training groups, and skills coaching in the milieu by direct care staff who participated in extensive training and ongoing consultation team meetings. As part of a facility-designed program evaluation, youth completed a battery of empirically validated assessments of mental health and emotion regulation prior to and following completion of the program.ResultsResults show that comprehensive DBT-A is feasible to implement in a juvenile correctional treatment center and overall, youth improved from pre- to post-treatment in mental health symptoms and emotion regulation, with small to medium effect sizes.ConclusionThese findings build upon a growing literature showing dialectical behavior therapy is a promising intervention for treating emotion dysregulation and mental health conditions and can be successfully implemented in juvenile forensic settings.

Abstract Background In 2012, the World Health Organization (WHO) recommended seasonal malaria chemoprevention (SMC) in areas of high seasonal transmission. Though implemented since 2013, the effectiveness of SMC in Togo was never evaluated. Methods This study concerned routine data from 2013 to 2020 mass SMC campaigns for children under five in all health facilities of three Regions of Togo. Treatment coverage, reasons for non-treatment, and SMC-attributable adverse reactions were analysed per year and treatment round. Random effect logistic models estimated SMC effectiveness per health district, year, and treatment round. Results The overall coverage was 98% (7,971,877 doses for 8,129,668 children). Contraindication was the main reason for non-administration. Over the study period, confirmed malaria cases decreased from 11,269 (1st round of 2016) to 1395 (4th round of 2020). Only 2,398 adverse reactions were reported (prevalence: 3/10,000), but no severe Lyell syndrome or Stevens-Johnson-type skin reaction. Compared to 2016, malaria prevalence decrease was estimated at 22.6% in 2017 (p

Abstract Background This study aimed to assess the seasonality of confirmed malaria cases in Togo and to provide new indicators of malaria seasonality to the National Malaria Control Programme (NMCP). Methods Aggregated data of confirmed malaria cases were collected monthly from 2008 to 2017 by the Togo’s NMCP and stratified by health district and according to three target groups: children

Abstract Objective The delivery of healthcare at home has expanded to intravenous infusions of monoclonal antibodies. A recently developed model of care for home infusions of natalizumab for people with relapsing‐remitting multiple sclerosis was evaluated. This pilot study of home infusions of natalizumab and usual care (attendance in a hospital out‐patients’ clinic) compared safety, feasibility, patient satisfaction, effectiveness and costs. Methods In this randomised AB/BA crossover trial, 37 adults were randomised to usual care (n = 19) or home infusions (n = 18). After three infusions, patients crossed over to the alternate treatment for another three infusions. Patient safety outcomes and adherence, satisfaction, quality of life, disability and costs were compared. Results No adverse events were recorded from 207 infusions from 35 patients across both home and clinic infusions. There was no difference in adherence (p = 0.71) and infection rates (p = 0.84) between home and clinic settings. Satisfaction with “convenience” of home infusions was significantly greater (p = 0.008) but there were no differences in quality of life measures. Excluding pharmacy, costs were A$74 lower per infusion at home, including A$16 of patients” out‐of‐pocket costs. Interpretation There were no differences in safety and effectiveness between clinic and home infusions of natalizumab. The home infusions were shown to be feasible, more convenient and less expensive than usual care. Larger scale studies are required to verify these preliminary findings, particularly around safety and management of hypersensitivity adverse events in the home setting and for equivalence of clinical outcomes.

Objective: The WHO Malaria Report 2019 stated that “globally, the burden of malaria was lower than ten years ago, but, in the last few years, there has been an increase in the number of malaria cases around the world”. This study reported changes in malaria cases and deaths at the Togo national level (2008–2017) and presented anti-malaria fight results and eradication chances by 2030 in Togo. Methods: Cases and deaths were collected from medical records, monthly reports, and notes of 6000 health workers; then summarized by Region, District, year, and specific subpopulations. Estimates of annual trends of numbers of cases and deaths were obtained through generalized linear models. Results: The number of cases increased by four times, whereas the population increased by 1.3 times (2008–2017). Increases affected all regions and subpopulations; the mean annual relative increases in children

Abstract Background In Togo, the National Malaria Control Programme, in collaboration with the Global Fund to Fight AIDS, Tuberculosis and Malaria, has implemented a pilot study for malaria sentinel surveillance since 2017, which consists of collecting information in real time and analysing this information for decision-making. The first 20 months of malaria morbidity and mortality trends, and malaria case management in health facilities included in the surveillance were assessed. Methods Since July 2017, 16 health facilities called sentinel sites, 4 hospitals and 12 peripheral care units located in 2 epidemiologically different health regions, have provided weekly data on malaria morbidity and mortality for the following 3 target groups:

Abstract Background Regions within the nuclear ribosomal operon are a major tool for inferring evolutionary relationships and investigating diversity in fungi. In spite of the prevalent use of ribosomal markers in fungal research, central features of nuclear ribosomal DNA (nrDNA) evolution are poorly characterized for fungi in general, including lichenized fungi. The internal transcribed spacer (ITS) region of the nrDNA has been adopted as the primary DNA barcode identification marker for fungi. However, little is known about intragenomic variation in the nrDNA in symbiotic fungi. In order to better understand evolution of nrDNA and the utility of the ITS region for barcode identification of lichen-forming fungal species, we generated nearly complete nuclear ribosomal operon sequences from nine species in the Rhizoplaca melanophthalma species complex using short reads from high-throughput sequencing. Results We estimated copy numbers for the nrDNA operon, ranging from nine to 48 copies for members of this complex, and found low levels of intragenomic variation in the standard barcode region (ITS). Monophyly of currently described species in this complex was supported in phylogenetic inferences based on the ITS, 28S, intergenic spacer region, and some intronic regions, independently; however, a phylogenetic inference based on the 18S provided much lower resolution. Phylogenetic analysis of concatenated ITS and intergenic spacer sequence data generated from 496 specimens collected worldwide revealed previously unrecognized lineages in the nrDNA phylogeny. Conclusions The results from our study support the general assumption that the ITS region of the nrDNA is an effective barcoding marker for fungi. For the R. melanophthalma group, the limited amount of potential intragenomic variability in the ITS region did not correspond to fixed diagnostic nucleotide position characters separating taxa within this species complex. Previously unrecognized lineages inferred from ITS sequence data may represent undescribed species-level lineages or reflect uncharacterized aspects of nrDNA evolution in the R. melanophthalma species complex.

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells' proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells' survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.

We developed a new model of care for home infusions of natalizumab for people with multiple sclerosis. The new model of care was then tested in a pilot study comparing home infusions of natalizumab with usual care (attendance in an ambulatory care day units) using an AB/BA randomised crossover trial. In addition to testing feasibility and safety of home infusions for people with natalizumab compared to usual care, we investigated if: (i) home infusions of natalizumab are acceptable to patients and healthcare staff, (ii) home infusions of natalizumab are as effective in treating symptoms, and (iii) home infusions of natalizumab are cost effective? There were 37 stable adult patients (at least 6 prior natalizumab infusions and assessed as safe by their neurologist) randomised to an AB or BA trial arm. After 3 infusions, patients crossed over to the alternate treatment for another 3 infusions.

INTRODUCTION: En février 2011, le gouvernement togolais a instauré un régime obligatoire d'assurance maladie au profit des agents publics et assimilés. Quatre ans plus tard, cette étude a enquêté sur la satisfaction des bénéficiaires de ce régime dans la commune de Lomé. METHODES: l'enquête a été réalisée auprès d'un échantillon de bénéficiaires à l'aide d'un questionnaire anonyme administré en face-à-face à la sortie de huit établissements de soins. Une analyse des réponses a permis de mesurer le degré de satisfaction. Les données quantitatives ont été décrites à l'aide de médianes et d'étendues interquartiles (EIQ) et les données qualitatives transcrites verbatim. RESULTATS: parmi 288 sujet sollicités, 279 ont accepté de participer dont 58% étaient des femmes et 88% des agents encore en activité. L'âge médian était de 38 ans (EIQ: 30-47). Une très grande majorité de répondants (93,5%) a considéré cette assurance maladie asatisfaisante . La note moyenne de satisfaction globale était de 6/10 (min: 5, max: 9). Les principaux éléments d'insatisfaction concernaient le refus de prise en charge des affections de longue durée (84% d'insatisfaits), la complexité des formalités administratives (84% d'insatisfaits), et les longueurs des délais de prise en charge (67% d'insatisfaits). CONCLUSION: le niveau de satisfaction très élevé encourage le maintien et le développement de ce régime d'assurance maladie au Togo. Toutefois, les éléments d'insatisfaction devraient faire l'objet d'une prompte attention et de véritables efforts de correction.

Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.

An autosomal recessive syndrome characterized by congenital hypotrichosis and short life expectancy has been described in the Birman cat breed (Felis silvestris catus). We hypothesized that a FOXN1 (forkhead box N1) loss-of-function allele, associated with the nude phenotype in humans, mice and rats, may account for the syndrome observed in Birman cats. To the best of our knowledge, spontaneous mutations in FOXN1 have never been described in non-human, non-rodent mammalian species. We identified a recessive c.1030_1033delCTGT deletion in FOXN1 in Birman cats. This 4-bp deletion was associated with the syndrome when present in two copies. Percentage of healthy carriers in our French panel of genotyped Birman cats was estimated to be 3.2%. The deletion led to a frameshift and a premature stop codon at position 547 in the protein. In silico, the truncated FOXN1 protein was predicted to lack the activation domain and critical parts of the forkhead DNA binding domain, both involved in the interaction between FOXN1 and its targets, a mandatory step to promote normal hair and thymic epithelial development. Our results enlarge the panel of recessive FOXN1 loss-of-function alleles described in mammals. A DNA test is available; it will help owners avoid matings at risk and should prevent the dissemination of this morbid mutation in domestic felines.

An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.

Voluntary medical male circumcision (VMMC) is capable of reducing the risk of sexual transmission of HIV from females to males by approximately 60%. In 2007, the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended making VMMC part of a comprehensive HIV prevention package in countries with a generalized HIV epidemic and low rates of male circumcision. Modeling studies undertaken in 2009-2011 estimated that circumcising 80% of adult males in 14 priority countries in Eastern and Southern Africa within five years, and sustaining coverage levels thereafter, could avert 3.4 million HIV infections within 15 years and save US$16.5 billion in treatment costs. In response, WHO/UNAIDS launched the Joint Strategic Action Framework for accelerating the scale-up of VMMC for HIV prevention in Southern and Eastern Africa, calling for 80% coverage of adult male circumcision by 2016. While VMMC programs have grown dramatically since inception, they appear unlikely to reach this goal. This review provides an overview of findings from the PLOS Collection "Voluntary Medical Male Circumcision for HIV Prevention: Improving Quality, Efficiency, Cost Effectiveness, and Demand for Services during an Accelerated Scale-up." The use of devices for VMMC is also explored. We propose emphasizing management solutions to help VMMC programs in the priority countries achieve the desired impact of averting the greatest possible number of HIV infections. Our recommendations include advocating for prioritization and funding of VMMC, increasing strategic targeting to achieve the goal of reducing HIV incidence, focusing on programmatic efficiency, exploring the role of new technologies, rethinking demand creation, strengthening data use for decision-making, improving governments' program management capacity, strategizing for sustainability, and maintaining a flexible scale-up strategy informed by a strong monitoring, learning, and evaluation platform.

Hereditary footpad hyperkeratosis (HFH) represents a palmoplantar hyperkeratosis, which is inherited as a monogenic autosomal recessive trait in several dog breeds, such as e.g. Kromfohrländer and Irish Terriers. We performed genome-wide association studies (GWAS) in both breeds. In Kromfohrländer we obtained a single strong association signal on chromosome 5 (p(raw) = 1.0×10(-13)) using 13 HFH cases and 29 controls. The association signal replicated in an independent cohort of Irish Terriers with 10 cases and 21 controls (p(raw) = 6.9×10(-10)). The analysis of shared haplotypes among the combined Kromfohrländer and Irish Terrier cases defined a critical interval of 611 kb with 13 predicted genes. We re-sequenced the genome of one affected Kromfohrländer at 23.5× coverage. The comparison of the sequence data with 46 genomes of non-affected dogs from other breeds revealed a single private non-synonymous variant in the critical interval with respect to the reference genome assembly. The variant is a missense variant (c.155G>C) in the FAM83G gene encoding a protein with largely unknown function. It is predicted to change an evolutionary conserved arginine into a proline residue (p.R52P). We genotyped this variant in a larger cohort of dogs and found perfect association with the HFH phenotype. We further studied the clinical and histopathological alterations in the epidermis in vivo. Affected dogs show a moderate to severe orthokeratotic hyperplasia of the palmoplantar epidermis. Thus, our data provide the first evidence that FAM83G has an essential role for maintaining the integrity of the palmoplantar epidermis.

Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p

Dilated cardiomyopathy (DCM) is a highly prevalent and often lethal disease in Irish wolfhounds. Complex segregation analysis indicated different loci involved in pathogenesis. Linear fixed and mixed models were used for the genome-wide association study. Using 106 DCM cases and 84 controls we identified one SNP significantly associated with DCM on CFA37 and five SNPs suggestively associated with DCM on CFA1, 10, 15, 21 and 17. On CFA37 MOGAT1 and ACSL3 two enzymes of the lipid metabolism were located near the identified SNP.

Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disorder observed both in humans and animals. Examples of Canine Compulsive Disorder (CD) include excessive tail chasing (TC), light/shadow chasing and flank sucking. We performed a questionnaire survey to investigate the characteristics of compulsive (TC) and its possible associations with environmental correlates and personality in a pet population of 368 dogs from four dog breeds. We observed an early onset of TC at 3-6 months of age and a large variation in TC frequency in all breeds, with an overrepresentation of milder cases. Almost half of the TC dogs showed lowered responsiveness during bouts and displayed also other types of compulsions more often than the controls. Interestingly, dogs that received dietary supplements, especially vitamins and minerals, expressed less TC compared to dogs that did not receive any supplements. Neutered females had less TC, suggesting an influence of ovarian hormones on TC. Tail chasers were shyer and had separated earlier from their mothers than the controls. Finally, our genetic study did not find an association between TC and CDH2, a locus previously associated with the canine flank sucking compulsion. In conclusion, the early-onset and the variable nature of the repetitive behaviour, which is affected by environmental factors such as micronutrients, neutering and maternal care, share several similar components between canine and human compulsions and supports canine TC as a model for human OCD.

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 × 10⁻⁶, p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.