Genome-wide linkage screen for testicular germ cell tumour susceptibility loci

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the diseas

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Investigating Farm Fragmentation as a Risk Factor for Bovine Tuberculosis in Cattle Herds: A Matched Case-Control Study from Northern Ireland

Bovine tuberculosis remains a challenging endemic pathogen of cattle in many parts of the globe. Spatial clustering of Mycoacterium bovis molecular types in cattle suggests that local factors are the primary drivers of spread. Northern Ireland’s agricultural landscape is comprised of highly fragmented farms, distributed across spatially discontinuous land parcels, and these highly fragmented farms are thought to facilitate localised spread. We conducted a matched case control study to quantify the risks of bovine tuberculosis breakdown with farm area, farm fragmentation, fragment dispersal, and contact with neighbouring herds. Whilst our results show small but significant increases in breakdown risk associated with each factor, these relationships were strongly confounded with the number of contiguous neighbours with bovine tuberculosis. Our key finding was that every infected neighbour led to an increase in the odds of breakdown by 40% to 50%, and that highly fragmented farms were almost twice as likely to have a bTB positive neighbour compared to nonfragmented farms. Our results suggest that after controlling for herd size, herd type, spatial and temporal factors, farm fragmentation increasingly exposes herds to infection originating from first-order spatial neighbours. Given Northern Ireland’s particularly fragmented landscape, and reliance on short-term leases, our data support the hypothesis that between-herd contiguous spread is a particularly important component of the region’s bovine tuberculosis disease system

Quantifying Land Fragmentation in Northern Irish Cattle Enterprises

Farmland fragmentation is considered to be a defining feature of Northern Ireland’s (NI) agricultural landscape, influencing agricultural efficiency, productivity, and the spread of livestock diseases. Despite this, the full extent of farmland fragmentation in cattle farms in NI is not well understood, and little is known of how farmland fragmentation either influences, or is influenced by, different animal production types. Here, we describe and quantify farmland fragmentation in cattle farms for all of NI, using GIS processing of land parcel data to associate individual parcels with data on the cattle business associated with the land. We found that 35% of farms consisted of five or more fragments, with dairy farms associated with greater levels of farmland fragmentation, fragment dispersal and contact with contiguous neighbours compared to other production types. The elevated levels of farmland fragmentation in dairy production compared to non-dairy, may be associated with the recent expansion of dairy farms by land acquisition, following the abolition of the milk quota system in 2015. The comparatively high levels of farmland fragmentation observed in NI cattle farms may also have important implications for agricultural productivity and epidemiology alike. Whilst highly connected pastures could facilitate the dissemination of disease, highly fragmented land could also hamper productivity via diseconomies of scale, such as preventing the increase of herd sizes or additionally, adding to farm costs by increasing the complexity of herd management

Quantifying land fragmentation in Northern Ireland Cattle Enterprises

Publication history: Accepted - 2 March 2022; Published online - 9 March 2022Farmland fragmentation is considered to be a defining feature of Northern Ireland’s (NI) agricultural landscape, influencing agricultural efficiency, productivity, and the spread of livestock diseases. Despite this, the full extent of farmland fragmentation in cattle farms in NI is not well understood, and little is known of how farmland fragmentation either influences, or is influenced by, different animal production types. Here, we describe and quantify farmland fragmentation in cattle farms for all of NI, using GIS processing of land parcel data to associate individual parcels with data on the cattle business associated with the land. We found that 35% of farms consisted of five or more fragments, with dairy farms associated with greater levels of farmland fragmentation, fragment dispersal and contact with contiguous neighbours compared to other production types. The elevated levels of farmland fragmentation in dairy production compared to non-dairy, may be associated with the recent expansion of dairy farms by land acquisition, following the abolition of the milk quota system in 2015. The comparatively high levels of farmland fragmentation observed in NI cattle farms may also have important implications for agricultural productivity and epidemiology alike. Whilst highly connected pastures could facilitate the dissemination of disease, highly fragmented land could also hamper productivity via diseconomies of scale, such as preventing the increase of herd sizes or additionally, adding to farm costs by increasing the complexity of herd management.This work was supported by the Department of Agriculture, Environment and Rural Affairs (DAERA), and was fully funded under grant 18/3/02 (48258)-FaRTHEr: Fragmentation As a Risk factor for TB in cattle Herds: impacts on Eradication

Quantifying Land Fragmentation in Northern Irish Cattle Enterprises

Farmland fragmentation is considered to be a defining feature of Northern Ireland’s (NI) agricultural landscape, influencing agricultural efficiency, productivity, and the spread of livestock diseases. Despite this, the full extent of farmland fragmentation in cattle farms in NI is not well understood, and little is known of how farmland fragmentation either influences, or is influenced by, different animal production types. Here, we describe and quantify farmland fragmentation in cattle farms for all of NI, using GIS processing of land parcel data to associate individual parcels with data on the cattle business associated with the land. We found that 35% of farms consisted of five or more fragments, with dairy farms associated with greater levels of farmland fragmentation, fragment dispersal and contact with contiguous neighbours compared to other production types. The elevated levels of farmland fragmentation in dairy production compared to non-dairy, may be associated with the recent expansion of dairy farms by land acquisition, following the abolition of the milk quota system in 2015. The comparatively high levels of farmland fragmentation observed in NI cattle farms may also have important implications for agricultural productivity and epidemiology alike. Whilst highly connected pastures could facilitate the dissemination of disease, highly fragmented land could also hamper productivity via diseconomies of scale, such as preventing the increase of herd sizes or additionally, adding to farm costs by increasing the complexity of herd management

Genome-wide linkage screen for testicular germ cell tumour susceptibility loci.

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease