Evaluation of the impact of artificial intelligence-assisted image interpretation on the diagnostic performance of clinicians in identifying pneumothoraces on plain chest X-ray: a multi-case multi-reader study.

BACKGROUND: Artificial intelligence (AI)-assisted image interpretation is a fast-developing area of clinical innovation. Most research to date has focused on the performance of AI-assisted algorithms in comparison with that of radiologists rather than evaluating the algorithms' impact on the clinicians who often undertake initial image interpretation in routine clinical practice. This study assessed the impact of AI-assisted image interpretation on the diagnostic performance of frontline acute care clinicians for the detection of pneumothoraces (PTX). METHODS: A multicentre blinded multi-case multi-reader study was conducted between October 2021 and January 2022. The online study recruited 18 clinician readers from six different clinical specialties, with differing levels of seniority, across four English hospitals. The study included 395 plain CXR images, 189 positive for PTX and 206 negative. The reference standard was the consensus opinion of two thoracic radiologists with a third acting as arbitrator. General Electric Healthcare Critical Care Suite (GEHC CCS) PTX algorithm was applied to the final dataset. Readers individually interpreted the dataset without AI assistance, recording the presence or absence of a PTX and a confidence rating. Following a 'washout' period, this process was repeated including the AI output. RESULTS: Analysis of the performance of the algorithm for detecting or ruling out a PTX revealed an overall AUROC of 0.939. Overall reader sensitivity increased by 11.4% (95% CI 4.8, 18.0, p=0.002) from 66.8% (95% CI 57.3, 76.2) unaided to 78.1% aided (95% CI 72.2, 84.0, p=0.002), specificity 93.9% (95% CI 90.9, 97.0) without AI to 95.8% (95% CI 93.7, 97.9, p=0.247). The junior reader subgroup showed the largest improvement at 21.7% (95% CI 10.9, 32.6), increasing from 56.0% (95% CI 37.7, 74.3) to 77.7% (95% CI 65.8, 89.7, p<0.01). CONCLUSION: The study indicates that AI-assisted image interpretation significantly enhances the diagnostic accuracy of clinicians in detecting PTX, particularly benefiting less experienced practitioners. While overall interpretation time remained unchanged, the use of AI improved diagnostic confidence and sensitivity, especially among junior clinicians. These findings underscore the potential of AI to support less skilled clinicians in acute care settings.

Watershed features shape spatial patterns of fish tissue mercury in a boreal river network.

Freshwater mercury (Hg) contamination is a widespread environmental concern but how proximate sources and downstream transport shape Hg spatial patterns in riverine food webs is poorly understood. We measured total Hg (THg) in slimy sculpin (Cottus cognatus) across the Kuskokwim River, a large boreal river in western Alaska and home to subsistence fishing communities which rely on fish for primary nutrition. We used spatial stream network models (SSNMs) to quantify watershed and instream conditions influencing sculpin THg. Spatial covariates for local watershed geology and slope accounted for 55 % of observed variation in sculpin THg and evidence for downstream transport of Hg in sculpins was weak. Empirical semivariograms indicated these spatial covariates accounted for most spatial autocorrelation in observed THg. Watershed geology and slope explained up to 70 % of sculpin THg variation when SSNMs accounted for instream spatial dependence. Our results provide network-wide predictions for fish tissue THg based largely on publicly available geospatial data and open-source software for SSNMs, and demonstrate how these emerging models can be used to understand contaminant behavior in spatially complex aquatic ecosystems.

The Canadian VirusSeq Data Portal & Duotang: open resources for SARS-CoV-2 viral sequences and genomic epidemiology.

The COVID-19 pandemic led to a large global effort to sequence SARS-CoV-2 genomes from patient samples to track viral evolution and inform public health response. Millions of SARS-CoV-2 genome sequences have been deposited in global public repositories. The Canadian COVID-19 Genomics Network (CanCOGeN - VirusSeq), a consortium tasked with coordinating expanded sequencing of SARS-CoV-2 genomes across Canada early in the pandemic, created the Canadian VirusSeq Data Portal, with associated data pipelines and procedures, to support these efforts. The goal of VirusSeq was to allow open access to Canadian SARS-CoV-2 genomic sequences and enhanced, standardized contextual data that were unavailable in other repositories and that meet FAIR standards (Findable, Accessible, Interoperable and Reusable). In addition, the Portal data submission pipeline contains data quality checking procedures and appropriate acknowledgement of data generators that encourages collaboration. From inception to execution, the portal was developed with a conscientious focus on strong data governance principles and practices. Extensive efforts ensured a commitment to Canadian privacy laws, data security standards, and organizational processes. This Portal has been coupled with other resources like Viral AI and was further leveraged by the Coronavirus Variants Rapid Response Network (CoVaRR-Net) to produce a suite of continually updated analytical tools and notebooks. Here we highlight this Portal, including its contextual data not available elsewhere, and the 'Duotang', a web platform that presents key genomic epidemiology and modeling analyses on circulating and emerging SARS-CoV-2 variants in Canada. Duotang presents dynamic changes in variant composition of SARS-CoV-2 in Canada and by province, estimates variant growth, and displays complementary interactive visualizations, with a text overview of the current situation. The VirusSeq Data Portal and Duotang resources, alongside additional analyses and resources computed from the Portal (COVID-MVP, CoVizu), are all open-source and freely available. Together, they provide an updated picture of SARS-CoV-2 evolution to spur scientific discussions, inform public discourse, and support communication with and within public health authorities. They also serve as a framework for other jurisdictions interested in open, collaborative sequence data sharing and analyses.

Structure and functionality of surface-active amylose-fatty amine salt inclusion complexes.

Novel value-added starch-based materials can be produced by forming amylose inclusion complexes (AIC) with hydrophobic compounds. There is currently little research on AIC use as polymeric emulsifiers, particularly for AIC with fatty amine salt ligands. This work evaluated AIC emulsifiers by studying the structure and functionality of AIC composed of high amylose corn starch and fatty amine salts (10-18 carbons, including a mixture simulating vegetable oil composition) produced via steam jet cooking. X-ray scattering verified successful AIC formation, with peaks located near 7.0°, 12.8° and 19.9° 2θ. AIC were easily dispersed in water (80-85 °C) and remained in suspension at room temperature for weeks, unlike the uncomplexed ligands or starch. AIC were highly effective emulsifying agents, with emulsifying activity indexes of 213-229 m2g-1 at pH 5, and zeta potentials, a measure of electrostatic repulsion, as high as 43.4 mV. AIC dispersions had surface tension ranging from 24 to 41 mN/m and displayed surface-active properties superior to amylose complexes formed from fatty acid salts and competitive with common starch-based emulsifiers. These findings demonstrate that fatty amine salt AIC are effective emulsifiers that can be made from low-cost sources of fatty amine salts, such as vegetable oil derivatives.

Pyroglutamate acidosis 2023. A review of 100 cases.

This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.

Substantial cost savings of ultrasound-based management over magnetic resonance imaging-based management in an inflammatory bowel disease service.

BACKGROUND: Imaging is used to monitor disease activity in small bowel Crohn's disease (CD). Magnetic Resonance Enterography is often employed as a first modality in the United Kingdom for assessment and monitoring; however, waiting times, cost, patient burden and limited access are significant. It is as yet uncertain if small bowel intestinal ultrasound (IUS) may be a quicker, more acceptable, and cheaper alternative for monitoring patients with CD. METHODS: A clinical service evaluation of imaging pathways was undertaken at a single NHS site in England, United Kingdom. Data were collected about patients who were referred and underwent an imaging analysis for their IBD. Only patients who underwent a therapy change were included in the analysis. Data were collected from care episodes between 01 January 2021-30 March 2022. RESULTS: A combined total of 193 patient care episodes were reviewed, 107 from the IUS pathway and 86 from the MRE pathway. Estimated costs per patient in the IUS pathway was £78.86, and £375.35 per patient in the MRE pathway. The MRE pathway had an average time from referral to treatment initiation of 91 days (SD= ±61) with patients in the IUS pathway waiting an average of 46 days (SD= ±17). CONCLUSIONS: Findings from this work indicate that IUS is a potential cost-saving option when compared to MRE when used in the management of CD. This is in addition to the cost difference of the radiological modalities. A large, multicentre, prospective study is needed to validate these initial findings.

What is already known on this topic ­ Ultrasound is a quick and accurate imaging investigation for patients living with Crohn's disease. Its effect on the cost utility of an Inflammatory Bowel Disease service is unknown.What this study adds ­ This work provides initial data suggesting that an ultrasound-based service may provide significant cost savings when compared to a magnetic resonance imaging-based service.How this study might affect research, practice, or policy ­ This work is part of a larger programme of work to investigate the barriers to wider ultrasound implementation in UK IBD services. This work will contribute to the design of an implementation and training package for intestinal ultrasound in the UK.

Association between body mass index and age of disease onset with clinical outcomes in paediatric-onset Crohn's Disease (CD): a UK nation-wide analyses using the NIHR-IBD BioResource.

BACKGROUND: The evidence on the relationship between adiposity and disease outcomes in paediatric Crohn's disease (CD) is limited and lacks consensus. AIM: To investigate the relationship between (a) body mass index (BMI) and clinical CD outcomes (hospitalisation, surgery, disease behaviour, biologic use, extra-intestinal manifestations (EIMs)) and (b) the age of CD onset with clinical outcomes. DESIGN: Clinical outcomes were examined in CD patients diagnosed at age <17 years and enroled in the National Institute for Health Research IBD-UK BioResource at a median age of 24 years. All outcomes and BMI were recorded at the time of enrolment. Participants were categorised into normal (<25 kg/m2) and high (≥25 kg/m2) BMI. Age at disease diagnosis was categorised into pre-puberty/early puberty (<11 years), puberty (11-14 years) and post-puberty (15-17 years). Spearman rank correlation was used to test the associations between continuous variables and chi-square test to compare categorical variables. RESULTS: 848 participants with CD were included (51.8% males) and median age at diagnosis was 14 years. Participants with high BMI experienced a greater frequency of EIMs (P = 0.05) than those with low BMI (1 type of EIM: 18.5% vs. 13.2%, respectively; ≥2 types of EIMs: 7.8% vs. 5.6%, respectively). Age at diagnosis and BMI showed weak correlations with corticosteroid use (ρ = 0.08, P = 0.03 and ρ = -0.09, P = 0.01; respectively). An early diagnosis (<11 years) was associated with higher occurrence of stenosing and penetrating disease behaviour (P = 0.01) and hospitalisations (P < 0.001). CONCLUSIONS: A higher BMI and an earlier age of disease onset are associated with worse CD clinical presentation.

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death.

Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Stable fixation of an ultra-short femoral neck-preserving hip prosthesis: a 5-year RSA, DXA, and clinical prospective outcome study of 48 patients.

BACKGROUND AND PURPOSE: We previously showed promising primary stability and preservation of bone stock with the ultra-short neck-loading hip implant in total hip arthroplasty (THA). The aim of this study was to evaluate clinical outcome, implant stability, and bone mineral density (BMD). METHODS: 50 patients were treated with the ultra-short neck Primoris hip implant at baseline and 48 were available for evaluation at 5-year follow-up. 5 different patient-reported outcome measures (PROMs) including hip-specific scores, disease-specific and generic quality of life outcome measures, and an activity score were used. Furthermore, implant stability using radiostereometric analysis (RSA) and assessment of periprosthetic BMD using dual-energy X-ray absorptiometry (DXA) were applied. RESULTS: By 1-year follow-up, all PROMs showed improvements and remained high at 5-year follow-up. After initial distal translation (subsidence) and negative rotation around the z-axis (varus tilt) the implant showed stable fixation at 5-year follow-up with no further migration beyond 12 months. In the regions of interest (ROI) 3 and 4, BMD remained stable. In ROI 2, further bone loss of 12% was found at 5-year follow-up. CONCLUSION: Clinical outcome including PROMs was satisfying throughout the 5-year follow-up period. The hip implant remains stable with both bone preservation and loss 5 years after surgery.

A Survey of Recently Discovered Naturally Occurring Organohalogen Compounds.

The discovery of naturally occurring organohalogen compounds has increased astronomically in the 55 years since they were first discovered─from fewer than 50 in 1968 to a combined 7,958 described examples in three comprehensive reviews. The present survey, which covers the period 2021-2023, brings the number of known natural organohalogens to approximately 8,400. The organization is according to species origin, and coverage includes marine and terrestrial plants, fungi, bacteria, marine sponges, corals, cyanobacteria, tunicates, and other marine organisms.

Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Female long-term sperm storage results in viable offspring in the Himalayan Mountain Pitviper, Ovophis monticola.

The ability of females to store sperm for extended periods in their reproductive tracts (termed long-term sperm storage, LTSS) has been reported across a diversity of vertebrate taxa. The evolutionary, ecological, and physiological significance of LTSS is wide-ranging and includes the ability to produce offspring when mates may be temporally scarce by way of decoupling copulation from ovulation, inbreeding avoidance, and the generation and maintenance of genetic diversity in progeny. Among vertebrate lineages, nonavian reptiles exhibit a remarkable capacity for LTSS, with the production of viable offspring reported after periods exceeding 6 years since prior contact with a potential mate. Given that female reptiles are able to store viable sperm for prolonged periods, it is important to disentangle LTSS from that of facultative parthenogenesis (FP), a reproductive trait which appears widespread among all reptile lineages. The implications of this distinction are particularly important in the context of the development and management of captive breeding programs. To accurately determine between the two reproductive strategies, genomic screening is highly recommended. Following a period of isolation for 13 months from a potential male mate, a female Himalayan Mountain Pitviper (Ovophis monticola) produced a clutch of three male offspring. Here, through genome-scale analyses of the female and her progeny, we document the first record of LTSS in this genus and exclude FP as the alternative hypothesis.

Biologic therapy for inflammatory bowel disease: Real-world comparative effectiveness and impact of drug sequencing in 13,222 patients within the UK IBD BioResource.

BACKGROUND AND AIMS: To compare effectiveness of different biologic therapies and sequences in patients with Inflammatory Bowel Disease (IBD) using real-world data from a large cohort with long exposure. METHODS: Demographic, disease, treatment and outcome data were retrieved for patients in the UK IBD BioResource. Effectiveness of treatment was based on persistence free of discontinuation or failure, analysed by Kaplan-Meier survival analysis with inverse probability of treatment weighting to adjust for differences between groups. RESULTS: 13,222 evaluable patients received at least one biologic. In ulcerative colitis (UC) first line vedolizumab (VDZ) demonstrated superior effectiveness over five years compared to anti-TNF agents (p=0.006). VDZ was superior to both infliximab (IFX) and adalimumab (ADA) after ADA and IFX failure respectively (p<0.001 and p<0.001). Anti-TNF therapy showed similar effectiveness when used first-line, or after failure of VDZ. In Crohn's disease (CD) we found significant differences between first line treatments over ten years (p=0.045), with superior effectiveness of IFX compared to ADA in perianal CD. Non-anti-TNF biologics were superior to a second anti-TNF after first line anti-TNF failure in CD (p=0.035). Patients with UC or CD experiencing TNF-failure due to delayed loss of response or intolerance had superior outcomes when switching to a non-anti-TNF biologic, rather than a second anti-TNF. CONCLUSIONS: We provide real-world evidence to guide biologic selection and sequencing in a range of common scenarios. Our findings challenge current guidelines regarding drug selection after loss of response to first anti-TNF.

Acceptance of and Adherence to a Four-Dose RTS,S/AS01 Schedule: Findings from a Longitudinal Qualitative Evaluation Study for the Malaria Vaccine Implementation Programme.

BACKGROUND: The WHO recommended the use of the RTS,S/AS01 malaria vaccine (RTS,S) based on a pilot evaluation in routine use in Ghana, Kenya, and Malawi. A longitudinal qualitative study was conducted to examine facilitators and barriers to uptake of a 4-dose RTS,S schedule. METHODS: A cohort of 198 caregivers of RTS,S-eligible children from communities where RTS,S was provided through the pilot were interviewed three times over a ≈22-month, 4-dose schedule. The interviews examined caregiver perceptions and behaviors. Children's vaccination history was obtained to determine dose uptake. RESULTS: 162 caregivers remained at round 3 (R3); vaccination history was available for 152/162 children. Despite early rumors/fears, the uptake of initial doses was high, driven by vaccine trust. Fears dissipated by R2, replaced with an enthusiasm for RTS,S as caregivers perceived its safety and less frequent and severe malaria. By R3, 98/152 children had received four doses; 34 three doses; 9 one or two doses; and 11 zero doses. The health system and information barriers were important across all under-dose cases. Fears about AEFIs/safety were important in zero-, one-, and two-dose cases. Competing life/livelihood demands and complacency were found in three-dose cases. Regardless of the doses received, caregivers had positive attitudes towards RTS,S by R3. CONCLUSIONS: Findings from our study will help countries newly introducing the vaccine to anticipate and preempt reasons for delayed acceptance and missed RTS,S doses.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

Hunting behavior and feeding ecology of Mojave rattlesnakes (Crotalus scutulatus), prairie rattlesnakes (Crotalus viridis), and their hybrids in southwestern New Mexico.

Predators must contend with numerous challenges to successfully find and subjugate prey. Complex traits related to hunting are partially controlled by a large number of co-evolved genes, which may be disrupted in hybrids. Accordingly, research on the feeding ecology of animals in hybrid zones has shown that hybrids sometimes exhibit transgressive or novel behaviors, yet for many taxa, empirical studies of predation and diet across hybrid zones are lacking. We undertook the first such field study for a hybrid zone between two snake species, the Mojave rattlesnake (Crotalus scutulatus) and the prairie rattlesnake (Crotalus viridis). Specifically, we leveraged established field methods to quantify the hunting behaviors of animals, their prey communities, and the diet of individuals across the hybrid zone in southwestern New Mexico, USA. We found that, even though hybrids had significantly lower body condition indices than snakes from either parental group, hybrids were generally similar to non-hybrids in hunting behavior, prey encounter rates, and predatory attack and success. We also found that, compared to C. scutulatus, C. viridis was significantly more active while hunting at night and abandoned ambush sites earlier in the morning, and hybrids tended to be more viridis-like in this respect. Prey availability was similar across the study sites, including within the hybrid zone, with kangaroo rats (Dipodomys spp.) as the most common small mammal, both in habitat surveys and the frequency of encounters with hunting rattlesnakes. Analysis of prey remains in stomachs and feces also showed broad similarity in diets, with all snakes preying primarily on small mammals and secondarily on lizards. Taken together, our results suggest that the significantly lower body condition of hybrids does not appear to be driven by differences in their hunting behavior or diet and may instead relate to metabolic efficiency or other physiological traits we have not yet identified.