NOACs versus warfarin for stroke prevention in patients with AF : a systematic review and meta-analysis

Acknowledgments Revman software was used for meta-analysis, a free download from the Cochrane Collaboration. GRADE pro software was used to formulate the GRADE summary of findings table, a free download from the GRADE working group.Peer reviewedPublisher PD

The evolution of shelter: ecology and ethology of chimpanzee nest building

Human beings of all cultures build some form of shelter, and the global distribution of Homo sapiens depends on this basic trait. All great apes (chimpanzee, bonobo, gorilla, and orangutan) build analogous structures (called nests or beds) at least once a day throughout their adult lives, which suggests that this elementary technology was present before the hominid lines separated. This thesis investigates the variability and function of specifically wild chimpanzee shelters. I compared characteristics of chimpanzee nests, nesting trees, nest shape, and architecture in two savanna-dwelling populations on opposite sides of Africa: Fongoli, Senegal, and Issa, Tanzania. Savanna habitats are the most extreme habitats in which chimpanzees survive today, and may represent a similar environment to that in which early hominins evolved in the Plio-Pleistocene (Chapter 2). Investigating variation in nest-building within and between these two extreme habitats made it possible to tackle hypotheses of the shelter function of nests (Chapter 3). The influence of environment, specifically the role of protection from disease vectors and fluctuating temperatures, was assessed through a novel experiment in which I slept overnight in arboreal chimpanzee nests and on the bare earth (Chapter 4). To assess whether or not nests serve as an anti-predation function, I compared nesting in Issa, where predators are abundant, to Fongoli, where they are absent (Chapter 5). I provided further support for the thermoregulatory function of nests by showing that chimpanzees build more insulating nests in adverse weather conditions (Chapter 6). Nest-building is a learned behaviour, but its ontogeny is little known. I investigated social sources of variation in nest building in Fongoli to examine whether sex and age differences exist in nest building duration, nest position, shape and architecture (Chapter 7). Finally, ecosystem engineering is a consequence of animal construction, from ants to humans. I investigated use-wear traces around nests to assess niche construction of nest- building. I showed that chimpanzees repeatedly re-used these specific nest-spots within trees, which are pre-fabricated for future building through repeated pruning and shaping of these structures (Chapter 8). Nest building in great apes may be the foundation of constructivity in hominids. This thesis describes proximate functions and influences on nest-building variation in wild chimpanzees that help to model the evolution of shelter in hominids.This work was supported by the Carnegie Trust for Universities of Scotland (Carnegie Scholarship, Carnegie Research Grant), Corpus Christi College for a Taylor Bursary, Harold Hyam Wingate Foundation, International Primatological Society, L.S.B. Leakey Foundation, and the Wenner Gren Foundation

Piloting the United Kingdon 'Prescribing Safety Assessment' with pharmacist prescribers in Scotland.

Background: Prescribing is a complex task requiring considerable knowledge and skills. The Prescribing Safety Assessment (PSA) was developed by the British Pharmacological Society and the United Kingdom (UK) Medical Schools Council. Between February and June 2014, over 7000 final year medical students undertook the PSA, with an overall pass rate of 94%. Independent prescribing for suitably trained pharmacists was introduced in the UK in 2006. To date there has been little focus on any objective measures of prescribing safety. Objective: To determine the PSA performance of a pilot group of pharmacist prescribers in Scotland relative to medical students and to test the feasibility and acceptability of running the PSA. Methods: A group of 59 pharmacist prescribers took part in ten events. The PSA consisted of 30 questions to be completed over 60 min. All questions had been used in the 2014 assessments for final year medical students. The PSA was undertaken online under invigilated conditions, mirroring the medical student assessment. One month later, participants were invited to complete an online evaluation questionnaire. Results: The mean overall PSA scores (±SD) were 87.5% ± 8.7 (range 52–98) compared to a 88.5% for medical students. Based on an Angoff passmark of 76.0%, 53 pharmacists (89.8%) passed compared to an overall pass rate in PSA 2014 of 94%. Pharmacists performed equivalently to medical students in all assessment areas, with a slightly lower performance in the prescribing, drug monitoring and data interpretation questions offset by better performance in prescription review and adverse drug reactions. Feedback was positive in relation to appropriateness, relevance and level of difficulty of the PSA although several commented that they were practicing in very specific clinical areas. Conclusion: These pilot events have benchmarked the PSA performance of pharmacist prescribers with final year medical students, and feedback confirmed feasibility and acceptability

Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS): a mixed-methods study to inform trial design

Background: Smoking in pregnancy and/or not breastfeeding have considerable negative health outcomes for mother and baby. Aim: To understand incentive mechanisms of action for smoking cessation in pregnancy and breastfeeding, develop a taxonomy and identify promising, acceptable and feasible interventions to inform trial design. Design: Evidence syntheses, primary qualitative survey, and discrete choice experiment (DCE) research using multidisciplinary, mixed methods. Two mother-and-baby groups in disadvantaged areas collaborated throughout. Setting: UK. Participants: The qualitative study included 88 pregnant women/recent mothers/partners, 53 service providers, 24 experts/decision-makers and 63 conference attendees. The surveys included 1144 members of the general public and 497 health professionals. The DCE study included 320 women with a history of smoking. Methods: (1) Evidence syntheses: incentive effectiveness (including meta-analysis and effect size estimates), delivery processes, barriers to and facilitators of smoking cessation in pregnancy and/or breastfeeding, scoping review of incentives for lifestyle behaviours; (2) qualitative research: grounded theory to understand incentive mechanisms of action and a framework approach for trial design; (3) survey: multivariable ordered logit models; (4) DCE: conditional logit regression and the log-likelihood ratio test. Results: Out of 1469 smoking cessation and 5408 breastfeeding multicomponent studies identified, 23 smoking cessation and 19 breastfeeding studies were included in the review. Vouchers contingent on biochemically proven smoking cessation in pregnancy were effective, with a relative risk of 2.58 (95% confidence interval 1.63 to 4.07) compared with non-contingent incentives for participation (four studies, 344 participants). Effects continued until 3 months post partum. Inconclusive effects were found for breastfeeding incentives compared with no/smaller incentives (13 studies) but provider commitment contracts for breastfeeding show promise. Intervention intensity is a possible confounder. The acceptability of seven promising incentives was mixed. Women (for vouchers) and those with a lower level of education (except for breastfeeding incentives) were more likely to disagree. Those aged ≤ 44 years and ethnic minority groups were more likely to agree. Agreement was greatest for a free breast pump and least for vouchers for breastfeeding. Universal incentives were preferred to those targeting low-income women. Initial daily text/telephone support, a quitting pal, vouchers for > £20.00 per month and values up to £80.00 increase the likelihood of smoking cessation. Doctors disagreed with provider incentives. A ‘ladder’ logic model emerged through data synthesis and had face validity with service users. It combined an incentive typology and behaviour change taxonomy. Autonomy and well-being matter. Personal difficulties, emotions, socialising and attitudes of others are challenges to climbing a metaphorical ‘ladder’ towards smoking cessation and breastfeeding. Incentive interventions provide opportunity ‘rungs’ to help, including regular skilled flexible support, a pal, setting goals, monitoring and outcome verification. Individually tailored and non-judgemental continuity of care can bolster women’s capabilities to succeed. Rigid, prescriptive interventions placing the onus on women to behave ‘healthily’ risk them feeling pressurised and failing. To avoid ‘losing face’, women may disengage. Limitations: Included studies were heterogeneous and of variable quality, limiting the assessment of incentive effectiveness. No cost-effectiveness data were reported. In surveys, selection bias and confounding are possible. The validity and utility of the ladder logic model requires evaluation with more diverse samples of the target population. Conclusions: Incentives provided with other tailored components show promise but reach is a concern. Formal evaluation is recommended. Collaborative service-user involvement is importan

Interactions Between Chimpanzees (Pan troglodytes schweinfurthii) and Cattle (Bos taurus) in the Issa Valley, Western Tanzania

Wildlife habitats are being degraded globally due to human activities. Pastoralism in Africa has been described as a major threat to habitats and a source of wildlife-livestock interactions and conflict. Chimpanzees in particular are affected by the use of land for livestock, most notably where cattle trample terrestrial food sources and may act as potential reservoirs of disease. Yet, despite extensive study of wild chimpanzees across their distribution, no detailed behavioural observations of chimpanzee-cattle interactions have been described. We report ten direct chimpanzee-cattle encounters that occurred from 2019-2021 in the Issa valley, Tanzania. We observed more interactions in the dry season, and these prompted more vigilance by chimpanzees than wet season interactions. The distance between chimpanzees and cattle may also affect chimpanzee behavioural responses. Our observations suggest that (1) chimpanzees remain vigilant but otherwise only minimally change their behavioural reactions towards cattle in ways that depend, at least in part, on chimpanzee party composition, with males reacting more overtly than females and (2) chimpanzees exhibit more aversive behaviour when cattle are accompanied by herders and dogs

High-sensitivity troponin and the application of risk stratification thresholds in patients with suspected acute coronary syndrome

Background: Guidelines acknowledge the emerging role of high-sensitivity cardiac troponin (hs-cTnl) for risk stratification and the early rule-out of myocardial infarction, but multiple thresholds have been described. We evaluate the safety and effectiveness of risk stratification thresholds in patients with suspected acute coronary syndrome. Methods: Consecutive patients with suspected acute coronary syndrome (n=48 282) were enrolled in a multicenter trial across 10 hospitals in Scotland. In a prespecified secondary and observational analysis, we compared the performance of the limit of detection (<2 ng/L) and an optimized risk stratification threshold (<5 ng/L) using the Abbott high-sensitivity troponin I assay. Patients with myocardial injury at presentation, with ≤2 hours of symptoms or with ST-segment elevation myocardial infarction were excluded. The negative predictive value was determined in all patients and in subgroups for a primary outcome of myocardial infarction or cardiac death within 30 days. The secondary outcome was myocardial infarction or cardiac death at 12 months, with risk modeled using logistic regression adjusted for age and sex. Results: In total, 32 837 consecutive patients (61±17 years, 47% female) were included, of whom 23 260 (71%) and 12,716 (39%) had hs-cTnl concentrations of <5 ng/L and <2 ng/L at presentation. The negative predictive value for the primary outcome was 99.8% (95% CI, 99.7%–99.8%) and 99.9% (95% CI, 99.8%–99.9%) in those with hs-cTnl concentrations of <5 ng/L and <2 ng/L, respectively. At both thresholds, the negative predictive value was consistent in men and women and across all age groups, although the proportion of patients identified as low risk fell with increasing age. Compared with patients with hs-cTnl concentrations of ≥5 ng/L but <99th centile, the risk of myocardial infarction or cardiac death at 12 months was 77% lower in those <5 ng/L (5.3% vs 0.7%; adjusted odds ratio, 0.23 [95% CI, 0.19–0.28]) and 80% lower in those <2 ng/L (5.3% vs 0.3%; adjusted odds ratio, 0.20 [95% CI, 0.14–0.29]). Conclusions: Use of risk stratification thresholds for hs-cTnl identify patients with suspected acute coronary syndrome and at least 2 hours of symptoms as low risk at presentation irrespective of age and sex

Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling

NAA10 polyadenylation signal variants cause syndromic microphthalmia

Background A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.Methods Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq.Results Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3′ UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS.Conclusion These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yi

Barriers to chimpanzee gene flow at the south-east edge of their distribution

Populations on the edge of a species' distribution may represent an important source of adaptive diversity, yet these populations tend to be more fragmented and are more likely to be geographically isolated. Lack of genetic exchanges between such populations, due to barriers to animal movement, can not only compromise adaptive potential but also lead to the fixation of deleterious alleles. The south-eastern edge of chimpanzee distribution is particularly fragmented, and conflicting hypotheses have been proposed about population connectivity and viability. To address this uncertainty, we generated both mitochondrial and MiSeq-based microsatellite genotypes for 290 individuals ranging across western Tanzania. While shared mitochondrial haplotypes confirmed historical gene flow, our microsatellite analyses revealed two distinct clusters, suggesting two populations currently isolated from one another. However, we found evidence of high levels of gene flow maintained within each of these clusters, one of which covers an 18,000 km2 ecosystem. Landscape genetic analyses confirmed the presence of barriers to gene flow with rivers and bare habitats highly restricting chimpanzee movement. Our study demonstrates how advances in sequencing technologies, combined with the development of landscape genetics approaches, can resolve ambiguities in the genetic history of critical populations and better inform conservation efforts of endangered species

The ecology and epidemiology of malaria parasitism in wild chimpanzee reservoirs

Chimpanzees (Pan troglodytes) harbor rich assemblages of malaria parasites, including three species closely related to P. falciparum (sub-genus Laverania), the most malignant human malaria parasite. Here, we characterize the ecology and epidemiology of malaria infection in wild chimpanzee reservoirs. We used molecular assays to screen chimpanzee fecal samples, collected longitudinally and cross-sectionally from wild populations, for malaria parasite mitochondrial DNA. We found that chimpanzee malaria parasitism has an early age of onset and varies seasonally in prevalence. A subset of samples revealed Hepatocystis mitochondrial DNA, with phylogenetic analyses suggesting that Hepatocystis appears to cross species barriers more easily than Laverania. Longitudinal and cross-sectional sampling independently support the hypothesis that mean ambient temperature drives spatiotemporal variation in chimpanzee Laverania infection. Infection probability peaked at similar to 24.5 degrees C, consistent with the empirical transmission optimum of P. falciparum in humans. Forest cover was also positively correlated with spatial variation in Laverania prevalence, consistent with the observation that forest-dwelling Anophelines are the primary vectors. Extrapolating these relationships across equatorial Africa, we map spatiotemporal variation in the suitability of chimpanzee habitat for Laverania transmission, offering a hypothetical baseline indicator of human exposure risk