Mortality and clinical outcomes in children treated with antiretroviral therapy in four African vertical programs during the first decade of paediatric HIV care, 2001-2010

Objective: To assess mortality and clinical outcomes in children treated with antiretroviral therapy (ART) in four African vertical programmes between 2001 and 2010. Methods: Cohort analysis of data from HIV-infected children (<15 years old) initiating ART in 4 sub-Saharan HIV programs in Kenya, Uganda and Malawi, between December 2001 and December 2010. Rates of mortality, program attrition and first-line clinico-immunological failure were calculated by age group (<2, 2-4 and 5-14 years), 1 or 2 years after ART initiation and risk factors were examined. Results: A total of 3,949 children, 22.7% aged <2 years, 32.2% 2-4 years, 45.1% aged 5-14 years, were included. At ART initiation 60.8% had clinical stage 3 or 4, and 46.5% severe immune-suppression. Overall mortality, attrition and 1-year failure rates were 5.1, 10.8 and 9.0 per 100 person-years, respectively. Immunosuppression, stage 3 or 4 and underweight were associated with increased rates of mortality, attrition and treatment failure. Adjusted estimates showed lower mortality hazard ratios (HR) among children aged 2-4 years (HR=0.57, 95%CI 0.42-0.77 compared to 5-14 years). One-year treatment failure incidence rate ratios (IRR) were similar regardless of age (IRR=0.91, 95%CI 0.67-1.25 for <2 years; 1.01, 95%CI 0.83-1.23 for 2-4 years, compared to 5-14 years). Conclusions: Good treatment outcomes were achieved during the first decade of HIV pediatric care despite the late start of therapy. Encouraging early HIV infant diagnosis in and outside prevention of mother-to-child-transmission programs, and linkage to care services for early ART initiation are needed to reduce mortality and delay treatment failure

Did aid promote democracy in Africa?: the role of technical assistance in Africa’s transitions

Did foreign aid impede or catalyze democratization in Africa in the 1990s? We argue that after the Cold War, donors increased their use of technical assistance in aid packages, improving their monitoring capacity and thus reducing autocrats’ ability to use aid for patronage. To remain in power, autocrats responded by conceding political rights to their opponents—from legalizing opposition parties to staging elections. We test our theory with panel data for all sub-Saharan African countries. While other factors played pivotal roles in Africa’s political liberalization, we find technical assistance helps to explain the timing and extent of Africa’s democratization

Genetic Characterization of Zika Virus Strains: Geographic Expansion of the Asian Lineage

Zika virus (ZIKV) is a mosquito-transmitted flavivirus found in both Africa and Asia. Human infection with the virus may result in a febrile illness similar to dengue fever and many other tropical infections found in these regions. Previously, little was known about the genetic relationships between ZIKV strains collected in Africa and those collected in Asia. In addition, the geographic origins of the strains responsible for the recent outbreak of human disease on Yap Island, Federated States of Micronesia, and a human case of ZIKV infection in Cambodia were unknown. Our results indicate that there are two geographically distinct lineages of ZIKV (African and Asian). The virus has circulated in Southeast Asia for at least the past 50 years, whereupon it was introduced to Yap Island resulting in an epidemic of human disease in 2007, and in 2010 was the cause of a pediatric case of ZIKV infection in Cambodia. This study also highlights the danger of ZIKV introduction into new areas and the potential for future epidemics of human disease

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Phylogenetic data matrix for Plesiosauria

Morphological phylogenetic data matrix for Plesiosauria analysed by Benson et al. "A giant pliosaurid skull from the Late Jurassic of England". The file is in Nexus format. The character list is available in doi:10.5061/dryad.v843v

Data from: A giant pliosaurid skull from the Late Jurassic of England

Pliosaurids were a long-lived and cosmopolitan group of marine predators that spanned 110 million years and occupied the upper tiers of marine ecosystems from the Middle Jurassic until the early Late Cretaceous. A well-preserved giant pliosaurid skull from the Late Jurassic Kimmeridge Clay Formation of Dorset, United Kingdom, represents a new species, Pliosaurus kevani. This specimen is described in detail, and the taxonomy and systematics of Late Jurassic pliosaurids is revised. We name two additional new species, Pliosaurus carpenteri and Pliosaurus westburyensis, based on previously described relatively complete, well-preserved remains. Most or all Late Jurassic pliosaurids represent a globally distributed monophyletic group (the genus Pliosaurus, excluding ‘Pliosaurus’ andrewsi). Despite its high species diversity, and geographically widespread, temporally extensive occurrence, Pliosaurus shows relatively less morphological and ecological variation than is seen in earlier, multi-genus pliosaurid assemblages such as that of the Middle Jurassic Oxford Clay Formation. It also shows less ecological variation than the pliosaurid-like Cretaceous clade Polycotylidae. Species of Pliosaurus had robust skulls, large body sizes (with skull lengths of 1.7–2.1 metres), and trihedral or subtrihedral teeth suggesting macropredaceous habits. Our data support a trend of decreasing length of the mandibular symphysis through Late Jurassic time, as previously suggested. This may be correlated with increasing adaptation to feeding on large prey. Maximum body size of pliosaurids increased from their first appearance in the Early Jurassic until the Early Cretaceous (skull lengths up to 2360 mm). However, some reduction occurred before their final extinction in the early Late Cretaceous (skull lengths up to 1750 mm)