Analysis of sociodemographic and clinical factors associated with Lassa fever disease and mortality in Nigeria.

Over past decades, there has been increasing geographical spread of Lassa fever (LF) cases across Nigeria and other countries in West Africa. This increase has been associated with significant morbidity and mortality despite increasing focus on the disease by both local and international scientists. Many of these studies on LF have been limited to few specialised centres in the country.

Psychosocial Impacts of Infertility among Omani Women with Polycystic Ovarian Syndrome: A Qualitative Study.

Background: To understand the psychosocial experience of infertility among women with polycystic ovarian syndrome in Oman.

Materials And Methods: In this qualitative study, semi-structured interviews were conducted with 20 Omani women diagnosed with polycystic ovarian syndrome (PCOS) and infertility across two fertility clinics, in Muscat-Oman. Interviews were audio-recorded, transcribed analysed verbatim and qualitatively using the framework approach.

Assessing the capacity of symptom scores to predict COVID-19 positivity in Nigeria: a national derivation and validation cohort study.

Objectives: This study aimed to develop and validate a symptom prediction tool for COVID-19 test positivity in Nigeria.

Design: Predictive modelling study.

Setting: All Nigeria States and the Federal Capital Territory.

Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic.

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics.

Opioids and the Risk of Fracture: A Self-Controlled Case Series Study in the Clinical Practice Research Datalink.

Self-controlled study designs can be used to assess the association between exposures and acute outcomes while controlling for important confounders. Using routinely collected health data, a self-controlled case series design was used to investigate the association between opioid use and bone fractures in 2008-2017 among adults registered in the United Kingdom Clinical Practice Research Datalink. The relative incidence of fracture was estimated, comparing periods when these adults were exposed and unexposed to opioids, adjusted for time-varying confounders.

Early childhood respiratory morbidity and antibiotic use in ex-preterm infants: a primary care population-based cohort study.

Background: Globally, bronchopulmonary dysplasia (BPD) continues to increase in preterm infants. Recent studies exploring subsequent early childhood respiratory morbidity have been small or focused on hospital admissions.

Aims: To examine early childhood rates of primary care consultations for respiratory tract infections (RTI), lower respiratory tract infections (LRTI), wheeze and antibiotic prescriptions in ex-preterm and term children.

Epidemiology of bronchiectasis in the UK: Findings from the British lung foundation's 'Respiratory health of the nation' project.

Key findings of this national survey of non-cystic fibrosis bronchiectasis epidemiology were that its prevalence, incidence and mortality have all increased over recent years; we estimate that around 212,000 people are currently living with bronchiectasis in the UK, very much higher than commonly quoted figures. Bronchiectasis is more common in females than males; 60% of diagnoses are made in the over-70 age group. Regional differences in prevalence, incidence, mortality, and hospital admission were identified.

Predicting fracture risk in patients with chronic obstructive pulmonary disease: a UK-based population-based cohort study.

Objective: To assess the incidence of hip fracture and all major osteoporotic fractures (MOF) in patients with chronic obstructive pulmonary disease (COPD) compared with non-COPD patients and to evaluate the use and performance of fracture risk prediction tools in patients with COPD. To assess the prevalence and incidence of osteoporosis.

Design: Population-based cohort study.

Assessment of discharge treatment prescribed to women admitted to hospital for hyperemesis gravidarum.

Aims: Prescribing drug treatment for the management of hyperemesis gravidarum (HG), the most severe form of nausea and vomiting in pregnancy, remains controversial. Since most manufacturers do not recommend prescribing antiemetics during pregnancy, little is known regarding which treatments are most prevalent among pregnant patients. Here, we report for the first time, evidence of actual treatments prescribed in English hospitals.

Linkage of national soil quality measurements to primary care medical records in England and Wales: a new resource for investigating environmental impacts on human health.

Background: Long-term, low-level exposure to toxic elements in soil may be harmful to human health but large longitudinal cohort studies with sufficient follow-up time to study these effects are cost-prohibitive and impractical. Linkage of routinely collected medical outcome data to systematic surveys of soil quality may offer a viable alternative.

Methods: We used the Geochemical Baseline Survey of the Environment (G-BASE), a systematic X-ray fluorescence survey of soil inorganic chemistry throughout England and Wales to obtain estimates of the concentrations of 15 elements in the soil contained within each English and Welsh postcode area.

Mitochondrial ROS cause motor deficits induced by synaptic inactivity: Implications for synapse pruning.

Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles.

Risk of fall in patients with COPD.

A matched cohort study was conducted to determine the incidence of falls in patients following a diagnosis of COPD using a UK primary care database. 44 400 patients with COPD and 175 545 non-COPD subjects were identified. The incidence rate of fall per 1000 person-years in patients with COPD was higher (44.

The recording and characteristics of pulmonary rehabilitation in patients with COPD using The Health Information Network (THIN) primary care database.

Unlabelled: Pulmonary rehabilitation is recommended for patients with COPD to improve physical function, breathlessness and quality of life. Using The Health Information Network (THIN) primary care database in UK, we compared the demographic and clinical parameters of patients with COPD in relation to coding of pulmonary rehabilitation, and to investigate whether there is a survival benefit from pulmonary rehabilitation. We identified patients with COPD, diagnosed from 2004 and extracted information on demographics, pulmonary rehabilitation and clinical parameters using the relevant Read codes.

Timing of onset of symptoms in people with idiopathic pulmonary fibrosis.

Little is known about when symptoms of idiopathic pulmonary fibrosis first develop. We identified incident cases of idiopathic pulmonary fibrosis-clinical syndrome (IPF-CS) from a UK primary care database and assessed the frequency of consultations for common symptoms in the 5 years prior to diagnosis. 1671 cases were identified with 5 years of data prior to diagnosis.

Adverse Maternal and Birth Outcomes in Women Admitted to Hospital for Hyperemesis Gravidarum: a Population-Based Cohort Study.

Background: Evidence for risks of adverse maternal and birth outcomes in women with hyperemesis gravidarum (HG) is predominantly from small studies, unknown, or conflicting.

Methods: A population-based cohort study using secondary health care records (Hospital Episode Statistics covering all of England from 1997 to 2012) was used to calculate odds ratios (OR) with 99% confidence intervals (CI) for the association between HG hospital admission and adverse outcomes, adjusting for maternal and pregnancy confounders.

Results: Within 8 211 850 pregnancies ending in live births or stillbirths, women with HG had increased odds of anaemia (OR 1.

Discovery of Spirocyclic Aldosterone Synthase Inhibitors as Potential Treatments for Resistant Hypertension.

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.

Discovery of novel non-steroidal reverse indole mineralocorticoid receptor antagonists.

Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure-activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound that demonstrated efficacy in an acute natriuresis rodent model comparable to marketed MR antagonists, spironolactone and eplerenone.

Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

A supervised adverse drug reaction signalling framework imitating Bradford Hill's causality considerations.

Big longitudinal observational medical data potentially hold a wealth of information and have been recognised as potential sources for gaining new drug safety knowledge. Unfortunately there are many complexities and underlying issues when analysing longitudinal observational data. Due to these complexities, existing methods for large-scale detection of negative side effects using observational data all tend to have issues distinguishing between association and causality.

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists.

Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure-activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.

Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety.

We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 μM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets.

What characteristics of primary care and patients are associated with early death in patients with lung cancer in the UK?

Background: The UK has poor lung cancer survival rates and high early mortality, compared to other countries. We aimed to identify factors associated with early death, and features of primary care that might contribute to late diagnosis.

Methods: All cases of lung cancer diagnosed between 2000 and 2013 were extracted from The Health Improvement Network database.

First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study.

Background: Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy.

Methods: We identified singleton children born to women aged 15-45 years between 1990 and 2010 from a large United Kingdom primary care database.