Assessment of the Operational Characteristics of Research Ethics Committees in Ghana.

There were eighteen Research Ethics Committees (RECs) operating in Ghana as of December 2019 but no empirical assessment of their operational characteristics had been conducted. We assessed the characteristics of Ghanaian RECs using an existing Self-Assessment Tool for RECs in Developing Countries. We present results from nine RECs that participated in this nation-wide assessment.

Beyond Optical Depth: Future Determination of Ionization History from the Cosmic Microwave Background.

We explore the fundamental limits to which reionization histories can be constrained using only large-scale cosmic microwave background (CMB) anisotropy measurements. The redshift distribution of the fractional ionization () affects the angular distribution of CMB polarization. We project constraints on the reionization history of the universe using low-noise full-sky temperature and E-mode measurements of the CMB.

Analytic Calculation of Covariance between Cosmological Parameters from Correlated Data Sets, with an Application to SPTpol.

Consistency checks of cosmological data sets are an important tool because they may suggest systematic errors or the type of modifications to ΛCDM necessary to resolve current tensions. In this work, we derive an analytic method for calculating the level of correlations between model parameters from two correlated cosmological data sets, which complements more computationally expensive simulations. This method is an extension of the Fisher analysis that assumes a Gaussian likelihood and a known data covariance matrix.

Current Status in the Discovery of Covalent Janus Kinase 3 (JAK3) Inhibitors.

The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases.

Evidence of galaxy cluster motions with the kinematic Sunyaev-Zel'dovich effect.

Using high-resolution microwave sky maps made by the Atacama Cosmology Telescope, we for the first time present strong evidence for motions of galaxy clusters and groups via microwave background temperature distortions due to the kinematic Sunyaev-Zel'dovich effect. Galaxy clusters are identified by their constituent luminous galaxies observed by the Baryon Oscillation Spectroscopic Survey, part of the Sloan Digital Sky Survey III. We measure the mean pairwise momentum of clusters, with a probability of the signal being due to random errors of 0.

Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines.

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases.

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution.

Long-term outcome of meningococcal sepsis-associated acute renal failure.

Setting: Twenty-one of 209 children admitted to the intensive care unit with meningococcal septicemia developed oliguric acute renal failure necessitating renal replacement therapy.

Patients: Twelve survivors underwent renal assessment at a median of 4.2 yrs postpresentation.

Longitudinal study of thyroid function in Down's syndrome in the first two decades.

Aims And Methods: Thyroid function tests were initially carried out on 122 children with Down's syndrome aged 6-14 years and then repeated four to six years later in 103 adolescents (85% of the group of 122) when they were aged 10-20 years (median 14.4 years). At the second test two were hypothyroid and two with isolated raised thyroid stimulating hormone (IR-TSH) were receiving thyroxine.

Does adjustment of GFR to extracellular fluid volume improve the clinical utility of cystatin C?

Background: Cystatin C measurement has been proposed as a replacement for creatinine as a serum measure of glomerular filtration rate (GFR). It has also been suggested that GFR itself should be adjusted to the extracellular fluid volume (ECV) of a child rather than the body surface area (BSA).

Aims: To assess the potential of cystatin C compared to serum creatinine in assessing GFR and to establish whether adjustment of GFR to ECV rather than BSA affects the potential usefulness of cystatin C.

Prenatal origin of acute lymphoblastic leukaemia in children.

Background: There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally.

Secondary analysis of economic data: a review of cost-benefit studies of neonatal screening for phenylketonuria.

Study Objective: To estimate the net financial benefit of neonatal screening for phenylketonuria (PKU): by a simple pooling of cost data from the literature; and by a more complex modelling approach.

Design: A systematic literature review was conducted to identify papers containing data on the monetary costs and benefits of neonatal screening for PKU. The methodological quality of the studies was appraised, and data were extracted on resource use and expenditure.

Plasma 1,5-anhydroglucitol concentrations are influenced by variations in the renal threshold for glucose.

Aims: Measurement of serum 1,5-anhydroglucitol (1,5AG) concentrations has been proposed as an alternative to HbA1c as both a marker of diabetic glycaemic control and as a screening test for diabetes. The sugar competes with glucose for renal tubular reabsorption, so hyperglycaemia leads to reduced serum 1,5AG concentrations through increased urinary loss. This study has sought to establish whether plasma 1,5AG can be influenced by not only hyperglycaemia, but by variations in renal threshold for glucose.

Linear growth in prepubertal children with atopic dermatitis.

Objective: To define the evolution of prepubertal growth in atopic dermatitis and the factors influencing that growth pattern.

Methods: Height and height velocity over two years, weight, triceps and subscapular skin fold thickness, and bone age were assessed in 80 prepubertal patients with atopic dermatitis and a control group of 71 healthy prepubertal school children.

Results: Height standard deviation scores (SDS) and height velocity SDS did not differ between patients and controls, and were not influenced by body surface area affected by atopic dermatitis, topical glucocorticoid potency, or coexisting asthma.

A systematic review of evidence for the appropriateness of neonatal screening programmes for inborn errors of metabolism.

Background: Developments in screening technology and increased understanding of the natural history and treatment of inborn errors of metabolism (IEMs) have produced pressure to extend neonatal screening programmes. This review aims to assess the evidence for the appropriateness of such programmes.

Methods: A formal systematic literature review was conducted.

Urinary IGF and IGF binding protein-3 in children with disordered growth. The North West Paediatric Endocrine Group.

Objective: Both IGF-I and IGFBP-3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF-I and IGFBP-3 measurements in the diagnosis of children with disordered growth.

Design: Serum IGF-I and IGFBP-3 radioimmunoassays (RIA) were developed, and modified for quantitation in urine.

Newborn screening for inborn errors of metabolism: a systematic review.

OBJECTIVES. To establish a database of literature and other evidence on neonatal screening programmes and technologies for inborn errors of metabolism. To undertake a systematic review of the data as a basis for evaluation of newborn screening for inborn errors of metabolism.

Changes in the urinary excretion of creatinine, albumin and N-acetyl-beta-D-glucosaminidase with increasing age and maturity in healthy schoolchildren.

Unlabelled: Raised urinary levels of albumin and N-acetyl-beta-D-glucosaminidase (NAG) are predictive of abnormal renal function and excretion of these substances is often expressed as a creatinine ratio. However, it is important to establish normal reference limits of albumin and NAG excretion for comparison of values from patients. For this reason, overnight excretion rates of creatinine, albumin and NAG were determined in timed overnight urine samples from 528 healthy schoolchildren (260 boys, 268 girls; 4-16 years) of normal size.

Acute biochemical effects of growth hormone treatment compared with conventional treatment in familial hypophosphataemic rickets.

Objective: Conventional treatment of familial hypophosphaiaemic rickets with oral phosphate and 1 alpha-hydroxycholecalciferol (1 alpha HCC) does not satisfactorily correct the metabolic or physical defects of the disease and can have adverse effects, such as nephrocalcinosis. Hyperoxaluria from increased oral phosphate intake may contribute to nephrocalcinosis. Growth hormone enhances renal tubular phosphate reabsorption and 1,25-dihydroxy-cholecalciferol production in normal and in GH deficient individuals, and may thus be of benefit to patients with familial hypophosphataemic rickets.

Insulin-like growth factor binding protein-3 generation: an index of growth hormone insensitivity.

GH insensitivity may be an inherited condition or may arise as a consequence of disease of malnutrition. Laron syndrome is the most severe form of GH insensitivity, arising from an absent or defective GH receptor. Less severe forms of GH insensitivity, however, may exist, resulting in short stature but in few other features of Laron syndrome.

Infradian rhythms in urinary growth hormone excretion.

All studies of urinary GH excretion in normal and disordered growth have revealed marked day to day (infradian) variation. We used serial overnight urinary GH estimations as an indirect measure of endogenous GH secretion in eight normal prepubertal children (aged 3.6-7.