UK paediatric trainee research involvement: A national mixed-methods survey to highlight opportunities and challenges [Letter]

Child health research is considered essential to paediatric training. However, due to service provision demands and workforce planning, research capacity within paediatric consultant contracts is declining.1 This affects paediatric trainees who perceive lack of leadership in this domain.2 Considering these concerns, in 2021, the Royal College of Paediatrics and Child Health (RCPCH) established the Trainee Research Network (TRN) to support regional research. To broadly evaluate trainee participation in research as a marker of future UK research capacity, we conducted a national survey of trainees’ experiences to help identify the breadth of research involvement and to identify barriers and facilitators to participation

The Case for Visual Analytics of Arsenic Concentrations in Foods

Arsenic is a naturally occurring toxic metal and its presence in food could be a potential risk to the health of both humans and animals. Prolonged ingestion of arsenic contaminated water may result in manifestations of toxicity in all systems of the body. Visual Analytics is a multidisciplinary field that is defined as the science of analytical reasoning facilitated by interactive visual interfaces. The concentrations of arsenic vary in foods making it impractical and impossible to provide regulatory limit for each food. This review article presents a case for the use of visual analytics approaches to provide comparative assessment of arsenic in various foods. The topics covered include (i) metabolism of arsenic in the human body; (ii) arsenic concentrations in various foods; (ii) factors affecting arsenic uptake in plants; (ii) introduction to visual analytics; and (iv) benefits of visual analytics for comparative assessment of arsenic concentration in foods. Visual analytics can provide an information superstructure of arsenic in various foods to permit insightful comparative risk assessment of the diverse and continually expanding data on arsenic in food groups in the context of country of study or origin, year of study, method of analysis and arsenic species

Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo

To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m-arsenite (As3+) on microtubule (MT) assembly in vitro (0–40 µM), in cultured rat lung fibroblasts (RFL6, 0–20 µM for 24 h) and in the rat animal model (intratracheal instillation of 2.02 mg As/kg body weight, once a week for 5 weeks). As3+ induced a dose-dependent disassembly of cellular MTs and enhancement of the free tubulin pool, initiating an autoregulation of tubulin synthesis manifest as inhibition of steady-state mRNA levels of βI-tubulin in dosed lung cells and tissues. Spindle MT injuries by As3+ were concomitant with chromosomal disorientations. As3+ reduced the binding to tubulin of [3H]N-ethylmaleimide (NEM), an -SH group reagent, resulting in inhibition of MT polymerization in vitro with bovine brain tubulins which was abolished by addition of dithiothreitol (DTT) suggesting As3+ action upon tubulin through -SH groups. In response to As3+, cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As3+ and NEM induced MT depolymerization. MT–associated proteins (MAPs) essential for the MT stability were markedly suppressed in As3+-treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As3+ damage to the lung triggering MT disassembly cascades

A guide to writing systematic reviews of rare disease treatments to generate FAIR-compliant datasets: Building a Treatabolome

Background: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families. Aims: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD. Results: Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence. Conclusions: This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments

Estimating glomerular filtration rate in diabetes: a comparison of cystatin-C-and creatinine-based methods

Abstract Aims/hypothesis: We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes. Subjects, materials and methods: In a crosssectional study of 251 consecutive clinic patients, the mean reference (plasma clearance of 99m Tc-diethylene-triaminepenta-acetic acid) GFR (iGFR) was 88±2 ml min . A regression equation describing the relationship between iGFR and 1/cystatin C levels was derived from a test population (n=125) to allow for the estimation of GFR by cystatin C (eGFR-cystatin C). The predictive performance of eGFR-cystatin C, the Modification of Diet in Renal Disease 4 variable formula (MDRD-4) and Cockcroft-Gault (C-G) formulas were then compared in a validation population (n=126). Results: There was no difference in renal function (ml min −1 1.73 m −

Care for perinatal illness in rural Nepal: a descriptive study with cross-sectional and qualitative components

BACKGROUND: Maternal, perinatal and neonatal mortality rates remain high in rural areas of developing countries. Most deliveries take place at home and care-seeking behaviour is often delayed. We report on a combined quantitative and qualitative study of care seeking obstacles and practices relating to perinatal illness in rural Makwanpur district, Nepal, with particular emphasis on consultation strategies. METHODS: The analysis included a survey of 8798 women who reported a birth in the previous two years [of whom 3557 reported illness in their pregnancy], on 30 case studies of perinatal morbidity and mortality, and on 43 focus group discussions with mothers, other family members and health workers. RESULTS: Early pregnancy was often concealed, preparation for birth was minimal and trained attendance at birth was uncommon. Family members were favoured attendants, particularly mothers-in-law. The most common recalled maternal complications were prolonged labour, postpartum haemorrhage and retained placenta. Neonatal death, though less definable, was often associated with cessation of suckling and shortness of breath. Many home-based care practices for maternal and neonatal illness were described. Self-medication was common. There were delays in recognising and acting on danger signs, and in seeking care beyond the household, in which the cultural requirement for maternal seclusion, and the perceived expense of care, played a part. Of the 760 women who sought care at a government facility, 70% took more than 12 hours from the decision to seek help to actual consultation. Consultation was primarily with traditional healers, who were key actors in the ascription of causation. Use of the government primary health care system was limited: the most common source of allopathic care was the district hospital. CONCLUSIONS: Major obstacles to seeking care were: a limited capacity to recognise danger signs; the need to watch and wait; and an overwhelming preference to treat illness within the community. Safer motherhood and newborn care programmes in rural communities, must address both community and health facility care to have an impact on morbidity and mortality. The roles of community actors such as mothers-in-law, husbands, local healers and pharmacies, and increased access to properly trained birth attendants need to be addressed if delays in reaching health facilities are to be shortened

Staff perspectives of barriers to women accessing birthing services in Nepal: A qualitative study

Background: Nepal has made significant progress with regard to reducing the maternal mortality ratio but a major challenge remains the under-utilisation of skilled birth attendants who are predominantly facility based. Studies have explored women's views of the barriers to facility birth; however the voices of staff who offer services have not been studied in detail. This research explores the views of staff as to the key reasons why pregnant women do not give birth in a maternity-care facility. Methods: This mixed methods study comprised qualitative interviews and non-participant observation. The study was conducted in two small non-governmental hospitals, one semi-rural and one urban, in Kathmandu Valley. Twenty interviews were conducted with health care providers and other staff in these hospitals. The interviews were undertaken with the aid of a Nepali translator, with some interviews being held in English. Twenty-five hours of non-participant observation was conducted in both maternity hospitals . Both observation and interview data were analysed thematically. Ethical approval was granted by the Nepal Research Health Council and Bournemouth University's Ethics Committee. Results: Key themes that emerged from the analysis reflected barriers that women experience in accessing services at different conceptual levels and resembled the three phases of delay model by Thaddeus and Maine. This framework is used to present the barriers. First Phase Delays are: 1) lack of awareness that the facility/services exist; 2) women being too busy to attend; 3) poor services; 4) embarrassment; and 5) financial issues. Themes for the second Phase of Delay are: 1) birthing on the way; and 2) by-passing the facility in favour of one further away. The final Phase involved: 1) absence of an enabling environment; and 2) disrespectful care. Conclusion: This study highlights a multitude of barriers, not all of the same importance or occuring at the same time in the pregnancy journey. It is clear that staff are aware of many of the barriers for women in reaching the facility to give birth, and these fit with previous literature of women's views. However, staff had limited insight into barriers occuring within the facility itself and were more likely to suggest that this was a problem for other institutions and not theirs

Protective Role of Taurine against Arsenic-Induced Mitochondria-Dependent Hepatic Apoptosis via the Inhibition of PKCδ-JNK Pathway

BACKGROUND: Oxidative stress-mediated hepatotoxic effect of arsenic (As) is mainly due to the depletion of glutathione (GSH) in liver. Taurine, on the other hand, enhances intracellular production of GSH. Little is known about the mechanism of the beneficial role of taurine in As-induced hepatic pathophysiology. Therefore, in the present study we investigated its beneficial role in As-induced hepatic cell death via mitochondria-mediated pathway. METHODOLOGY/PRINCIPAL FINDINGS: Rats were exposed to NaAsO(2) (2 mg/kg body weight for 6 months) and the hepatic tissue was used for oxidative stress measurements. In addition, the pathophysiologic effect of NaAsO(2) (10 microM) on hepatocytes was evaluated by determining cell viability, mitochondrial membrane potential and ROS generation. As caused mitochondrial injury by increased oxidative stress and reciprocal regulation of Bcl-2, Bcl-xL/Bad, Bax, Bim in association with increased level of Apaf-1, activation of caspase 9/3, cleavage of PARP protein and ultimately led to apoptotic cell death. In addition, As markedly increased JNK and p38 phosphorylation with minimal disturbance of ERK. Pre-exposure of hepatocytes to a JNK inhibitor SP600125 prevented As-induced caspase-3 activation, ROS production and loss in cell viability. Pre-exposure of hepatocytes to a p38 inhibitor SB2035, on the other hand, had practically no effect on these events. Besides, As activated PKCdelta and pre-treatment of hepatocytes with its inhibitor, rottlerin, suppressed the activation of JNK indicating that PKCdelta is involved in As-induced JNK activation and mitochondrial dependent apoptosis. Oral administration of taurine (50 mg/kg body weight for 2 weeks) both pre and post to NaAsO(2) exposure or incubation of the hepatocytes with taurine (25 mM) were found to be effective in counteracting As-induced oxidative stress and apoptosis. CONCLUSIONS/SIGNIFICANCE: Results indicate that taurine treatment improved As-induced hepatic damages by inhibiting PKCdelta-JNK signalling pathways. Therefore taurine supplementation could provide a new approach for the reduction of hepatic complication due to arsenic poisoning