The Proportion of Diploid 46,XX Cells Increases with Time in Women with Turner Syndrome-A 10-Year Follow-Up Study

In the normal population, loss of one of the sex chromosomes leading to monosomy (45,X) is a part of the aging process. In Turner syndrome (TS), the classic karyotype 45,X is found in up to 50% at birth, and others have a second cell line; mosaicism. The aim was to study if the chromosomal pattern in TS women changes over time. Fluorescence in situ hybridization was performed on buccal smear cells obtained twice, 10 years apart, from 42 women with TS aged 26-66 years (mean +/- standard deviation: 42.0 +/- 11.6). DNA probes specific for chromosomes X (DXZ1) and Y (DYZ3) were used and >100 cells were analyzed/patient. Nineteen women had monosomy (45,X) (<10% 46,XX), nine had 45,X/46,XX mosaicism, and 14 had iso, ring, or a marker chromosome at baseline. At 10 years, the percentage of diploid cells had increased in 29 of 42 women (69%), with an average increase of 5.7 +/- 13.0%. There was a positive correlation between age and % change in diploid 46,XX or 46,XY cells (r=0.38, p=0.023). This new finding might have relevance for the life expectancy in TS

Feasibility of engaging caregivers in at‐home surveillance of children with uncomplicated severe acute malnutrition

Abstract Many factors can contribute to low coverage of treatment for severe acute malnutrition (SAM), and a limited number of health facilities and trained personnel can constrain the number of children that receive treatment. Alternative models of care that shift the responsibility for routine clinical and anthropometric surveillance from the health facility to the household could reduce the burden of care associated with frequent facility‐based visits for both healthcare providers and caregivers. To assess the feasibility of shifting clinical surveillance to caregivers in the outpatient management of SAM, we conducted a pilot study to assess caregivers' understanding and retention of key concepts related to the surveillance of clinical danger signs and anthropometric measurement over a 28‐day period. At the time of a child's admission to nutritional treatment, a study nurse provided a short training to groups of caregivers on two topics: (a) clinical danger signs in children with SAM that warrant facility‐based care and (b) methods to measure and monitor their child's mid‐upper arm circumference. Caregiver understanding was assessed using standardized questionnaires before training, immediately after training, and 28 days after training. Knowledge of most clinical danger signs (e.g., convulsions, edema, poor appetite, respiratory distress, and lethargy) was low (0–45%) before training but increased immediately after and was retained 28 days after training. Agreement between nurse–caregiver mid‐upper arm circumference colour classifications was 77% (98/128) immediately after training and 80% after 28 days. These findings lend preliminary support to pursue further study of alternative models of care that allow for greater engagement of caregivers in the clinical and anthropometric surveillance of children with SAM

MUAC as the sole discharge criterion from community‐based management of severe acute malnutrition in Burkina Faso

The use of mid upper arm circumference (MUAC) measurement to screen and determine eligibility for admission to therapeutic feeding programs has been established, but evidence and programmatic experience to inform guidance on the use of MUAC as a discharge criterion is limited. We present results from a large‐scale nutritional program using MUAC for admission and discharge and compare program outcomes and response to treatment when determining eligibility for discharge by proportional weight gain versus discharge by MUAC. The study population included all children admitted to the Ministry of Health therapeutic feeding program supported by Médecins Sans Frontières in northern Burkina Faso from September 2007 to December 2011 (n = 50,841). Recovery was high overall using both discharge criteria, with low risks of death, nonresponse, and transfer to inpatient care and high daily gains in weight, MUAC, weight‐for‐height Z score, and height. When discharge was made by MUAC only, recovery increased, while all adverse program outcomes and length of stay decreased, with increasing MUAC on admission. MUAC‐based programming, where MUAC is integrated into program screening, admission, and discharge, is one of several new approaches that can be used to target resources to the most at‐risk malnourished children and improve program efficiency and coherency. This analysis provides additional programmatic experience on the use of MUAC‐based discharge criterion, but more work may be needed to inform optimal discharge thresholds across settings

Hand hygiene compliance and environmental contamination with gram-negative bacilli in a rural hospital in Madarounfa, Niger

Abstract Background Healthcare-associated infections pose a major, yet often preventable risk to patient safety. Poor hand hygiene among healthcare personnel and unsanitary hospital environments may contribute to this risk in low-income settings. We aimed to describe hand hygiene behaviour and environmental contamination by season in a rural, sub-Saharan African hospital setting. Methods We conducted a concurrent triangulation mixed-methods study combining three types of data at a hospital in Madarounfa, Niger. Hand hygiene observations among healthcare personnel during two seasons contributed quantitative data describing hand hygiene frequency and its variability in relation to seasonal changes in caseload. Semistructured interviews with healthcare personnel contributed qualitative data on knowledge, attitudes and barriers to hand hygiene. Biweekly environmental samples evaluated microbial contamination from October 2016 to December 2017. Triangulation identified convergences, complements and contradictions across results. Results Hand hygiene compliance, or the proportion of actions (handrubbing or handwashing) performed out of all actions required, was low (11% during non-peak and 36% during peak caseload seasons). Interviews with healthcare personnel suggesting good general knowledge of hand hygiene contradicted the low hand hygiene compliance. However, compliance by healthcare activity was convergent with poor knowledge of precise hand hygiene steps and the motivation to prevent personal acquisition of infection identified during interviews. Contamination of environmental samples with gram-negative bacilli was high (45%), with the highest rates of contamination observed during the peak caseload season. Conclusion Low hand hygiene compliance coupled with high contamination rates of hospital environments may increase the risk of hospital-acquired infections in sub-Saharan African settings. </jats:sec

Relapse and regression to severe wasting in children under 5 years: A theoretical framework.

Systematic reviews have highlighted that repeated severe wasting after receiving treatment is likely to be common, but standardised measurement is needed urgently. The Council of Research & Technical Advice for Acute Malnutrition (CORTASAM) released recommendations on standard measurement of relapse (wasting within 6 months after exiting treatment as per recommended discharge criteria), regression (wasting within 6 months after exiting treatment before reaching recommended discharge criteria) and reoccurrence (wasting after 6 months of exit from treatment as per recommended discharge criteria). We provide a theoretical framework of post-treatment relapse and regression to severe wasting to guide discussions, risk factor analyses, and development and evaluations of interventions. This framework highlights that there are factors that may impact risk of relapse and regression in addition to the impact of contextual factors associated with incidence and reoccurrence of severe wasting more generally. Factors hypothesised to be associated with relapse and regression relate specifically to the nutrition and health status of the child on admission to, during and exit from treatment and treatment interventions, platforms and approaches as well as type of exit from treatment (e.g., before reaching recommended criteria). These factors influence whether children reach full recovery, and poorer nutritional and immunological status at exit from treatment are more proximate determinants of risk of severe wasting after treatment, although post-treatment interventions may modify risks. The evidence base for many of these factors is weak. Our framework can guide research to improve our understanding of risks of relapse and regression and how to prevent them and inform programmes on what data to collect to evaluate relapse. Implementation research is needed to operationalise results in programmes and reduce post-treatment severe wasting at scale

Treatment of child wasting: results of a child health and nutrition research initiative (CHNRI) prioritisation exercise

Background: Child wasting is highly prevalent, with around 49.5 million children under five years affected globally. More evidence is needed to inform the scale up of effective treatment of wasted children worldwide. The aim of this study was to identify and prioritise the main outstanding research questions relating to the treatment of wasting to inform future research agendas. Methods: A research prioritisation exercise was undertaken using the Child Health and Nutrition Research Initiative method. Research gaps were identified from multiple sources, grouped in themes and condensed into a list of 53 research areas by a group of experts. An online survey was developed and circulated globally to individuals working in the global nutrition sector. Participants evaluated each research area according to four agreed criteria. Research areas were then ranked according to an overall research priority score. Results: A total of 394 individuals from 63 countries participated in the survey. Research areas prioritised by the group focused on the effective detection and diagnosis of ‘high risk’ wasted children in the community; provision of a continuum of care; and early life course interventions. The group also prioritised evidence to inform guidance on the impatient management of wasted children with diarrhoea; prevention of post-treatment relapse and mortality; and the optimisation of ready-to-use therapeutic foods in treatment programmes. Conclusions: Critical gaps in our understanding of the treatment of wasting must be filled to inform guidance, policy and programming to ensure that all wasted children receive the treatment services that they need. A coordinated research agenda across treatment and prevention is urgently needed to maximise the impact of funding investments towards the meeting of global targets to reduce child wasting

The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels

Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a similar to 10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs-the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heartderived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity

Low mid-upper arm circumference identifies children with a high risk of death who should be the priority target for treatment

Background: Severe acute malnutrition (SAM) is currently defined by the WHO as either a low mid-upper arm circumference (i.e. MUAC <115 mm), a low weight-for-height z-score (i.e. WHZ <- 3), or bilateral pitting oedema. MUAC and WHZ do not always identify the same children as having SAM. This has generated broad debate, as illustrated by the recent article by Grellety & Golden (BMC Nutr. 2016;2:10). Discussion: Regional variations in the proportion of children selected by each index seem mostly related to differences in body shape, including stuntedness. However, the practical implications of these variations in relation to nutritional status and also to outcome are not clear. All studies that have examined the relationship between anthropometry and mortality in representative population samples in Africa and in Asia have consistently showed that MUAC is more sensitive at high specificity levels than WHZ for identifying children at high risk of death. Children identified as SAM cases by low MUAC gain both weight and MUAC in response to treatment. The widespread use of MUAC has brought enormous benefits in terms of the coverage and efficiency of programs. As a large high-risk group responding to treatment, children with low MUAC should be regarded as a public health priority independently of their WHZ. Conclusion: While a better understanding of the mechanism behind the discrepancy between MUAC and WHZ is desirable, research in this area should not delay the implementation of programs aiming at effectively reducing malnutrition-related deaths by prioritising the detection and treatment of children with low MUAC

Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study

<p>Abstract</p> <p>Background</p> <p>Liver X receptor alpha <it>(LXRA</it>) and beta (<it>LXRB</it>) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in <it>LXRA </it>and <it>LXRB </it>associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.</p> <p>Methods</p> <p>Eight common single nucleotide polymorphisms in <it>LXRA </it>and <it>LXRB </it>were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMA_IRas measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal <it>LXRB </it>promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to <it>in silico </it>analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.</p> <p>Results</p> <p>Genotypes at two <it>LXRB </it>promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No <it>LXRA </it>or <it>LXRB </it>SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the <it>LXRB </it>gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.</p> <p>Conclusion</p> <p>Variations in the <it>LXRB </it>gene promoter may be part of the aetiology of T2D. However, the association between <it>LXRB </it>rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in <it>LXRA </it>is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.</p