Diarrhea is a Major killer of Children with Severe Acute Malnutrition Admitted to Inpatient Set-up in Lusaka, Zambia

<p>Abstract</p> <p>Introduction</p> <p>Mortality of children with Severe Acute Malnutrition (SAM) in inpatient set-ups in sub-Saharan Africa still remains unacceptably high. We investigated the prevalence and effect of diarrhea and HIV infection on inpatient treatment outcome of children with complicated SAM receiving treatment in inpatient units.</p> <p>Method</p> <p>A cohort of 430 children aged 6-59 months old with complicated SAM admitted to Zambia University Teaching Hospital's stabilization centre from August to December 2009 were followed. Data on nutritional status, socio-demographic factors, and admission medical conditions were collected up on enrollment. T-test and chi-square tests were used to compare difference in mean or percentage values. Logistic regression was used to assess risk of mortality by admission characteristics.</p> <p>Results</p> <p>Majority, 55.3% (238/430) were boys. The median age of the cohort was 17 months (inter-quartile range, IQR 12-22). Among the children, 68.9% (295/428) had edema at admission. The majority of the children, 67.3% (261/388), presented with diarrhea; 38.9% (162/420) tested HIV positive; and 40.5% (174/430) of the children died. The median Length of stay of the cohort was 9 days (IQR, 5-14 days); 30.6% (53/173) of the death occurred within 48 hours of admission. Children with diarrhea on admission had two and half times higher odds of mortality than those without diarrhea; Adjusted OR = 2.5 (95% CI 1.50-4.09, P < 0.001). The odds of mortality for children with HIV infection was higher than children without HIV infection; Adjusted OR = 1.6 (95% CI 0.99-2.48 P = 0.5).</p> <p>Conclusion</p> <p>Diarrhea is a major cause of complication in children with severe acute malnutrition. Under the current standard management approach, diarrhea in children with SAM was found to increase their odds of death substantially irrespective of other factors.</p

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

Columnar cell lesions and subsequent breast cancer risk: a nested case-control study

Introduction: Histologic and genetic evidence suggests that at least some columnar cell lesions (CCL) of the breast represent precursor lesions in the low-grade breast neoplasia pathway. However, the risk of subsequent breast cancer associated with the presence of CCL in a benign breast biopsy is poorly understood.Methods The authors examined the association between the presence of CCL and subsequent breast cancer risk in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies (394 cases, 1,606 controls). Benign breast biopsy slides were reviewed by pathologists and CCL presence assessed. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the association between CCL and breast cancer risk. Results: Women with CCL (140 cases, 448 controls) had an increased risk of breast cancer compared with those without CCL (OR = 1.44, 95% CI: 1.14 to 1.83), although this was attenuated and became non-significant after adjustment for the histologic category of BBD (OR = 1.20, 95% CI: 0.94 to 1.54). CCL presence was associated with the greatest risk of breast cancer for those with nonproliferative BBD (OR = 1.36, 95% CI: 0.79 to 2.37) and the lowest risk for those with atypical hyperplasia (AH) (OR = 1.10, 95% CI: 0.65 to 1.87); however, this apparent heterogeneity in risk across BBD categories was not significant (P for interaction between CCL presence and BBD category = 0.77). Conclusions: These results provide evidence that CCL may be an important marker of breast cancer risk in women with BBD but suggest that CCL do not increase breast cancer risk independently of concurrent proliferative changes in the breast

Phosphine Resistance in the Rust Red Flour Beetle, Tribolium castaneum (Coleoptera: Tenebrionidae): Inheritance, Gene Interactions and Fitness Costs

The recent emergence of heritable high level resistance to phosphine in stored grain pests is a serious concern among major grain growing countries around the world. Here we describe the genetics of phosphine resistance in the rust red flour beetle Tribolium castaneum (Herbst), a pest of stored grain as well as a genetic model organism. We investigated three field collected strains of T. castaneum viz., susceptible (QTC4), weakly resistant (QTC1012) and strongly resistant (QTC931) to phosphine. The dose-mortality responses of their test- and inter-cross progeny revealed that most resistance was conferred by a single major resistance gene in the weakly (3.2×) resistant strain. This gene was also found in the strongly resistant (431×) strain, together with a second major resistance gene and additional minor factors. The second major gene by itself confers only 12–20× resistance, suggesting that a strong synergistic epistatic interaction between the genes is responsible for the high level of resistance (431×) observed in the strongly resistant strain. Phosphine resistance is not sex linked and is inherited as an incompletely recessive, autosomal trait. The analysis of the phenotypic fitness response of a population derived from a single pair inter-strain cross between the susceptible and strongly resistant strains indicated the changes in the level of response in the strong resistance phenotype; however this effect was not consistent and apparently masked by the genetic background of the weakly resistant strain. The results from this work will inform phosphine resistance management strategies and provide a basis for the identification of the resistance genes

The rph1 Gene Is a Common Contributor to the Evolution of Phosphine Resistance in Independent Field Isolates of Rhyzopertha Dominica

Phosphine is the only economically viable fumigant for routine control of insect pests of stored food products, but its continued use is now threatened by the world-wide emergence of high-level resistance in key pest species. Phosphine has a unique mode of action relative to well-characterised contact pesticides. Similarly, the selective pressures that lead to resistance against field sprays differ dramatically from those encountered during fumigation. The consequences of these differences have not been investigated adequately. We determine the genetic basis of phosphine resistance in Rhyzopertha dominica strains collected from New South Wales and South Australia and compare this with resistance in a previously characterised strain from Queensland. The resistance levels range from 225 and 100 times the baseline response of a sensitive reference strain. Moreover, molecular and phenotypic data indicate that high-level resistance was derived independently in each of the three widely separated geographical regions. Despite the independent origins, resistance was due to two interacting genes in each instance. Furthermore, complementation analysis reveals that all three strains contain an incompletely recessive resistance allele of the autosomal rph1 resistance gene. This is particularly noteworthy as a resistance allele at rph1 was previously proposed to be a necessary first step in the evolution of high-level resistance. Despite the capacity of phosphine to disrupt a wide range of enzymes and biological processes, it is remarkable that the initial step in the selection of resistance is so similar in isolated outbreaks

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201

Interventions for families affected by HIV

Family-based interventions are efficacious for human immunodeficiency virus (HIV) detection, prevention, and care, but they are not broadly diffused. Understanding intervention adaptation and translation processes can support evidence-based intervention (EBI) diffusion processes. This paper provides a narrative review of a series of EBI for families affected by HIV (FAH) that were adapted across five randomized controlled trials in the US, Thailand, and South Africa over 15 years. The FAH interventions targeted parents living with HIV and their children or caregiver supports. Parents with HIV were primarily mothers infected through sexual transmission. The EBIs for FAH are reviewed with attention to commonalities and variations in risk environments and intervention features. Frameworks for common and robust intervention functions, principles, practice elements, and delivery processes are utilized to highlight commonalities and adaptations for each location, time period, and intervention delivery settings. Health care, housing, food, and financial security vary dramatically in each risk environment. Yet, all FAH face common health, mental health, transmission, and relationship challenges. The EBIs efficaciously addressed these common challenges and were adapted across contexts with fidelity to robust intervention principles, processes, factors, and practices. Intervention adaptation teams have a series of structural decision points: mainstreaming HIV with other local health priorities or not; selecting an optimal delivery site (clinics, homes, community centers); and how to translate intervention protocols to local contexts and cultures. Replication of interventions with fidelity must occur at the level of standardized functions and robust principles, processes, and practices, not manualized protocols. Adopting a continuous quality improvement paradigm will enhance rapid and global diffusion of EBI for FAH

Significantly Longer Envelope V2 Loops Are Characteristic of Heterosexually Transmitted Subtype B HIV-1 in Trinidad

In Trinidad and the wider Caribbean, subtype B Human Immunodeficiency Virus-type 1 (HIV-1B) overwhelmingly accounts for HIV infection among heterosexuals; this contrasts with the association of HIV-1B with homosexual transmission and injecting drug use globally. The HIV envelope contains genetic determinants of cell tropism and evasion from immune attack. In this study we investigate the genetic properties of the env V1-C4 of HIV-1B soon after transmission to Trinidadian heterosexuals. This will reveal distinctive genetic features of the strains that cause the HIV-1B epidemic in Trinidad and generate insights to better understand their properties.Quasispecies sampling was performed on the env V1-C4 of HIV-1B strains soon after transmission to heterosexual Trinidadians in a cohort of seroconverters. Phylogenetic relationships were determined for these quasispecies and the length and number of asparagine (N) linked glycosylation sites (NLGS) in their variable loops compared to that for HIV-1B globally. Signature amino acids within the constant domains of the env V1-C4 were identified for heterosexually transmitted HIV-1B from Trinidad relative to HIV-1B globally. HIV-1B obtained from Trinidadian heterosexuals soon after seroconversion had significantly longer V2 loops with one more glycosylation site, shorter V3 loops and no significant difference in V1 or V4 when compared to HIV-1B obtained soon after seroconversion from infected individuals in the rest of the world. HIV-1B soon after seroconversion and during chronic infection of Trinidadians was not significantly different, suggesting that distinctly long V2 loops are characteristic of HIV-1B in Trinidad. A threonine deletion at position 319 (T319-) along with the substitutions R315K and S440R were found to be distinctly associated with HIV-1B from Trinidad compared to HIV-1B globally.This finding of distinctive genetic features that are characteristic of HIV-1B strains from Trinidad is consistent with the Trinidad epidemic being established by a founder strain or closely related founder strains of HIV-1B

Clinical factors associated with fatigue over time in paediatric oncology patients receiving chemotherapy

The purpose of this study was to investigate the relationships between clinical factors (including haemoglobin value, chemotherapeutic agents, and corticosteroid use) and changing patterns of fatigue before and for the next 10 days following the start of a new round of chemotherapy in children with cancer. A prospective longitudinal design was used to collect data from 48 paediatric oncology patients who were about to begin a new round of chemotherapy and their parents. Fatigue levels were assessed using multidomain questionnaires with three categories of patient self-report (including ‘General Fatigue', ‘Sleep/Rest Fatigue', and ‘Cognitive Fatigue') and four categories of parent proxy-report (including ‘Lack of Energy', ‘Unable to Function', ‘Altered Sleep', and ‘Altered Mood'). The findings suggest that fatigue from both patient self-report and parent proxy-report changed significantly over time. The major findings from this study are that patients have more problems with fatigue in the first few days after the start of a cycle of chemotherapy. Corticosteroid use and haemoglobin value were associated with significant increases in fatigue that were sustained for several days and reached the highest level of fatigue at day 5 for those receiving concurrent steroids. The association of chemotherapeutic agents with fatigue varied between patient self-report and parent report, but the type of chemotherapeutic agents used was not associated with most changes in fatigue