Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance

Multi-parallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming

BACKGROUND: Although chronic morbidity in humans from soil transmitted helminth (STH) infections can be reduced by anthelmintic treatment, inconsistent diagnostic tools make it difficult to reliably measure the impact of deworming programs and often miss light helminth infections. METHODS: Cryopreserved stool samples from 796 people (aged 2-81 years) in four villages in Bungoma County, western Kenya, were assessed using multi-parallel qPCR for 8 parasites and compared to point-of-contact assessments of the same stools by the 2-stool 2-slide Kato-Katz (KK) method. All subjects were treated with albendazole and all Ascaris lumbricoides expelled post-treatment were collected. Three months later, samples from 633 of these people were re-assessed by both qPCR and KK, re-treated with albendazole and the expelled worms collected. RESULTS: Baseline prevalence by qPCR (n = 796) was 17 % for A. lumbricoides, 18 % for Necator americanus, 41 % for Giardia lamblia and 15% for Entamoeba histolytica. The prevalence was <1% for Trichuris trichiura, Ancylostoma duodenale, Strongyloides stercoralis and Cryptosporidium parvum. The sensitivity of qPCR was 98% for A. lumbricoides and N. americanus, whereas KK sensitivity was 70% and 32%, respectively. Furthermore, qPCR detected infections with T. trichiura and S. stercoralis that were missed by KK, and infections with G. lamblia and E. histolytica that cannot be detected by KK. Infection intensities measured by qPCR and by KK were correlated for A. lumbricoides (r = 0.83, p < 0.0001) and N. americanus (r = 0.55, p < 0.0001). The number of A. lumbricoides worms expelled was correlated (p < 0.0001) with both the KK (r = 0.63) and qPCR intensity measurements (r = 0.60). CONCLUSIONS: KK may be an inadequate tool for stool-based surveillance in areas where hookworm or Strongyloides are common or where intensity of helminth infection is low after repeated rounds of chemotherapy. Because deworming programs need to distinguish between populations where parasitic infection is controlled and those where further treatment is required, multi-parallel qPCR (or similar high throughput molecular diagnostics) may provide new and important diagnostic information

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.DG is supported by the EU-FP7-SUPPRESSTEM project. SN-Z is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome Beit Fellow. For more information, please visit the publisher's website

Nucleotide Discrimination with DNA Immobilized in the MspA Nanopore

Nanopore sequencing has the potential to become a fast and low-cost DNA sequencing platform. An ionic current passing through a small pore would directly map the sequence of single stranded DNA (ssDNA) driven through the constriction. The pore protein, MspA, derived from Mycobacterium smegmatis, has a short and narrow channel constriction ideally suited for nanopore sequencing. To study MspA's ability to resolve nucleotides, we held ssDNA within the pore using a biotin-NeutrAvidin complex. We show that homopolymers of adenine, cytosine, thymine, and guanine in MspA exhibit much larger current differences than in α-hemolysin. Additionally, methylated cytosine is distinguishable from unmethylated cytosine. We establish that single nucleotide substitutions within homopolymer ssDNA can be detected when held in MspA's constriction. Using genomic single nucleotide polymorphisms, we demonstrate that single nucleotides within random DNA can be identified. Our results indicate that MspA has high signal-to-noise ratio and the single nucleotide sensitivity desired for nanopore sequencing devices

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer

Effects of lowering body temperature via hyperhydration, with and without glycerol ingestion and practical precooling on cycling time trial performance in hot and humid conditions

Background: Hypohydration and hyperthermia are factors that may contribute to fatigue and impairment of endurance performance. The purpose of this study was to investigate the effectiveness of combining glycerol hyperhydration and an established precooling technique on cycling time trial performance in hot environmental conditions.Methods: Twelve well-trained male cyclists performed three 46.4-km laboratory-based cycling trials that included two climbs, under hot and humid environmental conditions (33.3 ± 1.1°C; 50 ± 6% r.h.). Subjects were required to hyperhydrate with 25 g.kg-1 body mass (BM) of a 4°C beverage containing 6% carbohydrate (CON) 2.5 h prior to the time trial. On two occasions, subjects were also exposed to an established precooling technique (PC) 60 min prior to the time trial, involving 14 g.kg-1 BM ice slurry ingestion and applied iced towels over 30 min. During one PC trial, 1.2 g.kg-1 BM glycerol was added to the hyperhydration beverage in a double-blind fashion (PC+G). Statistics used in this study involve the combination of traditional probability statistics and a magnitude-based inference approach.Results: Hyperhydration resulted in large reductions (-0.6 to -0.7°C) in rectal temperature. The addition of glycerol to this solution also lowered urine output (330 ml, 10%). Precooling induced further small (-0.3°C) to moderate (-0.4°C) reductions in rectal temperature with PC and PC+G treatments, respectively, when compared with CON (0.0°C, P\u3c0.05). Overall, PC+G failed to achieve a clear change in cycling performance over CON, but PC showed a possible 2% (30 s, P=0.02) improvement in performance time on climb 2 compared to CON. This improvement was attributed to subjects\u27 lower perception of effort reported over the first 10 km of the trial, despite no clear performance change during this time. No differences were detected in any other physiological measurements throughout the time trial.Conclusions: Despite increasing fluid intake and reducing core temperature, performance and thermoregulatory benefits of a hyperhydration strategy with and without the addition of glycerol, plus practical precooling, were not superior to hyperhydration alone. Further research is warranted to further refine preparation strategies for athletes competing in thermally stressful events to optimize health and maximize performance outcomes

Adverse Drug Reactions in Children—A Systematic Review

Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided

Correlates of tobacco cessation counseling among Hispanic physicians in the US: a cross-sectional survey study.

BACKGROUND: Physician advice is an important motivator for attempting to stop smoking. However, physicians\u27 lack of intervention with smokers has only modestly improved in the last decade. Although the literature includes extensive research in the area of the smoking intervention practices of clinicians, few studies have focused on Hispanic physicians. The purpose of this study was to explore the correlates of tobacco cessation counseling practices among Hispanic physicians in the US. METHODS: Data were collected through a validated survey instrument among a cross-sectional sample of self-reported Hispanic physicians practicing in New Mexico, and who were members of the New Mexico Hispanic Medical Society in the year 2001. Domains of interest included counseling practices, self-efficacy, attitudes/responsibility, and knowledge/skills. Returned surveys were analyzed to obtain frequencies and descriptive statistics for each survey item. Other analyses included: bivariate Pearson\u27s correlation, factorial ANOVAs, and multiple linear regressions. RESULTS: Respondents (n = 45) reported a low level of compliance with tobacco control guidelines and recommendations. Results indicate that physicians\u27 familiarity with standard cessation protocols has a significant effect on their tobacco-related practices (r = .35, variance shared = 12%). Self-efficacy and gender were both significantly correlated to tobacco related practices (r = .42, variance shared = 17%). A significant correlation was also found between self-efficacy and knowledge/skills (r = .60, variance shared = 36%). Attitudes/responsibility was not significantly correlated with any of the other measures. CONCLUSION: More resources should be dedicated to training Hispanic physicians in tobacco intervention. Training may facilitate practice by increasing knowledge, developing skills and, ultimately, enhancing feelings of self-efficacy

Representing 3D Space in Working Memory: Spatial Images from Vision, Hearing, Touch, and Language

The chapter deals with a form of transient spatial representation referred to as a spatial image. Like a percept, it is externalized, scaled to the environment, and can appear in any direction about the observer. It transcends the concept of modality, as it can be based on inputs from the three spatial senses, from language, and from long-term memory. Evidence is presented that supports each of the claimed properties of the spatial image, showing that it is quite different from a visual image. Much of the evidence presented is based on spatial updating. A major concern is whether spatial images from different input modalities are functionally equivalent— that once instantiated in working memory, the spatial images from different modalities have the same functional characteristics with respect to subsequent processing, such as that involved in spatial updating. Going further, the research provides some evidence that spatial images are amodal (i.e., do not retain modality-specific features)