Assessment of the patient, health system, and population eff ects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach

Background Several promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm. Methods We used an integrated model to assess the eff ects of diff erent algorithms of Xpert MTB/RIF and lightemitting diode (LED) fl uorescence microscopy in Tanzania. To understand the eff ects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the eff ects and cost-eff ectiveness of diff erent diagnostic options. Findings Among the diagnostic options considered, we identifi ed three strategies as cost eff ective in Tanzania. Full scale-up of Xpert would have the greatest population-level eff ect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36·9 million over 10 years. The incremental cost-eff ectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104–265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fl uorescence microscopy is the next most eff ective strategy with an ICER of$45 (95% CrI 25–74), followed by LED fl uorescence microscopy with an ICER of $29 (6–59). Compared with same-day LED fl uorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a followon test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania. Interpretation For Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-eff ective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

Recent case–control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 305 parent–offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at four genomic loci (15q13.1–13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case–control ADHD studies. Our study complements ADHD case–control genomic analyses and demonstrates the need for larger parent–offspring trio genetic studies to gain further insights into the complex aetiology of ADHD

Training using a simulation-based workshop reduces inaccuracies in estimations of testicular volume

Objectives Measuring testicular volume (TV) by orchidometer is routine in the clinic when staging male puberty. We have developed a simulation model for TV estimation and investigated whether training medical students, using a workshop with simulation models, could improve the accuracy and reliability of TV estimation. Methods All participating medical students watched a video representing standard undergraduate training in male pubertal assessment. Volunteers were then randomised directly to assessment or to attend a workshop consisting of a further video and four stations contextualising and practising the skills required for TV estimation, prior to assessment. Three child mannequins displaying testes of 3 mL, 4 mL (twice), 5, 10 and 20 mL were used for assessment. Participants were asked to return a fortnight later for repeat assessment to assess intra-observer reliability, the effect of repeated examinations on accuracy and time on skill retention. Results Ninety students participated (55F), 46 attended the workshop and were considered “trained”. There was no difference between the groups in numbers of correct estimations (29% trained, 27% untrained, p=0.593). However, the trained group’s estimations were closer to the true volume, with more from the trained group one bead away (p=0.002) and fewer more than three beads away from the true volume (p<0.001), compared to the untrained group. Trained participants were more accurate at the second assessment (n=80) (p<0.001) and had greater intra-observer reliability (p=0.004). Conclusions Overall TV estimation accuracy was poor. Workshop-style training improved accuracy, reliability and retention of skill acquisition and could be considered as a useful learning tool

Prenatal Excess Glucocorticoid Exposure and Adult Affective Disorders:A Role for Serotonergic and Catecholamine Pathways

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal ‘programming’ of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety‐ and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways

Abstracts from the NIHR INVOLVE Conference 2017

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Fetal brain 11β-hydroxysteroid dehydrogenase type 2 selectively determines programming of adult depressive-like behaviors and cognitive function, but not anxiety behaviors in male mice

Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11β-HSD2 within the midgestational fetal brain is unknown. To examine this, a brain-specific knockout of 11β-HSD2 (HSD2BKO) was generated and compared to wild-type littermates. HSD2BKO have markedly diminished fetal brain 11β-HSD2, but intact fetal body and placental 11β-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Seating Arrangement Optimization for Executive Round Table

A presentation in the Undergraduate Research Kaleidoscope: Library East Commons Performance Space, February 9, 2009Runtime: 06:36 minutes (Original)Runtime: 06:36 minutes (Edited)The Executive Round Table is an intellectual forum where students, faculty, and industry executives come together to pose solutions to issues facing our community. Executive Round Table revolves around monthly dinner meetings. With over 100 guests and over 316 million possibilities, seating arrangements are a daunting task. In the past, the organization has randomly sat members, but this leads to a poor dining experience. To create the optimal seating arrangement, our team is developing a heuristic algorithm that takes into account over twenty constraints and generates optimized seating charts using a proprietary Java application.Joel Soko