The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells

Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enable cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers

Regression discontinuity designs in health: a systematic review

Background: Regression discontinuity designs are non-randomized study designs that permit strong causal inference with relatively weak assumptions. Interest in these designs is growing but there is limited knowledge of the extent of their application in health. We aimed to conduct a comprehensive systematic review of the use of regression discontinuity designs in health research. Methods: We included studies that used regression discontinuity designs to investigate the physical or mental health outcomes of any interventions or exposures in any populations. We searched 32 health, social science, and grey literature databases (1 January 1960-1 January 2019). We critically appraised studies using eight criteria adapted from the What Works Clearinghouse Standards for regression discontinuity designs. We conducted a narrative synthesis, analyzing the forcing variables and threshold rules used in each study. Results: The literature search retrieved 7658 records, producing 325 studies that met the inclusion criteria. A broad range of health topics were represented. The forcing variables used to implement the design were age; socioeconomic measures; date or time of exposure or implementation; environmental measures such as air quality; geographic location; and clinical measures that act as a threshold for treatment. Twelve percent of the studies fully met the eight quality appraisal criteria. Fifteen percent of studies reported a pre-specified primary outcome or study protocol. Conclusions: This systematic review demonstrates that regression discontinuity designs have been widely applied in health research and could be used more widely still. Shortcomings in study quality and reporting suggest that the potential benefits of this method have not yet been fully realized

A novel ingestion strategy for sodium bicarbonate supplementation in a delayed-release form: a randomised crossover study in trained males

Background: Sodium bicarbonate (NaHCO3) is a well-established nutritional ergogenic aid, though gastrointestinal (GI) distress is a common side-effect. Delayed-release NaHCO3 may alleviate GI symptoms and enhance bicarbonate bioavailability following oral ingestion, although this has yet to be confirmed. Methods: In a randomised crossover design, pharmacokinetic responses and acid-base status were compared following two forms of NaHCO3, as were GI symptoms. Twelve trained healthy males (mean ± SD: age 25.8 ± 4.5 y; maximal oxygen uptake ("V" ̇O2max) 58.9 ± 10.9 mL∙kg∙min–1; height 1.8 ± 0.1 m; body mass 82.3 ± 11.1 kg; fat-free mass 72.3 ± 10.0 kg) underwent a control (CON) condition and two experimental conditions: 300 mg∙kg–1 body mass NaHCO3 ingested as an aqueous solution (SOL) and encased in delayed-release capsules (CAP). Blood bicarbonate concentration, pH and base excess (BE) were measured in all conditions over 180 min, as were subjective GI symptom scores. Results: Incidences of GI symptoms and overall severity were significantly lower (mean difference = 45.1%, P < 0.0005 and 47.5%, P < 0.0005 for incidences and severity, respectively) with the CAP than with the SOL. Symptoms displayed increases at 40 to 80 min post-ingestion with the SOL that were negated with CAP (P < 0.05). Time to reach peak bicarbonate concentration, pH and BE were significantly longer with CAP than with the SOL. Conclusions: In summary, CAP can mitigate GI symptoms induced with SOL and should be ingested earlier to induce similar acid-base changes. Furthermore, CAP may be more ergogenic in those who experience severe GI distress with SOL, although this warrants further investigation

Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial

Background Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the effi cacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM. Methods We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age Findings Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7–16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (lengthfor-age Z score Interpretation Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population.</p

A longitudinal investigation into the relative age effect in an English professional football club: Exploring the ‘underdog hypothesis’

Purpose: The relative age effect (RAE) refers to the bias influence of birthdate distribution, with athletes born later in the selection year being under-represented in talent development systems. However, the ‘underdog hypothesis’ suggests that younger birth quarter (BQ) athletes are over-represented among those who successfully transition from youth systems to senior professional status. Methods: Accordingly, the purpose of this study was twofold; (1) to provide further test of the RAE over twelve seasons (n= 556), and (2) to examine the BQ of professional contracts awarded to academy graduates at an English professional football club over eleven seasons (n= 364). Results: Significantly skewed (P< 0.001) birthdate distributions were found for academy players (BQ1 n= 224: BQ2 n= 168; BQ3 n= 88; BQ4 n= 76). The distribution from academy graduates was also significantly skewed for professional contracts awarded (P= 0.03), with greater BQ4 representation (n= 8) compared to other BQs (BQ1 n= 5; BQ2 n= 8; BQ3 n= 6). Conclusion: These findings are indicative that the RAE continues to manifest within an academy setting. Interestingly however, the underdog hypothesis shows BQ4s were approximately four times more likely to achieve senior professional status compared to BQ1s. Implications for talent identification and development in football are discussed

Novel Borna Virus in Psittacine Birds with Proventricular Dilatation Disease

Pyrosequencing of cDNA from brains of parrots with proventricular dilatation disease (PDD), an unexplained fatal inflammatory central, autonomic, and peripheral nervous system disease, showed 2 strains of a novel Borna virus. Real-time PCR confirmed virus presence in brain, proventriculus, and adrenal gland of 3 birds with PDD but not in 4 unaffected birds

Versatile additively manufactured (3D printed) wall-jet flow cell for high performance liquid chromatography- amperometric analysis: Application to the detection and quantification of New Psychoactive Substances (NBOMes)

Additive manufacturing (AM/3D printing) is an emerging technology of vast applicability, receiving significant interest in a plethora of industrial domains and scientific research since it allows the rapid translation of designs produced via computer software, into AM/3D printed objects. To date, AM/3D printed devices have been examined for their utilisation as convenient and cost-effective tools towards the detection and quantification of prevalent drugs of abuse. Herein, a novel AM/3D printed wall-jet flow cell was fabricated specifically for employment in high performance liquid chromatography-amperometric detection (HPLCAD) of various analytes (New Psychoactive Substances). Five sensing platforms were investigated, utilising different working electrodes, namely; screen-printed graphite electrodes (SPEs), AM/3D Proto-Pasta, AM/3D Black Magic, graphite sheet and AM/3D printed nanographite (NG) /polylactic acid (PLA)) towards the detection of New Psychoactive Substances. The flow cell was also optimised with respect to the cell geometry demonstrating significant benefits such as simple production and operation and the ability to tailor the platform to a variety of working electrodes. The AM/3D printed sensing platforms were characterised towards the (electro) analytical detection of four N-benzylmethoxy- derivatives: 25F-NBOMe, 25C-NBOMe, 25B-NBOMe and 25I-NBOMe. Furthermore, the (electro) analytical performance of the flow cell was compared with the findings in our previous work comprising of a commercially available impinging jet flow cell. The SPEs and the graphite sheet were found to demonstrate superior electrochemical (analytical) sensitivity and higher reproducibility towards the quantification of the drugs in question, followed by the NG/PLA AM, Proto-Pasta and the Black Magic. The working electrodes that exhibited satisfactory (electro) analytical responses were employed for the analysis of NBOMe derivatives in three simulated blotter papers

Systematic searching for theory to inform systematic reviews: is it feasible? Is it desirable?

Background In recognising the potential value of theory in understanding how interventions work comes a challenge – how to make identification of theory less haphazard? Objectives To explore the feasibility of systematic identification of theory. Method We searched PubMed for published reviews (1998–2012) that had explicitly sought to identify theory. Systematic searching may be characterised by a structured question, methodological filters and an itemised search procedure. We constructed a template (BeHEMoTh – Behaviour of interest; Health context; Exclusions; Models or Theories) for use when systematically identifying theory. The authors tested the template within two systematic reviews. Results Of 34 systematic reviews, only 12 reviews (35%) reported a method for identifying theory. Nineteen did not specify how they identified studies containing theory. Data were unavailable for three reviews. Candidate terms include concept(s)/conceptual, framework(s), model(s), and theory/theories/theoretical. Information professionals must overcome inadequate reporting and the use of theory out of context. The review team faces an additional concern in lack of ‘theory fidelity’. Conclusions Based on experience with two systematic reviews, the BeHEMoTh template and procedure offers a feasible and useful approach for identification of theory. Applications include realist synthesis, framework synthesis or review of complex interventions. The procedure requires rigorous evaluation

A randomized trial comparing treatments for varicose veins

Supported by a grant from the Health Technology Assessment Programme of the National Institute for Health Research (06/45/02). The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorate. We thank Janice Cruden for her secretarial support and data management; Gladys McPherson and the programming team at the Centre for Healthcare Randomised Trials; Tracey Davidson, Lynda Constable, Jackie Ellington, Laura Elliott, and Yvonne Fernie for help with scoring the Aberdeen Varicose Vein Questionnaire; Luke Vale and Laura Ternent, our original economists in the group; members of the Project Management Group for their ongoing advice and support of the trial; members of the study team (Graeme MacLennan, Maria Prior, and Denise Bolsover) who contributed to the behavioral recovery component of the trial; the independent members of the trial steering committee (Alun Davies [chair], Ian Loftus, and Jane Nixon) and the data and safety monitoring committee (Gerry Stansby [chair], Winston Banya, and Marcus Flather); and the staff members at recruitment sites (see the Supplementary Appendix) who facilitated recruitment, treatment, and follow-up of trial participants.Peer reviewedPublisher PD