Challenges of modelling approaches for network meta-analysis of time-to-event outcomes in the presence of non-proportional hazards to aid decision making: Application to a melanoma network.

BACKGROUND: Synthesis of clinical effectiveness from multiple trials is a well-established component of decision-making. Time-to-event outcomes are often synthesised using the Cox proportional hazards model assuming a constant hazard ratio over time. However, with an increasing proportion of trials reporting treatment effects where hazard ratios vary over time and with differing lengths of follow-up across trials, alternative synthesis methods are needed. OBJECTIVES: To compare and contrast five modelling approaches for synthesis of time-to-event outcomes and provide guidance on key considerations for choosing between the modelling approaches. METHODS: The Cox proportional hazards model and five other methods of estimating treatment effects from time-to-event outcomes, which relax the proportional hazards assumption, were applied to a network of melanoma trials reporting overall survival: restricted mean survival time, generalised gamma, piecewise exponential, fractional polynomial and Royston-Parmar models. RESULTS: All models fitted the melanoma network acceptably well. However, there were important differences in extrapolations of the survival curve and interpretability of the modelling constraints demonstrating the potential for different conclusions from different modelling approaches. CONCLUSION: The restricted mean survival time, generalised gamma, piecewise exponential, fractional polynomial and Royston-Parmar models can accommodate non-proportional hazards and differing lengths of trial follow-up within a network meta-analysis of time-to-event outcomes. We recommend that model choice is informed using available and relevant prior knowledge, model transparency, graphically comparing survival curves alongside observed data to aid consideration of the reliability of the survival estimates, and consideration of how the treatment effect estimates can be incorporated within a decision model

Prediction of 7-year psychopathology from mother-infant joint attention behaviours: a nested case–control study

<br>Background: To investigate whether later diagnosis of psychiatric disorder can be predicted from analysis of mother-infant joint attention (JA) behaviours in social-communicative interaction at 12 months.</br> <br>Method: Using data from a large contemporary birth cohort, we examined 159 videos of a mother-infant interaction for joint attention behaviour when children were aged one year, sampled from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Fifty-three of the videos involved infants who were later considered to have a psychiatric disorder at seven years and 106 were same aged controls. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorder, attention-deficit/hyperactivity disorder, pervasive development disorder, anxiety and depressive disorders. Psychiatric diagnoses were obtained using the Development and Wellbeing Assessment when the children were seven years old.</br> <br>Results: None of the three JA behaviours (shared look rate, shared attention rate and shared attention intensity) showed a significant association with the primary outcome of case–control status. Only shared look rate predicted any of the exploratory sub-diagnosis outcomes and was found to be positively associated with later oppositional-conduct disorders (OR [95% CI]: 1.5 [1.0, 2.3]; p = 0.041).</br><br>Conclusions: JA behaviours did not, in general, predict later psychopathology. However, shared look was positively associated with later oppositional-conduct disorders. This suggests that some features of JA may be early markers of later psychopathology. Further investigation will be required to determine whether any JA behaviours can be used to screen for families in need of intervention.</br&gt

Importance of reactive halogens in the tropical marine atmosphere: A regional modelling study using WRF-Chem

Abstract. This study investigates the impact of halogens on atmospheric chemistry in the tropical troposphere and explores the sensitivity of this to uncertainties in the fluxes of halogens to the atmosphere and the chemical processing. To do this the regional chemistry transport model WRF-Chem has been extended, for the first time, to include halogen chemistry (bromine, chlorine and iodine chemistry), including heterogeneous recycling reactions involving sea-salt aerosol and other particles, reactions of Br with volatile organic compounds (VOCs), along with oceanic emissions of halocarbons, VOCs and inorganic iodine. The study focuses on the tropical East Pacific using field observations from the TORERO campaign (Januaryndash;February 2012) to evaluate the model performance. Including all the new processes, the model does a reasonable job reproducing the observed mixing ratios of BrO and IO, albeit with some discrepancies, some of which can be attributed to difficulties in the model's ability to reproduce the observed halocarbons. This is somewhat expected given the large uncertainties in the air-sea fluxes of the halocarbons in a region where there are few observations of seawater concentrations. We see a considerable impact on the Bry partitioning when heterogeneous chemistry is included, with a greater proportion of the Bry in active forms such as BrO, HOBr and dihalogens. Including debromination of sea-salt increases BrO slightly throughout the free troposphere, but in the tropical marine boundary layer, where the sea-salt particles are plentiful and relatively acidic, debromination leads to overestimation of the observed BrO. However, it should be noted that the modelled BrO was extremely sensitive to the inclusion of reactions between Br and the VOCs, which convert Br to HBr, a far less reactive form of Bry. Excluding these reactions leads to modelled BrO mixing ratios greater than observed. The reactions between Br and aldehydes were found to be particularly important, despite the model underestimating the amount of aldehydes observed in the atmosphere. There are only small changes to Iy partitioning and IO when the heterogeneous reactions, primarly on sea-salt, are included. Our model results show that the tropospheric Ox loss due to halogens is 31%. This loss is mostly due to I (16%) and Br (14%) and it is in good agreement with other estimates from state-of-the-art atmospheric chemistry models

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

International Society of Sports Nutrition Position Stand:Probiotics

Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO). Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications. Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent. Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown. The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components. Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes’ exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections. Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes. Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise. The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product’s shelf life, as measured by colony forming units (CFU) or live cells. Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population

Association between different levels of dysglycemia and metabolic syndrome in pregnancy

<p>Abstract</p> <p>Background</p> <p>In this study, we sought to evaluate the prevalence of metabolic syndrome (MS) in a cohort of pregnant women with a wide range of glucose tolerance, prepregnancy risk factors for MS during pregnancy, and the effects of MS in the outcomes in the mother and in the newborn.</p> <p>Methods</p> <p>One hundred and thirty six women with positive screening for gestational diabetes mellitus (GDM) were classified by two diagnostic methods: glycemic profile and 100 g OGTT as normoglycemic, mild gestational hyperglycemic, GDM, and overt GDM. Markers of MS were measured between 2428^thduring the screening.</p> <p>Results</p> <p>The prevalence of MS was: 0%; 20.0%; 23.5% and 36.4% in normoglycemic, mild hyperglycemic, GDM, and overt GDM groups, respectively. Previous history of GDM with or without insulin use, BMI ≥ 25, hypertension, family history of diabetes in first degree relatives, non-Caucasian ethnicity, history of prematurity and polihydramnios were statistically significant prepregnancy predictors for MS in the index pregnancy, that by its turn increased the adverse outcomes in the mother and in the newborn.</p> <p>Conclusion</p> <p>The prevalence of MS increases with the worsening of glucose tolerance; impaired glycemic profile identifies pregnancies with important metabolic abnormalities even in the presence of a normal OGTT, in patients that are not classified as having GDM.</p