Twenty-year trajectories of cardio-metabolic factors among people with type 2 diabetes by dementia status in England: a retrospective cohort study.

To assess 20-year retrospective trajectories of cardio-metabolic factors preceding dementia diagnosis among people with type 2 diabetes (T2D). We identified 227,145 people with T2D aged > 42 years between 1999 and 2018. Annual mean levels of eight routinely measured cardio-metabolic factors were extracted from the Clinical Practice Research Datalink. Multivariable multilevel piecewise and non-piecewise growth curve models assessed retrospective trajectories of cardio-metabolic factors by dementia status from up to 19 years preceding dementia diagnosis (dementia) or last contact with healthcare (no dementia). 23,546 patients developed dementia; mean (SD) follow-up was 10.0 (5.8) years. In the dementia group, mean systolic blood pressure increased 16-19 years before dementia diagnosis compared with patients without dementia, but declined more steeply from 16 years before diagnosis, while diastolic blood pressure generally declined at similar rates. Mean body mass index followed a steeper non-linear decline from 11 years before diagnosis in the dementia group. Mean blood lipid levels (total cholesterol, LDL, HDL) and glycaemic measures (fasting plasma glucose and HbA1c) were generally higher in the dementia group compared with those without dementia and followed similar patterns of change. However, absolute group differences were small. Differences in levels of cardio-metabolic factors were observed up to two decades prior to dementia diagnosis. Our findings suggest that a long follow-up is crucial to minimise reverse causation arising from changes in cardio-metabolic factors during preclinical dementia. Future investigations which address associations between cardiometabolic factors and dementia should account for potential non-linear relationships and consider the timeframe when measurements are taken

Factors associated with unplanned reinterventions and their relation to early mortality after pediatric cardiac surgery

Objective: Unplanned reintervention (uRE) is used as an indicator of patient morbidity and quality of care in pediatric cardiac surgery. We investigated associated factors and early mortality after uREs. / Methods: Morbidity data were prospectively collected in 5 UK centers between 2015 and 2017; uRE included surgical cardiac, interventional transcatheter cardiac, permanent pacemaker, and diaphragm plication procedures. Mortality (30-day and 6-month) in uRE/no-uRE patients was reported before and after matching. Predicted 30-day mortality was calculated using the Partial Risk Adjustment in Surgery score. / Results: A total of 3090 procedures (2861 patients) were included (median age, 228 days). There were 146 uREs, resulting in an uRE rate of 4.7%. Partial Risk Adjustment in Surgery score, 30-day mortality and 6-month mortality in uRE and no-uRE groups were 2.4% versus 1.3%, 8.9% versus 1%, and 17.1% versus 2.4%, respectively. After matching, mortality at 6 months remained higher in uRE compared with no-uRE (12.2% vs 1.4%; P = .02; 74 pairs). In the uRE group, 21 out of 25 deaths at 6 months occurred when at least 1 additional postoperative complication was present. In multivariable analysis, neonatal age (P = .002), low weight (P = .009), univentricular heart (P < .001), and arterial shunt (P < .001) were associated with increased risk of uRE, but Partial Risk Adjustment in Surgery score was not (only in univariable analysis). / Conclusions: uREs are a relatively frequent complication after pediatric cardiac surgery and are associated with some patient characteristics, but not the Partial Risk Adjustment in Surgery risk score. Early mortality was higher after uRE, independent of preoperative factors, but linked to other postoperative complications

A randomised controlled trial of Caphosol mouthwash in management of radiation-induced mucositis in head and neck cancer.

Purpose This phase III, non-blinded, parallel-group, randomised controlled study evaluated the efficacy of Caphosol mouthwash in the management of radiation-induced oral mucositis (OM) in patients with head and neck cancer (HNC) undergoing radical (chemo)radiotherapy.Patients and methods Eligible patients were randomised at 1:1 to Caphosol plus standard oral care (intervention) or standard oral care alone (control), stratified by radiotherapy technique and use of concomitant chemotherapy. Patients in the intervention arm used Caphosol for 7weeks: 6weeks during and 1-week post-radiotherapy. The primary endpoint was the incidence of severe OM (CTCAE ⩾grade 3) during and up to week 8 post-radiotherapy. Secondary endpoints include pharyngeal mucositis, dysphagia, pain and quality of life.Results The intervention (n=108) and control (n=107) arms were well balanced in terms of patient demographics and treatment characteristics. Following exclusion of patients with missing data, 210 patients were available for analysis. The incidence of severe OM did not differ between the intervention and control arms (64.1% versus 65.4%, p=0.839). Similarly, no significant benefit was observed for other secondary endpoints. Overall, compliance with the recommended frequency of Caphosol was low.Conclusion Caphosol did not reduce the incidence or duration of severe OM during and after radiotherapy in HNC

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study

2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naı¨ve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P¼0.004). There was no interaction between AR and docetaxel status (P¼0.83 for OS, P¼0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; PA (p.L702H) and 520 3

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.

Background There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC.Methods We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial).Results In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts.Conclusion Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required.Clinical trial number NCT02288936 (PREMIERE trial)

SIMD parallel MCMC sampling with applications for big-data Bayesian analytics

Computational intensity and sequential nature of estimation techniques for Bayesian methods in statistics and machine learning, combined with their increasing applications for big data analytics, necessitate both the identification of potential opportunities to parallelize techniques such as Monte Carlo Markov Chain (MCMC) sampling, and the development of general strategies for mapping such parallel algorithms to modern CPUs in order to elicit the performance up the compute-based and/or memory-based hardware limits. Two opportunities for Single-Instruction Multiple-Data (SIMD) parallelization of MCMC sampling for probabilistic graphical models are presented. In exchangeable models with many observations such as Bayesian Generalized Linear Models (GLMs), child-node contributions to the conditional posterior of each node can be calculated concurrently. In undirected graphs with discrete-value nodes, concurrent sampling of conditionally-independent nodes can be transformed into a SIMD form. High-performance libraries with multi-threading and vectorization capabilities can be readily applied to such SIMD opportunities to gain decent speedup, while a series of high-level source-code and runtime modifications provide further performance boost by reducing parallelization overhead and increasing data locality for Non-Uniform Memory Access architectures. For big-data Bayesian GLM graphs, the end-result is a routine for evaluating the conditional posterior and its gradient vector that is 5 times faster than a naive implementation using (built-in) multi-threaded Intel MKL BLAS, and reaches within the striking distance of the memory-bandwidth-induced hardware limit. Using multi-threading for cache-friendly, fine-grained parallelization can outperform coarse-grained alternatives which are often less cache-friendly, a likely scenario in modern predictive analytics workflow such as Hierarchical Bayesian GLM, variable selection, and ensemble regression and classification. The proposed optimization strategies improve the scaling of performance with number of cores and width of vector units (applicable to many-core SIMD processors such as Intel Xeon Phi and Graphic Processing Units), resulting in cost-effectiveness, energy efficiency (‘green computing’), and higher speed on multi-core x86 processors

Stochastic newton sampler: The R package sns

The R package sns implements the stochastic Newton sampler (SNS), a MetropolisHastings Markov chain Monte Carlo (MCMC) algorithm where the proposal density function is a multivariate Gaussian based on a local, second-order Taylor-series expansion of log-density. The mean of the proposal function is the full Newton step in the NewtonRaphson optimization algorithm. Taking advantage of the local, multivariate geometry captured in log-density Hessian allows SNS to be more efficient than univariate samplers, approaching independent sampling as the density function increasingly resembles a multivariate Gaussian. SNS requires the log-density Hessian to be negative-definite everywhere in order to construct a valid proposal function. This property holds, or can be easily checked, for many GLM-like models. When the initial point is far from density peak, running SNS in non-stochastic mode by taking the Newton step - augmented with line search - allows the MCMC chain to converge to high-density areas faster. For high-dimensional problems, partitioning the state space into lower-dimensional subsets, and applying SNS to the subsets within a Gibbs sampling framework can significantly improve the mixing of SNS chains. In addition to the above strategies for improving convergence and mixing, sns offers utilities for diagnostics and visualization, sample-based calculation of Bayesian predictive posterior distributions, numerical differentiation, and log-density validation

Dose-limiting urinary toxicity with pembrolizumab combined with weekly hypofractionated radiation therapy in bladder cancer

There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose

Aortic valve replacement and the ross operation in children and young adults

Background There are several options available for aortic valve replacement (AVR), with few comparative reports in the literature. The optimal choice for AVR in each age group is not clear. Objectives The study sought to report and compare outcomes after AVR in the young using data from a national database. Methods AVR procedures were compared after advanced matching, both in pairs and in a 3-way manner, using a Bayesian dynamic survival model. Results A total of 1,501 patients who underwent AVR in the United Kingdom between 2000 and 2012 were included. Of these, 47.8% had a Ross procedure, 37.8% a mechanical AVR, 10.9% a bioprosthesis AVR, and 3.5% a homograft AVR, with Ross patients being significantly younger when compared to the other groups. Overall survival at 12 years was 94.6%. In children, the Ross procedure had a 12.7% higher event-free probability (death or any reintervention) at 10 years when compared to mechanical AVR (p = 0.05). We also compared all procedures except the homograft in a matched population of young adults, where the bioprosthesis had the lowest event-free probability of 78.8%, followed by comparable results in mechanical AVR and Ross, with 86.3% and 89.6%, respectively. Younger age was associated with mortality and pulmonary reintervention in the Ross group and with aortic reintervention in the mechanical AVR. Of all 3 options, only the patients undergoing the Ross procedure approached the survival of the general population. Conclusions AVR in the young achieves good results, with the Ross being overall better suited for this age group, especially in children. Although freedom from aortic valve reintervention is superior after the Ross procedure, the need for homograft reinterventions is an issue to take into account. All methods have advantages and limitations, with reinterventions being an issue in the long term for all, more crucially in smaller children

Age over 35 years is associated with increased mortality after pulmonary valve replacement in repaired tetralogy of Fallot: results from the UK National Congenital Heart Disease Audit database

OBJECTIVES: Many adults with repaired tetralogy of Fallot will require a pulmonary valve replacement (PVR), but there is no consensus on the best timing. In this study, we aim to evaluate the impact of age at PVR on outcomes. METHODS: This is a national multicentre retrospective study including all patients >15 years of age with repaired tetralogy of Fallot who underwent their first PVR between 2000 and 2013. The optimal age cut-off was identified using Cox regression and classification and regression tree analysis. RESULTS: A total of 707 patients were included, median age 26 (15-72) years. The mortality rate at 10 years after PVR was 4.2%, and the second PVR rate of 6.8%. Age at PVR of 35 years was identified as the optimal cut-off in relation to late mortality. Patients above 35 years of age had a 5.6 fold risk of death at 10 years compared with those with PVR under 35 years (10.4% vs 1.3%, P < 0.001), more concomitant tricuspid valve repair/replacement (15.1% vs 5.7%, P < 0.001) and surgical arrhythmia treatment (18.4% vs 5.9%, P < 0.001). In those under 50 years, there was an 8.7 fold risk of late death compared with the general population, higher for those with PVR after 35 than those with PVR below 35 years (hazard ratio 9.9 vs 7.4). CONCLUSIONS: Patients above 35 years of age with repaired tetralogy of Fallot have significantly worse mortality after PVR, compared with younger patients and a higher burden of mortality relative to the general population. This suggests that there are still cases where the timing of initial PVR is not optimal, warranting a re-evaluation of criteria for intervention