A single-blind, randomised, crossover study to reduce hypoglycaemia risk during postprandial exercise with closed-loop insulin delivery in adults with type 1 diabetes: announced (with or without bolus reduction) vs unannounced exercise strategies.

AIMS/HYPOTHESIS: For individuals living with type 1 diabetes, closed-loop insulin delivery improves glycaemic control. Nonetheless, maintenance of glycaemic control during exercise while a prandial insulin bolus remains active is a challenge even to closed-loop systems. We investigated the effect of exercise announcement on the efficacy of a closed-loop system, to reduce hypoglycaemia during postprandial exercise. METHODS: A single-blind randomised, crossover open-label trial was carried out to compare three strategies applied to a closed-loop system at mealtime in preparation for exercise taken 90 min after eating at a research testing centre: (1) announced exercise to the closed-loop system (increases target glucose levels) in addition to a 33% reduction in meal bolus (A-RB); (2) announced exercise to the closed-loop system and a full meal bolus (A-FB); (3) unannounced exercise and a full meal bolus (U-FB). Participants performed 60 min of exercise at 60% [Formula: see text] 90 min after eating breakfast. The investigators were not blinded to the interventions. However, the participants were blinded to the sensor glucose readings and to the insulin infusion rates throughout the intervention visits. RESULTS: The trial was completed by 37 adults with type 1 diabetes, all using insulin pumps: mean±SD, 40.0 ± 15.0 years of age, HbA1c 57.1 ± 10.8 mmol/mol (7.3 ± 1.0%). Reported results were based on plasma glucose values. During exercise and the following 1 h recovery period, time spent in hypoglycaemia (<3.9 mmol/l; primary outcome) was reduced with A-RB (mean ± SD; 2.0 ± 6.2%) and A-FB (7.0 ± 12.6%) vs U-FB (13.0 ± 19.0%; p < 0.0001 and p = 0.005, respectively). During exercise, A-RB had the least drop in plasma glucose levels: A-RB -0.3 ± 2.8 mmol/l, A-FB -2.6 ± 2.9 mmol/l vs U-FB -2.4 ± 2.7 mmol/l (p < 0.0001 and p = 0.5, respectively). Comparison of A-RB vs U-FB revealed a decrease in the time spent in target (3.9-10 mmol/l) by 12.7% (p = 0.05) and an increase in the time spent in hyperglycaemia (>10 mmol/l) by 21% (p = 0.001). No side effects were reported during the applied strategies. CONCLUSIONS/INTERPRETATION: Combining postprandial exercise announcement, which increases closed-loop system glucose target levels, with a 33% meal bolus reduction significantly reduced time spent in hypoglycaemia compared with the other two strategies, yet at the expense of more time spent in hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT0285530 FUNDING: JDRF (2-SRA-2016-210-A-N), the Canadian Institutes of Health Research (354024) and the Fondation J.-A. DeSève chair held by RR-L.

The impact of intraductal carcinoma of the prostate on the site and timing of recurrence and cancer-specific survival.

BACKGROUND: To investigate the effect of intraductal carcinoma of the prostate (IDC-P) in radical prostatectomy (RP) specimens in the context of the site of recurrence, time to recurrence, and cancer-specific survival in two academic cohorts of locally, regionally, or distantly recurrent prostate cancer. METHODS: Our cohort included men enrolled into two academic tissue repositories from 1993 to 2011, who were treated with first-line RP who later experienced local recurrence, regional recurrence, or distant metastasis (together termed clinical recurrence, CR). RP material was reviewed to identify IDC-P and to update grading to current standards. The primary endpoint was the initial location of CR. Secondary endpoints included time to CR and cancer-specific survival. Pearson's chi-square, Welch's t-test, Mann-Whitney U test and Fisher's exact test were performed for univariate analyses. Multinomial logistic regression was used for multivariate analyses. Cancer-specific survival was analyzed with the generalized Wilcoxon test and Cox regression. RESULTS: Eighty-five patients with CR were included in the analysis. IDC-P was present in 78.5% of patients from Center 1 and 70.0% from Center 2 (P = 0.547). IDC-P was independently associated with distant metastasis at initial CR (multivariate odds ratio = 6.27, P = 0.015). IDC-P status did not affect time to recurrence; median survival without recurrence was at 53 months for IDC-P(+) and at 50 months for IDC-P(-) (P = 0.441). Distant metastases at the initial CR event had a 36% reduction of cancer-specific survival compared to local recurrences (P = 0.007). Additionally, prostatic-bed radiotherapy (adjuvant or salvage for biochemical recurrence before distant metastasis) was associated with a 25% reduction in cancer-specific mortality compared to no radiotherapy (P = 0.023). Similar reduction in cancer-specific mortality was observed in the subgroup of patients with distant metastasis and IDC-P when treated with radiotherapy (29%, P = 0.050). CONCLUSIONS: In our cohort, presence of IDC-P was an independent factor for distant metastasis at initial CR, but did not have a significant impact on time to CR. Furthermore, metastatic patients showed statistically reduced cancer-specific mortality when treated with radiotherapy. This reduction in cancer-specific mortality was also identified in patients with IDC-P. Future large scale validation studies should take into account the presence of IDC-P and confirm its impact on disease progression.

Impact of macronutrient content of meals on postprandial glucose control in the context of closed-loop insulin delivery: A randomized cross-over study.

The aim of this randomized four-way cross-over study was to examine the effect of added protein and/or fat in standard meals with a fixed carbohydrate content on postprandial glucose control with closed-loop insulin delivery in adults with type 1 diabetes. Participants (n = 15) consumed breakfast meals with a fixed carbohydrate content (75 ± 1 g) and added protein and/or fat (35 ± 2 g): (1) carbohydrate-only (standard), (2) high protein (HP), (3) high fat (HF) and (4) high fat + protein (HFHP). The closed-loop insulin delivery algorithm generated insulin bolus and infusion rates. The addition of fat, protein or both did not impact 5-hour post-meal sensor glucose area under the curve (AUC) (main outcome), mean sensor glucose or glycaemic peak as compared with a standard meal (P > 0.05). However, time to glycaemic peak was delayed by 40 minutes (P = 0.03) and 5-hour post-meal basal insulin requirements were 39% higher (P = 0.04) with an HFHP meal compared with a standard meal. In conclusion, in the context of closed-loop insulin delivery, protein and/or fat meal content affects the timing of postprandial glycaemic peak, insulin requirements and late glycaemic excursion, without impacting overall 5-hour AUC.

Outpatient 60-hour day-and-night glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or sensor-augmented pump therapy in adults with type 1 diabetes: An open-label, randomised, crossover, controlled trial.

AIMS: To assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared to the single-hormone (insulin alone) artificial pancreas in outpatient settings during the day and night. MATERIAL AND METHODS: In a randomized, three-way, crossover trial we compared the dual-hormone artificial pancreas, the single-hormone artificial pancreas and sensor-augmented pump therapy (control) in 23 adults with type 1 diabetes. Each intervention was applied from 8 AM Day 1 to 8 PM Day 3 (60 hours) in outpatient free-living conditions. The primary outcome was time spent with sensor glucose levels below 4.0 mmol/L. A P value of less than .017 was regarded as significant. RESULTS: The median difference between the dual-hormone system and the single-hormone system was -2.3% (P = .072) for time spent below 4.0 mmol/L, -1.3% (P = .017) for time below 3.5 mmol/L, and -0.7% (P = .031) for time below 3.3 mmol/L. Both systems reduced (P < .017) hypoglycaemia below 4.0, 3.5 and 3.3 mmol/L compared to control therapy, but reductions were larger with the dual-hormone system than with the single-hormone system (medians -4.0% vs -3.4% for 4.0 mmol/L; -2.7% vs -2.2% for 3.5 mmol/L; and -2.2% vs -1.2% for 3.3 mmol/L). There were 34 hypoglycaemic events (<3.0 mmol/L for 20 minutes) with control therapy, 14 with the single-hormone system and 6 with the dual-hormone system. These differences in hypoglycaemia were observed while mean glucose level was low and comparable in all interventions (P = NS). CONCLUSIONS: The dual-hormone artificial pancreas had the lowest risk of hypoglycaemia, but the differences were not statistically significant. Larger studies are needed.

Efficacy of single-hormone and dual-hormone artificial pancreas during continuous and interval exercise in adult patients with type 1 diabetes: randomised controlled crossover trial.

AIMS/HYPOTHESIS: The aim of this study was to assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared with the single-hormone (insulin alone) artificial pancreas during two types of exercise. METHODS: An open-label randomised crossover study comparing both systems in 17 adults with type 1 diabetes (age, 37.2 ± 13.6 years; HbA1c, 8.0 ± 1.0% [63.9 ± 10.2 mmol/mol]) during two exercise types on an ergocycle and matched for energy expenditure: continuous (60% [Formula: see text] for 60 min) and interval (2 min alternating periods at 85% and 50% [Formula: see text] for 40 min, with two 10 min periods at 45% [Formula: see text] at the start and end of the session). Blocked randomisation (size of four) with a 1:1:1:1 allocation ratio was computer generated. The artificial pancreas was applied from 15:30 hours until 19:30 hours; exercise was started at 18:00 hours and announced 20 min earlier to the systems. The study was conducted at the Institut de recherches cliniques de Montréal. RESULTS: During single-hormone control compared with dual-hormone control, exercise-induced hypoglycaemia (plasma glucose <3.3 mmol/l with symptoms or <3.0 mmol/l regardless of symptoms) was observed in four (23.5%) vs two (11.8%) interventions (p = 0.5) for continuous exercise and in six (40%) vs one (6.25%) intervention (p = 0.07) for interval exercise. For the pooled analysis (single vs dual hormone), the median (interquartile range) percentage time spent at glucose levels below 4.0 mmol/l was 11% (0.0-46.7%) vs 0% (0-0%; p = 0.0001) and at glucose levels between 4.0 and 10.0 mmol/l was 71.4% (53.2-100%) vs 100% (100-100%; p = 0.003). Higher doses of glucagon were needed during continuous (0.126 ± 0.057 mg) than during interval exercise (0.093 ± 0.068 mg) (p = 0.03), with no reported side-effects in all interventions. CONCLUSIONS/INTERPRETATION: The dual-hormone artificial pancreas outperformed the single-hormone artificial pancreas in regulating glucose levels during announced exercise in adults with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01930110 FUNDING: : Société Francophone du Diabète and Diabète Québec.

Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

Adrenal Vein Sampling in Primary Aldosteronism: Sensitivity and Specificity of Basal Adrenal Vein to Peripheral Vein Cortisol and Aldosterone Ratios to Confirm Catheterization of the Adrenal Vein.

PURPOSE: To assess the sensitivity and specificity for ratios of adrenal vein cortisol level (Ca) to peripheral vein cortisol level (Cp), adrenal vein aldosterone level (Aa) to peripheral vein aldosterone level (Ap), and combined cortisol and aldosterone levels ("combined ratio") for the detection of successful adrenal vein catheterization ("selectivity") in adrenal vein sampling (AVS) without adrenocorticotropic hormone (ACTH) injection at different cutoff values. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. AVS was performed in 160 consecutive patients (49 women and 111 men; mean age, 53.6 years) between December 1989 and January 2014. Cortisol and aldosterone levels were measured in samples from the adrenal veins and left iliac vein every 5 minutes, two times before (basal) and three times after intravenous cosyntropin (ACTH 1-24) injection. Selectivity was defined by Ca/Cp or Aa/Ap ratio of at least 5 in at least one sampling after ACTH administration. Sensitivity and specificity for the detection of selective adrenal vein catheterization were calculated for basal Ca/Cp ratio, Aa/Ap ratio, and combined ratios for three cutoff values reported in the literature. The McNemar test was used to assess differences in sensitivity and specificity to detect selective adrenal vein catheterization. RESULTS: The sensitivity and specificity for the cutoff values of at least 3, at least 2, and at least 1.1 for the detection of AVS selectivity were respectively 50.4% and 100%, 70.8% and 100%, and 98.5% and 76.9% for Ca/Cp ratio; 61.3% and 100%, 70.8% and 100%, and 94.2% and 53.8% for Aa/Ap ratio; and 75.2% and 100%, 88.3% and 100%, and 99.3% and 46.2% for combined ratios (sensitivity at the ≥2 cutoff value: P < .0001 for combined ratio vs Ca/Cp ratio and for combined ratio vs Aa/Ap ratio). CONCLUSION: Basal combined ratio has the best sensitivity for the detection of AVS selectivity at all cutoff values, and for all ratios, the cutoff value of at least 2 has the best sensitivity for 100% specificity.

The empirical power of rare variant association methods: results from sanger sequencing in 1,998 individuals.

The role of rare genetic variation in the etiology of complex disease remains unclear. However, the development of next-generation sequencing technologies offers the experimental opportunity to address this question. Several novel statistical methodologies have been recently proposed to assess the contribution of rare variation to complex disease etiology. Nevertheless, no empirical estimates comparing their relative power are available. We therefore assessed the parameters that influence their statistical power in 1,998 individuals Sanger-sequenced at seven genes by modeling different distributions of effect, proportions of causal variants, and direction of the associations (deleterious, protective, or both) in simulated continuous trait and case/control phenotypes. Our results demonstrate that the power of recently proposed statistical methods depend strongly on the underlying hypotheses concerning the relationship of phenotypes with each of these three factors. No method demonstrates consistently acceptable power despite this large sample size, and the performance of each method depends upon the underlying assumption of the relationship between rare variants and complex traits. Sensitivity analyses are therefore recommended to compare the stability of the results arising from different methods, and promising results should be replicated using the same method in an independent sample. These findings provide guidance in the analysis and interpretation of the role of rare base-pair variation in the etiology of complex traits and diseases.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)

Carpal angles as measured on CT and MRI: can we simply translate radiographic measurements?

OBJECTIVE: To determine the reliability of carpal angles measured on CT and MRI compared to radiography and assess if these measurements are interchangeable. MATERIALS AND METHODS: Our institutional ethic research committee approved this study. For this retrospective study, two independent observers measured the scapholunate (SL), capitolunate (CL), radiolunate (RL), and radioscaphoid (RS) angles on 21 sets of exams, with each set including a radiograph, CT, and MRI of the same wrist. Inter- and intra-observer agreements were evaluated with the intraclass correlation coefficient (ICC). Linear mixed models and two-way contingency tables were used to determine if the angles measured on cross-sectional modalities were significantly different from those obtained on radiography. RESULTS: Inter-observer agreement was strong (ICC >0.8) for all angles, except for the RL angle measured on MRI (ICC 0.68). Intra-observer agreement was also strong for all angles, except for the CL angle measured on CT (ICC 0.66). SL angles measured on CT and MRI were not statistically different from those measured on radiographs (p = 0.37 and 0.36, respectively), unlike CL, RL, and RS angles (p < 0.05). Accuracy between modalities varied between 76 and 86% for the SL angle and ranged between 43 and 76% for the other angles. CONCLUSIONS: CL, RL, and RS angles showed large intermodality variability. Therefore, their measurements on CT or MRI could potentially lead to miscategorization. Conversely, our data showing no significant difference between modalities, SL angle could be measured on CT and MRI to assess wrist instability with a lower risk of error.

INSPECT: A Retrospective Study to Evaluate Long-term Effectiveness and Safety of Darvadstrocel in Patients With Perianal Fistulizing Crohn's Disease Treated in the ADMIRE-CD Trial.

BACKGROUND: The efficacy of a single administration of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells) for treating complex perianal fistulas in patients with Crohn's disease was demonstrated in a randomized, double-blind trial (ADMIRE-CD [Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn\'s Disease] trial). The current chart review study (INSPECT [A retrospectIve chart review study evaluatINg the longer-term effectiveneSs of darvadstrocel in PatiEnts who CompleTed ADMIRE-CD]) evaluated the longer-term effectiveness and safety of darvadstrocel. METHODS: Eligible patients had completed at least 52 weeks in the ADMIRE-CD trial. Data on clinical remission and fistula relapse outcomes were collected retrospectively at 104 and 156 weeks after treatment. Adverse events of special interest (tumorigenicity and ectopic tissue formation) were collected up to 208 weeks after treatment. RESULTS: Eighty-nine patients were included (43 darvadstrocel patients, 46 control subjects). At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively. In patients with clinical remission at week 52, this remission was sustained at 104 and 156 weeks after treatment in 19 (65.5%) of 29 and 16 (55.2%) of 29 darvadstrocel-treated patients and in 17 (70.8%) of 24 and 13 (54.2%) of 24 control subjects, respectively. Time to fistula relapse and incidence of fistula relapse or new fistula occurrence were not significantly different between groups. Tumorigenicity was reported for 1 (2.2%) patient in the control group (malignant epidermoid carcinoma). No ectopic tissue formation was reported. CONCLUSIONS: Real-world follow-up of patients from the ADMIRE-CD trial indicates that clinical remission of complex perianal fistulas can be sustained in the long term irrespective of whether it is achieved through darvadstrocel administration or maintenance treatment regimens and confirms a favorable long-term safety profile of darvadstrocel.

This retrospective chart review of patients treated with darvadstrocel indicates sustained remission and confirms a favorable safety profile up to 156 weeks after a single administration of stem cells for treatment of complex perianal fistulas in patients with Crohn's disease.

Common genetic determinants of vitamin D insufficiency: a genome-wide association study.

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Modeling continuous diagnostic test data using approximate Dirichlet process distributions.

There is now a large literature on the analysis of diagnostic test data. In the absence of a gold standard test, latent class analysis is most often used to estimate the prevalence of the condition of interest and the properties of the diagnostic tests. When test results are measured on a continuous scale, both parametric and nonparametric models have been proposed. Parametric methods such as the commonly used bi-normal model may not fit the data well; nonparametric methods developed to date have been relatively complex to apply in practice, and their properties have not been carefully evaluated in the diagnostic testing context. In this paper, we propose a simple yet flexible Bayesian nonparametric model which approximates a Dirichlet process for continuous data. We compare results from the nonparametric model with those from the bi-normal model via simulations, investigating both how much is lost in using a nonparametric model when the bi-normal model is correct and how much can be gained in using a nonparametric model when normality does not hold. We also carefully investigate the trade-offs that occur between flexibility and identifiability of the model as different Dirichlet process prior distributions are used. Motivated by an application to tuberculosis clustering, we extend our nonparametric model to accommodate two additional dichotomous tests and proceed to analyze these data using both the continuous test alone as well as all three tests together.

Long-term results following concomitant radiofrequency modified maze ablation for atrial fibrillation.

BACKGROUND AND AIM OF STUDY: This study evaluated the long-term outcome of linear, endocardial, radiofrequency (RF) atrial ablation for the treatment of atrial fibrillation (AF) concomitantly to open-heart procedures for acquired cardiac organic disease. METHODS: A saline-irrigated "pen-like" RF ablation catheter (Cardioblate(®), Medtronic, Minneapolis, MN, USA) was used to perform endocardial lines of conduction block in 293 patients with AF who underwent open-heart procedures between September 2000 and February 2008. RESULTS: Patients (age of 65 ± 11 years) underwent left atrial ablation for permanent (44%), paroxysmal (51%), or undetermined (4.4%) AF. Maintenance in sinus rhythm (SR) at discharge and at the end of follow-up (average 3.3 ± 1.2 years) was observed in 52% and 71% of patients, respectively. Preoperative type or duration of AF did not influence the results (p = NS). Multivariate analysis with a logistic regression model showed left atrial diameter and increasing age were independent predictors of recurrent AF. In this study, return to SR did not influence survival. CONCLUSIONS: This study confirmed that concomitant intraoperative RF ablation is an effective technique to restore long-term SR after cardiac surgery in patients with preoperative AF but does not influence long-term survival.

Long-acting antipsychotic medication as first-line treatment of first-episode psychosis with comorbid substance use disorder.

AIM: Substance use disorder (SUD) is highly prevalent among patients with first-episode psychosis (FEP) and associated with poor adherence and worst treatment outcomes. Although relapses are frequent in FEP, current literature on long-acting injectable antipsychotics (LAI-AP) use in FEP is scarce and studies often exclude patients with SUD. OBJECTIVES: To determine the impact of LAI-AP as first-line treatment on psychotic relapses or rehospitalizations in FEP patients with comorbid SUD (FEP-SUD). METHODS: This is a naturalistic, longitudinal, 3-year prospective and retrospective study on 237 FEP-SUD admitted in two EIS in Montreal, between 2005 and 2012. The patients were divided on the basis of first-line medication introduced, either oral antipsychotics (OAP, n = 206) or LAI-AP (n = 31). Baseline characteristics were compared using χ² test and analysis of variance, and Kaplan-Meier survival analysis was performed on relapse and rehospitalization. RESULTS: Compared to the OAP group, patients in the LAI-AP group presented worse prognostic factors (eg, history of homelessness). Despite this, the LAI-AP group presented a lower relapse rate (67.7% vs 76.7%), higher relapse-free survival time (694 vs 447 days, P = 0.008 in Kaplan-Meier analysis), and trends for reduced rehospitalization rates (48.4% vs 57.3%) and hospitalization-free survival time (813 vs 619 days, P = 0.065 Kaplan-Meier analysis). Of those receiving OAP as first-line, 41.3% were eventually switched to LAI-AP and displayed worst outcome in relapse and rehospitalization. CONCLUSION: LAI-AP should be strongly considered as first-line treatment of FEP-SUD patients since this pharmacological option reduces the risk of relapse and rehospitalization even in the individuals with poor prognostic factors.

Impact of early use of long-acting injectable antipsychotics on psychotic relapses and hospitalizations in first-episode psychosis.

Early relapse is frequent in the first-episode psychosis (FEP), often because of poor adherence to medication. Previous studies have shown positive impacts of long-acting injectable antipsychotics (LAI-AP) on relapse rates, while others have discerned no differences. This study describes the impact of early LAI-AP utilization on relapse and rehospitalization rates in FEP. A three-year, longitudinal, prospective, naturalistic study of all admissions of psychosis patients for early intervention services was conducted. Four hundred sixteen patients were subdivided into four groups according to the route of antipsychotic administration. Patients who received LAI-AP as their first treatment modality were more likely to exhibit poor prognostic factors at baseline. However, their relapse rate over time was similar to those with good prognostic factors at baseline who only received oral antipsychotics (OAP). Patients who were initially prescribed OAP and eventually switched to LAI-AP were more likely to relapse and to be rehospitalized, even if they manifested better functioning at baseline than those started on LAI-AP. Patients with poor prognosis in the early stage of their disease seem to benefit from early prescription of LAI-AP which can reduce and delay relapses and rehospitalizations. Because they are often still at school or at work at the time of their first episode of psychosis, relapse prevention seems particularly relevant to avoid functional deterioration.

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

Background: Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the µ-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of ß-arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids. Methods: Patients at 18 years of age or older, who underwent colorectal, orthopedic, cardiothoracic, bariatric, or general surgeries between June 2015 and May 2017 in 11 sites participating in the ATHENA trial who received postoperative analgesia either with IV oliceridine or with IV conventional opioids (e.g., morphine alone or in combination with other opioids) (CO cohort); and had a hospital stay >48 hours, were included in this retrospective analysis. Data from the ATHENA trial was used for the oliceridine cohort; and additional baseline characteristics were collected from medical charts. Data from medical charts were collected for all CO cohort patients. The two cohorts were balanced using an inverse probability weighting method. The primary outcome was the incidence of operationally defined opioid-induced respiratory depression (OIRD) in the two cohorts. Secondary outcomes included between-group comparison of the incidence of OIRD events among a subset of high-risk patients. Results: OIRD was significantly less in the oliceridine cohort compared to the CO cohort (8.0% vs. 30.7%; odds ratio: 0.139) (95% confidence interval [CI] 0.09-0.22; P < 0.0001). Likewise, the incidence of OIRD was lower among high-risk patients in the oliceridine cohort (9.1% vs. 34.7%; odds ratio: 0.136) (95% CI [0.09-0.22]; P < 0.0001) compared to the CO cohort. Conclusion: In this retrospective chart review study, patients receiving IV oliceridine for moderate to severe acute pain demonstrated a lower incidence of treatment emergent OIRD compared to patients who were treated with IV morphine either alone or with concomitant administration of other opioids.

Real-World Treatment Patterns and Characteristics Among Patients with Agitation and Dementia in the United States: Findings from a Large, Observational, Retrospective Chart Review.

BACKGROUND: Few studies have examined patient characteristics and treatment patterns among patients with dementia and agitation in the United States (US). OBJECTIVE: To examine real-world treatment patterns and characteristics of patients with agitation related to dementia who were treated with antipsychotics in US residential care and community-based settings. METHODS: This retrospective chart review collected US physician-level data from patients 55 to 90 years old initiated on an antipsychotic medication for the treatment of agitation related to dementia from January 2018 to May 2018. Clinical characteristics and treatment patterns were assessed overall and stratified by residential care and community-based settings. RESULTS: A total of 313 participating physicians, 59.5% of whom were primary care physicians, abstracted 801 patient charts (residential care: n = 312; community-based: n = 489). Of patients with agitation who were initiated on an antipsychotic, most patients (74.5%) were initiated within 3 months of the onset of their studied agitation episode, and 62.8% experienced multiple agitation episodes before initiation. While non-pharmacological therapies are recommended first-line approach for agitation in dementia, use of non-pharmacological therapy before initiation of antipsychotics was reported for only 37.8% of patients in residential care and 21.3% in community-based settings. CONCLUSION: Most patients were initiated on an antipsychotic treatment after multiple episodes of agitation and largely without initial non-pharmacological therapy, suggesting that current treatment guideline recommendations for first-line non-pharmacological intervention may not be adequately followed in clinical practice. Understanding the clinical burden and treatment patterns among dementia patients with agitation is imperative for effective disease management.

Matching-Adjusted Indirect Comparison of the Efficacy of Apalutamide and Enzalutamide with ADT in the Treatment of Non-Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Apalutamide and enzalutamide are next-generation androgen receptor inhibitors that demonstrated efficacy in placebo-controlled studies (SPARTAN for apalutamide; PROSPER for enzalutamide) when used in combination with androgen deprivation therapy (ADT) for treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the absence of comparative studies between these agents, the present study sought to indirectly compare metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC who received these therapies. METHODS: Individual patient-level data from SPARTAN (apalutamide plus ADT) and published data from PROSPER (enzalutamide plus ADT) were utilized. An anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting the patients from the SPARTAN study to match baseline characteristics reported for PROSPER. Hazard ratios (HRs) for MFS and OS were re-estimated for SPARTAN using weighted Cox proportional hazards models and indirectly compared with those of PROSPER using a Bayesian network meta-analysis. RESULTS: From the SPARTAN population (N = 1207), a total of 1171 patients were matched to the PROSPER population (N = 1401). The recalculated HRs (95% confidence interval) for apalutamide versus ADT based on the reweighted SPARTAN data to mimic the PROSPER patient population were 0.26 (0.21; 0.33) for MFS and 0.62 (0.41; 0.94) for OS. MAIC-based HRs (95% credible interval) for apalutamide versus enzalutamide were 0.91 (0.68; 1.22) for MFS and 0.77 (0.46; 1.30) for OS. The Bayesian probabilities of apalutamide being more effective than enzalutamide were 73.6% for MFS and 83.5% for OS. CONCLUSIONS: MAIC results suggest that nmCRPC patients treated with apalutamide have a higher probability of a more favorable MFS and OS compared with those treated with enzalutamide.