Introduction: Rapid diagnostic algorithms using high-sensitivity cardiac troponin can rapidly diagnose or exclude acute myocardial infarction (MI). However, multiple algorithms have been proposed and it is unclear if some outperform others. The objective of this study was to prospectively compare the diagnostic performance of 1- and 2-hour algorithms in clinical practice in a Canadian population. Methods: Emergency department patients with chest pain had high-sensitivity cardiac troponin-T (hs-cTnT) collected on presentation and 1- and 2-hours later at a single academic tertiary hospital and regional percutaneous coronary intervention site over a 2-year period. The primary outcome was index MI, the secondary outcome was 30-day major adverse cardiac events (MACE). All outcomes were 2 physician adjudicated. Results: We enrolled 1,167 patients with hs-cTnT collected on ED presentation. Of these, 350 had a valid 1-hour and 550 had a 2-hour hs-cTnT sample. Index MI prevalence was ~11%. Sensitivity of the 1- and 2-hour algorithms for index MI was 97.3% (95% CI 85.8-99.9%) and 100% (95% CI 91.6-100%) and for 30-day MACE was 80.9% (95% CI 66.7-90.9%) and 83.3% (95% CI 73.2-90.8%), respectively. The 1-hour algorithm was 96.3% specific for index MI (95% CI 93.8-98.2%) whereas specificity for the 2-hour algorithm was 97.9% (95% CI 96.3-100%). Both algorithms classified about one-quarter of patients in an indeterminate observational zone with an ~11% MI prevalence. Conclusion: Both the 1- and 2-hour algorithms were highly sensitive and specific for MI, but were less sensitive for 30-day MACE. However, the 2-hour algorithm trended toward better performance, likely because its larger delta cutoffs reduce the risk of misclassification owing to analytic variability. These findings suggest algorithms using larger delta cutoffs may provide a greater margin of safety. Further comparative evaluation of rapid diagnostic algorithms using different cutoffs and characterization of patients in the observational zone is warranted.

Introduction: Very low high-sensitivity troponin-T (hs-cTnT) concentrations on presentation can rule out acute myocardial infarction (AMI), but the ability to identify patients at low risk of 30-day major adverse cardiac events (MACE) is less clear. This study examines the sensitivity of low concentrations of hs-cTnT on presentation to rule out 30-day MACE. Methods: This prospective cohort study enrolled emergency department chest pain patients with non-ischemic ECGs who underwent AMI rule-out with an hs-cTnT assay. The primary outcome was 30-day MACE; secondary outcomes were individual MACE components. Because guidelines recommend using a single hs-cTnT strategy only for patients with more than 3-hours since symptom onset, a subgroup analysis was performed for this population. Outcomes were adjudicated based on review of medical records and telephone follow-up. Results: Of 1,167 patients enrolled, 125 (10.7%) experienced 30-day MACE and 97 (8.3%) suffered AMI on the index visit. More than one-third (35.6%) had presenting hs-cTnT concentrations below the limit of detection (5ng/L), which was 94.4% (95%CI 88.8-97.7%) sensitive for 30-day MACE and 99.0% (95%CI 94.5-100%) sensitive for index AMI. Of 292 (25.0%) patients with hs-cTnT < 5ng/L and at least 3-hours since symptom onset, only 3 experienced 30-day MACE (sensitivity 97.6%, 95%CI 93.2-100%) and none suffered AMI within 30-days (sensitivity 100%, 95%CI 96.3-100%). Conclusion: Among patients with non-ischemic ECGs and >3-hours since symptom onset, low hs-cTnT concentrations on presentation confer a very low risk of 30-day MACE. In the absence of a high risk clinical presentation, further risk stratification is likely to be low yield.

There is strong evidence that foods containing dietary fibre protect against colorectal cancer, resulting at least in part from its anti-proliferative properties. This study aimed to investigate the effects of supplementation with two non-digestible carbohydrates, resistant starch (RS) and polydextrose (PD), on crypt cell proliferative state (CCPS) in the macroscopically normal rectal mucosa of healthy individuals. We also investigated relationships between expression of regulators of apoptosis and of the cell cycle on markers of CCPS. Seventy-five healthy participants were supplemented with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design in a randomised, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study). CCPS was assessed, and the expression of regulators of the cell cycle and of apoptosis was measured by quantitative PCR in rectal mucosal biopsies. SCFA concentrations were quantified in faecal samples collected pre- and post-intervention. Supplementation with RS increased the total number of mitotic cells within the crypt by 60 % (P = 0·001) compared with placebo. This effect was limited to older participants (aged ≥50 years). No other differences were observed for the treatments with PD or RS as compared with their respective controls. PD did not influence any of the measured variables. RS, however, increased cell proliferation in the crypts of the macroscopically-normal rectum of older adults. Our findings suggest that the effects of RS on CCPS are not only dose, type of RS and health status-specific but are also influenced by age.

Major depressive disorder (MDD) is often associated with disturbed circadian rhythms. However, a definitive causal role for functioning circadian clocks in mood regulation has not been established. We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Furthermore, they displayed greater weight gain, which is frequently observed in MDD patients. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In fact, circadian rhythm disturbances have been linked to individual psychiatric and metabolic disorders, but circadian aspects of such disorders have not been considered previously in an integrated manner. Treating and preventing disturbances of circadian clocks in patients suffering psychiatric and metabolic symptoms may be a central element for therapies targeting both disorders concurrently.

We give a new proof of a result of Sullivan [Hyperbolic geometry and homeomorphisms, in Geometric topology (ed. J. C. Cantrell), pp. 543–555 (Academic Press, New York, 1979)] establishing that all finite volume hyperbolic n-manifolds have a finite cover admitting a spin structure. In addition, in all dimensions greater than or equal to 5, we give the first examples of finite-volume hyperbolic n-manifolds that do not admit a spin structure.

Knowledge of population structure and breed composition of a population can be advantageous for a number of reasons; these include designing optimal (cross)breeding strategies in order to maximise non-additive genetic effects, maintaining flockbook integrity by authenticating animals being registered and as a quality control measure in the genotyping process. The objectives of the present study were to 1) describe the population structure of 24 sheep breeds, 2) quantify the breed composition of both flockbook-recorded and crossbred animals using single nucleotide polymorphism BLUP (SNP-BLUP), and 3) quantify the accuracy of breed composition prediction from low-density genotype panels containing between 2000 and 6000 SNPs. In total, 9334 autosomal SNPs on 11 144 flockbook-recorded animals and 1172 crossbred animals were used. The population structure of all breeds was characterised by principal component analysis (PCA) as well as the pairwise breed fixation index (Fst). The total number of animals, all of which were purebred, included in the calibration population for SNP-BLUP was 2579 with the number of animals per breed ranging from 9 to 500. The remaining 9559 flockbook-recorded animals, composite breeds and crossbred animals represented the test population; three breeds were excluded from breed composition prediction. The breed composition predicted using SNP-BLUP with 9334 SNPs was considered the gold standard prediction. The pairwise breed Fst ranged from 0.040 (between the Irish Blackface and Scottish Blackface) to 0.282 (between the Border Leicester and Suffolk). Principal component analysis revealed that the Suffolk from Ireland and the Suffolk from New Zealand formed distinct, non-overlapping clusters. In contrast, the Texel from Ireland and that from New Zealand formed integrated, overlapping clusters. Composite animals such as the Belclare clustered close to its founder breeds (i.e., Finn, Galway, Lleyn and Texel). When all 9334 SNPs were used to predict breed composition, an animal that had a majority breed proportion predicted to be ≥0.90 was defined as purebred for the present study. As the panel density decreased, the predicted breed proportion threshold, used to identify animals as purebred, also decreased (≥0.85 with 6000 SNPs to ≥0.60 with 2000 SNPs). In all, results from the study suggest that breed composition for purebred and crossbred animals can be determined with SNP-BLUP using ≥5000 SNPs.

Despite trends towards greater LGBTQ (lesbian, gay, bisexual, transgender, and queer) rights in industrialized democracies, the rights of sexual minorities have become increasingly politicized and restricted throughout Africa. Recognizing religion's central role in shaping attitudes toward gays and lesbians, we hypothesize that local religious diversity could expose individuals to alternative religious perspectives, engender tolerance toward marginalized communities, and therefore dislodge dogmatic beliefs about social issues. Employing cross-national Afrobarometer survey data from 33 countries with an index of district-level religious concentration, we find that respondents living in religiously pluralistic communities are 4–5 points more likely to express tolerance of homosexual neighbors (50% increase) compared to those in homogeneous locales. This effect is not driven by outlier countries, the existence of specific religious affiliations within diverse communities, respondents' religiosity, or other observable and latent factors at the country, sub-national, district, and individual level. Further robustness checks address potential threats to validity. We conclude that religious diversity can foster inclusion of sexual minorities in Africa.

Discrete episodes of overconsumption may induce a positive energy balance and impair metabolic control. However, the effects of an ecologically relevant, single day of balanced macronutrient overfeeding are unknown. Twelve healthy men (of age 22 (sd 2) years, BMI 26·1 (sd 4·2) kg/m2) completed two 28 h, single-blind experimental trials. In a counterbalanced repeated measures design, participants either consumed their calculated daily energy requirements (energy balance trial (EB): 10 755 (sd 593) kJ) or were overfed by 50 % (overfeed trial (OF): 16 132 (sd 889) kJ) under laboratory supervision. Participants returned to the laboratory the next day, after an overnight fast, to complete a mixed-meal tolerance test (MTT). Appetite was not different between trials during day 1 (P>0·211) or during the MTT in the fasted or postprandial state (P>0·507). Accordingly, plasma acylated ghrelin, total glucagon-like peptide-1 and total peptide YY concentrations did not differ between trials during the MTT (all P>0·335). Ad libitum energy intake, assessed upon completion of the MTT, did not differ between trials (EB 6081 (sd 2260) kJ; OF 6182 (sd 1960) kJ; P=0·781). Plasma glucose and insulin concentrations were not different between trials (P>0·715). Fasted NEFA concentrations were lower in OF compared with EB (P=0·005), and TAG concentrations increased to a greater extent on OF than on EB during the MTT (P=0·009). The absence of compensatory changes in appetite-related variables after 1 d of mixed macronutrient overfeeding highlights the limited physiological response to defend against excess energy intake. This supports the concept that repeated discrete episodes of overconsumption may promote weight gain, while elevations in postprandial lipaemia may increase CVD risk.

We previously demonstrated that electrode architectures comprising nanoscale birnessite-like MnOx affixed to three-dimensional carbon nanofoam (CNF) scaffolds offer performance advantages when used as cathodes in rechargeable zinc-ion cells. To discern chemical and physical changes at the MnOx@CNF electrode upon deep charge/discharge in aqueous Zn2+-containing electrolytes, we deploy electroanalytical methods and ex situ characterization by microscopy, elemental analysis, x-ray photoelectron spectroscopy, x-ray diffraction, and x-ray pair distribution function analyses. Our findings verify that redox processes at the MnOx are accompanied by reversible precipitation/dissolution of crystalline zinc hydroxide sulfate (Zn4(OH)6(SO4)·xH2O), mediated by the more uniformly reactive electrode structure inherent to the CNF scaffold.

Bowel cancer risk is strongly influenced by lifestyle factors including diet and physical activity. Several studies have investigated the effects of adherence to the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations on outcomes such as all-cause and cancer-specific mortality, but the relationships with molecular mechanisms that underlie the effects on bowel cancer risk are unknown. This study aimed to investigate the relationships between adherence to the WCRF/AICR cancer prevention recommendations and wingless/integrated (WNT)-pathway-related markers of bowel cancer risk, including the expression of WNT pathway genes and regulatory microRNA (miRNA), secreted frizzled-related protein 1 (SFRP1) methylation and colonic crypt proliferative state in colorectal mucosal biopsies. Dietary and lifestyle data from seventy-five healthy participants recruited as part of the DISC Study were used. A scoring system was devised including seven of the cancer prevention recommendations and smoking status. The effects of total adherence score and scores for individual recommendations on the measured outcomes were assessed using Spearman’s rank correlation analysis and unpaired t tests, respectively. Total adherence score correlated negatively with expression of Myc proto-oncogene (c-MYC) (P=0·039) and WNT11 (P=0·025), and high adherers had significantly reduced expression of cyclin D1 (CCND1) (P=0·042), WNT11 (P=0·012) and c-MYC (P=0·048). Expression of axis inhibition protein 2 (AXIN2), glycogen synthase kinase (GSK3β), catenin β1 (CTNNB1) and WNT11 and of the oncogenic miRNA miR-17 and colonic crypt kinetics correlated significantly with scores for individual recommendations, including body fatness, red meat intake, plant food intake and smoking status. The findings from this study provide evidence for positive effects of adherence to the WCRF/AICR cancer prevention recommendations on WNT-pathway-related markers of bowel cancer risk.

Introduction: ex-specific diagnostic cutoffs may improve the test characteristics of high-sensitivity troponin assays for the diagnosis of myocardial infarction. Sex-specific cutoffs for ruling in MI improve the sensitivity of the assay for MI among women, and improve the specificity of diagnosis among men. We hypothesized that the use of sex-specific high-sensitivity Troponin T (hsTnT) cutoffs for ruling out MI at the time of ED arrival would improve the classification efficiency of the assay by enabling more patients to have MI ruled out at the time of ED arrival while maintaining diagnostic sensitivity. The objective of this study was to quantify the test characteristics of sex-specific cutoffs of an hsTnT assay for acute myocardial infarction (AMI) when performed at ED arrival in patients with chest pain. Methods: This retrospective study included consecutive ED patients with suspected cardiac chest pain evaluated in four urban EDs were, excluding those with ST-elevation AMI, cardiac arrest or abnormal kidney function. The primary outcomes was AMI at 7 days. Secondary outcomes included major adverse cardiac events (MACE: all-cause mortality, AMI and revascularization) and the individual MACE components. We quantified test characteristics (sensitivity, negative predictive value, likelihood ratios and proportion of patients ruled out) for multiple combinations of sex-specific rule-out cutoffs. We calculated net reclassification improvement compared to universal rule-out cutoffs of 5ng/L (the assays limit of detection) and 6ng/L (the FDA-approved limit of quantitation for US laboratories). Results: 7130 patients, including 3931 men and 3199 women, were included. The 7-day incidence of AMI was 7.38% among men and 3.78% among women. Universal cutoffs of 5 and 6 ng/L ruled out AMI with 99.7% sensitivity in 33.6 and 42.2% of patients. The best-performing combination of sex-specific cutoffs (8g/L for men and 6ng/L for men) ruled out AMI with 98.7% sensitivity in 51.9% of patients. Conclusion: Sex-specific hsTnT cutoffs for ruling out AMI at ED arrival may achieve substantial improvement in classification performance, enabling more patients to be ruled out at ED arrival, while maintaining acceptable diagnostic sensitivity for AMI. Universal and sex-specific rule-out cutoffs differ by only small changes in hsTnT concentration. Therefore, these findings should be confirmed in other datasets.

Introduction: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular events, and have worse outcomes following acute myocardial infarction (AMI). Cardiac troponin is often elevated in CKD, making the diagnosis of AMI challenging in this population. We sought to quantify test characteristics for AMI of a high-sensitivity troponin T (hsTnT) assay performed at emergency department (ED) arrival in CKD patients with chest pain, and to derive rule-out cutoffs specific to patient subgroups stratified by estimated glomerular filtration rate (eGFR). We also quantified the sensitivity and classification performance of the assays limit of detection (5 ng/L) and the FDA-approved limit of quantitation (6 ng/L) for ruling out AMI at ED arrival. Methods: Consecutive patients in four urban EDs from the 2013 calendar year with suspected cardiac chest pain who had a Roche Elecsys hsTnT assay performed on arrival were included f. This analysis was restricted to patients with an eGFR< 60 ml/min/1.73m2. The primary outcome was 7-day AMI. Secondary outcomes included major adverse cardiac events (death, AMI and revascularization). Test characteristics were calculated and ROC curves were generated for eGFR subgroups. Results: 1416 patients were included. 7-day AMI incidence was 10.1%. 73% of patients had an initial hsTnT concentration greater than the assays 99th percentile (14 ng/L). TCurrently accepted cutoffs to rule out MI at ED arrival ( 5 ng/L and 6 ng/L) had 100% sensitivity for AMI, but no patients with an eGFR less than 30 ml/min/1.73M had hsTnT concentrations below these thresholds. We derived eGFR-adjusted cutoffs to rule out MI with sensitivity >98% at ED arrival, which were able to rule out 6-42% of patients, depending on eGFR category. The proportion of patients able to be accurately ruled-in with a single hsTnT assay was substantially lower among patients with an eGFR <30 ml/min/1.73m2 (6-20% vs 25-43%). We also derived eGFR-adjusted cutoffs to rule-in AMI with specificity >90%, which accurately ruled-in up to 18% of patients. Conclusion: Cutoffs achieving acceptable diagnostic performance for AMI using single hsTnT sampling on ED arrival may have limited clinical utility, particularly among patients with very low eGFR. The ideal diagnostic strategy for AMI in patients with CKD likely involves serial high-sensitivity troponin testing with diagnostic thresholds customized to different eGFR categories.