The neighbourhood environment and profiles of the metabolic syndrome

Background: There is a dearth of studies on how neighbourhood environmental attributes relate to the metabolic syndrome (MetS) and profiles of MetS components. We examined the associations of interrelated aspects of the neighbourhood environment, including air pollution, with MetS status and profiles of MetS components. Methods: We used socio-demographic and MetS-related data from 3681 urban adults who participated in the 3rd wave of the Australian Diabetes, Obesity and Lifestyle Study. Neighbourhood environmental attributes included area socio-economic status (SES), population density, street intersection density, non-commercial land use mix, percentages of commercial land, parkland and blue space. Annual average concentrations of NO2 and PM2.5 were estimated using satellite-based land-use regression models. Latent class analysis (LCA) identified homogenous groups (latent classes) of participants based on MetS components data. Participants were then classified into five metabolic profiles according to their MetS-components latent class and MetS status. Generalised additive mixed models were used to estimate relationships of environmental attributes with MetS status and metabolic profiles. Results: LCA yielded three latent classes, one including only participants without MetS ("Lower probability of MetS components" profile). The other two classes/profiles, consisting of participants with and without MetS, were "Medium-to-high probability of high fasting blood glucose, waist circumference and blood pressure" and "Higher probability of MetS components". Area SES was the only significant predictor of MetS status: participants from high SES areas were less likely to have MetS. Area SES, percentage of commercial land and NO2 were associated with the odds of membership to healthier metabolic profiles without MetS, while annual average concentration of PM2.5 was associated with unhealthier metabolic profiles with MetS. Conclusions: This study supports the utility of operationalising MetS as a combination of latent classes of MetS components and MetS status in studies of environmental correlates. Higher socio-economic advantage, good access to commercial services and low air pollution levels appear to independently contribute to different facets of metabolic health. Future research needs to consider conducting longitudinal studies using fine-grained environmental measures that more accurately characterise the neighbourhood environment in relation to behaviours or other mechanisms related to MetS and its components

The associations of COVID-19 lockdown restrictions with longer-term activity levels of working adults with type 2 diabetes : Cohort study

Background: Lockdown restrictions reduce COVID-19 community transmission; however, they may pose challenges for noncommunicable disease management. A 112-day hard lockdown in Victoria, Australia (commencing March 23, 2020) coincided with an intervention trial of reducing and breaking up sitting time in desk workers with type 2 diabetes who were using a provided consumer-grade activity tracker (Fitbit). Objective: This study aims to compare continuously recorded activity levels preceding and during COVID-19 lockdown restrictions among working adults with type 2 diabetes participating in a sitting less and moving more intervention. Methods: A total of 11 participants (n=8 male; mean age 52.8, SD 5 years) in Melbourne, Australia had Fitbit activity tracked before (mean 122.7, SD 47.9 days) and during (mean 99.7, SD 62.5 days) citywide COVID-19 lockdown restrictions. Regression models compared device (Fitbit Inspire HR)–derived activity (steps; metabolic equivalent tasks [METs]; mean time in sedentary, lightly, fairly, and very active minutes; and usual bout durations) during restrictions to prerestrictions. Changes in activity were statistically significant when estimates (Δ%) did not intercept zero. Results: Overall, there was a decrease in mean steps (–1584 steps/day; Δ% –9%, 95% CI –11% to –7%); METs (–83 METs/day; Δ% –5%, 95% CI –6% to –5%); and lightly active (Δ% –4%, 95% CI –8% to –1%), fairly active (Δ% –8%, 95% CI –21% to –15%), and very active (Δ% –8%, 95% CI –11% to –5%) intensity minutes per day, and increases in mean sedentary minutes per day (51 mins/day; Δ% 3%, 95% CI 1%-6%). Only very active (+5.1 mins) and sedentary (+4.3 mins) bout durations changed significantly. Conclusions: In a convenience sample of adults with type 2 diabetes, COVID-19 lockdown restrictions were associated with decreases in overall activity levels and increases in very active and sedentary bout durations. A Fitbit monitor provided meaningful continuous long-term data in this context. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12618001159246; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261800115924

Benefits for Type 2 Diabetes of Interrupting Prolonged Sitting With Brief Bouts of Light Walking or Simple Resistance Activities

OBJECTIVE To determine whether interrupting prolonged sitting with brief bouts of light-intensity walking (LW) or simple resistance activities (SRA) improves postprandial cardiometabolic risk markers in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men 62 ± 6 years old) underwent the following 8-h conditions on three separate days (with 6–14 days washout): uninterrupted sitting (control) (SIT), sitting plus 3-min bouts of LW (3.2 km · h−1) every 30 min, and sitting plus 3-min bouts of SRA (half-squats, calf raises, gluteal contractions, and knee raises) every 30 min. Standardized meals were consumed during each condition. Incremental areas under the curve (iAUCs) for glucose, insulin, C-peptide, and triglycerides were compared between conditions. RESULTS Compared with SIT, both activity-break conditions significantly attenuated iAUCs for glucose (SIT mean 24.2 mmol · h · L−1 [95% CI 20.4–28.0] vs. LW 14.8 [11.0–18.6] and SRA 14.7 [10.9–18.5]), insulin (SIT 3,293 pmol · h · L−1 [2,887–3,700] vs. LW 2,104 [1,696–2,511] and SRA 2,066 [1,660–2,473]), and C-peptide (SIT 15,641 pmol · h · L−1 [14,353–16,929] vs. LW 11,504 [10,209–12,799] and SRA 11,012 [9,723–12,301]) (all P < 0.001). The iAUC for triglycerides was significantly attenuated for SRA (P < 0.001) but not for LW (SIT 4.8 mmol · h · L−1 [3.6–6.0] vs. LW 4.0 [2.8–5.1] and SRA 2.9 [1.7–4.1]). CONCLUSIONS Interrupting prolonged sitting with brief bouts of LW or SRA attenuates acute postprandial glucose, insulin, C-peptide, and triglyceride responses in adults with T2D. With poor adherence to structured exercise, this approach is potentially beneficial and practical

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Active aging and public health : Evidence, implications, and opportunities

By 2050, 20% of the world's population will be over the age of 65 years, with projections that 80% of older adults will be living in low- to middle-income countries. Physical inactivity and sedentary time are particularly high in older adults, presenting unique public health challenges. In this article, we first review evidence that points to multiple beneficial outcomes of active aging, including better physical function, cognitive function, mental health, social health, and sleep and suggest the need to shift the research focus from chronic disease outcomes to more relevant outcomes that affect independence and quality of life. Second, we review the critical role of age-friendly environments in facilitating active aging equitably across different countries and cultures. Finally, we consider emerging opportunities related to social engagement and technology-enabled mobility that can facilitate active aging. In all these contexts, it is a priority to understand and address diversity within the global aging population

Sitting less and moving more: Improved glycaemic control for type 2 diabetes prevention and management

Epidemiological evidence indicates that excessive time spent in sedentary behaviours ( too much sitting ) is associated with an increased risk of type 2 diabetes ( T2D ). Here, we highlight findings of experimental studies corroborating and extending the epidemiological evidence and showing the potential benefits for T2D of reducing and breaking up sitting time across the whole day. We also discuss future research opportunities and consider emerging implications for T2D prevention and management. This new evidence is stimulating an expansion of diabetes-related physical activity guidelines—suggesting that in addition to moderate-vigorous physical activity, reducing and regularly interrupting prolonged sitting time is likely to have important and varied benefits across the spectrum of diabetes risk

Breaking Sitting Time with Physical Activity Increases Energy Expenditure but Does Not Alter Postprandial Metabolism in Girls

Purpose: Young people spend a substantial proportion of their time at school sedentary; therefore, this setting represents an important target for interventions aimed at displacing sedentary time with physical activity. This study aimed to examine the postprandial metabolic effects of breaking sedentary time by accumulating walking and repeated bouts of nonambulatory standing during simulated school days in inactive adolescent girls. Methods: Seventeen girls (mean ± SD = 12.8 ± 0.4 yr) completed two 3-d experimental conditions. On days 1 and 2 of the standing + walking (STD-WLK) experimental trial, participants interrupted sedentary time by completing 4 × 10 min bouts of self-paced walking and accumulated 18 × 5 min standing bouts during each simulated school day. On day 3 of STD-WLK, participants attended school as normal with no additional physical activity or standing prescribed. On all 3 d of the control condition (CON), participants attended school as normal with no physical activity intervention. On days 2 and 3 of both STD-WLK and CON, a baseline capillary blood sample was provided to determine fasting [TAG] and [glucose]. Participants then consumed a standardized breakfast (0 h) and lunch (4.7 h), and blood samples were provided postprandially at 2.7, 5.3, and 7.3 h for [TAG] and [glucose]. Results: Energy expenditure was 28% (95% confidence interval = 8% to 52%) higher during school hours on day 1 and day 2 during STD-WLK compared with CON (2171 vs 1693 kJ; effect size = 0.89, P = 0.008). However, no reduction of fasting or postprandial [TAG] or [glucose] was observed on day 2 or day 3 (P ≥ 0.245). Conclusions: Two consecutive days of breaking prolonged sitting with self-paced walking and intermittent standing had no meaningful effect on postprandial metabolism in adolescent girls

Label-Free (XIC) Quantification of Venom Procoagulant and Neurotoxin Expression in Related Australian Elapid Snakes Gives Insight into Venom Toxicity Evolution

This study demonstrates a direct role of venom protein expression alteration in the evolution of snake venom toxicity. Avian skeletal muscle contractile response to exogenously administered acetylcholine is completely inhibited upon exposure to South Australian and largely preserved following exposure to Queensland eastern brown snake <i>Pseudonaja textilis</i> venom, indicating potent postsynaptic neurotoxicity of the former and lack thereof of the latter venom. Label-free quantitative proteomics reveals extremely large differences in the expression of postsynaptic three-finger α-neurotoxins in these venoms, explaining the difference in the muscle contractile response and suggesting that the type of toxicity induced by venom can be modified by altered expression of venom proteins. Furthermore, the onset of neuromuscular paralysis in the rat phrenic nerve-diaphragm preparation occurs sooner upon exposure to the venom (10 μg/mL) with high expression of α-neurotoxins than the venoms containing predominately presynaptic β-neurotoxins. The study also finds that the onset of rat plasma coagulation is faster following exposure to the venoms with higher expression of venom prothrombin activator subunits. This is the first quantitative proteomic study that uses extracted ion chromatogram peak areas (MS1 XIC) of distinct homologous tryptic peptides to directly show the differences in the expression of venom proteins