Microbial Features Linked to Medication Strategies in Cardiometabolic Disease Management.

Human gut microbiota are recognized as critical players in both metabolic disease and drug metabolism. However, medication-microbiota interactions in cardiometabolic diseases are not well understood. To gain a comprehensive understanding of how medication intake impacts the gut microbiota, we investigated the association of microbial structure with the use of single or multiple medications in a cohort of 134 middle-aged adults diagnosed with cardiometabolic disease, recruited from Alberta's Tomorrow Project. Predominant cardiometabolic prescription medication classes (12 total) were included in our analysis. Multivariate Association with Linear Model (MaAsLin2) was employed and results were corrected for age, BMI, sex, and diet to evaluate the relationship between microbial features and single- or multimedication use. Highly individualized microbiota profiles were observed across participants, and increasing medication use was negatively correlated with α-diversity. A total of 46 associations were identified between microbial composition and single medications, exemplified by the depletion of Akkermansia muciniphila by ß-blockers and statins, and the enrichment of Escherichia/Shigella and depletion of Bacteroides xylanisolvens by metformin. Metagenomics prediction further indicated alterations in microbial functions associated with single medications such as the depletion of enzymes involved in energy metabolism encoded by Eggerthella lenta due to ß-blocker use. Specific dual medication combinations also had profound impacts, including the depletion of Romboutsia and Butyriciocccus by statin plus metformin. Together, these results show reductions in bacterial diversity as well as species and microbial functional potential associated with both single- and multimedication use in cardiometabolic disease.

Dose-Responsive Effects of Iron Supplementation on the Gut Microbiota in Middle-Aged Women.

Oral iron supplementation is the first-line treatment for addressing iron deficiency, a concern particularly relevant to women who are susceptible to sub-optimal iron levels. Nevertheless, the impact of iron supplementation on the gut microbiota of middle-aged women remains unclear. To investigate the association between iron supplementation and the gut microbiota, healthy females aged 40-65 years (n = 56, BMI = 23 ± 2.6 kg/m2) were retrospectively analyzed from the Alberta's Tomorrow Project. Fecal samples along with various lifestyle, diet, and health questionnaires were obtained. The gut microbiota was assessed by 16S rRNA sequencing. Individuals were matched by age and BMI and classified as either taking no iron supplement, a low-dose iron supplement (6-10 mg iron/day), or high-dose iron (>100 mg/day). Compositional and functional analyses of microbiome data in relation to iron supplementation were investigated using various bioinformatics tools. Results revealed that iron supplementation had a dose-dependent effect on microbial communities. Elevated iron intake (>100 mg) was associated with an augmentation of Proteobacteria and a reduction in various taxa, including Akkermansia, Butyricicoccus, Verrucomicrobia, Ruminococcus, Alistipes, and Faecalibacterium. Metagenomic prediction further suggested the upregulation of iron acquisition and siderophore biosynthesis following high iron intake. In conclusion, adequate iron levels are essential for the overall health and wellbeing of women through their various life stages. Our findings offer insights into the complex relationships between iron supplementation and the gut microbiota in middle-aged women and underscore the significance of iron dosage in maintaining optimal gut health.

KDM4C promotes mouse hippocampal neural stem cell proliferation through modulating ApoE expression.

KDM4C is implicated in the regulation of cell proliferation, differentiation, and maintenance in various stem cell types. However, its function in neural stem cells (NSCs) remains poorly understood. Therefore, this study aims to investigate the role and regulatory mechanism of KDM4C in NSCs. Primary hippocampal NSCs were isolated from neonatal mice, and both in vivo and in vitro lentivirus-mediated overexpression of KDM4C were induced in these hippocampal NSCs. Staining results revealed a significant increase in BrdU- and Ki-67-positive cells, along with an elevated number of cells in S phases due to KDM4C overexpression. Subsequently, RNA-seq was employed to analyze gene expression changes following KDM4C upregulation. GO enrichment analysis, KEGG analysis, and GSEA highlighted KDM4C-regulated genes associated with development, cell cycle, and neurogenesis. Protein-protein interaction analysis uncovered that ApoE protein interacts with several genes (top 10 upregulated and downregulated) regulated by KDM4C. Notably, knocking down ApoE mitigated the proliferative effect induced by KDM4C overexpression in NSCs. Our study demonstrates that KDM4C overexpression significantly upregulates ApoE expression, ultimately promoting proliferation in mouse hippocampal NSCs. These findings provide valuable insights into the molecular mechanisms governing neurodevelopment, with potential implications for therapeutic strategies in neurological disorders.

Comparison of the analgesic effect of dezocine and esketamine in combination with sufentanil respectively after laparoscopic cholecystectomy: a prospective randomized controlled study.

BACKGROUND: Sufentanil in combination with dezocine or esketamine is often used for postoperative analgesia. However, there is a lack of clinical evidence of efficacy. This study compares the analgesic effects of esketamine and dezocine combined with sufentanil for relieving pain after laparoscopic cholecystectomy(LC). METHODS: A total of 58 patients were randomly assigned to the esketamine group (ES group) and dezocine group (DE group). In the ES group, 1.5 mg/kg esketamine was used. In the DE group, 0.3 mg/kg dezocine was used. Primary outcome measures were Visual Analog Scale (VAS) score at 4 h, 8 h, 24 h and 48 h after surgery. The second outcome measures were Interleukin-6 (IL-6) and C-reactive protein (CRP) levels in the serum 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery. RESULTS: The VAS scores at 4 h, 8 h, 24 h and 48 h after the surgery in the ES group vs DE group were 2.70 vs 3.50(P=0.013),2.35 vs 3.15(P=0.004),1.69 vs 2.58(P=0.002), and 1.50 vs 2.26(P=0.002), respectively. The serum IL-6 concentrations 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery in the ES group and DE group were 34.39 and 34.12(P=0.901),112.33 and 129.60(P=0.014), and 89.69 and 108.46(P<0.001), respectively. The CRP levels in serum 10 minutes before anesthesia induction, and at 24 h and 48 h after the surgery in the ES group and DE group were 5.99 and 5.86(P=0.639), 28.80 and 35.37(P<0.001), and 23.17 and 30.11(P<0.001), respectively. CONCLUSION: For postoperative pain after LC, 1.5mg/kg esketamine provided better analgesia and reduced inflammation levels than 0.3mg/kg dezocine. TRIAL REGISTRATION: This trial was registered in the China Clinical Research Information Center in 31/05/2023 : https://www.chictr.org.cn/bin/home (Registration number: ChiCTR2300072011).

Factors associated with mental health service use during the pandemic: Initiation and barriers.

BACKGROUND: Scarce are the studies focusing on initiation of new mental health service use (MHSU) and distinguishing individuals who have sought services but have been unsuccessful in accessing these. AIMS: Assessing the factors associated with initiating new MHSU as compared to no MHSU due to self-reported no need, no MHSU due to health system and personal barriers and MHSU using resources already in place. METHODS: The sample included participants (n = 16,435) in the five established regional cohorts of the Canadian Partnership for Tomorrow's Health (CanPath) who responded to the CanPath COVID-19 health surveys (May-December 2020 and January-June 2021). Multinomial regression analyses were carried out to study MHSU since the pandemic (March 2020) as a function of predisposing, enabling and need factors. Analyses were carried out in the overall sample and restricted to those with moderate and severe symptoms (MSS) of depression and/or anxiety (n = 2,237). RESULTS: In individuals with MSS of depression and/or anxiety, 14.4% reported initiating new MHSU, 22.0% had no MHSU due to barriers and personal reasons and 36.7% had no MHSU due to self-reported no need. Age, living alone, lower income, a decrease in income during the pandemic and health professional status were associated with MHSU. Younger adults were more likely to initiate MHSU during the pandemic than older adults who reported not being comfortable to seek mental health care or self-reported no need. Individuals living alone and with lower income were more likely to report not being able to find an appointment for mental health care. CONCLUSIONS: Awareness campaigns focusing on older adults that explain the importance of seeking treatment is needed, as well as sensitising health professionals as to the importance of informing and aiding individuals at risk of social isolation and lower socio-economic status as to available mental health resources and facilitating access to care.

Factors associated with change in moderate or severe symptoms of anxiety and depression in community-living adults and older adults during the COVID-19 pandemic.

OBJECTIVES: Few are the longitudinal studies on the changes in moderate or severe symptoms of anxiety or depression (MSS-ANXDEP) from before to during the COVID-19 pandemic in Canada. The aim was to study the change in MSS-ANXDEP and associated sociodemographic, economic, psychosocial, health behaviour and lifestyle, and clinical factors. METHODS: The current sample includes 59,997 adults aged ≥ 35 years participating in the 2018 and 2020 health surveys of the 5 established cohorts of the Canadian Partnership for Tomorrow's Health (CanPath). MSS-ANXDEP was based on a cutoff score ≥ 10 on the 7-item Generalized Anxiety Disorder Scale and Patient Health Questionnaire (PHQ-8). Change in MSS-ANXDEP was categorized as follows: no MSS-ANXDEP, remitted, incident, and persistent. Multinomial regressions were used to study MSS-ANXDEP as a function of sociodemographic, economic, psychosocial, health behaviours and lifestyle, and clinical factors. RESULTS: Sociodemographic and economic (i.e. age, gender, cohort, race/ethnicity, lower income, decreased in income, work status, being an essential worker), lifestyle and health behaviours (i.e. smoking, cannabis and alcohol use, drinking more alcohol), psychosocial (i.e. provide help to others, information and instrumental support, and change in relationships with friends, family, and partner) and clinical factors (i.e. lifetime mental disorder and multimorbidity) were associated with remitted, incident, and persistent MSS-ANXDEP. CONCLUSION: Health and socio-economic factors were associated with changes in symptoms of anxiety and depression during the pandemic, further increasing inequities in mental health needs. Public health campaigns on the importance of healthy behaviours should continue and health policies should reduce economic and social barriers to integrated substance use and mental health care.

RéSUMé: OBJECTIFS: Les études longitudinales sur l'évolution des symptômes modérés ou sévères d'anxiété ou de dépression (SMS-ANXDEP) avant et pendant la pandémie de COVID-19 au Canada sont rares. L'objectif était d'étudier l'association entre l'évolution des SMS-ANXDEP et les facteurs sociodémographiques, économiques, psychosociaux, cliniques et liés aux comportements et au mode de vie, avant et pendant la pandémie. MéTHODES: Ce grand échantillon comprend 59 997 adultes âgés de ≥ 35 ans qui ont participé aux enquêtes de santé 2018 et 2020 des 5 cohortes établies du Partenariat canadien pour la santé de demain (CanPath). La présence de SMS-ANXDEP a été définie par un résultat ≥ 10 sur les échelles Generalized Anxiety Disorder Scale à 7 items (GAD-7) et Patient Health Questionnaire (PHQ-8). Les changements dans les SMS-ANXDEP ont été catégorisés selon les patrons temporels suivants : absence, rémission, incidence et persistance de SMS-ANXDEP. Des régressions multinomiales multivariées ont été utilisées pour étudier les patrons temporels de SMS-ANXDEP en fonction, des facteurs socio-démographiques, économiques, associés au style de vie et aux comportements de santé, psychosociaux et cliniques. RéSULTATS: Les facteurs socio-démographiques et économiques (âge, genre, cohorte, race/ethnie, revenu inférieur, diminution du revenu, statut d'emploi, être un travailleur essentiel), associés au style de vie et aux comportements de santé (tabagisme, consommation de cannabis et d'alcool, consommation accrue d'alcool), psychosociaux (offrir de l'aide pendant la pandémie, soutien en information et instrumental, changement dans les relations avec les amis, la famille et la personne partenaire) et cliniques (trouble mental au cours de la vie, multimorbidité) étaient associés à la présence de SMS-ANXDEP en rémission, incident et persistant. CONCLUSION: Les patrons temporels des SMS-ANXDEP pendant la pandémie étaient associés aux facteurs socio-économiques et de santé, suggérant des inégalités accrues en matière de besoins de santé mentale. Les campagnes de santé publique sur l'importance d'adopter des comportements sains devraient continuer et les politiques de santé devraient réduire les barrières économiques et sociales aux soins intégrés de santé mentale et de toxicomanie.

Reduced incidence of diabetes during the COVID-19 pandemic in Alberta: A time-segmented longitudinal study of Alberta's Tomorrow Project.

AIM: To characterize the impact of the COVID-19 pandemic on diabetes diagnosis using data from Alberta's Tomorrow Project (ATP), a population-based cohort study of chronic diseases in Alberta, Canada. MATERIALS AND METHODS: The ATP participants who were free of diabetes on 1 April 2018 were included in the study. A time-segmented regression model was used to compare incidence rates of diabetes before the COVID-19 pandemic, during the first two COVID-19 states of emergency, and in the period when the state of emergency was relaxed, after adjusting for seasonality, sociodemographic factors, socioeconomic status, and lifestyle behaviours. RESULTS: Among 43 705 ATP participants free of diabetes (65.5% females, age 60.4 ± 9.5 years in 2018), the rate of diabetes was 4.75 per 1000 person-year (PY) during the COVID-19 pandemic (up to 31 March 2021), which was 32% lower (95% confidence interval [CI] 21%, 42%; p < 0.001) than pre-pandemic (6.98 per 1000 PY for the period 1 April 2018 to 16 March 2020). In multivariable regression analysis, the first COVID-19 state of emergency (first wave) was associated with an 87.3% (95% CI -98.6%, 13.9%; p = 0.07) reduction in diabetes diagnosis; this decreasing trend was sustained to the second COVID-19 state of emergency and no substantial rebound (increase) was observed when the COVID-19 state of emergency was relaxed. CONCLUSIONS: The COVID-19 public health emergencies had a negative impact on diabetes diagnosis in Alberta. The reduction in diabetes diagnosis was likely due to province-wide health service disruptions during the COVID-19 pandemic. Systematic plans to close the post-COVID-19 diagnostic gap are required in diabetes to avoid substantial downstream sequelae of undiagnosed disease.

Using Bayesian Neural Networks to Select Features and Compute Credible Intervals for Personalized Survival Prediction.

An Individual Survival Distribution (ISD) models a patient's personalized survival probability at all future time points. Previously, ISD models have been shown to produce accurate and personalized survival estimates (for example, time to relapse or to death) in several clinical applications. However, off-the-shelf neural-network-based ISD models are usually opaque models due to their limited support for meaningful feature selection and uncertainty estimation, which hinders their wide clinical adoption. Here, we introduce a Bayesian-neural-network-based ISD (BNN-ISD) model that produces accurate survival estimates but also quantifies the uncertainty in model's parameter estimation, which can be used to (1) rank the importance of the input features to support feature selection and (2) compute credible intervals around ISDs for clinicians to assess the model's confidence in its prediction. Our BNN-ISD model utilized sparsity-inducing priors to learn a sparse set of weights to enable feature selection. We provide empirical evidence, on 2 synthetic and 3 real-world clinical datasets, that BNN-ISD system can effectively select meaningful features and compute trustworthy credible intervals of the survival distribution for each patient. We observed that our approach accurately recovers feature importance in the synthetic datasets and selects meaningful features for the real-world clinical data as well, while also achieving state-of-the-art survival prediction performance. We also show that these credible regions can aid in clinical decision-making by providing a gauge of the uncertainty of the estimated ISD curves.

Impact of Comorbidity on Hospitalization and Emergency Room Visits in Adults With Diabetes: A Longitudinal Study of Alberta's Tomorrow Project.

OBJECTIVE: Our aim in this study was to characterize the impact of comorbidities, including number and types, on hospitalization and emergency room (ER) visits in people with diabetes. METHODS: Incident cases of diabetes from Alberta's Tomorrow Project with >24 months of follow-up were included. Comorbidities, classified by Elixhauser conditions, were updated every 12 months after diagnosis. A generalized estimating equation model was used to examine the association (by incidence rate ratio [IRR]) between time-varying comorbidity profile and hospitalization and ER visits per year of follow-up after adjusting for sociodemographic factors, lifestyle behaviours, and historic health-care utilization in the previous 5 years. RESULTS: Among 2,110 incident cases of diabetes (51.0% females; median age at diagnosis: 59.5 years; median follow-up: 7.19 years), the average number of Elixhauser comorbidities was 1.9±1.6 in the first year of diagnosis and 3.3±2.0 in year 15 after diagnosis. The number of comorbidities in the previous year was positively associated with risk of hospitalization (IRR=1.33 [95% confidence interval {CI}: 1.04 to 1.70] and 2.14 [95% CI: 1.67 to 2.74] for 1 or 2 and ≥2 comorbidities, respectively) and ER visits (IRR=1.31 [95% CI: 1.15 to 1.50] and 1.62 [95% CI: 1.41 to 1.87] for 1 or 2 and ≥2 comorbidities, respectively) in the subsequent year. Cardiovascular diseases, peripheral vascular diseases, cancer, liver disease, fluid and electrolyte disorders, and depression were the conditions most typically associated with increased health-care utilization. CONCLUSIONS: The number of comorbidities was a major risk factor of health-care utilization for people with diabetes. Vascular diseases, cancer, and conditions closely related to diabetic frailty (e.g. fluid and electrolyte disorders and depression) were the main drivers of hospital care and ER visits.

Mental health service use and associated predisposing, enabling and need factors in community living adults and older adults across Canada.

OBJECTIVES: Using Andersen's model of health care seeking behavior, we examined the predisposing, enabling, and need factors associated with mental health service use (MHSU) during the first wave of the COVID-19 pandemic across Canada. METHODS: The sample included n = 45,542 participants in the 5 established regional cohorts of the Canadian Partnership for Tomorrow's Health (CanPath) and who responded to the CanPath COVID-19 health survey (May-December 2020), with complete data on MHSU. Multivariable logistic regression analyses were carried out to study MHSU as a function of predisposing, enabling, and need factors. Analyses were stratified by regional cohort. RESULTS: Among the need factors, individuals reporting moderate/severe symptoms of depression and anxiety and poorer self-rated mental health were more likely to report MHSU. Among the enabling factors, receipt of informational/financial/practical support was associated with increased MHSU. While income was not consistently associated with MHSU, reported decrease in income was marginally associated with reduced MHSU. Among the predisposing factors, identifying as female or other gender minority was associated with increased MHSU, as was the presence of past-year cannabis use. In contrast, older age and alcohol consumption were associated with reduced MHSU. CONCLUSION: Need factors were consistently associated with MHSU. Although income inequities in MHSU were not observed, changes such as reduced income during the pandemic may lead to barriers in accessing mental health services. Future research should focus on better identifying contextual enabling factors and policies that overcome financial barriers to MHSU.

Physical activity-induced alterations of the gut microbiota are BMI dependent.

Physical inactivity is one of the leading causes of chronic metabolic disease including obesity. Increasing physical activity (PA) has been shown to improve cardiometabolic and musculoskeletal health and to be associated with a distinct gut microbiota composition in trained athletes. However, the impact of PA on the gut microbiota is inconclusive for individuals performing PA in their day-to-day life. This study examined the role of PA and hand-grip strength on gut microbiome composition in middle-aged adults (40-65 years, n = 350) with normal (18.5-24.9 kg/m2 ) and overweight (25-29.9 kg/m2 ) body mass index (BMI). PA was recorded using the International Physical Activity Questionnaire, and hand-grip strength was measured using a dynamometer. Serum samples were assessed for lipidomics while DNA was extracted from fecal samples for microbiome analysis. Overweight participants showed a higher concentration of triacylglycerols, and lower concentrations of cholesteryl esters, sphingomyelin, and lyso-phosphotidylcholine lipids (p < .05) compared with those with normal BMI. Additionally, overweight participants had a lower abundance of the Oscillibacter genus (p < .05). The impact of PA duration on the gut microbiome was BMI dependent. In normal but not overweight participants, high PA duration showed greater relative abundance of commensal taxa such as Actinobacteria and Proteobacteria phyla, as well as Collinsella and Prevotella genera (p < .05). Furthermore, in males with normal BMI, a stronger grip strength was associated with a higher relative abundance of Faecalibacterium and F. prausnitzii (p < .05) compared with lower grip strength. Taken together, data suggest that BMI plays a significant role in modeling PA-induced changes in gut microbiota.

Patterns and predictors of adherence to breast cancer screening recommendations in Alberta's Tomorrow Project.

Breast cancer screening is an important prevention component as it can reduce cancer mortality and improve survival. Understanding patterns of adherence to screening recommendations is essential to guide health promotion strategies and policy implementation efforts. The 1999 Alberta screening guidelines were used to determine screening status for eligible female participants in Alberta's Tomorrow Project (n = 4,972), a longitudinal province-based cohort. Screening patterns were derived based on screening status assessed at enrollment (2001-2008) and follow-up (2008-2011). Information on reason for screening was also collected at each time point. Multinomial logistic regression was used to assess potential predictors of adherence to screening recommendations. The majority of participants were up-to-date with screening at enrollment (79.3 %), and follow-up (75.2 %). Among all participants, 66.3 % were up-to-date at both time points (considered 'regular screeners'), 8.9 % were not up-to-date or never at enrollment but up-to-date at follow-up (considered 'new screeners'), 21.6 % were not up-to-date at follow-up (considered 'episodic screeners') and 3.2 % had never participated in screening (considered 'non-screeners'). Having a family doctor was the strongest factor associated with being a regular screener (OR (95 % CI): 0.37 (0.24 0.57) when compared with new screeners. Current smokers were more likely to be non-regular screeners. The primary reason for screening was routine screening or age. In conclusions, non-regular screening patterns were more prevalent among women without a family doctor. This finding suggests having a family doctor is an important mechanism to encourage screening. Further work is required to raise awareness of current recommendations and to understand and address reasons for non-adherence.

Personalized breast cancer onset prediction from lifestyle and health history information.

We propose a method to predict when a woman will develop breast cancer (BCa) from her lifestyle and health history features. To address this objective, we use data from the Alberta's Tomorrow Project of 18,288 women to train Individual Survival Distribution (ISD) models to predict an individual's Breast-Cancer-Onset (BCaO) probability curve. We show that our three-step approach-(1) filling missing data with multiple imputations by chained equations, followed by (2) feature selection with the multivariate Cox method, and finally, (3) using MTLR to learn an ISD model-produced the model with the smallest L1-Hinge loss among all calibrated models with comparable C-index. We also identified 7 actionable lifestyle features that a woman can modify and illustrate how this model can predict the quantitative effects of those changes-suggesting how much each will potentially extend her BCa-free time. We anticipate this approach could be used to identify appropriate interventions for individuals with a higher likelihood of developing BCa in their lifetime.

Intraspecific and sex-dependent variation of leaf traits along altitude gradient in the endangered dioecious tree Taxus fuana Nan Li & R.R. Mill.

Plant intraspecific trait variation (ITV) including sex-dependent differences are matters of many ecological consequences, from individual to ecosystem, especially in endangered and rare species. Taxus fuana is an endangered dioecious species with small and isolated populations endemic to the Himalayas region. Little is known about its trait variation between sexes, and among populations. In this study, 18 leaf traits from 179 reproductive trees (males and females) along the altitude (2600-3200m a.s.l.) of the T. fuana populations distributed in Gyirong County, Tibet, China, were measured. ITV and sources of variation in leaf traits were assessed. The relationship between leaf traits of males and females and altitude was analyzed separately. Variations in leaf traits of T. fuana ranged from 3.1% to 24.2%, with the smallest in leaf carbon content and the largest in leaf thickness to area ratio. On average 78.13% of the variation in leaf traits was from within populations and 21.87% among populations. The trends in leaf width, leaf nitrogen to phosphorus ratio, leaf carbon to nitrogen ratio, leaf carbon isotope ratio, and leaf nitrogen isotope ratio in relation to altitude were the same for males and females. Leaf length to width ratio varied significantly with altitude only in males, while leaf phosphorus content, leaf nitrogen content, and leaf carbon to phosphorus ratio varied significantly with altitude only in females. The correlation coefficients of most leaf traits of females with altitude were larger than that of males. In the relationship between leaf traits, there was a high similarity among males and females, but the altitude accounted for more explanation in females than in males. Our results suggested that the variation in leaf traits of T. fuana was small and did not dominate the interspecific competition in the local communities. Adaptation to the altitude gradient of T. fuana might be through altering nutrient storage processes and water use efficiency. Adaptation of male and female T. fuana to environmental changes showed differences, where the males were more tolerant and the females responded greatly to altitude. The differences in adaptation strategies between male and female T. fuana may be detrimental to the maintenance of their populations.

Anti-Hyperglycemic Medication Adherence and Health Services Utilization in People with Diabetes: A Longitudinal Study of Alberta's Tomorrow Project.

Background: Little is known about the long-term (>2 years) relationship between the time-varying drug adherence and healthcare utilization for patients with diabetes. Objective: To characterize the relationship between time-varying anti-hyperglycemic medication adherence and healthcare utilization in patients with diabetes, using data from Alberta's Tomorrow Project, a population-based cohort study in Alberta, Canada. Methods: Incident cases of diabetes with at least 24 months of follow-up were included in the study. Anti-hyperglycemic drug adherence was measured by proportion of days covered (PDC) in the past 12 months for each year after diagnosis. The rate of healthcare utilization was assessed for the subsequent 12 months, 36 months and 60 months. A time-varying, negative binomial generalized estimating equation model was used to examine the association between medication adherence and healthcare utilization. Results: Among 2155 incident cases of diabetes, average age at diagnosis was 59.6±9.3, 51.0% were female and average duration of follow-up was 7.3±3.7 (range, 2.0-16.2) years. The proportion of patients taking anti-hyperglycemic medications was 47.6% during the first year of diagnosis, which increased to 77.3% by the end of follow-up. Compared to adherent patients (PDC≥0.8), non-adherent patients (PDC<0.8) had substantially higher rate of all-cause hospitalization [incident rate ratio, IRR=1.48 (1.22-1.79), ED visits [1.30 (1.15-1.47)] and GP visits [1.17 (1.08-1.27)] in the subsequent 12 months. However, these associations became weaker with longer follow-up [eg, IRR=1.18 (0.98-1.39) and 1.05 (0.94-1.18) for all-cause hospitalization in the subsequent 36 and 60 months, respectively]. Conclusion: Poor adherence among diabetic patients was associated with substantially higher rate of healthcare utilization in the short term (eg, 12 months); however, this association weakened over a longer period (eg, 36-60 months).

[Characteristic chromatogram and index components content of substance benchmark of Xuanfu Daizhe Decoction].

The methods for determining the characteristic chromatogram and index components content of Xuanfu Daizhe Decoction were established to provide a scientific basis for the quality evaluation of substance benchmarks and preparations. Eighteen batches of Xuanfu Daizhe Decoction were prepared with the decoction pieces of different batches and of the same batch were prepared respectively, and the HPLC characteristic chromatograms of these samples were established. The similarities of the chromatographic fingerprints were analyzed. With liquiritin, glycyrrhizic acid, 6-gingerol, ginsenoside Rg_1, and ginsenoside Re as index components, the high performance liquid chromatography was established for content determination with no more than 70%-130% of the mass average as the limit. The results showed that there were 19 characteristic peaks corresponding to the characteristic chromatograms of 18 batches of Xuanfu Daizhe Decoction, including 8 peaks representing liquiritin, 1,5-O-dicaffeoylqunic acid, ginsenoside Rg_1, ginsenoside Re, 1-O-acetyl britannilactone, ginsenoside Rb_1, glycyrrhizic acid, and 6-gingerol, and the fingerprint similarity was greater than 0.97. The contents of liquiritin, glycyrrhizic acid, 6-gingerol, and ginsenosides Rg_1 + Re in the prepared Xuanfu Daizhe Decoction samples were 0.53%-0.86%, 0.61%-1.2%, 0.023%-0.068%, and 0.33%-0.66%, respectively. Except for several batches, most batches of Xuanfu Daizhe Decoction showed stable contents of index components, with no discrete values. The characteristic chromatograms and index components content characterized the information of Inulae Flos, Ginseng Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, and Zingiberis Rhizoma Recens in Xuanfu Daizhe Decoction. This study provides a scientific basis for the further research on the key chemical properties of substance benchmark and preparations of Xuanfu Daizhe Decoction.

A dietary carbohydrate - gut Parasutterella - human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes.

Recent rodent microbiome experiments suggest that besides Akkermansia, Parasutterella sp. are important in type 2 diabetes and obesity development. In the present translational human study, we aimed to characterize Parasutterella in our European cross-sectional FoCus cohort (n = 1,544) followed by validation of the major results in an independent Canadian cohort (n = 438). In addition, we examined Parasutterella abundance in response to a weight loss intervention (n = 55). Parasutterella was positively associated with BMI and type 2 diabetes independently of the reduced microbiome α/ß diversity and low-grade inflammation commonly found in obesity. Nutritional analysis revealed a positive association with the dietary intake of carbohydrates but not with fat or protein consumption. Out of 126 serum metabolites differentially detectable by untargeted HPLC-based MS-metabolomics, L-cysteine showed the strongest reduction in subjects with high Parasutterella abundance. This is of interest, since Parasutterella is a known high L-cysteine consumer and L-cysteine is known to improve blood glucose levels in rodents. Furthermore, metabolic network enrichment analysis identified an association of high Parasutterella abundance with the activation of the human fatty acid biosynthesis pathway suggesting a mechanism for body weight gain. This is supported by a significant reduction of the Parasutterella abundance during our weight loss intervention. Together, these data indicate a role for Parasutterella in human type 2 diabetes and obesity, whereby the link to L-cysteine might be relevant in type 2 diabetes development and the link to the fatty acid biosynthesis pathway for body weight gain in response to a carbohydrate-rich diet in obesity development.

Towards refining World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations for red and processed meat intake: insights from Alberta's Tomorrow Project cohort.

Current cancer prevention recommendations advise limiting red meat intake to <500 g/week and avoiding consumption of processed meat, but do not differentiate the source of processed meat. We examined the associations of processed meat derived from red v. non-red meats with cancer risk in a prospective cohort of 26 218 adults who reported dietary intake using the Canadian Diet History Questionnaire. Incidence of cancer was obtained through data linkage with Alberta Cancer Registry with median follow-up of 13·3 (interquartile range (IQR) 5·1) years. Multivariable Cox proportional hazards regression models were adjusted for covariates and stratified by age and sex. The median consumption (g/week) of red meat, processed meat from red meat and processed meat from non-red meat was 267·9 (IQR 269·9), 53·6 (IQR 83·3) and 11·9 (IQR 31·8), respectively. High intakes (4th Quartile) of processed meat from red meat were associated with increased risk of gastrointestinal cancer adjusted hazard ratio (AHR): 1·68 (95 % CI 1·09, 2·57) and colorectal cancers AHR: 1·90 (95 % CI 1·12, 3·22), respectively, in women. No statistically significant associations were observed for intakes of red meat or processed meat from non-red meat. Results suggest that the carcinogenic effect associated with processed meat intake may be limited to processed meat derived from red meats. The findings provide preliminary evidence towards refining cancer prevention recommendations for red and processed meat intake.

Bioequivalence study of two formulations of terazosin hydrochloride capsule in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: This study was conducted to assess the pharmacokinetic and safety profiles between a new oral formulation of terazosin hydrochloride capsule compared with the brand-name drug. MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-period crossover study under fasting or fed conditions was conducted in healthy Chinese subjects. 24 individuals were selected, respectively. Each subject was randomized at the beginning to receive a 2-mg capsule of the test or the reference terazosin during the first period and then received the alternate formulation during the second period following a 1-week washout period. Blood samples were collected at pre-dose and up to 60 hours after administration. Plasma terazosin was quantified by a validated LC-MS/MS method. RESULTS: 48 healthy subjects were enrolled, and 47 completed the study. Cmax, AUC0-t, and AUC0-∞ were similar and the 90% CIs for the geometric mean ratios of these parameters between the two groups were all bounded within the predefined bioequivalence criterion of 80 - 125% under both fasting and fed conditions. Throughout the study period, a total of 30 treatment-emergent adverse events (TEAEs) were reported under fasting condition. 35 TEAEs were observed under fed conditions. No serious adverse event was observed. CONCLUSION: The test and reference formulations of terazosin were bioequivalent and well tolerated under both fasting and fed conditions.