Understanding genetic variability: exploring large-scale copy number variants through non-invasive prenatal testing in European populations.

Large-scale copy number variants (CNVs) are structural alterations in the genome that involve the duplication or deletion of DNA segments, contributing to genetic diversity and playing a crucial role in the evolution and development of various diseases and disorders, as they can lead to the dosage imbalance of one or more genes. Massively parallel sequencing (MPS) has revolutionized the field of genetic analysis and contributed significantly to routine clinical diagnosis and screening. It offers a precise method for detecting CNVs with exceptional accuracy. In this context, a non-invasive prenatal test (NIPT) based on the sequencing of cell-free DNA (cfDNA) from pregnant women's plasma using a low-coverage whole genome MPS (WGS) approach represents a valuable source for population studies. Here, we analyzed genomic data of 12,732 pregnant women from the Slovak (9,230), Czech (1,583), and Hungarian (1,919) populations. We identified 5,062 CNVs ranging from 200 kbp and described their basic characteristics and differences between the subject populations. Our results suggest that re-analysis of sequencing data from routine WGS assays has the potential to obtain large-scale CNV population frequencies, which are not well known and may provide valuable information to support the classification and interpretation of this type of genetic variation. Furthermore, this could contribute to expanding knowledge about the central European genome without investing in additional laboratory work, as NIPTs are a relatively widely used screening method.

Survival trends among patients with metastatic non-small cell lung cancer before and after the approval of immunotherapy in the United States: A Surveillance, Epidemiology, and End Results database-based study.

BACKGROUND: In 2015, the US Food and Drug Administration approved nivolumab as the first immunotherapy for patients with advanced non-small cell lung cancer (NSCLC). However, population-based survival benefit studies after the introduction of immunotherapy in lung cancer are lacking. This study examined overall survival (OS) and cancer-specific survival in patients with NSCLC in the pre immunotherapy and immunotherapy eras. METHODS: This study used the Surveillance, Epidemiology, and End Results database, which spanned 17 registries from 2000 to 2020. Two cohorts were delineated: preimmunotherapy (2010-2014) and immunotherapy (2015-2020), which coincided with nivolumab's approval. RESULTS: This study included 191,802 patients, 90,807 in the preimmunotherapy era and 100,995 in the immunotherapy era. OS was significantly higher in the immunotherapy era, as shown by Kaplan-Meier curves (1-year OS, 40.1% vs. 33.5%; 3-year OS, 17.8% vs. 11.7%; 5-year OS, 10.7% vs. 6.8%; median OS, 8 vs. 7 months; p < .001 by log-rank test). Similarly, cancer-specific survival improved in the immunotherapy era (1-year survival, 44.0% vs. 36.8%; 3-year survival, 21.7% vs. 14.4%; 5-year survival, 14.3% vs. 9.0%; median OS, 10 vs. 8 months; p < .001 by log-rank test). Survival rates were significantly better in the immunotherapy era, as confirmed by multivariate analysis with a Cox proportional hazards model after adjusting for age, sex, race, income, and geographical area (adjusted hazard ratio, 0.830; 95% CI, 0.821-0.840; p < .001). CONCLUSIONS: In summary, the survival rate of patients with metastatic NSCLC has improved since the introduction of immunotherapy.

Sequenced-based Rwanda population provides insights into demographic history.

Rwanda is known as the heart of Africa, reflecting the history of the world. Colonization and genocide have led to Rwanda's existing genetic structure. Herein, we used massively parallel sequencing to analyze 296 loci in 185 Rwandans and constructed a database for Rwandan forensic data for the first time. We found the following results: First, forensic parameters demonstrated that all loci were highly informative and could be used for forensic identification and paternity tests in Rwandans. Second, we found that the differences in genetic background between Rwandans and other African populations were similar but slight, as indicated by the massively parallel sequencing panel. Rwandans belonged to the African population and were inseparable from populations from neighboring countries. Also, Rwandans were closer to the European and American populations because of colonization, war, and other reasons. There was no scientific basis for racial classification established by colonization. Further research still needs to be carried out on more loci and larger Rwandan samples.

A history of recurrent pregnancy loss is associated with increased perinatal complications, but not necessarily a longer birth interval: a population study spanning 18 years.

STUDY QUESTION: Is there a difference in the time interval between the first and second live births among individuals with and without recurrent pregnancy loss (RPL)? SUMMARY ANSWER: Primary RPL (two or more pregnancy losses before the first live birth) is associated with a shorter time interval between the first and second live births compared with individuals without RPL, but this association is reversed in patients with secondary RPL (RPL patients with no or one pregnancy loss before the first live birth). WHAT IS KNOWN ALREADY: There is limited information regarding the ability to have more than one child for patients with RPL. Previous studies have investigated the time to live birth and the live birth rate from the initial presentation to clinical providers. Most of the previous studies have included only patients treated at specialized RPL clinics and thus may be limited by selection bias, including patients with a more severe condition. STUDY DESIGN, SIZE, DURATION: We conducted a population-based retrospective cohort study of 184 241 participants who delivered in British Columbia, Canada, and had at least two recorded live births between 2000 and 2018. The aim was to study the differences in the time interval between the first and second live births and the prevalence of pregnancy complications in patients with and without RPL. Additionally, 198 319 individuals with their first live birth between 2000 and 2010 were studied to evaluate cumulative second live birth rates. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among individuals with at least two recorded live births between 2000 and 2018, 12 321 patients with RPL and 171 920 participants without RPL were included. RPL was defined as at least two pregnancy losses before 20 weeks gestation. Patients with primary RPL had at least two pregnancy losses occurring before the first live birth, while patients with secondary RPL had no or one pregnancy loss before the first live birth. We compared the time interval from the first to second live birth in patients with primary RPL, those with secondary RPL, and participants without RPL using generalized additive models to allow for a non-linear relationship between maternal age and time interval between first and second live births. We also compared prevalence of pregnancy complications at the first and second live births between the groups using non-parametric Kruskal-Wallis H test and Fisher's exact test for continuous and categorical variables, respectively. We assessed the cumulative second live birth rates in patients with primary RPL and those without RPL, among participants who had their first live birth between 2000 and 2010. Cox proportional hazards model was used to estimate and compare hazard ratios between the two groups using a stratified modelling approach. MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted time interval between the first and second live births was the longest in patients with secondary RPL, followed by individuals without RPL, and the shortest time interval was observed in patients with primary RPL: 4.34 years (95% CI: 4.09-4.58), 3.20 years (95% CI: 3.00-3.40), and 3.05 years (95% CI: 2.79-3.32). A higher frequency of pregnancy losses was associated with an increased time interval between the first and second live births. The prevalence of pregnancy complications at the first and second live births, including gestational diabetes, hypertensive disorder of pregnancy, preterm birth, and multiple gestations was significantly higher in patients with primary RPL compared with those without RPL. The cumulative second live birth rate was significantly lower in patients with primary RPL compared with individuals without RPL. LIMITATIONS, REASONS FOR CAUTION: This study may be limited by its retrospective nature. Although we adjusted for multiple potential confounders, there may be residual confounding due to a lack of information about pregnancy intentions and other factors, including unreported pregnancy losses. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide information that will help clinicians in the counselling of RPL patients who desire a second child. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by a grant from the Canadian Institutes of Health Research (CIHR): Reference Number W11-179912. M.A.B. reports research grants from CIHR and Ferring Pharmaceutical. He is also on the advisory board for AbbVie, Pfizer, and Baxter. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT04360564.

Regions of Homozygocity size patterns among diverse ethnic groups in Israel: Toward tailored diagnostic reporting thresholds.

Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023. ROH segments on autosomal chromosomes were retrieved, and samples lacking ROH segments were excluded. The cohort was categorized based on reported ethnic origins, and TRPS and ROH segment size were analyzed for each origin. Distinct TRPS values were noted among different ethnic groups, ranging from median 0.36% in Ethiopian Jewish cohort and up to 6.42% in the Bedouin population. Wide range of 99th percentiles of ROH segment size for various origins was noted, ranging from 10.6 to 51.5 Mb. A significant correlation between ROH segment sizes and TRPS was noted in each origin. Statistically significant differences in ROH segment sizes were noted between the Jewish and the Israeli Arab/Druze origins in TRPS from 1% to 9.99%, whereas extremities of low (0.11%-0.99%) and high (over 10%) TRPS yielded no significant differences. In conclusion, as fixed absolute size thresholds may overlook pathogenic segments in certain populations while generating excessive reports in others, tailored approaches to define ROH reporting thresholds can be considered to facilitate the accuracy and clinical relevance of genomic analyses.

Global trends in the burden of chronic kidney disease attributable to type 2 diabetes: An age-period-cohort analysis.

AIM: To assess temporal trends of chronic kidney disease (CKD) attributable to type 2 diabetes (T2D) globally and in five sociodemographic index (SDI) regions. MATERIALS AND METHODS: We extracted the population data and CKD burden attributable to T2D from the Global Burden of Disease Study 2019. We evaluated the trends of disability-adjusted life years (DALYs), mortality, prevalence and incidence through age-period-cohort modelling, and calculated net drifts (overall annual percentage changes), local drifts (annual percentage changes in each age group), longitudinal age curves (fitted longitudinal age-specific rates), period relative risks (RRs) and cohort RRs. RESULTS: From 1990 to 2019, the global burden of CKD attributable to T2D showed increasing trends in general. The burden of CKD attributable to T2D was highest in the middle SDI region and lowest in the low SDI region. Age effects increased with age, and peaked at the ages of 75-79 and 80-84 years for incidence and prevalence, respectively. Period RRs in the burden of CKD attributable to T2D increased, with the high SDI being the most remarkable in DALYs and mortality, and the middle SDI being the most notable in incidence. Cohort RRs showed unfavourable trends in incidence and prevalence among recent cohorts. CONCLUSIONS: After a lengthy period of multi-initiative diabetes management, the high-middle SDI region exhibited improvement. However, unresolved issues and improvement gaps were still remarkable. Future efforts to reduce the burden of CKD attributable to T2D in the population should prioritize addressing the unfavourable patterns identified.

Incremental burden on health-related quality of life, health service utilization and direct medical expenditures associated with cognitive impairment among non-institutionalized people with diabetes aged 65 years and older.

AIMS: To quantify the incremental health and economic burden associated with cognitive impairment (CI) among non-institutionalized people with diabetes ≥65 years in the United States. MATERIALS AND METHODS: Using 2016-2019 Medical Expenditure Panel Surveys data, we identified participants ≥65 years with diabetes. We used propensity score weighting to quantify the CI-associated incremental burden on health-related quality of life measured by the 12-item Short Form Survey (SF-12), including the mental component summary score, physical component summary score and health utility. We also compared the annual health service utilization and expenditures on ambulatory visits, prescriptions, home care, emergency room (ER), hospitalizations and total annual direct medical expenditures. RESULTS: We included 5094 adults aged ≥65 with diabetes, of whom 804 had CI. After propensity score weighting, CI was associated with a lower mental component summary score (-8.4, p < .001), physical component summary score (-5.2, p < .001) and health utility (-0.12, p < .001). The CI group had more ambulatory visits (+4.4, p = .004) and prescriptions (+9.9, p < .001), with higher probabilities of having home care (+11.3%, p < .001) and ER visits (+8.2%, p = .001). People with CI spent $5441 (p < .001) more annually, $2039 (p = .002) more on prescriptions, $2695 (p < .001) more on home care and $118 (p < .001) more on ER visits. There is no statistically significant difference in the utilization and expenditure of hospitalizations. CONCLUSION: CI was associated with worse health-related quality of life, higher health service utilization and expenditures. Our findings can be used to monitor the health and economic burden of CI in non-institutionalized older persons with diabetes.

Genetic influences, lifestyle and psychosocial aspects in relation to metabolically healthy obesity and conversion to a metabolically unhealthy state.

AIMS: About 10%-30% of individuals with obesity are metabolically healthy, but the specific characteristics of the metabolically healthy obesity (MHO) phenotype remain unclear. We aimed to examine how physical activity, education, depressive symptoms and genetic predisposition to obesity differ between individuals with MHO and those with metabolically unhealthy obesity (MUO), and whether these factors predict stability in MHO or conversion to a metabolically unhealthy state. MATERIALS AND METHODS: We retrieved data on 9809 individuals with obesity from the Health and Retirement Study collected between 2006 and 2016. We compared how physical activity, education, depressive symptoms and a polygenic score for higher body mass index (BMI) (PGSBMI) differed cross-sectionally between MHO and MUO using logistic regression. We then examined if the same factors predict conversion to a metabolically unhealthy state over 4 years in individuals with MHO. RESULTS: Individuals with MHO had higher physical activity (odds ratio [OR] = 0.81), higher education (OR = 0.83) and lower depressive symptoms (OR = 1.14) compared to those with MUO but did not differ in the PGSBMI. The associations were slightly attenuated in mutually adjusted models. None of the factors were associated with conversion from MHO to a metabolically unhealthy state. However, a higher PGSBMI indicated 24% lower risk of conversion to a metabolically unhealthy state (p = 0.07). CONCLUSIONS: Physical activity, education and depressive symptoms differed between MHO and MUO, even when mutually adjusted for, but did not predict conversion from a metabolically healthy to unhealthy state. Although not statistically significant, the results indicated that those with genetically predicted high BMI are more likely to maintain MHO and not convert to a metabolically unhealthy state.

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.

One-hour post-load glucose levels are associated with hepatic steatosis assessed by transient elastography.

AIM: To examine the association between 1-hour plasma glucose (PG) concentration and markers of non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE). METHODS: We performed TE in 107 metabolically well-characterized non-diabetic White individuals. Controlled attenuation parameter (CAP) was used to quantify liver steatosis, while liver stiffness marker (LS) was used to evaluate fibrosis. RESULTS: Controlled attenuation parameter correlated significantly with 1-hour PG (r = 0.301, P < 0.01), fasting insulin (r = 0.285, P < 0.01), 2-hour insulin (r = 0.257, P < 0.02), homeostasis model assessment index of insulin resistance (r = 0.252, P < 0.01), high-density lipoprotein cholesterol (r = -0.252, P < 0.02), body mass index (BMI; r = 0.248, P < 0.02) and age (r = 0.212, P < 0.03), after correction for age, sex and BMI. In a multivariable linear regression analysis, 1-hour PG (ß = 0.274, P = 0.008) and fasting insulin levels (ß = 0.225, P = 0.029) were found to be independent predictors of CAP. After excluding subjects with prediabetes, 1-hour PG was the sole predictor of CAP variation (ß = 0.442, P < 0.001). In a logistic regression model, we observed that the group with 1-hour PG ≥ 8.6 mmol/L (155 mg/dL) had a significantly higher risk of steatosis (odds ratio 3.98, 95% confidence interval 1.43-11.13; P = 0.008) than individuals with 1-hour PG < 8.6 mmol/L, after correction for potential confounders. No association was observed between 1-hour PG and LS. CONCLUSION: Our data confirm that 1-hour PG ≥ 8.6 mmol/L is associated with higher signs of NAFLD, even among individuals with normal glucose tolerance, categorized as low risk by canonical diagnostic standards. TE is a safe low-impact approach that could be employed for stratifying the risk profile in these patients, with a high level of accuracy.

Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.

Socio-economic disparities in hospital care among Dutch patients with diabetes mellitus.

AIM: Socio-economic status (SES) influences diabetes onset, progression and treatment. In this study, the associations between SES and use of hospital care were assessed, focusing on hospitalizations, technology and cardiovascular complications. MATERIALS AND METHODS: This was an observational cohort study comprising 196 695 patients with diabetes (all types and ages) treated in 65 hospitals across the Netherlands from 2019 to 2020 using reimbursement data. Patients were stratified in low, middle, or high SES based on residential areas derived from four-digit zip codes. RESULTS: Children and adults with low SES were hospitalized more often than patients with middle or high SES (children: 22%, 19% and 15%, respectively; p < .001, adults: 28%, 25% and 23%; p < .001). Patients with low SES used the least technology: no technology in 48% of children with low SES versus 40% with middle SES and 38% with high SES. In children, continuous subcutaneous insulin infusion (CSII) and real-time continuous glucose monitoring (rtCGM) use was higher in high SES {CSII: odds ratio (OR) 1.54 [95% confidence interval (CI) 1.35-1.76]; p < .001; rtCGM OR 1.39 [95% CI 1.20-1.61]; p < .001} and middle SES [CSII: OR 1.41 (95% CI 1.24-1.62); p < .001; rtCGM: OR 1.27 (95% CI 1.09-1.47); p = .002] compared with low SES. Macrovascular (OR 0.78 (95% CI 0.75-0.80); p < .001) and microvascular complications [OR 0.95 (95% CI 0.93-0.98); p < .001] occurred less in high than in low SES. CONCLUSIONS: Socio-economic disparities were observed in patients with diabetes treated in Dutch hospitals, where basic health care is covered. Patients with low SES were hospitalized more often, used less technology, and adults with high SES showed fewer cardiovascular complications. These inequities warrant attention to guarantee equal outcomes for all.

Ten-year progression of obesity-related complications in a population with overweight and obesity in the UK: A retrospective open cohort study.

AIM: To assess the prevalence of individual obesity-related complications (ORCs) and multimorbidity (≥ 1, ≥ 2 and ≥ 3 ORCs), and multimorbidity-associated healthcare costs, over 10 years. METHODS: This retrospective open cohort study used Discover, a UK database of linked primary and secondary electronic health records. Adults were stratified by body mass index (BMI; overweight: 25-< 30 kg/m2; obesity class I: 30-< 35 kg/m2; obesity class II: 35-< 40 kg/m2; obesity class III: ≥ 40 kg/m2). Outcomes by year since baseline were assessed for serial cross sections across the study period (1 January 2004 to 31 December 2019; the index date was the date of first eligible BMI measurement). RESULTS: Across 1 410 146 individuals (overweight: 1 008 101; obesity class I: 278 782; obesity class II: 80 621; obesity class III: 42 642), ORC prevalence was higher in successive BMI groups, and increases over time were generally greater for obesity relative to overweight. In those with ORC multimorbidity, both higher BMI and the presence of more ORCs were associated with higher annual per-person healthcare costs. Costs increased over time in those individuals with obesity and one or more ORC, as well as in those with obesity and two or more ORCs. CONCLUSIONS: Higher BMI was associated with higher baseline ORC prevalence and a greater increase in ORC prevalence over time, and with higher healthcare costs in those with multimorbidity. To reduce the burden of overweight and obesity on patients and healthcare systems, the presence, number and type of ORCs should be considered in developing effective, targeted prevention and management care pathways.

Variations in healthcare costs by body mass index and obesity-related complications in a UK population: A retrospective open cohort study.

AIMS: To estimate healthcare resource utilization (HCRU) and healthcare costs by body mass index (BMI) in a UK cohort and to explore how this varied by defined BMI strata. MATERIALS AND METHODS: This retrospective open cohort study used Discover, a linked primary and secondary electronic health records database covering 2.7 million individuals. Adults were stratified by BMI as: overweight (25-<30 kg/m2); obesity class I (30-<35 kg/m2); obesity class II (35-<40 kg/m2); or obesity class III (≥40 kg/m2). Cost data, comprising primary care, secondary care (inpatient admissions, outpatient appointments and emergency room visits) and prescriptions, were reported for 2015-2019. RESULTS: Overall, 1 008 101 individuals were overweight, 278 782 had obesity class I; 80 621 had obesity class II, and 42 642 had obesity class III. Healthcare costs and HCRU events per person per year increased over time (2015: £851-£1321 and 10.6-13.4 events; 2019: £1143-£1871 and 11.4-14.9 events), and were higher for each successive BMI group. Groups with chronic kidney disease or cardiovascular disease incurred particularly high costs. In 270 493 individuals with obesity in 2019, more than 72% of total healthcare costs were incurred by the highest cost quintile, which had a higher mean age and more obesity-related complications (ORCs) than lower cost quintiles. CONCLUSIONS: The economic impact of obesity could be alleviated by weight management support based on unmet need, to limit the effects of BMI progression and ORC development.

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

AIM: The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. MATERIALS AND METHODS: This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. RESULTS: Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. CONCLUSIONS: At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Smoking timing, genetic susceptibility and the risk of incident type 2 diabetes: A cohort study from the UK Biobank.

AIM: To prospectively assess the association of smoking timing with the risk of type 2 diabetes (T2D) and examine whether smoking amount or genetic susceptibility might modify the relationship. MATERIALS AND METHODS: A total of 294 815 participants without diabetes from the UK Biobank, including non-smokers and smokers with data on the time from waking to first cigarette, were included. Cox proportional hazards models were used to evaluate the association between smoking timing and the risk of incident T2D. RESULTS: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented. Compared with non-smokers, a shorter time from waking to first cigarette was significantly associated with a higher risk of incident T2D (P for trend < .001). In the fully adjusted model, the hazard ratios (HRs) (95% confidence interval) associated with smoking timing were 1.46 (1.17-1.81) for more than 2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes and 2.01 (1.60-2.54) for less than 5 minutes. We found that even among those who reported being light smokers, those with the shortest time from waking to first cigarette had a 105% higher risk of T2D with an HR of 2.05 (1.52-2.76), which was comparable with heavy smokers. The genetic risk score for T2D did not modify this association (P-interaction = .51). CONCLUSIONS: Our findings indicate that shorter time from waking to first cigarette is significantly associated with a higher risk of incident T2D.

Associations of a proinflammatory diet, habitual salt intake, and the onset of type 2 diabetes: A prospective cohort study from the UK Biobank.

AIM: To explore the relationship between proinflammatory diet, habitual salt intake and the onset of type 2 diabetes. METHODS: This prospective study was conducted among 171 094 UK Biobank participants who completed at least one 24-h dietary questionnaire and were free of diabetes at baseline. Participants were followed up until 1 March 2023 for type 2 diabetes incidence, with diagnosis information obtained from linked medical records. An Energy-adjusted Diet Inflammatory Index (E-DII) was calculated based on 28 food parameters. Habitual salt intake was determined through the self-reported frequency of adding salt to foods. The associations between E-DII, habitual salt intake and type 2 diabetes incidence were tested by the Cox proportional hazard regression model. RESULTS: Over a median follow-up period of 13.5 years, 6216 cases of type 2 diabetes were documented. Compared with participants with a low E-DII (indicative of an anti-inflammatory diet), participants with a high E-DII (indicative of a proinflammatory diet) had an 18% heightened risk of developing type 2 diabetes. The association between E-DII and type 2 diabetes tends to be linear after adjustment for major confounders. Participants with a proinflammatory diet and always adding salt to foods had the highest risk of type 2 diabetes incidence (hazard ratio 1.60, 95% confidence interval 1.32-1.94). CONCLUSIONS: Our findings indicate that a proinflammatory diet and higher habitual salt intake were associated with an increased risk of type 2 diabetes. These results support the public health promotion of an anti-inflammatory diet and reducing salt intake to prevent the onset of type 2 diabetes.

Persistent disparities in insulin pump uptake despite a universal pump programme for type 1 diabetes in Ontario, Canada.

AIM: To evaluate associations between social disadvantage and insulin pump use among adults with type 1 diabetes (T1D) in the context of a universal publicly funded insulin pump programme in Ontario, Canada, and to ascertain whether social disparities in insulin pump programme enrolment have decreased over time. METHODS: Population-based cross-sectional studies were conducted using administrative healthcare data in Ontario, Canada. First, among adults aged older than 18 years diagnosed with T1D before 31 March 2021, logistic regression was used to assess the association between neighbourhood social disadvantage (Ontario marginalization index quintiles) and insulin pump use. Second, among all paediatric and adult applicants to the insulin pump programme from 1 September 2006 to 31 March 2022, ordinal logistic regression was used to evaluate associations between year of insulin pump initiation and social disadvantage. RESULTS: Among 27 453 adults with T1D, 60% used insulin pumps. Greater social disadvantage was associated with lower odds of insulin pump use (adjusted odds ratio [OR] 0.44 [95% confidence interval {CI} 0.39-0.48] for greatest vs. lowest social disadvantage quintile). Among 21 002 paediatric and adult applicants to the insulin pump programme, social disparities in pump use decreased in the first 3 years of the programme, plateaued until 2020, then increased from 2020 to 2022, with no change in the odds of being in a higher social deprivation quintile for 2022 relative to 2007 (OR 1.09 [95% CI 0.83-1.44]). CONCLUSIONS: Despite a universal pump programme for individuals with T1D, disparities by social disadvantage persist. Residual financial and non-financial barriers must be addressed to promote equitable insulin pump uptake.

The impact of type 2 diabetes and glycaemic control on mortality and clinical outcomes in hospitalized patients with COVID-19 in the capital region of Denmark.

AIM: To explore the impact of type 2 diabetes (T2D), glycaemic control and use of glucose-lowering medication on clinical outcomes in hospitalized patients with COVID-19. MATERIALS AND METHODS: For all patients admitted to a hospital in the Capital Region of Denmark (1 March 2020 to 1 December 2021) with confirmed COVID-19, we extracted data on mortality, admission to intensive care unit (ICU), demographics, comorbidities, medication use and laboratory tests from the electronic health record system. We compared patients with T2D to patients without diabetes using Cox proportional hazards models adjusted for available confounding variables. Outcomes were 30-day mortality and admission to an ICU. For patients with T2D, we also analysed the association of baseline haemoglobin A1c (HbA1c) levels and use of specific glucose-lowering medications with the outcomes. RESULTS: In total, 4430 patients were analysed, 1236 with T2D and 2194 without diabetes. The overall 30-day mortality was 19% (n = 850) and 10% (n = 421) were admitted to an ICU. Crude analyses showed that patients with T2D both had increased mortality [hazard ratio (HR) 1.37; 95% CI 1.19-1.58] and increased risk of ICU admission (HR 1.28; 95% CI 1.04-1.57). When adjusted for available confounders, this discrepancy was attenuated for both mortality (adjusted HR 1.13; 95% CI 0.95-1.33) and risk of ICU admission (adjusted HR 1.01; 95% CI 0.79-1.29). Neither baseline haemoglobin A1c nor specific glucose-lowering medication use were significantly associated with the outcomes. CONCLUSION: Among those hospitalized for COVID-19, patients with T2D did not have a higher risk of death and ICU admission, when adjusting for confounders.

Risk of stroke within 3, 7, 14, 21 and 30 days after influenza vaccination in Alberta, Canada: A population-based study.

BACKGROUND AND PURPOSE: Influenza vaccination is associated with a longer-term protective effect against stroke; however, it has a short-term inflammatory response which may increase short-term risk of stroke. The aim was to investigate the association between influenza vaccination and short-term risk of stroke in adults. METHODS: Administrative data were obtained from the Alberta Health Care Insurance Plan for all adults in Alberta, Canada, from September 2009 to December 2018. The hazard of any stroke (acute ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage and transient ischaemic attack) within 3, 7, 14, 21 and 30 days of influenza vaccination compared to unexposed time was analysed using Andersen-Gill Cox models, with adjustment for age, sex, anticoagulant use, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, income quintile, and rural or urban home location. RESULTS: In the entire cohort consisting of 4,141,209 adults (29,687,899 person-years), 1,769,565 (42.7%) individuals received at least one vaccination. In total 38,126 stroke events were recorded with 1309 occurring within 30 days of a vaccination event. Influenza vaccination was associated with a significantly reduced hazard of stroke within 3 days (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.73-0.93), 7 days (HR 0.87, 95% CI 0.80-0.95), 14 days (HR 0.87, 95% CI 0.81-0.93), 21 days (HR 0.85, 95% CI 0.80-0.91) and 30 days (HR 0.66, 95% CI 0.65-0.68). CONCLUSIONS: An increased early risk associated with vaccination was not observed. The risk of stroke was reduced at all time points within 30 days after influenza vaccination.