Expert Opinion on Current Trends in the Use of Insulin in the Management of People with Type 2 Diabetes from the South-Eastern European Region and Israel.

Despite the availability of various antihyperglycaemic therapies and comprehensive guidelines, glycaemic control in diabetes management has not improved significantly during the last decade in the real-world clinical setting. Treatment inertia arising from a complex interplay among patient-, clinician- and healthcare-system-related factors is the prime reason for this suboptimal glycaemic control. Also, the key factor leading to inadequate glycaemic levels remains limited communication between healthcare professionals (HCPs) and people with type 2 diabetes (PwT2D). Early insulin administration has several advantages including reduced glucotoxicity, high efficacy and preserved ß-cell mass/function, leading to lowering the risk of diabetes complications. The current publication is based on consensus of experts from the South-Eastern European region and Israel who reviewed the existing evidence and guidelines for the treatment of PwT2D. Herein, the experts emphasised the timely use of insulin, preferably second-generation basal insulin (BI) analogues and intensification using basal-plus therapy, as the most-potent glucose-lowering treatment choice in the real-world clinical setting. Despite an increase in the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the experts urged timely insulin initiation for inadequate glycaemic control in PwT2D. Furthermore, the combination of BI and GLP-1 RA addressing both fasting plasma glucose and post-prandial excursions as a free- or fixed-ratio combination was identified to reduce treatment complexity and burden. To minimise discontinuation and improve adherence, the experts reiterated quality, regular interactions and discussions between HCPs and PwT2D/carers for their involvement in the diabetes management decision-making process. Clinicians and HCPs should consider the opinions of the experts in accordance with the most recent recommendations for diabetes management.

The Semmelweis Study: a longitudinal occupational cohort study within the framework of the Semmelweis Caring University Model Program for supporting healthy aging.

The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Effect of school lockdown due to the COVID-19 pandemic on screen time among adolescents in Hungary: a longitudinal analysis.

Introduction: Studies indicate that due to school lockdown during the Coronavirus Disease 2019 (COVID-19) pandemic, screen time increased more steeply than pre-pandemic years. The aim of our study was to examine changes in screen time and its components (screen time spent on videos, games, homework, and other activities) of adolescents affected by COVID-19 school closures compared to controls from pre-pandemic years and to assess the effect of family structure and family communication. Methods: Two sets of ninth-grader boys and girls transitioning into 10th grade were included in the analysis. The 'pre-COVID classes' (controls) completed the baseline survey in February 2018 and the follow-up survey in March 2019. 'COVID classes' (cases) completed the baseline survey in February 2020 (1 month before the COVID-19-related school lockdowns) and the follow-up survey in March 2021. Linear mixed models stratified by sex were built to assess the change in screen time over one year adjusted for family structure and communication. Results: Our study population consisted of 227 controls (128 girls, 99 boys) and 240 cases (118 girls, 122 boys). Without COVID-19, overall screen time did not change significantly for boys, but there was a decrease in screen time for gaming by 0.63 h, which was accompanied by an increase of 1.11 h in screen time for other activities (consisting mainly of social media and communication). Because of the pandemic, all components increased by 1.44-2.24 h in boys. Girls' screen time and its components remained stable without school lockdown, while it increased for videos and homework by 1.66-2.10 h because of school lockdown. Living in a single-parent household was associated with higher, while better family communication resulted in lower screen time. Discussion: Our results indicate that COVID-19-related school lockdowns modified the age-specific increase in screen time for boys and girls as well. This trend, however, may be counterbalanced by improving communication between family members.

Survival and longevity of European rulers: geographical influences and exploring potential factors, including the Mediterranean diet - a historical analysis from 1354 to the twentieth century.

Significant regional variability in lifespan in Europe is influenced by environmental factors and lifestyle behaviors, including diet. This study investigates the impact of geographical region on the lifespan of European rulers spanning from the fourteenth century to the present day. By analyzing historical records and literature, we aim to identify region-specific dietary patterns and lifestyle factors that may have contributed to longer lifespans among rulers. The hypothesis to be tested is that rulers from Southern European countries, where the traditional Mediterranean diet is consumed by the local people, may exhibit longer lifespans compared to rulers from other regions, due to the well-documented health benefits associated with this dietary pattern. We extracted comprehensive information for each ruler, encompassing their sex, birth and death dates, age, age of enthronement, duration of rulership, country, and cause of death (natural vs. non-natural). To determine their nationality, we coded rulers based on their hypothetical present-day residence (2023). Utilizing the EuroVoc Geographical classification, we categorized the countries into four regions: Northern, Western, Southern, Central and Eastern Europe. While Cox regression models did not find significant differences in survival rates among regions, further analysis stratified by time periods revealed intriguing trends. Contrary to our initial predictions, the Northern region displayed better survival rates compared to the Southern region between 1354 and 1499, whereas survival rates were similar across regions from 1500 to 1749. However, after 1750, all regions, except the Southern region, exhibited significantly improved survival rates, suggesting advancements in healthcare and lifestyle factors. These findings underscore the dynamic influence of both region and time period on health and longevity. Interestingly, despite the prevalence of the Mediterranean diet in the Southern region of Europe, rulers from this region did not demonstrate longer lifespans compared to their counterparts in other regions. This suggests that additional lifestyle factors may have played a more prominent role in their longevity. In conclusion, our study sheds light on the intricate relationship between region, time period, and lifespan among European rulers. Although the Mediterranean diet is often associated with health benefits, our findings indicate that it alone may not account for differences in ruler longevity across regions. Further research is warranted to explore the impact of other lifestyle factors on the health and lifespan of European rulers throughout history.

The impact of COVID-19 infection before the vaccination era on the hospitalized patients requiring hemodialysis: a single-center retrospective cohort.

Due to effective vaccinations, the COVID-19 (coronavirus disease 2019) infection that caused the pandemic has a milder clinical course. We aimed to assess the mortality of hospitalized COVID-19 patients before the vaccination era. We investigated the mortality in those patients between 1 October 2020 and 31 May 2021 who received hemodialysis treatment [patients with previously normal renal function (nCKD), patients with chronic kidney disease previously not requiring hemodialysis (CKDnonHD), chronic kidney disease (CKD), and patients on regular hemodialysis (pHD)]. In addition, participants were followed up for all-cause mortality in the National Health Service database until 1 December 2021. In our center, 83 of 108 (76.9%) were included in the analysis due to missing covariates. Over a median of 26 (interquartile range 11-266) days of follow-up, 20 of 22 (90.9%) of nCKD, 23 of 24 (95.8%) of CKDnonHD, and 17 of 37 (45.9%) pHD patients died (p < 0.001). In general, patients with nCKD had fewer comorbidities but more severe presentations. In contrast, the patients with pHD had the least severe symptoms (p < 0.001). In a model adjusted for independent predictors of all-cause mortality (C-reactive protein and serum albumin), CKDnonHD patients had increased mortality [hazard ratio (HR) 1.91, 95% confidence interval (CI), 1.02-3.60], while pHD patients had decreased mortality (HR 0.41, 95% CI 0.20-0.81) compared to nCKD patients. After further adjustment for the need for intensive care, the difference in mortality between the nCKD and pHD groups became non-significant. Despite the limitations of our study, it seems that the survival of previously hemodialysis patients was significantly better.

Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures.

The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age-related diseases affecting the cardiovascular system and central nervous system is discussed, with a specific focus on Alzheimer's disease, Parkinson's disease, stroke, small vessel disease, and vascular cognitive impairment (VCI). Aging is a major risk factor for these diseases. Their pathogenesis involves cellular and molecular mechanisms of aging such as increased oxidative stress, impaired mitochondrial function, DNA damage, and inflammation and is influenced by environmental factors. Environmental toxicants, including ambient particulate matter, pesticides, heavy metals, and organic solvents, have been identified as significant contributors to cardiovascular and brain aging disorders. These toxicants can inflict both macro- and microvascular damage and many of them can also cross the blood-brain barrier, inducing neurotoxic effects, neuroinflammation, and neuronal dysfunction. In conclusion, environmental factors play a critical role in modulating cardiovascular and brain aging. A deeper understanding of how environmental toxicants exacerbate aging processes and contribute to the pathogenesis of neurodegenerative diseases, VCI, and dementia is crucial for the development of preventive strategies and interventions to promote cardiovascular, cerebrovascular, and brain health. By mitigating exposure to harmful environmental factors and promoting healthy aging, we can strive to reduce the burden of age-related cardiovascular and brain pathologies in the aging population.

Pregnancy outcomes of women with untreated 'mild' gestational diabetes (gestational diabetes by the WHO 2013 but not by the WHO-1999 diagnostic criteria) - A population-based cohort study.

AIMS: We compared pregnancy outcomes of untreated 'mild' GDM (GDM by WHO 2013 but not by WHO-1999) to normal glucose tolerant women (NGT). METHODS: In a universal screening program 4333 pregnant women had a 3-point 75 g OGTT in Hungary in 2009-2013. By WHO-2013 untreated NGT was diagnosed in n = 3303, 'mild' GDM in n = 336 cases. RESULTS: 'Mild' GDM women were older (mean difference, SE: 1.4, 0.3 yrs), had higher fasting (1.0, 0.02), 60-minute (1.0, 0.09), and 120-minute (0.4, 0.06 mmol/l) blood glucose, and blood pressure (2.6, 0.5/2.0, 0.5 mmHg). Weight gain was similar in both groups (-0.3, 0.3 kg). GDM newborns were heavier (142, 50 g) and were more frequently macrosomic (>4000 g, OR 1.85, 95 %CI 1.35-2.54). Hypertension during pregnancy was more prevalent in the GDM group (OR 1.55, 95 %CI 1.05-2.28), as well as induced (OR 1.38, 95 %CI 1.10-1.74) and instrumental delivery (OR 1.34, 95 %CI 1.07-1.68), and acute caesarean section (OR 1.32, 95 %CI 1.04-1.64). Most of these differences substantially attenuated or became non-significant after adjustment for pre-pregnancy BMI. CONCLUSIONS: Pregnancy outcomes of 'mild' GDM were worse compared to normal glucose tolerant women however these differences were explained by the pre-pregnancy BMI difference between groups.

Trend of pregnancy outcomes in type 1 diabetes compared to control women: a register-based analysis in 1996-2018.

Introduction: In 1989, the St Vincent declaration aimed to approximate pregnancy outcomes of diabetes to that of healthy pregnancies. We aimed to compare frequency and trends of outcomes of pregnancies affected by type 1 diabetes and controls in 1996-2018. Methods: We used anonymized records of a mandatory nation-wide registry of all deliveries between gestational weeks 24 and 42 in Hungary. We included all singleton births (4,091 type 1 diabetes, 1,879,183 controls) between 1996 and 2018. We compared frequency and trends of pregnancy outcomes between type 1 diabetes and control pregnancies using hierarchical Poisson regression. Results: The frequency of stillbirth, perinatal mortality, large for gestational age, caesarean section, admission to neonatal intensive care unit (NICU), and low Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score was 2-4 times higher in type 1 diabetes compared to controls, while the risk of congenital malformations was increased by 51% and SGA was decreased by 42% (all p<0.05). These observations remained significant after adjustment for confounders except for low APGAR scores. We found decreasing rate ratios comparing cases and controls over time for caesarean sections, low APGAR scores (p<0.05), and for NICU admissions (p=0.052) in adjusted models. The difference between cases and controls became non-significant after 2009. No linear trends were observed for the other outcomes. Conclusions: Although we found that the rates of SGA, NICU care, and low APGAR score improved in pregnancies complicated by type 1 diabetes, the target of the St Vincent Declaration was only achieved for the occurrence of low APGAR scores.

Autonomic dysfunction is associated with the development of arterial stiffness: the Whitehall II cohort.

This study aims to examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness. Autonomic nervous function was assessed in 4901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997 and 2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007 and 2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2). A decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results. People who experience a steeper decline in autonomic nervous function have higher levels of arterial stiffness. The association was stronger in younger people.

Neutrophil-to-Lymphocyte Ratio Is an Independent Risk Factor for Coronary Artery Disease in Central Obesity.

Several inflammatory biomarkers were found to be associated with an increased risk of cardiovascular disease. Neutrophil-to-lymphocyte ratio (NLR) is a marker of subclinical inflammation that increases with the stress response. Visceral adiposity index (VAI) calculated as a combination of anthropometric and metabolic parameters reflects both the extent and function of visceral adipose tissue. Given the association of subclinical inflammation with both obesity and cardiovascular diseases, it is plausible that the inflammation-CVD association is modulated by the amount and function of adipose tissue. Thus, our aim was to examine the association between NLR and coronary artery calcium score (CACS), an intermediate marker of coronary artery disease in asymptomatic patients across VAI tertiles. Methods: Data from 280 asymptomatic participants of a cardiovascular screening program were analysed. In addition to the collection of lifestyle and medical history, a non-contrast cardiac CT scan and laboratory tests were performed on all participants. Multivariate logistic regression was conducted with CACS > 100 as the outcome and with conventional cardiovascular risk factors and NLR, VAI, and NLR by VAI tertile as predictors. Results: We found an interaction between VAI tertiles and NLR; NLR values were similar in the lower VAI tertiles, while they were higher in the CACS > 100 in the 3rd VAI tertile (CACS ≤ 100: 1.94 ± 0.58 vs. CACS > 100: 2.48 ± 1.1, p = 0.008). According to multivariable logistic regression, the interaction between NLR and VAI tertiles remained: NLR was associated with CACS > 100 in the 3rd VAI tertile (OR = 1.67, 95% CI 1.06-2.62, p = 0.03) but not in the lower tertiles even after adjustment for age, sex, smoking, history of hypertension, hyperlipidaemia, and diabetes mellitus, as well as high-sensitivity C-reactive protein. Our findings draw attention to the independent association between subclinical, chronic, systemic inflammation and subclinical coronary disease in obesity.

Comparison of Efficacy and Safety of Commercially Available Fixed-Ratio Combinations of Insulin Degludec/Liraglutide and Insulin Glargine/Lixisenatide: A Network Meta-analysis.

OBJECTIVES: Our aim in this study was to compare the efficacy and safety of commercially available fixed-ratio combinations (FRCs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and basal insulins by a network meta-analysis of randomized controlled trials (RCTs) of people with type 2 diabetes. METHODS: We present a systematic review and network meta-analyses of RCTs of individuals with type 2 diabetes randomized to FRCs or to their components for ≥24 weeks. All reports were obtained from PubMed or ClinicalTrials.gov up to February 28, 2022. The primary outcome was glycated hemoglobin (A1C) level attained. Secondary outcomes included fasting plasma glucose, change in body weight, and incident hypoglycemia. Treatment effects were estimated as mean difference (MD) and standard error (SE), or as odds ratio (OR) with 95% confidence interval (CI) using the fixed combination of insulin glargine 100 IU/mL and lixisenatide (iGlarLixi) as reference. RESULTS: We included 29 RCTs from among the 1,404 articles identified. No direct comparisons between FRCs were found. After excluding some insulin-capped trials to reach model consistency, both FRCs were more efficacious regarding A1C than their components, but no difference between FRCs was found (MD, -0.10%; SE, 0.10%). The effect of the fixed combination of insulin degludec and liraglutide (IDegLira) (MD, -0.47 mmol/L; SE, 0.24 mmol/L) and basal insulins was similar to that of iGlarLixi (reference) on fasting glucose, whereas GLP-1RAs had lower efficacy than iGlarLixi. Weight gain was lower with GLP-1RAs and IDegLira (MD, -0.72 kg; SE, 0.32 kg) than with iGlarLixi (reference) and higher with basal insulins. Incident hypoglycemia (based on different definitions) was least frequent with GLP-1RAs, followed by IDegLira (OR, 0.78; 95% CI, 0.39 to 1.57), iGlarLixi (reference), and basal insulins. CONCLUSIONS: For A1C, both FRCs were more efficacious over their individual components, with similar efficacies of the 2 FRCs.

Decreased lifespan in female "Munchkin" actors from the cast of the 1939 film version of The Wizard of Oz does not support the hypothesis linking hypopituitary dwarfism to longevity.

In laboratory mice, pituitary dwarfism caused by genetic reduction or elimination of the activity of growth hormone (GH) significantly extends lifespan. The effects of congenital pituitary dwarfism on human longevity are not well documented. To analyse the effects of untreated pituitary dwarfism on human lifespan, the longevity of a diverse group of widely known little people, the 124 adults who played "Munchkins" in the 1939 movie The Wizard of Oz was investigated. Survival of "Munchkin" actors with those of controls defined as cast members of The Wizard of Oz and those of other contemporary Academy Award winning Hollywood movies was compared. According to the Kaplan-Meier survival curves, survival of female and male "Munchkin" actors was shorter than cast controls and Hollywood controls of respective sexes. Cox regression analyses showed that female "Munchkin" actors had significantly higher risk ratios compared to both female cast controls (RR, 1.70; 95% CI, 1.05 to 2.77) and female Hollywood controls (RR, 1.52; 95% CI, 1.03 to 2.24). Similar trends were also discernible for men, albeit point estimates were not significant. The lack of lifespan extension in "Munchkin" actors does not support the hypothesis that hereditary GH deficiency regulates longevity in humans.

Real-world effectiveness of IDegLira compared with intensified conventional insulin therapy in adults with type 2 diabetes: a retrospective cohort study.

BACKGROUND: IDegLira is a fixed-ratio combination of insulin degludec and liraglutide with proven efficacy against simpler regimens and non-inferiority against basal-bolus insulin therapy. However, the evaluation of its real-world effectiveness is hindered by technical issues and requires further exploration. Thus we aimed to compare effectiveness of insulin degludec/liraglutide (IDegLira) versus intensified conventional insulin therapy (ICT) for type 2 diabetes in a real-world setting. METHODS: This retrospective cohort study from an outpatient clinic in Hungary included people who initiated IDegLira due to inadequate glycaemic control (HbA1c > 7.0% [53.0 mmol/mol]) with oral and/or injectable antidiabetic drugs. Data were compared with a historical cohort who initiated ICT. Outcomes included HbA1c, body weight, and hypoglycaemia differences over 18 months of follow-up. RESULTS: Data were included from 227 and 72 people who initiated IDegLira and ICT, respectively. Estimated mean difference (MD) in HbA1c at 18 months favoured IDegLira versus ICT (MD 0.60, 95% CI 0.88-0.32 [MD 6.6 mmol/mol, 95% CI 9.6-3.5]). More people reached target HbA1c ≤7.0% (53.0 mmol/mol) with IDegLira than ICT (odds ratio 3.36, 95% CI 1.52-7.42). IDegLira treatment was associated with weight loss compared with gain for ICT (MD 6.7 kg, 95% CI 5.0-8.5). The hazard ratio for hypoglycaemia comparing IDegLira with ICT was 0.18 (95% CI 0.08-0.49). CONCLUSIONS: Treatment with IDegLira over 18 months resulted in greater HbA1c reductions, weight loss versus gain, and a lower rate of hypoglycaemia versus ICT in people with type 2 diabetes.

Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study.

BACKGROUND: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease. METHODS: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants. RESULTS: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population. CONCLUSIONS: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Association of Metabolic Syndrome With Incident Dementia: Role of Number and Age at Measurement of Components in a 28-Year Follow-up of the Whitehall II Cohort Study.

OBJECTIVE: Previous research suggests an inconsistent association between Metabolic syndrome (MetS) and incident dementia. We examined the role of number of MetS components and age at their assessment for incident dementia. RESEARCH DESIGN AND METHODS: MetS components (fasting glucose, triglycerides, waist circumference, blood pressure, and HDL cholesterol) on 7,265, 6,660, and 3,608 participants at <60, 60 to <70, and ≥70 years of age were used to examine associations with incident dementia using cause-specific Cox regression. RESULTS: Analyses of MetS measured at <60, 60 to <70, and ≥70 years involved 393 (5.4%), 497 (7.5%), and 284 (7.9%) dementia cases over a median follow-up of 20.8, 10.4, and 4.2 years, respectively. Every additional MetS component before 60 (hazard ratio [HR] 1.13 [95% CI 1.05, 1.23]) and 60 to <70 (HR 1.08 [95% CI 1.00, 1.16]) but not ≥70 years (HR 1.04 [95% CI 0.96, 1.13]) was associated with higher dementia risk. MetS defined conventionally (≥3 components) before 60 years (HR 1.23 [95% CI 0.96, 1.57]), between 60 and 70 years (HR 1.14 [95% CI 0.91, 1.42]), or >70 years of age (HR 1.10 [95% CI 0.86, 1.40]) was not associated with incident dementia. Multistate models showed higher risk of dementia in those with ≥1 (HR 1.99 [95% CI 1.08, 3.66]) and ≥2 MetS components (HR 1.69 [95% CI 1.12, 2.56]) before 60 years of age, even when they remained free of cardiovascular disease over the follow-up. CONCLUSIONS: Risk of incident dementia increases with every additional MetS component present in midlife rather than after accumulation of three components; only part of this risk is mediated by cardiovascular disease.

Different patterns of excess all-cause mortality by age and sex in Hungary during the 2nd and 3rd waves of the COVID-19 pandemic.

It is well accepted that COVID-19-related mortality shows a strong age dependency. However, temporal changes in the age distribution of excess relative mortality between waves of the pandemic are less frequently investigated. We aimed to assess excess absolute mortality and the age-distribution of all-cause mortality during the second and third waves of the COVID-19 pandemic in Hungary compared to the same periods of non-pandemic years. Rate ratios for excess all-cause mortality with 95% confidence intervals and the number of excess deaths for the second (week 41 of 2020 through week 4 of 2021) and third waves (weeks 7-21 of 2021) of the COVID pandemic for the whole of Hungary compared to the same periods of the pre-pandemic years were estimated for 10-year age strata using Poisson regression. Altogether, 9771 (95% CI: 9554-9988) excess deaths were recorded during the second wave of the pandemic, while it was lower, 8143 (95% CI: 7953-8333) during the third wave. During the second wave, relative mortality peaked for ages 65-74 and 75-84 (RR 1.37, 95%CI 1.33-1.41, RR 1.38, 95%CI 1.34-1.42). Conversely, during the third wave, relative mortality peaked for ages 35-44 (RR 1.43, 95%CI 1.33-1.55), while those ≥65 had substantially lower relative risks compared to the second wave. The reduced relative mortality among the elderly during the third wave is likely a consequence of the rapidly increasing vaccination coverage of the elderly coinciding with the third wave. The hugely increased relative mortality of those 35-44 could point to non-biological causes, such as less stringent adherence to non-pharmaceutical measures in this population.

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies.

OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted ß -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted ß -0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted ß -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Association of Cardiovascular Autonomic Neuropathy and Distal Symmetric Polyneuropathy with All-Cause Mortality: A Retrospective Cohort Study.

BACKGROUND: People with diabetic cardiovascular autonomic neuropathy (CAN) have increased cardiovascular mortality. However, the association between distal symmetric polyneuropathy (DSPN) or CAN with all-cause mortality is much less investigated. Thus, we set out to examine the effect of CAN and DSPN on all-cause mortality in a well-phenotyped cohort. METHODS: All diabetes cases (n = 1,347) from the catchment area of a secondary diabetes care centre who had medical examination including neuropathy assessment between 1997 and 2016 were followed up for all-cause mortality in the NHS Hungary reimbursement database until 2018. We investigated the association of CAN (Ewing tests) and DSPN (Neurometer) with all-cause mortality using Cox models stratified by diabetes type. RESULTS: Altogether, n = 131/1,011 persons with type 1/type 2 diabetes were included. Of the participants, 53%/43% were male, mean age was 46 ± 12/64 ± 10 years, diabetes duration was 13 ± 10/7 ± 8 years, 42%/29% had CAN, and 39%/37% had DSPN. During the 9 ± 5/8 ± 5-year follow-up, n = 28/494 participants died. In fully adjusted models, participants with type 1 diabetes patients with versus without DSPN had an increased mortality (HR 2.99, 95% CI 1.4-8.63), while no association with CAN was observed. In type 2 diabetes, both DSPN and CAN independently increased mortality (HR 1.32, 95% CI: 1.07-1.64, and HR 1.44, 95% CI: 1.17-1.76). CONCLUSIONS: Our results are compatible with an increased risk of mortality in people with type 1 diabetes and DSPN. Furthermore, we report a similarly strong association between DSPN and CAN and all-cause mortality in type 2 diabetes mellitus.