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Aims/hypothesis The aim of this study was to assess the impact of invitation to screening for type 2 diabetes and related cardiovascular risk factors on population mortality. Methods This was a parallel-group population-based cohort study including all men and women aged 40-65 years, free of known diabetes, registered with a single practice in Ely, UK (n = 4,936). In 1990-1992, approximately one-third (n = 1,705) were randomly selected to receive an invitation to screening for diabetes (with an OGTT) and related cardiovascular risk factors. In the remaining two-thirds of the population, 1,705 individuals were randomly selected for invitation to screening in 2000-2003 and 1,526 were not invited at any point during the follow-up period. All individuals were flagged for mortality until January 2008. Results There were 345 deaths between 1990 and 1999 (median 10 years follow-up). Compared with those not invited, individuals who were invited to the 1990-1992 screening round had a non-significant 21% lower all-cause mortality (HR 0.79 [95% CI 0.63-1.00], p = 0.05) after adjustment for age, sex and deprivation. There were 291 deaths between 2000 and 2008 (median 8 years follow-up), with no significant difference in mortality between invited and non-invited participants in 2000-2003. Compared with the non-invited group, participants who attended for screening at any time point had a significantly lower mortality and those who did not attend had a significantly higher mortality. Conclusions/interpretation Invitation to screening was associated with a non-significant reduction in mortality in the Ely cohort between 1990 and 1999, but this was not replicated in the period 2000-2008. This study contributes to the evidence concerning the potential benefits of population screening for diabetes and related cardiovascular risk factors.

Aims There are continuing uncertainties about how much screening for type 2 diabetes brings forward the clinical diagnosis and the impact that earlier diagnosis has on health outcomes. We compared the duration of diabetes and health outcomes in a population invited for diabetes screening at 5-yearly intervals from 1990 (screened population) with those in a similar population not invited for screening (unscreened population). Methods This was a parallel-group, cohort study of people aged 40–65 years, free of known diabetes, identified from the population register of a general practice in Ely, Cambridgeshire, UK ( n  = 4,936). In 1990–1992, one-third ( n  = 1,705), selected randomly, received an invitation for screening for diabetes and cardiovascular risk factors at 5-yearly intervals (screened population). From the remainder of the sampling frame, 1,705 randomly selected individuals were invited to diabetes screening 10 years later (unscreened population). Patients with diabetes from both populations were invited for a health assessment, including biochemical, anthropometric and questionnaire measures, and testing for the presence of diabetic complications Results Of the 199 eligible individuals with diabetes diagnosed during follow-up, 152 (76%) attended for health assessment. The median duration of clinically recognised diabetes was significantly longer in cases arising in the screened (5.0 years) compared with the unscreened population (1.7 years; p  = 0.006). Clinical measures, prescribed medication and functional status were similar between screened and unscreened populations. Conclusions Diabetes screening resulted in cases being identified on average 3.3 years earlier, a difference significantly shorter than previous estimates. Earlier diagnosis did not appear to impact on health outcomes. Further evidence is needed to justify the introduction of population-based screening.

Ingo Kurth and colleagues show that a specific de novo missense mutation in SCN11A results in an inability to experience pain. They further show that mutant channels display higher activity at resting voltages, causing sustained depolarization of pain receptors, impaired generation of action potentials and aberrant synaptic transmission. The sensation of pain protects the body from serious injury 1 , 2 , 3 . Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Na v 1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system 4 , 5 . Mutant Na v 1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

Paul Boutros, Robert Bristow and colleagues report a molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer. They find that multifocal tumors are highly heterogeneous, and they identify a novel recurrent amplification of MYCL1 . Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL , which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Background Geroscience focuses on interventions to mitigate molecular changes associated with aging. Lifestyle modifications, medications, and social factors influence the aging process, yet the complex molecular mechanisms require an in-depth exploration of the epigenetic landscape. The specific epigenetic clock and predictor effects of a vegan diet, compared to an omnivorous diet, remain underexplored despite potential impacts on aging-related outcomes. Methods This study examined the impact of an entirely plant-based or healthy omnivorous diet over 8 weeks on blood DNA methylation in paired twins. Various measures of epigenetic age acceleration (PC GrimAge, PC PhenoAge, DunedinPACE) were assessed, along with system-specific effects (Inflammation, Heart, Hormone, Liver, and Metabolic). Methylation surrogates of clinical, metabolite, and protein markers were analyzed to observe diet-specific shifts. Results Distinct responses were observed, with the vegan cohort exhibiting significant decreases in overall epigenetic age acceleration, aligning with anti-aging effects of plant-based diets. Diet-specific shifts were noted in the analysis of methylation surrogates, demonstrating the influence of diet on complex trait prediction through DNA methylation markers. An epigenome-wide analysis revealed differentially methylated loci specific to each diet, providing insights into the affected pathways. Conclusions This study suggests that a short-term vegan diet is associated with epigenetic age benefits and reduced calorie intake. The use of epigenetic biomarker proxies (EBPs) highlights their potential for assessing dietary impacts and facilitating personalized nutrition strategies for healthy aging. Future research should explore the long-term effects of vegan diets on epigenetic health and overall well-being, considering the importance of proper nutrient supplementation. Trial registration Clinicaltrials.gov identifier: NCT05297825

Background Laparoscopic cholecystectomy with ultrasonic dissection presents a compelling alternative to conventional electrocautery. The evidence for elective cholecystectomy supports the adoption of ultrasonic dissection, citing advantages such as reduced operating time, diminished bleeding, shorter hospital stays and decreased postoperative pain and nausea. However, the efficacy of this procedure in emergency surgery and patients diagnosed with acute cholecystitis remains uncertain. The aim of this study was to compare outcomes of electrocautery and ultrasonic dissection in patients with acute cholecystitis. Methods A randomized, parallel, double-blinded, multicentre controlled trial was conducted across eight Swedish hospitals. Eligible participants were individuals aged ≥ 18 years with acute cholecystitis lasting ≤ 7 days. Laparoscopic cholecystectomy was performed in the emergency setting as soon as local circumstances permitted. Random allocation to electrocautery or ultrasonic dissection was performed in a 1:1 ratio. The primary endpoint was the total complication rate, analysed using an intention-to-treat approach. The primary outcome was analysed using logistic generalized estimated equations. Patients, postoperative caregivers, and follow-up personnel were blinded to group assignment. Results From September 2019 to March 2023, 300 patients were enrolled and randomly assigned to electrocautery dissection (n = 148) and ultrasonic dissection (n = 152). No significant difference in complication rate was observed between the groups (risk difference [RD] 1.6%, 95% confidence interval [CI], − 7.2% to 10.4%, P  = 0.720). No significant disparities in operating time, conversion rate, hospital stay or readmission rates between the groups were noted. Haemostatic agents were more frequently used in electrocautery dissection (RD 10.6%, 95% CI, 1.3% to 19.8%, P  = 0.025). Conclusions Ultrasonic dissection and electrocautery dissection demonstrate comparable risks for complications in emergency surgery for patients with acute cholecystitis. Ultrasonic dissection is a viable alternative to electrocautery dissection or can be used as a complementary method in laparoscopic cholecystectomy for acute cholecystitis. Trial registration The trial was registered prior to conducting the research on http://clinical.trials.gov , NCT03014817.

AbstractObjectiveTo estimate the effect of a moderate to high intensity aerobic and strength exercise training programme on cognitive impairment and other outcomes in people with mild to moderate dementia.DesignMulticentre, pragmatic, investigator masked, randomised controlled trial.SettingNational Health Service primary care, community and memory services, dementia research registers, and voluntary sector providers in 15 English regions.Participants494 people with dementia: 329 were assigned to an aerobic and strength exercise programme and 165 were assigned to usual care. Random allocation was 2:1 in favour of the exercise arm.InterventionsUsual care plus four months of supervised exercise and support for ongoing physical activity, or usual care only. Interventions were delivered in community gym facilities and NHS premises.Main outcome measuresThe primary outcome was score on the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) at 12 months. Secondary outcomes included activities of daily living, neuropsychiatric symptoms, health related quality of life, and carer quality of life and burden. Physical fitness (including the six minute walk test) was measured in the exercise arm during the intervention.ResultsThe average age of participants was 77 (SD 7.9) years and 301/494 (61%) were men. By 12 months the mean ADAS-cog score had increased to 25.2 (SD 12.3) in the exercise arm and 23.8 (SD 10.4) in the usual care arm (adjusted between group difference −1.4, 95% confidence interval −2.6 to −0.2, P=0.03). This indicates greater cognitive impairment in the exercise group, although the average difference is small and clinical relevance uncertain. No differences were found in secondary outcomes or preplanned subgroup analyses by dementia type (Alzheimer’s disease or other), severity of cognitive impairment, sex, and mobility. Compliance with exercise was good. Over 65% of participants (214/329) attended more than three quarters of scheduled sessions. Six minute walking distance improved over six weeks (mean change 18.1 m, 95% confidence interval 11.6 m to 24.6 m).ConclusionA moderate to high intensity aerobic and strength exercise training programme does not slow cognitive impairment in people with mild to moderate dementia. The exercise training programme improved physical fitness, but there were no noticeable improvements in other clinical outcomes.Trial registrationCurrent Controlled Trials ISRCTN10416500.

Background There is some evidence of reduced major cardiovascular event (MACE) rates associated with moderate coffee consumption in the general population. However, there is concern about the potential risks of coffee consumption in patients with atrial fibrillation (AF). Therefore, we aimed to investigate the association between coffee consumption and MACE in AF patients. Methods Data of patients with documented AF enrolled in two large prospective observational multicenter cohort studies (Swiss-AF and Beat-AF) were analyzed. Follow-up information was obtained on a yearly basis. Coffee consumption was categorized into two main groups: “daily” and “not-daily” coffee consumers as well as additional subcategories. The primary endpoint was MACE, defined as a composite of stroke or systemic embolism, myocardial infarction, hospitalization for acute heart failure, and cardiovascular mortality. Secondary endpoints were the individual components of MACE and all-cause mortality. We performed time-updated multivariable adjusted Cox regression analyses to investigate the association between coffee consumption and MACE. Results The incidence rate for MACE was 5.09 per 100 person-years (py) in daily and 7.49 per 100 py in not-daily consumers (median follow-up duration: 4.7 years). After adjustment for pre-selected confounding variables, daily coffee consumption was associated with a 23% lower hazard for MACE compared to not-daily consumption (hazard ratio (HR) (95% confidence interval (CI)) 0.77 (0.66; 0.89)). Patients with moderate coffee consumption (2–3 cups/day) had the lowest hazard for MACE compared to patients with not-daily coffee consumption (HR (95% CI) 0.74 (0.63; 0.87)). Conclusions In a population of AF patients, daily coffee consumption was associated with a reduced risk for MACE, hospitalization for acute heart failure, and all-cause mortality. The results were inconclusive for stroke or systemic embolism, myocardial infarction, and cardiovascular death. In this analysis, we found no evidence of an unfavourable association of daily coffee consumption in AF Patients with adverse outcome events. Trial registration ClinicalTrials.gov Identifier: NCT02105844.

AimsTo study the correlation between clinicopathological risk factors and the risk for intervention-requiring cancer recurrence in patients with small papillary thyroid cancers (sPTCs).Materials and methodsRecords for 397 patients with sPTC (T1 ≤ 20mm) were obtained from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) between 2010 and 2016. Follow-up time was at least 5 years. Data regarding intervention-requiring cancer recurrence were obtained from patient medical records and analysed regarding lymph node (LN) status (N0, N1a and N1b) and recurrence.ResultsAge was significantly lower in the N1a and N1b groups compared to N0 (45 vs. 40.5 vs. 49 years, respectively; p = 0.002). Tumour size was smaller in the N1a group compared to N1b group (9 vs. 11.8 mm; p <0.01). The mean number of metastatic LNs at initial surgery was higher in the N1b compared to N1a group (6.6 vs. 3; p = 0.001), and in the recurrent compared to the non-recurrent group (7 versus 3.9; p <0.01). The recurrence rate was higher in the N1b group than the N1a and N0 groups (25% vs. 2.4% vs. 1.4%, respectively; p = 0.001).ConclusionsLymph node stage N1b at diagnosis, and having five or more metastatic nodes, are strong risk factors for cancer recurrence and decreased disease-free survival in sPTC. The management of patients with sPTC should include thorough lymph node mapping for optimal treatment and individual risk stratification.

To examine the validity of the short, last 7-day, self-administered form of the International Physical Activity Questionnaire (IPAQ). All subjects wore an accelerometer for seven consecutive days and completed the IPAQ questionnaire on the eighth day. Criterion validity was assessed by linear regression analysis and by modified Bland-Altman analysis. Specificity and sensitivity were calculated for classifying respondents according to the physical activity guidelines of the American College of Sports Medicine/Centers for Disease Control and Prevention. Workplaces in Uppsala, Sweden. One hundred and eighty-five (87 males) participants, aged 20 to 69 years. Total self-reported physical activity (PA) (MET-min day(-1)) was significantly correlated with average intensity of activity (counts min(-1)) from accelerometry (r = 0.34, P < 0.001). Gender, age, education and body mass index did not affect this relationship. Further, subcomponents of self-reported PA (time spent sitting, time in PA, time in moderate and vigorous activity (MVPA)) were significantly correlated with objectively measured PA (P < 0.05). Self-reported time in PA was significantly different from time measured by accelerometry (mean difference: -25.9 min day(-1); 95% limits of agreement: -172 to 120 min day(-1); P < 0.001). IPAQ identified 77% (specificity) of those who met the current PA guidelines of accumulating more than 30 min day(-1) in MVPA as determined by accelerometry, whereas only 45% (sensitivity) of those not meeting the guidelines were classified correctly. Our results indicate that the short, last 7-days version of the IPAQ has acceptable criterion validity for use in Swedish adults. However, the IPAQ instrument significantly overestimated self-reported time spent in PA. The specificity to correctly classify people achieving current PA guidelines was acceptable, whereas the sensitivity was low.