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Abstract Background Hip fractures are a major health concern for older adults, often leading to reduced walking ability. Individuals with dementia may experience worse recovery outcomes. This study aims to explore whether dementia is associated with greater declines in walking ability following hip fractures. Methods This register study used data from the Swedish Hip Fracture Register, including data on four-months follow-up on walking ability. The register data was linked to information on dementia diagnosis from other national registers prior to the fracture. All patients > 60 years who suffered a hip fracture in Sweden between 2010 and 2018 were included. Binary logistic regression was used to analyze the loss of walking ability after the hip fracture with adjustment for confounding factors. Stratified analyses were done in four groups based on pre-fracture walking ability: Alone outdoors, Assisted outdoors, Alone indoors, and Assisted indoors. Results The analysis included 59,402 patients with a hip fracture, of which 17% had dementia prior to the fracture. Having dementia was associated with a complete loss of walking ability four months after hip fracture; the multivariable-adjusted odds ratio for complete loss of walking ability in the dementia group, using the non-dementia group as a reference, was 1.60 (95% Confidence Interval [CI] 1.49–1.72. In analyses stratified by pre-fracture walking ability, the odds ratios were 2.34 (95% Confidence Interval [CI] 2.03–2.69) for Alone outdoors, 1.53 (95% CI 1.29–1.81) for Assisted outdoors, 1.41 (95% CI 1.27–1.56) for Alone indoors, and 1.29 (95% CI 1.09–1.51) for Assisted indoors. Conclusions This study demonstrates that patients with dementia have a greater risk of complete loss of walking ability. The most notable difference was observed in patients who had high walking ability prior to the fracture. These findings suggest the need for tailored rehabilitation programs and enhanced post-operative care protocols for patients with dementia undergoing hip fracture surgery, particularly for those who had high walking ability before the fracture.

Abstract Background Patients surgically treated for lumbar spinal stenosis or cervical radiculopathy report improvement in approximately two out of three cases. Advancements in Machine Learning and the utility of large datasets have enabled the development of prognostic prediction models within spine surgery. This trial investigates if the use of the postoperative outcome prediction model, the Dialogue Support, can alter patient-reported outcome and satisfaction compared to current practice. Methods This is a prospective, multicenter clinical trial. Patients referred to a spine clinic with cervical radiculopathy or lumbar spinal stenosis will be screened for eligibility. Participants will be assessed at baseline upon recruitment and at 12 months follow-up. The Dialogue Support will be used on all participants, and they will thereafter be placed into either a surgical or a non-surgical treatment arm, depending on the decision made between patient and surgeon. The surgical treatment group will be studied separately based on diagnosis of either cervical radiculopathy or lumbar spinal stenosis. Both the surgical and the non-surgical group will be compared to a retrospective matched control group retrieved from the Swespine register, on which the Dialogue Support has not been used. The primary outcome measure is global assessment regarding leg/arm pain in the surgical treatment group. Secondary outcome measures include patient satisfaction, Oswestry Disability Index (ODI), EQ-5D, and Numeric Rating Scales (NRS) for pain. In the non-surgical treatment group primary outcome measures are EQ-5D and mortality, as part of a selection bias analysis. Discussion The findings of this study may provide evidence on whether the use of an advanced digital decision tool can alter patient-reported outcomes after surgery. Trial registration The trial was retrospectively registered at ClinicalTrials.gov on April 17th, 2023, NCT05817747. Protocol version 1. Trial design Clinical multicenter trial.

Abstract Background Venous thromboembolism (VTE) has a high mortality rate and can be the first manifestation of cancer. We investigated the incidence of cancer after first-ever VTE and the association between VTE and all-cause mortality. Methods A Swedish cohort study that included 105,997 participants without previous cancer who underwent a health examination from 1985–2014 was conducted. Manually validated first-ever VTE events, incident cancer according to the Swedish cancer registry, and mortality were registered. Participants were followed until September 5, 2014. Results The mean age at inclusion was 46.2 years, and 50.3% of participants were female. We identified 1303 persons in the cohort with a VTE and no previous cancer. Among these, 179 (13.7%) were diagnosed with cancer after the VTE event, resulting in a cancer incidence of 26.4 (95% CI 22.8–30.6) cases per 1000 person-years. The incidence was highest during the first 6 months after the VTE. In the study population, VTE was associated with an increased risk of cancer (HR 1.95 [95% CI 1.67–2.29] in a multivariable model). VTE was also associated with an increased risk of death (HR 6.30 [95% CI 5.82–6.81]) in a multivariable model). There was an interaction between sex and VTE in relation to both risk of cancer and mortality, with a stronger association in women. Conclusions The incidence of cancer is high after first-ever VTE, especially close to the VTE event. VTE seems to be a stronger risk marker in women than in men for both cancer and death.

The incidence of recurrent venous thromboembolism (VTE) changes over time from the first VTE event and depends on the presence of risk factors. In this study, we aimed to determine the yearly incidence of VTE recurrence during five years of follow-up after a first-ever VTE event. For this cohort study, we identified persons who experienced a validated first-ever VTE between 2006–2014 in northern Sweden. These patients’ medical records were reviewed to identify recurrent VTE events during five years of follow-up. The yearly incidence rates (IRs) of recurrent VTE per 100 person-years were calculated and stratified into three groups defined by characteristics at the first-ever VTE event: no risk factors, cancer, or other risk factors. A total of 1413 persons experienced a first-ever VTE during the study period, of whom 213 experienced a recurrent VTE. Among persons without risk factors, the IR was 4.2 during the first year of follow-up, and 4.1 during the fifth year. Among persons with cancer, the IR was 9.5 during the first year, and 5.4 during the fifth year. Among persons with other risk factors, the corresponding IRs were 6.1 and 2.3. In conclusion, after a first-ever VTE event, persons with cancer had the highest recurrence rate during the first years of follow-up. Among persons with cancer who were alive after five years, the incidence of recurrent VTE during the fifth year was similar to that in participants without risk factors.

Abstract Objective Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2‐item scale polygenic score with anxiety in MS. Methods Using a case–control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview‐diagnosed, and lifetime self‐report physician‐diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome‐wide association study and was tested using regression. Results A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta‐analyses identified that in MS, each 1‐SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09–1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. Interpretation Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Abstract Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters. In addition, we attempted replication in T1D using a genome-wide association study (N = 3,945) and direct genotyping (N = 3,263), and in the general population from the large-scale population-wide FinnGen project and UK Biobank summary statistics. We identified a rare missense variant on SREBF1 exome-wide significantly associated with stroke (rs114001633, p.Pro227Leu, p-value = 7.30 × 10–8), which replicated for hemorrhagic stroke in T1D. Using gene aggregate analysis, we identified exome-wide significant genes: ANK1 and LRRN1 displayed replication evidence in T1D, and LRRN1, HAS1 and UACA in the general population (UK Biobank). Furthermore, we performed sliding-window analyses and identified 14 genome-wide significant windows for stroke on 4q33-34.1, of which two replicated in T1D, and a suggestive genomic window on LINC01500, which replicated in T1D. Finally, we identified a suggestively stroke-associated TRPM2-AS promoter (p-value = 5.78 × 10–6) with borderline significant replication in T1D, which we validated with an in vitro cell-based assay. Due to the rarity of the identified genetic variants, future replication of the genomic regions represented here is required with sequencing of individuals with T1D. Nevertheless, we here report the first genome-wide analysis on stroke in individuals with diabetes.

Abstract Background As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. Methods We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. Results During median 18.0 (14.1–19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no–very mild (ETDRS 10–20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02–3.15) in non-proliferative (ETDRS 35–53), and 1.69 (1.02–2.82) in proliferative (ETDRS 61–85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91–3.10) in non-proliferative and 1.35 (0.77–2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66–12.28) in non-proliferative and 4.31 (1.16–16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). Conclusions Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

Introduction Diabetes is linked to neurodegenerative diseases (NDs), but data in type 1 diabetes are scarce. Our aim was to assess the standardized incidence ratios (SIRs) of different NDs in type 1 diabetes, and to evaluate the impact of diabetic vascular complications and age at diabetes onset.Research design and methods In this observational cohort study, we included 4261 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy study, and 11 653 matched population-based controls without diabetes. NDs were identified from registers until the end of 2017. Diabetic complications were assessed at the baseline study visit. SIRs were calculated from diabetes onset, except for impact of complications that was calculated from baseline study visit.Results The SIRs for NDs were increased in type 1 diabetes: any dementia 2.24 (95% CI 1.79 to 2.77), Alzheimer’s disease 2.13 (95% CI 1.55 to 2.87), vascular dementia 3.40 (95% CI 2.08 to 5.6), other dementias 1.70 (95% CI 1.22 to 2.31), and Parkinson’s disease 1.61 (95% CI 1.04 to 2.37). SIR showed a twofold increased incidence already in those without albuminuria (1.99 (1.44–2.68)), but further increased in presence of diabetic complications: kidney disease increased SIR for Alzheimer’s disease, while cardiovascular disease increased SIR for both Alzheimer’s disease and other dementias. Diabetes onset

Background Psychological resilience refers to an individual’s ability to cope with and adapt to challenging life circumstances and events.Objective This study aims to explore the association between psychological resilience and all-cause mortality in a national cohort of US older adults by a cross-sectional study.Methods The Health and Retirement Study (2006–2008) included 10 569 participants aged ≥50. Mortality outcomes were determined using records up to May 2021. Multivariable Cox proportional hazards models were used to analyse the associations between psychological resilience and all-cause mortality. Restricted cubic splines were applied to examine the association between psychological resilience and mortality risk.Findings During the follow-up period, 3489 all-cause deaths were recorded. The analysis revealed an almost linear association between psychological resilience and mortality risk. Higher levels of psychological resilience were associated with a reduced risk of all-cause mortality in models adjusting for attained age, sex, race and body mass index (HR=0.750 per 1 SD increase in psychological resilience; 95% CI 0.726, 0.775). This association remained statistically significant after further adjustment for self-reported diabetes, heart disease, stroke, cancer and hypertension (HR=0.786; 95% CI 0.760, 0.813). The relationship persisted even after accounting for smoking and other health-related behaviours (HR=0.813; 95% CI 0.802, 0.860).Conclusions This cohort study highlights the association between psychological resilience and all-cause mortality in older adults in the USA.Clinical implications Psychological resilience emerges as a protective factor against mortality, emphasising its importance in maintaining health and well-being.

Abstract The clinical translation of induced pluripotent stem cells (iPSCs) holds great potential for personalized therapeutics. However, one of the main obstacles is that the current workflow to generate iPSCs is expensive, time‐consuming, and requires standardization. A simplified and cost‐effective microfluidic approach is presented for reprogramming fibroblasts into iPSCs and their subsequent differentiation into neural stem cells (NSCs). This method exploits microphysiological technology, providing a 100‐fold reduction in reagents for reprogramming and a ninefold reduction in number of input cells. The iPSCs generated from microfluidic reprogramming of fibroblasts show upregulation of pluripotency markers and downregulation of fibroblast markers, on par with those reprogrammed in standard well‐conditions. The NSCs differentiated in microfluidic chips show upregulation of neuroectodermal markers (ZIC1, PAX6, SOX1), highlighting their propensity for nervous system development. Cells obtained on conventional well plates and microfluidic chips are compared for reprogramming and neural induction by bulk RNA sequencing. Pathway enrichment analysis of NSCs from chip showed neural stem cell development enrichment and boosted commitment to neural stem cell lineage in initial phases of neural induction, attributed to a confined environment in a microfluidic chip. This method provides a cost‐effective pipeline to reprogram and differentiate iPSCs for therapeutics compliant with current good manufacturing practices.

Common methods for treating surface waters involve chemical flocculation, for which a significant factor contributing to the total cost and climate impact is the consumption of chemicals, chiefly coagulants and pH-adjusting chemicals. The amount of chemicals required for treating surface waters and achieving suitable flocculation pH depends greatly on the alkalinity of the source water. This study investigates the viability of mixing two surface waters with different chemical properties with the aim of reducing the amount of chemicals used during chemical flocculation. Bench-scale experiments were carried out, and the results were compared with full-scale operations at a surface water treatment plant (WTP). The WTP uses ferric chloride as a coagulant, which effectively removes natural organic matter, but consumes large amounts of hydroxide to manage pH before and after flocculation. As an alternative process, this study tested the use of aluminum sulfate, polyaluminum chloride and ferric chloride at varying dosages in combination with different source water mixtures to achieve suitable flocculation pH. The results showed that pH-adjusting chemicals could be omitted by adding a small amount of high alkalinity surface water to the primary source water, thereby reducing costs and climate impact substantially. HIGHLIGHTS Mixing raw waters with different properties could substantially reduce costs and climate impact.; Aluminum sulfate offered potential cost savings of up to 40% and a reduction in climate impact by up to 36% compared to conventional ferric chloride precipitation.; Polyaluminum chloride with high basicity offered a broader coagulant dosage range, reducing the need for pH adjustment and potentially allowing for higher dosages.;

Abstract Background It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT). Methods This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated. Results Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes. Conclusions Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations. Trial registration details Not applicable.

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions.

Purpose: In the literature there is limited knowledge about how to prepare students for a corporate entrepreneurial career. The purpose is therefore to develop a framework for understanding the role corporate development projects play in corporate entrepreneurship education, and to examine the potential role of the design of the project. The study defines a corporate development project as a project being part of an academic education to provide students with working experiences situated in an experiential learning process. Design/methodology/approach: Based on work-integrated learning literature, the authors first develop a conceptual framework. Thereafter, they undertake a multiple case study using data from a Master's Program in Corporate Entrepreneurship. Starting from the conceptual framework, the authors employ deductive thematic analysis in order to analyze data and finally to develop an elaborated framework. Findings: In the framework, the authors identify and label five categories of learning outcomes from the corporate development project. The framework helps understand the interplay between the different learning outcomes in students' learning process and shows how the design of the project shapes the learning process. Practical implications: The framework can assist educators in designing and integrating the corporate development project as a key module within a corporate entrepreneurship academic program. Originality/value: Based on the framework, the study develops the knowledge about the design of corporate entrepreneurship education. Future research should test the framework using data from other academic programs in corporate entrepreneurship.

Purpose: This study aims to examine the role of gender balance in forming individuals' understanding of entrepreneurship as manifested in the graduates' occupational choices, asking: Does gender balance in entrepreneurship education influence start-up behaviour after graduation? Based on gender mainstreaming, this study builds on the assumption that gender balance influences classroom and student community discourses. This study presents two hypotheses suggesting a positive relationship between gender balance (student and mentor gender balance, respectively) and the likelihood of engaging in start-up behaviour after graduation. Design/methodology/approach: The context is an international one-year master's programme in entrepreneurship and innovation, which adopts an experienced-based pedagogical approach to support learning. This study applies binary logistic regression analysis to test the hypotheses on a sample of 107 graduates who responded to a web-based questionnaire on post-graduation career paths. Findings: This study finds support for the first hypothesis indicating that student gender balance in the classroom has a significant positive impact on graduates' likelihood of engaging in start-up activity post-graduation. In the interpretation of these findings, this study emphasizes that a master's programme in entrepreneurship is an important arena where students' attitudes, values, aspirations and intentions towards entrepreneurship are shaped and their identity developed. Originality/value: While studies have demonstrated gender bias in the discourses on entrepreneurship education and content, there is little evidence of its consequences or how it is addressed. Findings of this study point directly to this gap by revealing that improved gender balance is not only beneficial to the underrepresented gender, but to the overall student group.

Introduction Inflammatory joint diseases (IJD), including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis/spondyloarthropathies (AS), and juvenile idiopathic arthritis (JIA), are more common in patients with depression. However, it remains unclear whether the strength of this association varies with the severity or level of treatment resistance of the depressive episode. Objectives To assess the risk for IJD in patients with severe depression and TRD compared to population comparators and patients with non-severe and non-treatment resistant depression. Methods We conducted parallel cohort studies among 600,404 patients with a depressive episode identified in Swedish nationwide administrative registers. The prospective risk for IJD, both overall and per IJD condition, in patients with depression of any severity was compared to matched population comparators. Additionally, we assessed the same associations comparing patients with depression to those with severe or treatment-resistant depression. Analyses were adjusted for comorbidities and sociodemographic covariates. Results Overall, patients with depression were at increased risk for later IJD compared to population comparators (adjusted hazard ratio (aHR) for any IJD 1.34 [95% CI 1.30-1.39]; RA 1.27 [1.15-1.41]; PsA 1.45 [1.29-1.63]; AS 1.32 [1.15-1.52]). The associations were not significantly different for patients with severe depression or TRD. Conclusions Patients with severe and treatment resistant depression are at higher risk for inflammatory joint disease than population comparators. This association does not seem to be stronger than for patients with non-severe or non-resistant depression. Severity and treatment resistance of a depressive episode as identified in register data may not be valid depressive phenotypes for predicting risk for inflammatory joint disease. Disclosure of Interest P. Brenner Grant / Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., J. Askling Grant / Research support from: Karolinska Institutet has entered into agreements with the following companies, with JA as PI: Abbvie, BMS, Eli Lilly, Galapagos, Janssen, Pfizer, Roche, Samsung Bioepis and Sanofi., D. Hägg Grant / Research support from: Affiliated employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., L. Brandt Grant / Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., P. Stang Employee of: Former employee of Janssen Research & Development, LLC. The work on this study was part of the employment., J. Reutfors Grant / Research support from: employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies.

Introduction: This work systematically investigates the effect of chloride level, temperature, and the water system’s oxidative power on the pitting corrosion performance of stainless steels in pH-neutral environments.Methods: Two test programs were set to a) develop a robust method for constructing the pitting engineering diagrams and b) construct the pitting engineering diagrams based on the obtained method from the first test program. The various electrochemical techniques were selected to assess and understand factors that affect the corrosion behavior of stainless steel. Extensive testing was performed with short-term electrochemical measurements and long-term immersion tests.Results and Discussion: The obtained results demonstrate that the electrochemical methods are sufficient to define pitting diagrams showing the boundaries between pitting and no pitting as a function of chloride concentration, temperature, and the water system’s oxidation potential. The laboratory long-term electrochemical test results correspond the best to real applications and clearly underline the importance of an induction time for pit initiation. Accordingly, two sets of pitting engineering diagrams were constructed based on the water system’s oxidation potential. Measurements at the applied potential of 150 mV vs. saturated calomel electrode (SCE) correspond to applications in sterile tap water, whereas the applied potential of 400 mV vs. SCE corresponds to slightly chlorinated water or water with some biological activity. Pitting engineering diagrams were proved to be very useful tools to aid material selection in water application. However, it is important to realize that additional factors, such as different surface conditions and the presence of other environmental species, crevice design, or weld will affect the exact position of the boundaries between pitting and no pitting.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Abstract Background Saliva measures are generally more accessible than blood, especially in vulnerable populations. However, connections between aging biology biomarkers in different body tissues remain unknown. Methods The present study included individuals (N = 2406) who consented for saliva and blood draw in the Health and Retirement Telomere length study in 2008 and the Venous blood study in 2016 who had complete data for both tissues. We assessed biological aging based on telomere length in saliva and DNA methylation and physiology measures in blood. DNA methylation clocks combine information from CpGs to produce the aging measures representative of epigenetic aging in humans. We analyzed DNA methylation clocks proposed by Horvath (353 CpG sites), Hannum (71 CpG sites), Levine or PhenoAge, (513 CpG sites), GrimAge, (epigenetic surrogate markers for select plasma proteins), Horvath skin and blood (391 CpG sites), Lin (99 CpG sites), Weidner (3 CpG sites), and VidalBralo (8 CpG sites). Physiology measures (referred to as phenotypic age) included albumin, creatinine, glucose, [log] C-reactive protein, lymphocyte percent, mean cell volume, red blood cell distribution width, alkaline phosphatase, and white blood cell count. The phenotypic age algorithm is based on parametrization of Gompertz proportional hazard models. Average telomere length was assayed using quantitative PCR (qPCR) by comparing the telomere sequence copy number in each patient’s sample (T) to a single-copy gene copy number (S). The resulting T/S ratio was proportional to telomere length, mean. Within individual, relationships between aging biology measures in blood and saliva and variations according to sex were assessed. Results Saliva-based telomere length showed inverse associations with both physiology-based and DNA methylation-based aging biology biomarkers in blood. Longer saliva-based telomere length was associated with 1 to 4 years slower biological aging based on blood-based biomarkers with the highest magnitude being Weidner (β = − 3.97, P = 0.005), GrimAge (β = − 3.33, P

BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.