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Objective Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank (UKB). Methods To avoid immortal time biases in pharmacoepidemiologic studies, Mendelian randomization was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with glycated haemoglobin (HbA1c), serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% CI. Results A total of 407 159 participants were analysed, including 9126 EOP and 3324 LOP. The AMPK genetic risk score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022–1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062–1.395) in male psoriasis patients. Conclusions AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed. [ABSTRACT FROM AUTHOR]

Background: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. Methods: A cross‐sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case–control study was then conducted to determine the biomarker for pruritus. Arsenite‐treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double‐blind, placebo‐controlled trial was conducted to test the efficacy of naloxone in arsenic‐exposed patients with pruritus in Shimen. Results: Hair arsenic (μg/g) showed a dose–response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate‐to‐severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum β‐endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of β‐endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic‐exposed participants in 2 weeks (β = −0.98, p = 0.04). Conclusion: Arsenic exposure is associated with pruritus, and β‐endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis. [ABSTRACT FROM AUTHOR]

We use the gravity model to examine the causal link between economic policy uncertainty (EPU) and inbound tourism (ITM) in the United Kingdom. The results for the full sample demonstrate that EPU Granger causes ITM. This finding shows that association is misappropriated due to structural changes. We apply the time-varying rolling window technique to revisit the dynamic association between EPU and ITM. The findings for the subsamples indicate that EPU has a negative effect on ITM. In contrast, ITM has a positive effect on EPU in the subsamples. These results support the gravity model, which states that as EPU increases, the level of ITM decreases. The results have noteworthy implications for policymakers in the form of consistency in policies and short-term shock forecasting that is capable of greater shock-absorbing capacity to lessen the revocation of tourist programs. A stable exchange rate regime in the destination country will make tourism cheaper and more attractive to tourists. Decision-makers should consider time-varying attributes to establish tourism activities for effective and accurate predictions. [ABSTRACT FROM AUTHOR]

Elderly-onset atopic dermatitis (AD) is a remarkable subtype and has been put on the agenda owing to its difficulty to control. Understanding the influence of genetic and environmental exposures is crucial to preventing elderly-onset AD. To explore the association between genes and air pollution on incident elderly-onset AD. This study was based on UK Biobank that recruited over 500,000 participants. The genetic risks were categorized into low, intermediate, and high groups according to tertiles of polygenic risk scores. Mixed exposure to various air pollutants was assessed using the weighted quantile sum (WQS) and also categorized based on tertiles. Within each genetic risk group, whether air pollutant mixture was associated with incident elderly-onset AD was estimated. 337,910 participants were included in the final analysis, and the mean age was 57.1. The median years for follow-up were 12.0, and the incident cases of AD were 2545. The medium and high air pollution mixture was significantly associated with incident AD compared with the low pollution group, with HRs of 1.182 (P = 0.003) and 1.359 (P < 0.001), respectively. In contrast, HR for medium and high genetic susceptibility was only 1.065 (P = 0.249) and 1.153 (P = 0.008). The population-attributable fraction of air pollution and genetic risk was 15.5 % (P < 0.001) and 6.4 % (P = 0.004). Additionally, compared with low genetic risk and low air pollution, high genetic risk and high air pollution was significantly associated with the incidence of elderly-onset AD with a HR of up to 1.523 (P < 0.001). There were no interactive effects between each group of genetic risks and air pollution. When grouped by sex, females could observe a stronger effect by genetic and air pollutant mixture exposure. Air pollution and genetics both independently enhance the risk of newly developed AD, and the effect of air pollutants is stronger than the investigated genes. • The effect of air pollutant mixtures on incident AD was examined. • Exposure to air pollutants has a larger contribution than genetic variants. • Air pollution is associated with AD independent of genetic susceptibility. [ABSTRACT FROM AUTHOR]

• Higher C-reactive protein at baseline was associated with a reduced risk of Parkinson's disease. • No assication was identified between interleukin 6 level at baseline and risk of Parkinson's disease. • Significant and negative genetic correlation was identified between C-reactive protein level and risk of PD. • Higher polygenic risk score of C-reactive protein was associated with a lower risk of PD. Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79–0.90, P = 4.23E−07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: −0.14, P = 6.31E−05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = −0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB , HNF4A , PPM1G , ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials. [ABSTRACT FROM AUTHOR]

• Higher prevalence of frailty and accelerated biological age with SMI than those without SMI. • In this cohort study with over 12 years of follow-up in the UK Biobank, biological aging was strongly and positively associated with the incidence risk of CMDs among people with SMI. • Findings highlight the important implications for concerning about the high incidence of CMDs comorbidities and intervention of aging in people with SMI and may reduce premature mortality and improve life expectancy. Cardiometabolic diseases (CMDs) comorbidities among people with severe mental illnesses (SMI) are associated with a high healthcare burden and premature mortality. This study aims to evaluate whether biological aging has an interaction with SMI on incident CMDs, and to examine the association of four biological aging indicators with CMDs incidence in this population. Data were sourced from the UK Biobank, a large prospective cohort study. Four indicators were used to assess biological aging including frailty phenotype, frailty index, KDM-biological age acceleration and phenotypic age acceleration. Cox proportional hazards regression models were used to examine the associations. We observed higher prevalence of frailty and accelerated biological age with SMI than those without SMI. Further analysis found significant interaction effect of pre-frailty and SMI (P Pre-frail*SMI =0.005) as well as biological age acceleration and SMI (P Q3 (>P75)*SMI =0.038). 14.7 % of the participants with SMI developed CMDs during the follow-up. Compared with non-frail participants, those with frailty (frailty phenotype: HR=1.68, 95 % CI: 1.50, 1.88, P < 0.001; frailty index: HR=2.44, 95 % CI: 2.11–2.81, P < 0.001) and biological age acceleration (KDM-biological age acceleration (Q3): HR=1.91, 95 % CI: 1.74, 2.11, P < 0.001; phenotypic age acceleration (Q3): HR=2.07, 95 % CI: 1.86, 2.30, P < 0.001) had a significantly higher risk of CMDs in the adjusted model. A series of sensitivity analyses were conducted to illustrate the robustness of the findings. These findings highlight the important implications for concerning about the high incidence of CMDs comorbidities and intervention of aging in people with SMI. [ABSTRACT FROM AUTHOR]

Background: Previous studies on the associations between socioeconomic status (SES) and cutaneous malignant melanoma (CMM) failed to distinguish the effects of different SES factors under an individual-data-based prospective study design., Methods: Based on UK Biobank (UKB) and China Kadoorie Biobank (CKB), we estimated the effects of four SES factors on transitions from baseline to CMM in situ, subsequently to invasive CMM and further CMM mortality by applying multistate models. We further explored to which extent the associations between SES and CMM incidence could be explained by potential mediators including sun exposure, lifestyle and ageing in UKB., Results: In multistate analyses, good household income was independently associated with an increased risk of CMM in situ (HR=1.38, 95% CI: 1.21 to 1.58) and invasive CMM (HR=1.34, 95% CI: 1.22 to 1.48) in UKB. These findings were partly validated in CKB. Especially in UKB, we observed an increased risk of CMM in situ and invasive CMM among participants with good type of house; only good education was independently associated with lower risk of evolving to invasive CMM among patients with CMM in situ (HR=0.69, 95% CI: 0.52 to 0.92); only good household income was independently associated with lower risk of CMM mortality among patients with CMM (HR=0.65, 95% CI: 0.45 to 0.95). In mediation analysis, the proportions attributable to the mediating effect were <6% for all selected variables, including self-reported sun exposure-related factors., Conclusion: SES factors have different effects on the incidence and progression of CMM. The association between SES and incident CMM is neither causal nor well explained by selected mediators., Competing Interests: Competing interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. This research has been conducted using the China Kadoorie Biobank (CKB) resource (www.ckbiobank.org, Request No. DAR-2023-00149). Publication of results does not require or imply approval by the membership of the CKB Collaborative Group., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Limited evidence demonstrated the potential relationship between dietary sugar intake and dementia. This association demands further clarification in a large-scale population., Methods: A total of 210,832 participants from the UK Biobank cohort were included in this prospective cohort study. Absolute and relative sugar intake and high-sugar dietary scores were utilized to reflect dietary sugar intake. Absolute sugar intake was identified by the Oxford WebQ in the UK Biobank. Relative sugar intake was calculated by dividing the absolute sugar intake by total diet energy. High-sugar dietary pattern was identified using the method of reduced rank regression. Cox proportional hazards regression analyses and restricted cubic splines were performed to examine the longitudinal associations between dietary sugar intake and all-cause dementia and its main subtype, Alzheimer's disease. Explorative mediation analyses were conducted to explore underlying mechanisms., Results: Increased absolute sugar intake (g/day) was significantly associated with a higher risk of all-cause dementia (HR = 1.003, [95%CI: 1.002-1.004], p < 0.001) and Alzheimer's disease (1.002, [1.001-1.004], 0.005). Relative sugar intake (%g/kJ/day) also demonstrated significant associations with all-cause dementia (1.317, [1.173-1.480], p < 0.001) and Alzheimer's disease (1.249, [1.041-1.500], 0.017), while the high-sugar dietary score was only significantly associated with a higher risk of all-cause dementia (1.090, [1.045-1.136], p < 0.001). In addition, both sugar intake and high-sugar dietary score demonstrated significant non-linear relationships with all-cause dementia and Alzheimer's disease (all p values for non-linearity < 0.05)., Conclusions: Our study provided evidence that excessive sugar intake was associated with dementia. Controlling the excess consumption of dietary sugar may be of great public health implications for preventing dementia., (© 2024. The Author(s).)

Although a peak incidence of psoriasis in women aged around 60 years has been observed, the link between reproductive lifespan and late-onset psoriatic diseases is underexplored. This study aims to elucidate the association between reproductive lifespan and the risk of late-onset psoriasis and psoriatic arthritis (PsA). Utilizing the UK Biobank data, we conducted a prospective cohort study in postmenopausal women without baseline psoriatic diseases. The exposure variables included age at natural menopause (ANM) and duration from menarche to menopause, termed reproductive years. The outcome variables were incident psoriasis and PsA. We employed Cox regression analysis, factoring in polygenic risk scores for psoriatic diseases and recognized risk factors. We found that later ANM and longer reproductive years were significantly associated with decreased risks of late-onset psoriasis and PsA in a dose-dependent manner (P<.05). ANM after age 55 years led to a 34 and 46% risk reduction in late-onset psoriasis and PsA, respectively, compared with ANM before age 45 years (P<.001). The population-attributable risks of ANM were 17.4% for late-onset psoriasis and 21.6% for PsA. In conclusion, reproductive lifespan, with its inherent homeostasis, plays a pivotal yet overlooked role in late-onset psoriatic diseases. Investigations into estrogen-centric causes and sex-specific interventions are imperative., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The impact of early-life tobacco exposure on dementia has remained unknown., Methods: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted., Results: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk., Discussion: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks., Highlights: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The association between dyslipidemia and psoriasis has been studied widely. However, which individual indicators of serum lipids determine an increasing risk of incident psoriasis is still underappreciated in prospective cohorts. On the basis of UK Biobank, we investigate the causal relationship between four serum lipids and incident psoriasis by Cox proportional hazard model and Mendelian randomization analysis. After adjusting for covariates, high-density lipoprotein deficiency (<1.0 mmol/l for men, <1.3 mmol/l for women) and high triglyceride level (≥1.7 mmol/l) at baseline were associated with 16.6% and 10.6% increased risk of incident psoriasis, respectively. The effects were more pronounced in women, with 16.9 and 19.7% additional risk of psoriasis, respectively. The effects in the younger group (aged <60 years) and obese group in women were also more pronounced. No similar effect was observed in low-density lipoprotein and total cholesterol. Our subsequent Mendelian randomization analysis reinforced the main finding that high-density lipoprotein deficiency and high triglyceride cause incident psoriasis genetically. In conclusion, serum high-density lipoprotein/triglyceride levels predict psoriasis, particularly in women, indicating a distinct role of lipids engaging in the pathogenesis of psoriasis modified by sex. More metabolic-targeted, sex-specific management of psoriasis is suggested in the future., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Whether the lifestyle is associated with the risk of psoriasis in the presence of different genetic risk levels remains unknown., Objective: To examine the gene-behavior interaction in association with incident psoriasis., Methods: This study is based on the data from the UK Biobank, which recruited 500,000 participants. Genetic risk was categorized into low, intermediate, and high groups. The lifestyle score comprised the body mass index, smoking, physical activity, and diet and was also categorized into the ideal, intermediate, and poor groups. Within each genetic risk group, the risks of incident psoriasis associated with each lifestyle level were investigated and compared with the low genetic risk and ideal lifestyle group., Results: Compared with the low genetic risk and ideal lifestyle group, the poor lifestyle and high genetic risk group was associated with a hazard ratio of up to 4.625 (95% confidence interval [CI], 2.920-7.348) for psoriasis. There was no interaction between genetic risk and lifestyle. The population attributable fractions of lifestyle and genetic risk were 32.2% (95% CI, 25.1%-38.6%) and 13.0% (95% CI, 3.2%-21.8%), respectively., Limitations: No verification in other independently ascertained populations., Conclusion: Lifestyle factors are predictive of the risk of incident psoriasis independent of genetic risk, and the relative impact of lifestyle factors was greater than that of genetic risk., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. All rights reserved.)