Search Results (1,406)

Coffee consumption is globally widespread and has become a lifestyle habit. This study investigated coffee consumption and liver-related survival in a large cohort of 455,870 individuals with UK biobank, categorized into without steatosis, metabolic dysfunction-associated steatotic liver disease (MASLD), and MASLD and increased alcohol intake (MetALD). Inverse probability of treatment weighting (IPTW) adjusted for confounding variables was used, followed by Kaplan–Meier analysis. Moderate coffee consumption (1–2 cups per day) was associated with lower all-cause mortality across the entire cohort, without the steatosis, MASLD (p < 0.0001), and MetALD cohorts (p = 0.0047 for pre-IPTW, p = 0.027 for post-IPTW). Before IPTW adjustment, consuming one or more cups of coffee per day appeared to significantly reduce liver-related mortality in the overall (p = 0.015) and MASLD cohorts (p = 0.011). However, post-IPTW application, no significant differences in liver-related mortality were observed between the coffee intake groups (p = 0.778, 0.319, 0.564, 0.238 for each group). While increased coffee consumption initially seemed to reduce liver-related mortality, after IPTW adjustment, only all-cause mortality significantly decreased (p < 0.0001 and p = 0.027). These findings suggest that previous studies might have overestimated the favorable effect of coffee intake on chronic liver disease due to confounding factors. Full article

Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10⁻⁸, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10⁻⁶. In comparison with BBJ (180K), RARB (retinoic acid receptor-β) was detected as a candidate at a significant level of p < 5 × 10⁻⁸ in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus. Full article

The intricate dynamics of brain aging, especially the neurodegenerative mechanisms driving accelerated (ABA) and resilient brain aging (RBA), are pivotal in neuroscience. Understanding the temporal dynamics of these phenotypes is crucial for identifying vulnerabilities to cognitive decline and neurodegenerative diseases. Currently, there is a lack of comprehensive understanding of the temporal dynamics and neuroimaging biomarkers linked to ABA and RBA. This study addressed this gap by utilizing a large-scale UK Biobank (UKB) cohort, with the aim to elucidate brain aging heterogeneity and establish the foundation for targeted interventions. Employing Lasso regression on multimodal neuroimaging data, structural MRI (sMRI), diffusion MRI (dMRI), and resting-state functional MRI (rsfMRI), we predicted the brain age and classified individuals into ABA and RBA cohorts. Our findings identified 1949 subjects (6.2%) as representative of the ABA subpopulation and 3203 subjects (10.1%) as representative of the RBA subpopulation. Additionally, the Discriminative Event-Based Model (DEBM) was applied to estimate the sequence of biomarker changes across aging trajectories. Our analysis unveiled distinct central ordering patterns between the ABA and RBA cohorts, with profound implications for understanding cognitive decline and vulnerability to neurodegenerative disorders. Specifically, the ABA cohort exhibited early degeneration in four functional networks and two cognitive domains, with cortical thinning initially observed in the right hemisphere, followed by the temporal lobe. In contrast, the RBA cohort demonstrated initial degeneration in the three functional networks, with cortical thinning predominantly in the left hemisphere and white matter microstructural degeneration occurring at more advanced stages. The detailed aging progression timeline constructed through our DEBM analysis positioned subjects according to their estimated stage of aging, offering a nuanced view of the aging brain’s alterations. This study holds promise for the development of targeted interventions aimed at mitigating age-related cognitive decline. Full article

Biobanks are infrastructures essential for research involving multi-disciplinary teams and an increasing number of stakeholders. In the field of personalized medicine, biobanks play a key role through the provision of well-characterized and annotated samples protecting at the same time the right of donors. The Andalusian Public Health System Biobank (SSPA Biobank) has implemented a global information management system made up of different modules that allow for the recording, traceability and monitoring of all the information associated with the biobank operations. The data model, designed in a standardized and normalized way according to international initiatives on data harmonization, integrates the information necessary to guarantee the quality of results from research, benefiting researchers, clinicians and donors. Full article

The relationship between vitamin A supplementation and myopia has been a topic of debate, with conflicting and inconclusive findings. We aimed to determine whether there is a causal relationship between vitamin A supplementation and the risk of myopia using Mendelian randomization (MR) and meta-analytical methods. Genetic variants from the UK Biobank and FinnGen studies associated with the response to vitamin A supplementation were employed as instrumental variables to evaluate the causal relationship between vitamin A supplementation and myopia. Fixed-effects meta-analysis was then used to combine MR estimates from multiple sources for each outcome. The meta-analysis of MR results found no convincing evidence to support a direct causal relationship between vitamin A supplementation and myopia risk (odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.82–1.20, I² = 0%, p = 0.40). The analysis of three out of the four sets of MR analyses indicated no direction of causal effect, whereas the other set of results suggested that higher vitamin A supplementation was associated with a lower risk of myopia (OR = 0.002, 95% CI 1.17 × 10⁻⁶–3.099, p = 0.096). This comprehensive MR study and meta-analysis did not find valid evidence of a direct association between vitamin A supplementation and myopia. Vitamin A supplementation may not have an independent effect on myopia, but intraocular processes associated with vitamin A may indirectly contribute to its development. Full article

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10⁻⁸). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy. Full article

COVID-19 is no longer a public health emergency of international concern, but long COVID’s effects are yet to be fully understood. Hence, globally, SARS-CoV-2 is still a profound threat to public health and of perilous nature as a zoonotic disease. Timely vaccination provided to individuals worldwide during the pandemic phase was under a certain degree of control; however, few studies have reported the effectiveness of vaccines administered in Mexico, and its surveillance is paramount. Furthermore, an unknown proportion of Mexican individuals have not yet received any vaccine, and the circulation of the Omicron, Pirola, and FLiRT variants is ongoing. A cross-sectional serology survey study design was employed, involving 150 individuals from Southern Mexico (Oaxaca) whose humoral immune responses after vaccination were tested by an ELISA; the receptor-binding domain of the SARS-CoV-2 spike protein served as a recombinant antigen in the ELISA. One hundred thirty-nine out of 150 individuals (92.6%; 95%-CI = 87–95%) examined were positive for the ELISA, but in 11 individuals, the vaccines did not induce any immune response. Interestingly, the immune responses (antibody prevalence and levels) of females (58%) were higher (T= −2.21; p-value = 0.02) than those of males (41%). However, in this sample population of Southern Mexico, age, vaccine type, comorbidity, and body mass index did not have any effect (p > 0.05) after COVID-19 vaccination. Taking all results together, here, we present factors that affected immune responses of individuals during the first vaccination campaign in Oaxaca, Mexico; however, vaccine surveillance during the post-pandemic phase needs further investigation. Full article

Background and Aims: Type 2 diabetes (T2D) is a global and complex public health challenge, and dietary management is acknowledged as critical in its prevention. Recent studies have highlighted the involvement of micronutrients in T2D pathophysiology; our study aims to assess the association between B vitamin intake and T2D risks and the mediating role of inflammation. Methods: In a prospective cohort design, data on B vitamins intake, including thiamine (B1), riboflavin (B2), niacin (B3), pyridoxine (B6), folate (B9), and cobalamin (B12), was obtained using a validated food frequency questionnaire (FFQ), and blood inflammatory biomarkers were analyzed according to standard protocol in the local hospitals at baseline from 44,960 adults in the Shanghai Suburban Adult Cohort and Biobank (SSACB). Incident T2D cases were identified according to a physician’s diagnosis or medication records from the electronic medical information system. We employed logistic and weighted quantile sum regression models to explore the associations of single and combined levels of B vitamins with T2D and mediation analyses to investigate the effects of inflammation. Results: Negative correlations between B vitamins and T2D were observed in the single-exposure models, except for B3. The analyses of joint exposure (B1, B2, B6, B9, and B12) also showed an inverse association (OR 0.80, 95% CI 0.71 to 0.88), with vitamin B6 accounting for 45.58% of the effects. Further mediation analysis indicated a mediating inflammatory impact, accounting for 6.72% of the relationship. Conclusions: Dietary intake of B vitamins (B1, B2, B6, B9, B12) was associated with a reduced T2D risk partially mediated by inflammation in Shanghai residents. Full article

The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs). Methods: This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by ¹⁸FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria. Results: Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients’ outcomes with OS (HR = 2.6, p = 0.0001) and PFS (HR = 2.2, p = 0.001). Conclusions: Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification. Full article

Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding its role in cardiac surgery remains limited. Therefore, we aimed to investigate perioperative changes in IDO activity and pathway metabolites, along with their impact on clinical outcomes in adult patients undergoing cardiac surgery. As an observational cohort study conducted at the Inselspital in Bern from January to December 2019, we retrospectively analyzed the data of prospectively collected biobank samples of patients undergoing cardiac surgery with the use of cardiopulmonary bypass. IDO pathway metabolite analysis was conducted by mass spectrometry. Perioperative dynamics were descriptively assessed and associated with pre-defined clinical outcome measures (30-day mortality, 1-year mortality, incidence of stroke and myocardial infarction, and length of hospital stay) through a multi-step exploratory regression analysis. A cohort of 192 adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass were included (median age 67.0, IQR 60.0–73.0, 75.5% male). A significant perioperative decrease in the kynurenine/tryptophan (Kyn/Trp) ratio (−2.298, 95% CI −4.028 to −596, p = 0.009) and significant perioperative dynamics in the associated metabolites was observed. No association of perioperative changes in IDO activity and pathway metabolites with clinical outcomes was found. A significant decrease in the Kyn/Trp ratio among adult patients undergoing cardiac surgery indicates a perioperative downregulation of IDO, which stands in contrast to other pro-inflammatory conditions. Further studies are needed to investigate IDO in the setting of perioperative immunomodulation, which is a key driver of postoperative complications in cardiac surgery patients. Full article

Background: Intraoperative frozen sections (FS) are frequently used to establish the diagnosis of lung cancer when preoperative examinations are not conclusive. The downside of FS is its resource-intensive nature and the risk of tissue depletion when small lesions are assessed. Ex vivo fluorescence confocal microscopy (FCM) is a novel microimaging method for loss-free examinations of native materials. We tested its suitability for the intraoperative diagnosis of lung tumors. Methods: Samples from 59 lung resection specimens containing 45 carcinomas were examined in the FCM. The diagnostic performance in the evaluation of malignancy and histological typing of lung tumors was evaluated in comparison with FS and the final diagnosis. Results: A total of 44/45 (98%) carcinomas were correctly identified as malignant in the FCM. A total of 33/44 (75%) carcinomas were correctly subtyped, which was comparable with the results of FS and conventional histology. Our tests documented the excellent visualization of cytological features of normal tissues and tumors. Compared to FS, FCM was technically less demanding and less personnel intensive. Conclusions: The ex vivo FCM is a fast, effective, and safe method for diagnosing and subtyping lung cancer and is, therefore, a promising alternative to FS. The method preserves the tissue without loss for subsequent examinations, which is an advantage in the diagnosis of small tumors and for biobanking. Full article

The identification of ALK fusions in advanced non-small-cell lung carcinoma (aNSCLC) is mandatory for targeted therapy. The current diagnostic approach employs an algorithm using ALK immunohistochemistry (IHC) screening, followed by confirmation through ALK FISH and/or next-generation sequencing (NGS). Challenges arise due to the infrequency of ALK fusions (3–7% of aNSCLC), the suboptimal specificity of ALK IHC and ALK FISH, and the growing molecular demands placed on small tissue samples, leading to interpretative, tissue availability, and time-related issues. This study investigates the effectiveness of RNA NGS as a reflex test for identifying ALK fusions in NSCLC, with the goal of replacing ALK IHC in the systematic screening process. The evaluation included 1246 NSCLC cases using paired techniques: ALK IHC, ALK FISH, and ALK NGS. ALK IHC identified 51 positive cases (4%), while RNA NGS detected ALK alterations in 59 cases (4.8%). Of the 59 ALK-positive cases identified via NGS, 53 (89.8%) were confirmed to be positive. This included 51 cases detected via both FISH and IHC, and 2 cases detected only via FISH, as they were completely negative according to IHC. The combined reporting time for ALK IHC and ALK FISH averaged 13 days, whereas ALK IHC and RNA NGS reports were obtained in an average of 4 days. These results emphasize the advantage of replacing systematic ALK IHC screening with RNA NGS reflex testing for a more comprehensive and accurate assessment of ALK status. Full article

Background: The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been proposed, but no study has linked this epigenetic variance with regrowth potential and the clinical heterogeneity of nonfunctioning pituitary adenomas. This study aimed to investigate whether DNA methylation profiling can be useful as a clinical prognostic marker. Methods: A DNA methylation analysis by Illumina’s MethylationEPIC array was performed on 54 pituitary macroadenomas from patients who underwent transsphenoidal surgery during 2007–2017. Twelve patients were excluded due to an incomplete postoperative follow-up, degenerated biobank-stored tissue, or low DNA methylation quality. For the quantitative measurement of the tumor regrowth rate, we conducted a 3D volumetric analysis of tumor remnant volume via annual magnetic resonance imaging. A linear mixed effects model was used to examine whether different DNA methylation clusters had different regrowth patterns. Results: The DNA methylation profiling of 42 tissue samples showed robust DNA methylation clusters, comparable with previous findings. The subgroup of 33 nonfunctioning pituitary adenomas of an SF1-lineage showed five subclusters with an approximately unbiased score of 86%. There were no overall statistically significant differences when comparing hazard ratios for regrowth of 100%, 50%, or 0%. Despite this, plots of correlated survival estimates suggested higher regrowth rates for some clusters. The mixed effects model of accumulated regrowth similarly showed tendencies toward an association between specific DNA methylation clusters and regrowth potential. Conclusion: The DNA methylation profiling of nonfunctioning pituitary adenomas may potentially identify adenomas with increased growth and recurrence potential. Larger validation studies are needed to confirm the findings from this explorative pilot study. Full article

Numerous risk factors play a role in the causation of stroke, and the cardiometabolic condition is a one of the most important. In Korea, various treatment methods are employed based on the constitutional type, which is known to differ significantly in cardiometabolic disease. In this study, we compared the estimates obtained for different groups by applying the Mendelian randomization method to investigate the causal effects of genetic characteristics on stroke, according to constitutional type. In clinical analysis, the subtypes differ significantly in diabetes or dyslipidemia. The genetic association estimates for the stroke subtype risk were obtained from MEGASTROKE, the International Stroke Genetics Consortium (ISGC), UKbiobank, and BioBank Japan (BBJ), using group-related SNPs as instrumental variables. The TE subtypes with higher risk of metabolic disease were associated with increased risk (beta = 4.190; s.e. = 1.807; p = 0.035) of cardioembolic stroke (CES), and the SE subtypes were associated with decreased risk (beta = −9.336, s.e. = 1.753; p = 3.87 × 10⁻⁵) of CES. The findings highlight the importance of personalized medicine in assessing disease risk based on an individual’s constitutional type. Full article

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP. Full article