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Background: Vitamin B 12 deficiency is widely prevalent in all age groups which is of major concern. However, there is no valid Food Frequency Questionnaire (FFQ) for dietary vitamin B 12 estimation. Hence, we aimed to develop and validate an FFQ for the estimation of dietary intake of Vitamin B 12 ., Materials and Methods: Commonly consumed B 12 -rich food items were selected from literature and filtered using a market survey. For concordant and discriminant validation, B 12 and homocysteine levels were estimated. To establish convergent validity, the Cobalamin Intake in North Indians by Food Frequency Questionnaire (COIN-FFQ) and 72-hour dietary recall (72HrDR) were both administered to the same subjects. The COIN-FFQ was readministered after initial administration for test-retest reliability. Internal consistency of the FFQ was then tested using Cronbach's alpha., Results: We enrolled 115 adults with a mean age and weight of 31.9 ± 8.7 years and 66.0 ± 11.8 kg, respectively. In total, 19.1% were vegetarian. The dietary B 12 using COIN-FFQ ( n = 60; mean = 4.3 ± 1.8 µg/d) was significantly correlated ( r = 0.255; P = 0.049) with serum levels (mean = 120.1 ± 62.6 pmol/L) establishing concordant validity. A significant difference was noted between the dietary, serum B 12 , and homocysteine levels of vegetarians versus nonvegetarians establishing discriminant validity (mean diff 1.4 (0.5-2.4), P = 0.004; Z-statistic -2.182, P value 0.029, and Z-statistic -2.438; P value 0.015), respectively. FFQ was strongly correlated with 72HrDR and test-retest FFQ ( n = 27; r = 0.814, P < 0.001 and r = 0.869, P < 0.001, respectively) establishing convergent validity and test-retest reliability. The internal consistency with Cronbach's alpha was in the acceptable range, 0.631 ( n = 115)., Conclusion: The newly developed COIN-FFQ is valid and reliable in estimating dietary B 12 intake., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Community Medicine.)

The microbial processes occurring in constructed wetlands (CWs) are difficult to understand owing to the complex interactions occurring between a variety of substrates, microorganisms, and plants under the given physicochemical conditions. This frequently leads to very large unexplained nitrogen losses in these systems. In continuation of our findings on Anammox contributions, our research on full-scale field CWs has suggested the significant involvement of the sulfur cycle in the conventional C-N cycle occurring in wetlands, which might closely explain the nitrogen losses in these systems. This paper explored the possibility of the sulfur-driven autotrophic denitrification (SDAD) pathway in different types of CWs, shallow and deep and passive and aerated systems, by analyzing the metagenomic bacterial communities present within these CWs. The results indicate a higher abundance of SDAD bacteria (Paracoccus and Arcobacter) in deep passive systems compared to shallow systems and presence of a large number of SDAD genera (Paracoccus, Thiobacillus, Beggiatoa, Sulfurimonas, Arcobacter, and Sulfuricurvum) in aerated CWs. The bacteria belonging to the functional category of dark oxidation of sulfur compounds were found to be enriched in deep and aerated CWs hinting at the possible role of the SDAD pathway in total nitrogen removal in these systems. As a case study, the percentage nitrogen removal through SDAD pathway was calculated to be 15-20% in aerated wetlands. The presence of autotrophic pathways for nitrogen removal can prove highly beneficial in terms of reducing sludge generation and hence reducing clogging, making aerated CWs a sustainable wastewater treatment solution., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

This study investigates the association between protected characteristics and inequalities in mental health care in the UK. Multinomial regression was used to model the association between protected characteristics and self-reported distress. Data was extracted from waves 6-10 (2014-2019) of the UK Household Longitudinal Study. Two risk categories were constructed: "undiagnosed distress" referred to a General Health Questionnaire-12 (GHQ-12) score above "caseness" along with no history of mental health diagnosis; "diagnosis without self-report symptoms" referred to a GHQ-12 score consistently below "caseness" within the study time frame but having received a mental health diagnosis. Compared to people without a disability, people with a disability are at considerably greater risk of both undiagnosed distress (Relative risk ratios (RRR) 2.76; Confidence Interval (CI): 2.55, 2.99) and diagnosis without self-reported symptoms (RRR 3.61; CI: 2.80, 4.66). Likewise, women were more likely than men to report undiagnosed distress (RRR = 1.49; CI: 1.38,1.61) or a diagnosis without self-reported symptoms (RRR = 1.38; CI: 1.08, 1.76. Lesbian, gay, and bisexual people are at greater risk of undiagnosed distress compared with heterosexual people (RRR 1.42; CI: 1.19, 1.70). Adults aged 16-24 years were at greatest risk compared to all other age groups. People from a minority ethnic background had a reduced risk of diagnosis without self-report symptoms compared with people from a White ethnic background (RRR 0.34; CI: 0.20, 0.61). Education, employment and income variables moderated some of these associations. This is the first study to examine diagnosis without self-report symptoms alongside undiagnosed distress. Findings suggest that addressing inequality in mental health care requires increased understanding of the needs and strengths within different groups and to provide appropriate forms of social, medical or psychosocial intervention rather than a singular focus on increasing detection, diagnosis and treatment. People with a disability appear to be at greatest disadvantage, requiring greater attention in policy and practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wicks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Educational attainment is associated with multiphysiological wear and tear. However, associations with measures of socioeconomic position (SEP) across different life-stages are not established., Methods: Using regression models and data from 8105 participants from the UK Household Longitudinal Study (Understanding Society), we examined associations of lifecourse SEP with an overall biological health score (BHS). BHS is broader than usual measures of biological 'wear and tear' and is based on six physiological subsystems (endocrine, metabolic, cardiovascular, inflammatory/immune, liver, and kidney), with higher scores indicating worse health. Lifecourse SEP was based on respondents' parental, first, and most recent occupations., Results: Associations with SEP at all life-stages demonstrated higher BHS with increasing disadvantage (e.g. slope index of inequality (SII) (95 % CI) for most recent SEP: 0.04 (0.02, 0.06)). There was little difference in the magnitude of associations for SEP measured at each life-stage. Cumulative disadvantage across the lifecourse showed a stepped association with increasing BHS (SII (95 % CI): 0.05 (0.04, 0.07)). Associations were largely driven by metabolic, cardiovascular, and inflammatory systems., Conclusion: Our results suggest that disadvantaged SEP across the lifecourse contributes cumulatively to poorer biological health, highlighting that every life-stage should be a target for public health policies and intervention., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 University of Glasgow. Published by Elsevier Inc. All rights reserved.)

The contemporary literature provides conflicting evidence regarding the precedence of laparoscopic mesh rectopexy over laparoscopic suture rectopexy for full-thickness rectal prolapse. This study aimed to compare the clinical outcomes of mesh and suture rectopexy to improve the surgical management of complete rectal prolapse. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to extract studies based on mesh versus suture rectopexy and published from 2001 to 2023. The articles of interest were obtained from PubMed Central, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Journal Storage (JSTOR), Web of Science, Embase, Scopus, and the Cochrane Library. The primary outcomes included rectal prolapse recurrence, constipation improvement, and operative time. The secondary endpoints included the Cleveland Clinic Constipation Score, Cleveland Clinic Incontinence Score, intraoperative bleeding, hospital stay duration, mortality, overall postoperative complications, and surgical site infection. A statistically significant low recurrence of rectal prolapse (odds ratio: 0.41, 95% confidence interval (CI) 0.21-0.80; p=0.009) and longer mean operative duration (mean difference: 27.05, 95% CI 18.86-35.24; p<0.00001) were observed in patients with mesh rectopexy versus suture rectopexy. Both study groups, however, had no significant differences in constipation improvement and all secondary endpoints (all p>0.05). The laparoscopic mesh rectopexy was associated with a low postoperative rectal prolapse recurrence and a longer operative duration compared to laparoscopic suture rectopexy. Prospective randomized controlled trials should further evaluate mesh and suture rectopexy approaches for postoperative outcomes to inform the surgical management of complete rectal prolapse., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kumari et al.)

Introduction The inguino-scrotal/labial region, anatomically defined as the juncture where the thigh meets the lower abdomen, encompassing the ipsilateral scrotal area in men and the inguino-labial area in women, exhibits a broad spectrum of masses. Traditionally, these swellings were clinically diagnosed with high accuracy, primarily due to the prevalence of simple hernias and hydroceles. However, contemporary observations reveal a surge in complex inguino-scrotal/labial swellings, particularly in referral hospitals, necessitating additional radiological and imaging modalities for precise diagnosis. Our interest in this subject was sparked by the escalating numbers of intricate inguino-scrotal/labial masses encountered in our medical setting, posing challenges for clinical diagnosis in both pediatric and adult populations. Materials and methods A prospective, observational study was conducted over two years (August 2021 to March 2023) involving 210 patients presenting with inguino-scrotal/labial swellings at our institute. Clinical data were meticulously collected using a designed pro forma, following informed consent procedures. Results Among the 210 patients with inguino-scrotal/labial swellings, males predominated (194) compared to females (16). The paediatric age group comprised 84 patients, while 126 were adults. Radiological investigations played a crucial role in diagnosing 40 patients and provided significant additional information in 12 cases. Radiological investigations contributed to the diagnosis in 52 patients (24.76%). The study revealed a spectrum of new entities in the inguino-scrotal/labial region, including malignancies, lymph nodal masses in the groin, and vascular, inflammatory, and congenital lesions, which might have been overlooked if solely relying on clinical parameters for diagnosis. Conclusion Inguino-scrotal/labial swelling patients, especially those facing diagnostic dilemmas or harbouring complex lesions, should undergo radiological assessment as an indispensable criterion, particularly when such facilities are readily accessible., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Vinoth et al.)

Background: Research has shown that cultural activities may bring about improved health. However, large-scale quantitative analyses on cultural engagement and biomarkers are lacking to date. As a result, the mechanisms through which cultural activities may be associated with health are unclear., Aim: Test quantitative associations between cultural engagement pattern (including active and passive engagement in arts, sports, and heritage activities) and indicators of biological dysregulation in a large dataset., Subjects and Methods: Understanding Society data were used to conduct cross-sectional linear regression analyses between a data-driven latent class model of cultural engagement and indicators of anthropometric, cardiovascular, metabolic, immune, and neuroendocrine function. Analyses were adjusted for age, gender, ethnicity, childcare responsibility, urbanicity, leisure time satisfaction, capacity-related factors, socioeconomic position, social and economic capital indicators, physical activity, and medication use., Results: More culturally participants had better indicators of biological health, such as lower waist circumference and fibrinogen blood concentration. Specific associations between cultural engagement pattern and the different biological outcomes were also observed. The associations were explained in part by correlated factors (accounting for around half of the association)., Conclusions: Cultural engagement is cross-sectionally associated with biomarkers, although the characteristics of people who engage with culture are an important consideration when interpreting these findings.

Biomass briquetting is a viable densification technique that converts waste biomass materials into useful products and alternative energy. This work explores the characteristics and optimization of hybrid bio-briquette production by combining crop residues (paddy straw) and solid biomass materials (sawdust and sugarcane bagasse). A total number of 20 briquettes were fabricated with three input factors: sawdust (SD), sugarcane bagasse (SB), and paddy straw (PS) based on the faced-centered central composite design (FCCCD) approach in the laboratory to investigate the calorific value (CV) and ash content (AC). The bomb calorimeter technique was used to evaluate the briquette's calorific value and ash content. The proposed work focused on optimizing the briquette input parameters (SD, SB, and PS) and output responses (CV and AC) using analysis of variance (ANOVA) and response surface methodology (RSM) and hybrid artificial neural network-integrated with multi-objective genetic algorithms (ANN-MOGA). This study shows that the MOGA-ANN-based model results in the best value of CV (17.07 MJ/kg) and AC (1.95%) with optimal input parameters SD (39.99 g), SB (29.02 g), and PS (69.02 g). The optimal results observed from the MOGA-ANN model have also been validated experimentally. The Fourier transform infrared (FTIR) spectroscopy investigation reveals that biomass briquettes are the sustainable and environment-friendly option of fossil fuels for power generation and indoor cooking. The study suggests a strategy for minimizing agro-waste, which may be converted into future fuel in the form of briquettes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Interpersonal touch is an essential aspect of human interaction that has the ability to regulate physiological stress responses. Prolonged exposure to stress can have cumulative multiphysiological effects; for example, allostatic load. Despite the increased susceptibility of social isolation for older adults, there is a paucity of research on the efficacy of touch in regulating stress responses among this population. It is also unknown whether touch confers benefits regardless of the person with whom it is shared. This study investigates the difference in physiological stress based on the frequency of touch (hugs, holding, or other close physical contact) shared with romantic partners as compared to other close adults (family, friends, and neighbours) in an older adult population. Data were analysed from 1419 respondents (aged 57-85 years) of the National Social Life, Health, and Aging Project (NSHAP) in 2005-2006. Principal components analysis determined whether the eight markers of allostatic load measured in the NSHAP function as a singular system or as distinct components. Analyses revealed three components of allostatic load: metabolic, cardiovascular, and neuroendocrine health. The results of multiple regression revealed that a higher frequency of interpersonal touch shared with romantic partners was associated with better neuroendocrine health (β = 0.13, p = 0.004) following adjustment for a variety of covariates (but not with better metabolic or cardiovascular health), with no associations apparent for touch from other close adults. These findings highlight the importance of promoting interpersonal touch with romantic partners for older adults' neuroendocrine health., Competing Interests: Declaration of Competing Interest GN is funded by the ESRC-BBSRC Soc-B Centre for Doctoral Training (ES/T00200X/1, project reference 2442358). MK is partially funded by the Economic and Social Research Council (ES/T014083/1, ES/S012486/1)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Numerous aspects of housing are associated with health. However, the pathways between housing and health, particularly the psychosocial elements of housing, are less well understood. Epigenetic information alongside social survey data offers an opportunity to explore biological ageing, measured using DNA methylation, as a potential pathway through which housing affects health., Methods: We use data on housing and DNA methylation from the UK Household Longitudinal Study, linked with prior survey responses from the British Household Panel Survey, covering adults in Great Britain. We explore the association between epigenetic ageing and housing circumstances, both contemporary and historical, using hierarchical regression., Results: We find that living in a privately rented home is related to faster biological ageing. Importantly, the impact of private renting (coefficient (SE) 0.046 years (0.011) vs owned outright, p<0.001) is greater than the impact of experiencing unemployment (coefficient 0.027 years (0.012) vs employed, p<0.05) or being a former smoker (coefficient 0.021 years (0.005) vs never smoker, p<0.001). When we include historical housing circumstances in the analysis, we find that repeated housing arrears and exposure to pollution/environmental problems are also associated with faster biological ageing., Conclusion: Our results suggest that challenging housing circumstances negatively affect health through faster biological ageing. However, biological ageing is reversible, highlighting the significant potential for housing policy changes to improve health., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Cobalt(II) complexes of biphenyl-2-ol of composition, CoCl 2-n (OC 6 H 4 C 6 H 5 -2) n (H 2 O) 4 (where n  = 1 or 2), were prepared by reacting cobaltous(II) chloride with equi- and bimolar ratios of sodium salt of biphenyl-2-ol. The structural characterization of the synthesized complexes was accomplished by NMR, FTIR, thermogravimetry (TGA), high resolution mass spectroscopy (HRMS), electronic spectroscopic techniques coupled with density functional theory (DFT). The stability of the complexes in different pH media of solvent was studied. Chemical reactivity parameters of the newly synthesized complexes, computed using DFT, indicated greater reactivity of complex 2 over complex 1 and free ligand as indicated by its low HOMO-LUMO energy gap corresponding to 1.71 eV. Molecular docking (MD) studies were carried out in order to study the binding affinities between amino acid residues of DNA duplex (PDB ID: 1BNA) and SARS-CoV-2 (PDB ID: 7T9K) with newly synthesized complexes. Complex 2 has shown promising antivirus behaviour with an inhibition constant value of 0.0423 µmol -1 with amino acid residues of SARS-CoV-2 virus. Toxicity of the complexes was predicted using ProTox-II online server. Antibacterial studies have indicated the complexes to exhibit greater efficacy than the free ligand, while the antioxidant activities have suggested them to display enhanced antioxidant behaviour as compared to reference compounds.Communicated by Ramaswamy H. Sarma.

Although a significant body of research has shown that married people are healthier and live longer, empirical research on sex differences in the link between marital status and health suggests results are mixed. Moreover, the sex disparities in marital status and health relationships vary across adulthood. The literature on partnership status and measures of ageing is largely focused on older age groups and is limited in its view of early adulthood. Data from waves 2 and 3 (2010-2012) of Understanding Society: UKHLS were used to examine the association of current partnership status with epigenetic age acceleration (AA) assessed with DNA methylation (DNAm) algorithms 'Phenoage' and ' DunedinPACE ' in 3492 participants (aged 16-97). Regression models were estimated separately for men and women, and further stratified by age groups. Divorced/separated and widowed people showed positive age acceleration compared to the married/cohabiting people (reference group). Some sex differences were apparent, especially, among the single and divorced/separated groups. Age differences were also apparent, for example in men, being single was negatively associated with DNAmAA in the youngest group, but positively in the oldest group compared to partnered counterparts. These findings illustrate the importance of partnerships on the ageing process, in particular marital change through divorce and widowhood for positive age acceleration in adults. For single groups, observations were heterogenous by age and sex., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Published by Elsevier Ltd.)

The structural, magnetic, electronic, elastic, vibrational, optical, thermodynamic as well as thermoelectric properties of newly predicted quaternary LiZrCoX (X = Ge, Sn) Heusler compounds are evaluated intricately with the aid of ab initio techniques developed under the framework of density functional theory. The computed structural properties are found to be in tandem with the existing analogous theoretical and experimental facts. Structural optimization has been carried out in three different structural arrangements, i.e. , Type-1, Type-2, and Type-3. Further analysis of the optimization curves reveals that the Type-3 phase, which has the least amount of energy, is the most stable structure for the compounds under consideration. The tabulated cohesive energy and formation energy of these compounds depict their chemical as well as thermodynamic stability. The absence of negative phonon frequencies in the phonon band spectrum of the studied compounds depicts their dynamic stability. Similarly, the tabulated second-order elastic constants ( C ij ) and the linked elastic moduli show their stability in the cubic phase. The calculated value of Pugh's ratio and Cauchy pressure reveal that LiZrCoGe is brittle whereas LiZrCoSn is ductile. Additionally, the optical characteristics of the compounds are studied in terms of the dielectric function, refractive index, extinction coefficient, absorption coefficient, reflectivity, energy loss function, and optical conductivity. The obtained high value of power factor and figure of merit of the studied lithium-based quaternary compounds predict good thermoelectric behavior in these compounds. Thus, LiZrCoX (X = Ge, Sn) compounds can therefore be used to create innovative and intriguing thermoelectric materials as well as optoelectronic and energy-harvesting equipment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Background: Classically subclavian vein catheterization is done in neutral arm position; recently, it has been done in different arm positions to compare success rate and catheter misplacement. There is a paucity of literature for comparing abducted and neutral arm position for right infraclavicular subclavian vein cannulation., Aim: Comparison of success rate of abducted and neutral arm position for right infraclavicular subclavian vein cannulation under real-time ultrasound guidance in patients undergoing elective neurosurgery under general anesthesia., Design: Randomized comparative study., Materials and Methods: After approval from Institutional Review Board and Ethical Committee, 100 patients of 18-70 years of age, of either sex, posted for elective neurosurgery under general anesthesia, requiring right subclavian vein cannulation were included in our study. They were randomly divided into two groups: abducted arm position (group 1-AG) and neutral arm position (group 2-NG) using sealed envelope technique., Results: First attempt success rate was higher in AG group compared to NG group (P value- 0.741). Times taken (seconds) for cannulation in NG and AG group, catheter misplacement and hematoma (P value- 0.37, P value- 0.37, P value- 1, respectively) were lesser in AG Group., Conclusion: For USG-guided infraclavicular subclavian vein cannulation, abducted arm position, and neutral arm position in terms of first attempt success rate, number of attempts and associated complications has comparable results; however, further studies with larger group of patients are required to assess the overall advantage of abducted arm position over neutral arm position.

Background: Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function., Methods: In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer's disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer's Project (N = 54,162), respectively. Both strong (P < 5 × 10 -8 ) and suggestive (P < 1 × 10 -5 ) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism., Results: BOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10 -3 ). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: β IVW  = 7.89 × 10 -2 , P IVW  = 1.03 × 10 -2 ; weighted median: β W-Median  = 8.65 × 10 -2 , P W-Median  = 9.60 × 10 -3 ) and a protective effect on AD (β IVW  =  - 0.31, odds ratio: OR = 0.74, P IVW  = 3.06 × 10 -2 ). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment., Conclusions: Triangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Dried blood spot (DBS) sample collection has been suggested as a less invasive, cheaper and more convenient alternative to venepuncture, which requires trained personnel, making it a potentially viable approach for self-collection of blood on a large scale. We examine whether participants in a longitudinal survey were willing to provide a DBS sample in different interview settings, and how resulting cardiovascular risk biomarkers compared with those from venous blood to calculate clinical risk. Participants of the Understanding Society Innovation Panel, a representative sample of UK households, were randomly assigned to three modes of interview. Most participants (84%) were interviewed in their allocated mode. Participants (n = 2162) were interviewed by a nurse who collected both a blood sample by venepuncture and a DBS card ('nurse collection') or participants were seen by an interviewer or took part in the survey online to self-collect a DBS card ('self-collection'). All DBS cards were returned in the post after the sample had dried. Lipids (total cholesterol, HDL-cholesterol, triglycerides), HbA1c and C-reactive protein were measured in venous and DBS samples and equivalence was calculated. The resultant values were used to confirm equivalent prevalence of risk of cardiovascular disease in each type of blood sample by mode of participation. Of participants interviewed by a nurse 69% consented to venous blood sample and 74% to a DBS sample, while in the self-collection modes, 35% consented to DBS collection. Demographic characteristics of participants in self-collection mode was not different to those in nurse collection mode. The percentage of participants with clinically raised biomarkers did not significantly differ between type of blood collection (for example, 62% had high cholesterol (> 5 mmol/l) measured by venepuncture and 67% had high cholesterol within the self-collected DBS sample (p = 0.13)). While self-collected DBS sampling had a lower response rate to DBS collected by a nurse, participation did not vary by key demographic characteristics. This study demonstrates that DBS collection is a feasible method of sample collection that can provide acceptable measures of clinically relevant biomarkers, enabling the calculation of population levels of cardiovascular disease risk., (© 2023. Springer Nature Limited.)

Immunotherapy has emerged as a pioneering therapeutic approach that harnesses the immune system's abilities to combat diseases, particularly in the field of oncology where it has led to significant advancements. However, despite its significant impact in the field of oncology, the potential of immunotherapy in the context of cardiovascular disease (CVD) has not been thoroughly investigated. The purpose of this narrative review is to address the existing knowledge and potential uses of immunotherapy in the field of cardiovascular disease (CVD), with the intention of filling the existing gap in understanding. Furthermore, the review thoroughly examines the future prospects of this swiftly advancing field, providing insights into the aspects that necessitate further investigation and addressing the forthcoming challenges. The review is organized into four distinct sections to enhance comprehension. The first section introduces immunotherapy, presenting the fundamental concepts and principles. The second section explores the immunomodulatory mechanisms in cardiovascular disease (CVD), with a specific focus on the intricate interplay between the immune system and the development of cardiovascular pathogenesis. The utilization of immunotherapy in specific cardiovascular conditions will be examined, investigating the application of immunotherapy in the context of different cardiovascular diseases. The future prospects and challenges in immunotherapy for cardiovascular diseases will be discussed, highlighting the potential areas for future research and addressing the barriers that must be overcome to effectively implement immunotherapeutic interventions in the management of cardiovascular diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Jyotsna et al.)

Exosomes play a role in tissue/organ development and differentiation. Retinoic acid induces differentiation of P19 cells (UD-P19) to P19 neurons (P19N) that behave like cortical neurons and express characteristic neuronal genes such as NMDA receptor subunits. Here we report P19N exosome-mediated differentiation of UD-P19 to P19N. Both UD-P19 and P19N released exosomes with characteristic exosome morphology, size, and common protein markers. P19N internalized significantly higher number of Dil-P19N exosomes as compared to UD-P19 with accumulation in the perinuclear region. Continuous exposure of UD-P19 to P19N exosomes for six days induced formation of small-sized embryoid bodies that differentiated into MAP2-/GluN2B-positive neurons recapitulating RA-induction of neurogenesis. Incubation with UD-P19 exosomes for six days did not affect UD-P19. Small RNA-seq identified enrichment of P19N exosomes with pro-neurogenic non-coding RNAs (ncRNAs) such as miR-9, let-7, MALAT1 and depleted with ncRNAs involved in maintenance of stem cell characteristics. UD-P19 exosomes were rich with ncRNAs required for maintenance of stemness. P19N exosomes provide an alternative method to genetic modifications for cellular differentiation of neurons. Our novel findings on exosomes-mediated differentiation of UD-P19 to P19 neurons provide tools to study pathways directing neuron development/differentiation and develop novel therapeutic strategies in neuroscience., (© 2023. The Author(s).)

Background: While medical studies generally provide health feedback to participants, in observational studies this is not always the case due to logistical and financial difficulties, or concerns about changing observed behaviours. However, evidence suggests that lack of feedback may deter participants from providing biological samples. This paper investigates the effect of offering feedback of blood results on participation in biomeasure sample collection., Methods: Participants aged 16 and over from a longitudinal study - the Understanding Society Innovation Panel-were randomised to three arms - nurse interviewer, interviewer, web survey - and invited to participate in biomeasures data collection. Within each arm they were randomised to receive feedback of their blood results or not. For those interviewed by a nurse both venous and dried blood samples (DBS) were taken in the interview. For the other two arms, they were asked if they would be willing to take a sample, and if they agreed a DBS kit was left or sent to them so the participant could take their own sample and return it. Blood samples were analysed and, if in the feedback arms, participants were sent their total cholesterol and HbA1c results. Response rates for feedback and non-feedback groups were compared: overall; in each arm of the study; by socio-demographic and health characteristics; and by previous study participation. Logistic regression models of providing a blood sample by feedback group and data collection approach controlling for confounders were calculated., Results: Overall 2162 (80.3% of individuals in responding households) took part in the survey; of those 1053 (48.7%) consented to provide a blood sample. Being offered feedback had little effect on overall participation but did increase consent to provide a blood sample (unadjusted OR 1.38; CI: 1.16-1.64). Controlling for participant characteristics, the effect of feedback was highest among web participants (1.55; 1.11-2.17), followed by interview participants (1.35; 0.99 -1.84) and then nurse interview participants (1.30; 0.89-1.92)., Conclusions: Offering feedback of blood results increased willingness to give samples, especially for those taking part in a web survey., (© 2023. The Author(s).)

It is important to understand the role of polypills on medication adherence and clinical outcomes in patients with or at high risk of cardiovascular diseases (CVD) to help decision-makers make robust guidelines on using polypills in these people. Therefore, the current meta-analysis was conducted to assess the impact of polypills on medication adherence and clinical outcomes in patients with or at high risk of CVD. The present meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We searched the electronic databases PubMed, Embase, and the Cochrane Library for randomized control trials (RCTs) from inception to January 1, 2023. The outcomes assessed in the present meta-analysis were adherence to prescribed drugs at the study end, the incidence of cardiovascular events, and change in low-density lipoprotein cholesterol (LDL-C), total cholesterol, and high-density lipoprotein (HDL) from baseline to the study end in mmol/l. A total of six studies were included in the present meta-analysis, with a total sample size of 13139 (6577 in the polypill group and 6562 in the control group). Meta-analysis showed that medication adherence was significantly higher in patients receiving polypills compared to the control group (relative risk (RR): 1.38, 95% confidence interval (CI): 1.22-1.56, p-value: 0.001). The risk of a cardiovascular event was significantly lower in the polypill group (RR: 0.72, 95% CI: 0.63-0.82, p-value: 0.001). No significant differences were found in the changes in LDL-C and total cholesterol between the two groups. This meta-analysis shows a significant impact of polypills on medication adherence. We also found that polypills can reduce the incidence of cardiovascular events in patients with or at high risk of CVD. Our study has also shown that regardless of the history of CVD, polypills play an important role in promoting medication adherence in patients with and without a history of CVD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Memon et al.)

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery., Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism., Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., (© 2022. The Author(s).)

Disadvantaged socio-economic position (SEP) is associated with greater biological age, relative to chronological age, measured by DNA methylation (positive 'age acceleration', AA). Social mobility has been proposed to ameliorate health inequalities. This study aimed to understand the association of social mobility with positive AA. Diagonal reference modelling and ordinary least square regression techniques were applied to explore social mobility and four measures of age acceleration (first-generation: 'Horvath', 'Hannum' and second-generation: 'Phenoage', DunedinPoAm) in n = 3140 participants of the UK Household Longitudinal Study. Disadvantaged SEP in early life is associated with positive AA for three (Hannum, Phenoage and DunedinPoAm) of the four measures examined while the second generation biomarkers are associated with SEP in adulthood (p < 0.01). Social mobility was associated with AA measured with Hannum only such that compared to no mobility, upward mobility was associated with greater age independently of origin and destination SEP. Compared to continuously advantaged groups, downward mobility was associated with positive Phenoage (1.06y [- 0.03, 2.14]) and DunedinPoAm assessed AA (0.96y [0.24, 1.68]). For these two measures, upward mobility was associated with negative AA (Phenoage, - 0.65y [- 1.30, - 0.002]; DunedinPoAm, - 0.96y [- 1.47, - 0.46]) compared to continually disadvantaged groups. While we find some support for three models of lifecourse epidemiology with early life as a sensitive period, SEP across the lifecourse and social mobility for age acceleration measured with DNA methylation, our findings suggest that disadvantaged SEP across the lifecourse is most consistently associated with positive AA., (© 2022. The Author(s).)

The molecular geometry of new titanium(IV) and oxidozirconium(IV) phenylacetohydroxamate complexes [TiCl 2 (L1) 2 ] (I) and [ZrO(L1) 2 ] (II) (where L1 = Potassium phenylacetohydroxamate = C 6 H 5 CH 2 CONHOK) computed by B3LYP/6-311++G(d,p) method has shown these to be distorted octahedral and square pyramidal, respectively. A comparison of computed characteristic bond lengths (CO, CN, and NO) of complexes with that of free ligand has shown chelation through carbonyl and hydroxamic oxygen atoms (O, O coordination). The TiO/ZrO bond lengths in complexes are suggestive of weak coordination through (carbonyl CO) and strong covalent (hydroxamic NO) bonding of the ligand. The magnitude of ClTiCl bond angle involving two chloride atoms is suggestive of cis-conformation at titanium metal in (I). The thermodynamic parameters Gibbs free energy, enthalpy, entropy, nuclear internal energy, constant volume heat capacity, and internal energy of ligand and complexes have been computed. From the energies of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), the global reactivity descriptors such as ionization potential (IP), electron affinity (EA), chemical potential (μ), hardness (η), softness (S), electronegativity (χ), electrophilicity index (ω), and dipole moment have been calculated. The computed vibrational frequencies, 1 H and 13 C NMR spectra have substantiated the molecular structure of complexes. The thermal behavior of complexes has been studied by thermogravimetric techniques (TGA, DTG, and DTA) in N 2 atmosphere has shown complexes are thermally stable., (© 2022 Wiley Periodicals LLC.)

Over the past few decades, the dynamic progress in the synthesis and screening of heterocyclic compounds against various targets has made a significant contribution in the field of medicinal chemistry. Among the wide array of heterocyclic compounds, triazole moiety has attracted the attention of researchers owing to its vast therapeutic potential and easy preparation via copper and ruthenium-catalyzed azide-alkyne cycloaddition reactions. Triazole skeletons are found as major structural components in a different class of drugs possessing diverse pharmacological profiles including anti-cancer, anti-bacterial, anti-fungal, anti-viral, anti-oxidant, anti-inflammatory, anti-diabetic, anti-tubercular, and anti-depressant among various others. Furthermore, in the past few years, a significantly large number of triazole hybrids were synthesized with various heterocyclic moieties in order to gain the added advantage of the improved pharmacological profile, overcoming the multiple drug resistance and reduced toxicity from molecular hybridization. Among these synthesized triazole hybrids, many compounds are available commercially and used for treating different infections/disorders like tazobactam and cefatrizine as potent anti-bacterial agents while isavuconazole and ravuconazole as anti-fungal activities to name a few. In this review, we will summarize the biological activities of various 1,2,3-triazole hybrids with copious oxygen-containing heterocycles as lead compounds in medicinal chemistry. This review will be very helpful for researchers working in the field of molecular modeling, drug design and development, and medicinal chemistry., (© 2021 John Wiley & Sons Ltd.)

The identification of x-ray crystal structure of cathepsin B (CTSB) in the early 90's enabled researchers to embark on a journey to understand and demystify its multiple catalytic mechanisms (endopeptidase/carboxypeptidase/peptidyl-dipeptidase) in diverse physiological processes and their switching into one another under different conditions. The engagement of CTSB in different pathological conditions due to its over-expression further highlighted the enhanced research interest around the domain. The occurrence of over-expressed CTSB in various diseases like Alzheimer's, cancer, arthritis, cardiovascular, etc., and the use of CTSB inhibitors for the treatment of these diseases have established its involvement in different pathological conditions. Such an understanding tempted researchers to design, synthesize, and screen diverse classes of compounds against CTSB. This in turn, helped in understanding their interactions with the active sites of the enzyme. Heterocyclic compounds comprise a very rich and broad class of medicinally important compounds that also hold great potential for CTSB inhibition. This review covers the CTSB inhibition potential of various natural and synthetic heterocyclic scaffolds. Researchers working in the fields of molecular modeling, drug design and development, and enzyme inhibitors can benefit significantly from this review., Competing Interests: Declaration of competing interest Dr. Suresh Kumar reports financial support was provided by Haryana State Council of Science, Innovation and Technology. Bhavna Saroha reports financial support was provided by Council of Scientific & Industrial Research. Gourav Kumar reports financial support was provided by University Grant Commission, New Delhi. Dr. Suresh Kumar reports administrative support was provided by Kurukshetra University, Kurukshetra., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic in the UK and subsequent lockdown may have affected the mental health of the population. This study examines whether there was an increase in the prevalence and incidence of common mental disorders (CMD) in the UK adult population during the first months of lockdown and whether changes in CMD were associated with stressors related to the pandemic and lockdown., Methods: Longitudinal data from the UK Household Longitudinal Study waves 10-11: 2019-2020 and waves 1-4 of the COVID-19 monthly surveys in April ( n = 17 761) to July 2020 ( n = 13 754), a representative sample of UK adult population, were analysed. CMD was measured using the 12-item General Health Questionnaire (GHQ-12) (cut-off >2). Changes in CMD were analysed in relation to COVID-19 and social stressors., Results: Around 29% of adults without CMD less than a year earlier had a CMD in April 2020. However, by July 2020, monthly incidence of CMD had reduced to 9%. Most employment, financial and psychological 'shocks' were at their highest levels in April and reduced steadily in later months. Despite the lifting of some lockdown conditions by July, stressors related to loneliness, unemployment, financial problems and domestic work continued to influence CMD., Conclusion: Some COVID-19 policy responses such as furloughing may have been effective in mitigating the increase in CMD for some groups of employees. Despite some reduction in levels of pandemic and lockdown-related stressors by the middle of 2020, loneliness and financial stressors remained key determinants of incidence in CMD among the UK adult population.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)

Most epigenetic epidemiology to date has utilized microarrays to identify positions in the genome where variation in DNA methylation is associated with environmental exposures or disease. However, these profile less than 3% of DNA methylation sites in the human genome, potentially missing affected loci and preventing the discovery of disrupted biological pathways. Third generation sequencing technologies, including Nanopore sequencing, have the potential to revolutionize the generation of epigenetic data, not only by providing genuine genome-wide coverage but profiling epigenetic modifications direct from native DNA. Here we assess the viability of using Nanopore sequencing for epidemiology by performing a comparison with DNA methylation quantified using the most comprehensive microarray available, the Illumina EPIC array. We implemented a CRISPR-Cas9 targeted sequencing approach in concert with Nanopore sequencing to profile DNA methylation in three genomic regions to attempt to rediscover genomic positions that existing technologies have shown are differentially methylated in tobacco smokers. Using Nanopore sequencing reads, DNA methylation was quantified at 1779 CpGs across three regions, providing a finer resolution of DNA methylation patterns compared to the EPIC array. The correlation of estimated levels of DNA methylation between platforms was high. Furthermore, we identified 12 CpGs where hypomethylation was significantly associated with smoking status, including 10 within the AHRR gene. In summary, Nanopore sequencing is a valid option for identifying genomic loci where large differences in DNAm are associated with a phenotype and has the potential to advance our understanding of the role differential methylation plays in the etiology of complex disease., (© The Author(s) 2022. Published by Oxford University Press.)

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology., Competing Interests: Declaration of interests G.C.-P. is currently an employee of 23andMe Inc. M.J.C. is the Chief Scientist for Genomics England, a UK Government company. B.M. Psaty serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. G. Thorleifsson, A.H., D.F.G., H. Holm, U.T., and K.S. are employees of deCODE/Amgen Inc. V.S. has received honoraria for consultations from Novo Nordisk and Sanofi and has an ongoing research collaboration with Bayer Ltd. M. McCarthy has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global and has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. M. McCarthy and A. Mahajan are employees of Genentech and holders of Roche stock. M.S. receives funding from Pfizer Inc. for a project unrelated to this work. M.E.K. is employed by SYNLAB MVZ Mannheim GmbH. W.M. has received grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH , grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, and other from Synlab Holding Deutschland GmbH, all outside the submitted work. A.V.K. has served as a consultant to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color Genomics; received speaking fees from Illumina and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research, and reports a patent related to a genetic risk predictor (20190017119). S. Kathiresan is an employee of Verve Therapeutics and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; and he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). D.K. accepts consulting fees from Regeneron Pharmaceuticals. D.O.M.-K. is a part-time clinical research consultant for Metabolon, Inc. D. Saleheen has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech, and Eli Lilly pharmaceuticals. P.N. reports investigator-initated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. The spouse of C.J.W. is employed by Regeneron., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Video laryngoscopes (VL) assist in securing the airway faster and more accurately in difficult airways. However, data regarding its usefulness in patients with normal airways are sparse., Aim: We designed this study to compare the ease and success of endotracheal intubation between C-MAC and Macintosh direct laryngoscope (DL) in adult patients with no anticipated airway difficulty., Settings and Design: The design involves prospective randomized case - control study., Subjects and Methods: One hundred and twenty adult patients with predicted normal airway were randomized into two groups and were intubated using VL (C-MAC VL) and DL (Macintosh DL), respectively. The Cormack-Lehane (CL) grade, time taken for intubation, attempts taken (number), and need for laryngeal maneuvers or stylets were recorded and analyzed for statistical significance., Results: Thirty-eight patients in the DL group and 48 patients in the VL group had CL I view, 20 patients in the DL group and 16 patients in the VL group had CL II, and two patients in the DL group had CL III view. None of the patients in Group VL had CL III view. In seven out of 60 cases in the DL group, difficulty was experienced during insertion of the laryngoscope blade as compared to two cases out of 60 in the VL group. The mean time taken for intubation was lesser in Group DL (28.48 s) as compared to 39.3 s in Group VL. Nine patients in Group DL and 16 patients in Group VL required external laryngeal manipulation. Stylets were used, in seven patients in group DL and in 11 patients in group VL., Conclusions: In patients with a predicted normal airway, C-MAC provides a better glottic view compared to Macintosh DL. Time taken for intubation using the C-MAC video laryngoscope was more. However, success rates on the first attempt at endotracheal intubation and the number of intubation attempts with either laryngoscope were similar., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Anesthesia: Essays and Researches.)

Background: Sex differences are known to play a role in disease aetiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood by performing a discovery (n = 1171) and validation (n = 2471) analysis., Results: We identified and validated 396 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be female-biased CpGs (74%). These saDMP's are enriched in CpG islands and CpG shores and located preferentially at 5'UTRs, 3'UTRs and enhancers. Additionally, we identified 266 significant sex-associated differentially methylated regions overlapping genes, which have previously been shown to exhibit epigenetic sex differences, and novel genes. Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and ESR1., Conclusion: Our study reports a reliable catalogue of sex-associated CpG sites and elucidates several characteristics of these sites using large-scale discovery and validation data sets. This resource will benefit future studies aiming to investigate sex specific epigenetic signatures and further our understanding of the role of DNA methylation in sex differences in human whole blood., (© 2022. The Author(s).)

Evidence suggests that there are social inequalities in multimorbidity, with a recent review indicating that area levels of deprivation are consistently associated with greater levels of multimorbidity. Definitions of multimorbidity, the most common of which is the co-occurrence of more than one long term condition, can include long term physical conditions, mental health conditions or both. The most commonly used measure of deprivation in England and Wales is the Index of Multiple Deprivation (IMD), an index of seven different deprivation domains. It is unclear which features of IMD may be mediating associations with multimorbidity. Thus, there may be associations because of the individual characteristics of those living in deprived areas, characteristics of the areas themselves or overlap in definitions. Data from over 25,000 participants (aged 16+) of Understanding Society (Wave 10, 1/2018-3/2020) were used to understand the most salient features of multimorbidity associated with IMD and whether physical or mental conditions are differentially associated with the seven domains of IMD. 24% of participants report multimorbidity. There is an increased prevalence of multimorbidity composed of only long-term physical conditions in the most deprived decile of deprivation (22%, 95% CI[19,25]) compared to the least deprived decile (16%, 95% CI[14,18]). Mental health symptoms but not reporting of conditions vary by decile of IMD. Associations with multimorbidity are limited to the health, income, education and employment domains of IMD. We conclude that multimorbidity represents a substantial population burden, particularly in the most deprived areas in England and Wales., (© 2022. The Author(s).)

Background Infants need to be exclusively breastfed up to six months of age, and breastfeeding should be continued up to two years of age along with complementary food. In Pakistan, the majority of newborns are not exclusively breastfed. This study was done to compare weight gain between breastfed infants and non-breastfed infants at a tertiary care hospital in Karachi, Pakistan. Methodology This observational cohort study was conducted at the well-baby clinic and vaccination center of the National Institute of Child Health, Karachi, Pakistan, from January 2021 to December 2021. A total of 360 normal term babies (180 in each group) with age below 11 months on either exclusively breastfeeding or other milk feed were included. Data were collected by the duty senior staff nurse of the well-baby clinic and monitored on daily basis by the researchers. The sociodemographic characteristics of mothers of breastfed and non-breastfed babies and birth weight, length, and BMI Z scores of babies in both groups were compared. Results In a total of 360 babies, there were 192 (53.3%) boys and 168 (46.7%) girls. Overall, the mean maternal age was calculated to be 28.1±6.2 years, ranging between 18 and 37 years. The employment status of mothers (p=0.0117) and monthly income of parents (p=0.0388) were significantly different between groups. The mean weight gain in the exclusively breastfeeding group was 4.0±0.5 kg between the first and fifth visit (final visit) in comparison with 4.5±0.5 kg in the non-breastfeeding group (p<0.0001). Conclusion Non-breastfed babies gained significantly more weight in comparison with exclusively breastfed babies. More multicenter trials involving a large proportion of populations are needed to further verify the findings of the present study., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Bai et al.)

Exosomes of endosomal origin are one class of extracellular vesicles that are important in intercellular communication. Exosomes are released by all cells in our body and their cargo consisting of lipids, proteins and nucleic acids has a footprint reflective of their parental origin. The exosomal cargo has the power to modulate the physiology of recipient cells in the vicinity of the releasing cells or cells at a distance. Harnessing the potential of exosomes relies upon the purity of exosome preparation. Hence, many methods for isolation have been developed and we provide a succinct summary of several methods. In spite of the seclusion imposed by the blood-brain barrier, cells in the CNS are not immune from exosomal intrusive influences. Both neurons and glia release exosomes, often in an activity-dependent manner. A brief description of exosomes released by different cells in the brain and their role in maintaining CNS homeostasis is provided. The hallmark of several neurodegenerative diseases is the accumulation of protein aggregates. Recent studies implicate exosomes' intercellular communicator role in the spread of misfolded proteins aiding the propagation of pathology. In this review, we discuss the potential contributions made by exosomes in progression of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Understanding contributions made by exosomes in pathogenesis of neurodegeneration opens the field for employing exosomes as therapeutic agents for drug delivery to brain since exosomes do cross the blood-brain barrier.

Despite numerous studies on social relationships and health, the empirical focus has often been on middle-aged or older adults, even though young adulthood is a period of considerable change in social networks. We investigated whether the associations between social relationships and allostatic load, a multisystem physiological dysregulation index that reflects chronic stress responses, vary by type of relationship and stages of the lifecourse. Relationships with spouse/partner, immediate family and friends were assessed in terms of emotional support and social strain. Poisson regression models on multiple imputed data sets from waves 2-3 (2010-2012) of the UK Household Longitudinal Study (N = 10,380) were estimated. Social strain, particularly from partners and immediate family, appeared to elicit greater stress related dysregulation during early adulthood (age 21-34 years), corresponding to a predicted difference in the allostatic load index (range 0-12) between high and low strained relationships of 1.1 (95% CI: 0.5-1.6) among young women and 0.6 (95% CI: -0.04 to 1.2) among young men. There was little evidence of an association between allostatic load and any of the social relationships among older men and women. Models of social relationships over the lifecourse need to take account of how stressful social relationships become biologically embedded in early adulthood., (© 2021 Foundation for the Sociology of Health & Illness.)

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The positive direct relation between stress and the development of cardiovascular disease has increasingly been recognized. However, the link between hypothalamic-pituitary-adrenal (HPA) dysregulation and subclinical cardiovascular disease has not been studied longitudinally. We investigated the relation of diurnal salivary cortisol, as a biological marker of stress levels, with progression of aortic stiffness over five years., Methods: A total of 3281 people (mean age 65.5) in the Whitehall II prospective study provided six saliva samples on a single weekday. We assessed the diurnal salivary cortisol using the daytime slope and bedtime level. Aortic stiffness was measured by carotid-femoral pulse wave velocity (PWV) at baseline (2007-2009) and five years later (2012-2013). Linear mixed models were used to estimate the association of diurnal salivary cortisol with baseline PWV and five-year longitudinal changes., Results: Diurnal salivary cortisol were not associated with PWV at baseline. Among women but not men, a 1-SD shallower salivary cortisol slope at baseline was associated with a five-year increase in PWV (β = 0.199; 95% CI = 0.040, 0.358 m/s) and higher bedtime cortisol level (β = 0.208, 95% CI = 0.062, 0.354 m/s)., Conclusions: Dysregulation of the HPA axis measured using salivary cortisol (shallower slope, higher bedtime level) predicted the rate of progression of aortic stiffness among women., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence., Materials and Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction., Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10 -8 ). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure ( MARCO ) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 ( EDN1 ) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001)., Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 ( EDN1 ), associated with urgency incontinence, and macrophage receptor with collagenous structure ( MARCO ), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.

Background: Parent-child separation has been shown to increase the risk of a range of mental and physical health conditions later in life. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may help to explain this association. However, few studies have examined the effect of maternal separation on cortisol in late adulthood., Methods: We examined the relationship between maternal separation in childhood and hair cortisol concentrations in late adulthood, using data from the Whitehall II study (n = 3969, mean age: 70 y, range: 60-83 y). Additionally, the role of childhood (adverse childhood experiences (ACEs), material disadvantage, and parenting), adult (marital status and social position), and health (health behaviors, cardiovascular health and medication, and depression) measures in this association were examined. Finally, we examined age of separation and reason for separation. Analysis was carried out using linear regression., Results: Hair cortisol concentrations (pg/mg) among participants who reported maternal separation during childhood were higher (B=0.179, 95% CI 0.041-0.317, p = 0.01) compared to their non-separated counterparts. This effect was robust to adjustment by childhood, adult, and health measures. Among participants who reported separation, age at onset and reason for separation were not significantly associated with hair cortisol concentrations., Conclusion: In older age individuals, hair cortisol concentrations were higher in those who reported maternal separation during childhood. This effect was independent of a wide variety of factors suggesting that there are lifelong pathways between early life separation and HPA functioning in old age., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent., Objectives and Methods: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration., Results: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10 -32 ; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10 -78 ; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument., Conclusion: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D., (© 2021. The Author(s).)

The number of critically-ill coronavirus disease 2019 (Covid-19) patients requiring mechanical ventilation is on the rise. Most guidelines suggest keeping the patient intubated and delay elective tracheostomy. Although the current literature does not support early tracheostomy, the number of patients undergoing it is increasing. During the pandemic, it is important that surgeons and anesthesiologists know the different aspects of tracheostomy in terms of indication, procedure, tube care and complications. A literature search was performed to identify different guidelines and available evidence on tracheostomy in Covid-19 patients. The purpose of the present article is to generate an essential scientific evidence for life-saving tracheostomy procedures., (Fundação Otorrinolaringologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Sex is an important covariate of epigenome-wide association studies due to its strong influence on DNA methylation patterns across numerous genomic positions. Nevertheless, many samples on the Gene Expression Omnibus (GEO) frequently lack a sex annotation or are incorrectly labelled. Considering the influence that sex imposes on DNA methylation patterns, it is necessary to ensure that methods for filtering poor samples and checking of sex assignment are accurate and widely applicable., Results: Here we presented a novel method to predict sex using only DNA methylation beta values, which can be readily applied to almost all DNA methylation datasets of different formats (raw IDATs or text files with only signal intensities) uploaded to GEO. We identified 4345 significantly (p<0.01) sex-associated CpG sites present on both 450K and EPIC arrays, and constructed a sex classifier based on the two first principal components of the DNA methylation data of sex-associated probes mapped on sex chromosomes. The proposed method is constructed using whole blood samples and exhibits good performance across a wide range of tissues. We further demonstrated that our method can be used to identify samples with sex chromosome aneuploidy, this function is validated by five Turner syndrome cases and one Klinefelter syndrome case., Conclusions: This proposed sex classifier not only can be used for sex predictions but also applied to identify samples with sex chromosome aneuploidy, and it is freely and easily accessible by calling the 'estimateSex' function from the newest wateRmelon Bioconductor package ( https://github.com/schalkwyk/wateRmelon ).

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10 -8 ), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology., (© The Author(s) 2021. Published by Oxford University Press.)

Background/objectives: The mediating role of eating behaviors in genetic susceptibility to weight gain during mid-adult life is not fully understood. This longitudinal study aims to help us understand contributions of genetic susceptibility and appetite to weight gain., Subjects/methods: We followed the body-mass index (BMI) trajectories of 2464 adults from 45 to 65 years of age by measuring weight and height on four occasions at 5-year intervals. Genetic risk of obesity (gene risk score: GRS) was ascertained, comprising 92 BMI-associated single-nucleotide polymorphisms and split at a median (=high and low risk). At the baseline, the Eating Inventory was used to assess appetite-related traits of 'disinhibition', indicative of opportunistic eating or overeating and 'hunger' which is susceptibility to/ability to cope with the sensation of hunger. Roles of the GRS and two appetite-related scores for BMI trajectories were examined using a mixed model adjusted for the cohort effect and sex., Results: Disinhibition was associated with higher BMI (β = 2.96; 95% CI: 2.66-3.25 kg/m 2 ), and accounted for 34% of the genetically-linked BMI difference at age 45. Hunger was also associated with higher BMI (β = 1.20; 0.82-1.59 kg/m 2 ) during mid-life and slightly steeper weight gain, but did not attenuate the effect of disinhibition., Conclusions: Appetite disinhibition is most likely to be a defining characteristic of genetic susceptibility to obesity. High levels of appetite disinhibition, rather than hunger, may underlie genetic vulnerability to obesogenic environments in two-thirds of the population of European ancestry.