Associations between the severity of menopausal symptoms and musculoskeletal pain in postmenopausal Portuguese women.

OBJECTIVE: To analyze the association of the severity of the menopausal symptoms with musculoskeletal pain in Portuguese postmenopausal women. METHODS: A cross-sectional, observational study was conducted on 167 women (63.85 ± 9.36 years). The Menopause Rating Scale was used to evaluate the menopausal symptoms severity, while the Nordic Musculoskeletal Questionnaire was employed to assess the localization of the musculoskeletal pain, and multi-located pain was determined if two or more body regions were affected. Depression (Hospital Anxiety and Depression Scale), age, body mass index (BMI) and physical activity level were considered as potential confounders. RESULTS: A greater severity of the somato-vegetative menopausal symptoms was related to the prevention from usual activities because of pain in the neck, shoulders, elbows, wrists/hands and knees (R2 of Nagelkerke = 0.064, 0.043, 0.074, 0.045 and 0.045, respectively). Associations were also observed between greater age and pain in the knees, ankles and feet (R2 of Nagelkerke = 0.036 and 0.034, respectively), and being physically inactive with upper back pain (R2 of Nagelkerke = 0.060). Higher depressive symptoms were linked to pain in the hip/thighs and knees (R2 of Nagelkerke = 0.067 and 0.085, respectively), as well as being physically inactive was related ton in the neck (R2 of Nagelkerke = 0.053). Only a greater BMI was related to multi-located pain in the last 7 days (R2 of Nagelkerke = 0.041). CONCLUSIONS: The findings of our study showed that, taking into account possible confounders, greater severity of the menopausal symptoms at a somatic-vegetative level was associated with more anatomical regions with musculoskeletal pain.

Influence of Strict Lockdown on Vitamin D Deficiency in Pregnant Women: A Word of Caution.

The main source of vitamin D results from skin sunlight exposure. Vitamin D deficiency (VDD) is linked to several adverse events during pregnancy. While performing a cross-sectional study with 886 pregnant women in Elda (Spain) from September 2019 to July 2020 to determine the association of VDD with gestational diabetes mellitus in relation to body mass index, a strict lockdown (SL) due to the COVID-19 pandemic was declared from 15 March 2020 to 15 May 2020. To determine if VDD prevalence in the local population of pregnant women was influenced by SL, a retrospective cross-sectional study was conducted to estimate the prevalence odds ratio (POR) for the association of VDD and SL. A crude logistic regression model was calculated, and then further adjusted by the biweekly measured vitamin D-specific UVB dose in our geographical area. The POR during SL was 4.0 (95%CI = 2.7-5.7), with a VDD prevalence of 77.8% in the quarantine period. Our results revealed that VDD prevalence in pregnant women was influenced by SL. This valuable information could guide us in future if public officials order the population to stay indoors for any given reason.

High-intensity interval training among middle-aged and older adults for body composition and muscle strength: A systematic review.

Background: The aging of population is leading to the investigation of new options to achieve healthy aging. One of these options is high-intensity interval training (HIIT), although its effects on body composition and muscle strength are currently unclear. The objective of this systematic review is to examine the scientific publications on the effects of HIIT on the body composition and muscle strength of middle-aged and older adults. Methods: The search was carried out in the PubMed, Cochrane Plus, Web of Science, CINAHL and SciELO databases without limitation of publication dates. The literature search, data extraction and systematic review were performed following the PRISMA standards and the risk of bias of the selected studies was assessed using the Cochrane Collaboration Risk-of-Bias. Results: Initially 520 publications were identified, out of which a total of 8 articles were finally selected to be included in this systematic review. Improvements in body composition were seen in six of the selected items and an increase in muscle strength in seven of the eight. Regarding physical function, improvements were found in both gait speed and balance. Conclusions: This systematic review found that HIIT is effective in improving body composition and increasing muscle strength. However, when comparing HIIT to moderate-intensity continuous training, it is not clear that HIIT is more beneficial; a firm conclusion cannot be drawn due to the scarcity of published studies, their variety in methodology and the ambiguity of their results, so it is suggested to carry out more research in this area.

Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature.

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

SARC-F and the Risk of Falling in Middle-Aged and Older Community-Dwelling Postmenopausal Women.

(1) Background: The objective of the present study was to determine the ability of the SARC-F questionnaire to identify individuals at risk of falling among middle-aged and older community-dwelling postmenopausal women. (2) Methods: An analytical cross-sectional study was conducted on 157 women (70.80 ± 8.37 years). The SARC-F questionnaire was used to screen for risk of sarcopenia. Fear of falling and balance confidence, as measured by the Falls Efficacy Scale-International (FES-I) and the Activities-Specific balance Scale-16 items (ABC-16) respectively, were used to assess risk of falling. Anxiety and depression (Hospital Anxiety and Depression Scale), fatigue (Fatigue Severity Scale), body mass index, waist-to-hip ratio, and sleep duration were also determined. (3) Results: Logistic regression showed that higher risk of falling as assessed by FES-I was associated with higher SARC-F scores (OR = 1.656), anxiety levels (OR = 1.147), and age (OR = 1.060), while increased SARC-F scores (OR = 1.612), fatigue (OR = 1.044), and shorter sleep duration (OR = 0.75) were related to ABC-16 scores. In addition, a SARC-F cutoff of 1.50 (83.33% sensitivity and 59.13% specificity) and 3.50 (44.44% sensitivity and 89.26% specificity) were shown to be able to discriminate participants at risk of falling according to the FES-I and the ABC-16, respectively. (4) Conclusions: our results show that SARC-F is an independent predictor of the risk of falling among middle-aged and older community-dwelling postmenopausal women.

Expression Quantitative Trait Locus Analysis in Systemic Sclerosis Identifies New Candidate Genes Associated With Multiple Aspects of Disease Pathology.

OBJECTIVE: To identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease. METHODS: We performed an eQTL analysis using whole-blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc genome-wide association study (GWAS) data. We integrated our findings from expression modeling, differential expression analysis, and transcription factor binding site enrichment with key clinical features of SSc. RESULTS: We detected 49,123 validated cis-eQTLs from 4,539 SSc-associated single-nucleotide polymorphisms (SNPs) (PGWAS < 10-5 ). A total of 1,436 genes were within 1 Mb of the 4,539 SSc-associated SNPs. Of those 1,436 genes, 565 were detected as having ≥1 eQTL with an SSc-associated SNP. We developed a strategy to prioritize disease-associated genes based on their expression variance explained by SSc eQTLs (r2 > 0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in the blood cells, skin, or lung tissue of SSc patients. Transcription factor binding site analysis revealed enriched motifs of 24 transcription factors (5%) among SSc eQTLs, 5 of which were found to be differentially regulated in the blood cells (ELF1 and MGA), skin (KLF4 and ID4), and lungs (TBX4) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune-mediated diseases, of which only 3 have been tested in clinical trials in patients with SSc. CONCLUSION: The findings of the present study indicate a new layer to the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.

Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Vitamin D Deficiency and Gestational Diabetes Mellitus in Relation to Body Mass Index.

A relationship between vitamin D deficiency (VDD) and gestational diabetes mellitus (GDM) has been described. Considering that GDM prevalence depends on body mass index (BMI), our main objective was to determine if VDD is associated with GDM, independent of BMI. A cross-sectional study with 886 pregnant women was conducted in Elda (Spain) from September 2019 to June 2020. To assess the association, Poisson regression models with robust variance were used to estimate the prevalence ratio (PR). The observed GDM prevalence was 10.5%, while the VDD prevalence was 55.5%. In the crude model, both VDD and obesity were associated with GDM, but in the adjusted model, only VDD was statistically significant (PR = 1.635, p = 0.038). A secondary event analysis did not detect differences in VDD, but BMI yielded a higher frequency of births by cesarean section and newborns with a >90 percentile weight in the obesity group. In conclusion, VDD is associated with GDM, independent of BMI. Future longitudinal studies could provide information on causality.

Postoperative Plasma Mitochondrial DNA and Cytokine Profiles of Elderly Patients Undergoing Minimally Invasive Aortic Valve Replacement.

INTRODUCTION: Mitochondrial DNA (mtDNA) is gaining increasing interest as a marker of cellular damage and could also act as an inflammatory mediator in cardiopulmonary bypass induced postoperative inflammatory response. Although minimally invasive heart valve surgery reportedly reduces inflammation, the mtDNA and cytokine profile in this context remains unclear. MATERIALS AND METHODS: Here, we report a prospective series of 40 elderly patients with aortic stenosis who underwent bioprosthetic aortic valve replacement (AVR) through upper ministernotomy with either a sutureless (n = 20) or a conventional (n = 20) valve. Primary end points included serial plasma levels of mtDNA (T1: at baseline; T2: 4 hours after surgery; and T3: 24s hour after surgery), cytokines (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]), and myocardial necrosis biomarkers (MNBs), whereas secondary end points included clinical and echocardiographic data. RESULTS: Significant increases in the postoperative plasma levels (T2) of mtDNA, cytokines, and MNBs were observed in all patients. The postoperative plasma levels of mtDNA, TNF-α, and MNBs showed no significant differences between the treatment groups, although there was a trend toward lower levels in the sutureless group. The decreases in aortic cross-clamp and cardiopulmonary bypass times seen in the sutureless group were associated with significant lower postoperative levels (T2 and T3) of IL-6. CONCLUSION: AVR through upper ministernotomy was associated with a significant increase in postoperative plasma levels of mtDNA and cytokines. There was no difference in the mtDNA levels between the sutureless and conventional valve groups, suggesting a similar level of inflammation in both groups. However, the shorter operation time observed in the sutureless valve group was associated with significantly lower postoperative levels of IL-6, indicating potential clinical benefits.

Saliva as a non-invasive tool for assessment of metabolic and inflammatory biomarkers in children.

BACKGROUND & AIMS: Epidemiological studies in school-age children are challenging, particularly those that aim to analyse metabolic markers on blood samples obtained via invasive and stressful procedures. The objective of this paper is to evaluate the use of saliva, as a non-invasive tool in epidemiological studies performed in school-age children, to capture metabolic changes associated with body mass index (BMI), dietary characteristics and physical activity in both boys and girls. METHODS: This is an observational study in which healthy children of ages between 8 and 12 years (n = 129, 60 girls and 69 boys) from three schools in a Mediterranean area of Spain were included. A panel of biomarkers was measured in serum and saliva and correlated with BMI, dietary characteristics and physical activity. RESULTS: Significant positive correlation between serum and salivary levels were detected for CRP (r = 0.770) in all included children, and boys (r = 0.805) and girls (r = 0.775) separately (P < 0.001, in all cases) and for insulin in girls (r = 0.442; P < 0.05). Among all studied salivary biomarkers, insulin was significantly correlated with the three factors studied: positively with BMI and negatively with dietary characteristics (intake and composition) and physical activity (P < 0.05). Obesity and diet composition were both positively associated to pro-inflammatory biomarkers, CRP and IL1b; while diet composition shared with physical activity levels the correlation with IL6 (positive with energy, fat, carbohydrate and saturated fatty acid intake, and negative with cholesterol intake and average physical activity in boys), NGF and glucose (in both cases correlations were negative with diet composition and physical activity variables) (P < 0.05, in all cases). Sex differences were detected in serum glucose and TNFα. CONCLUSIONS: Biomarkers in saliva are able to capture differences in BMI, dietary characteristics and physical activity levels in school-age children. Saliva may potentially constitute a useful non-invasive and stress-free tool to evaluate metabolic markers of inflammation and/or metabolism related to BMI and lifestyle in a sex-dependent manner.

Epigenome-Wide Comparative Study Reveals Key Differences Between Mixed Connective Tissue Disease and Related Systemic Autoimmune Diseases.

Mixed Connective Tissue Disease (MCTD) is a rare complex systemic autoimmune disease (SAD) characterized by the presence of increased levels of anti-U1 ribonucleoprotein autoantibodies and signs and symptoms that resemble other SADs such as systemic sclerosis (SSc), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Due to its low prevalence, this disease has been very poorly studied at the molecular level. We performed for the first time an epigenome-wide association study interrogating DNA methylation data obtained with the Infinium MethylationEPIC array from whole blood samples in 31 patients diagnosed with MCTD and 255 healthy subjects. We observed a pervasive hypomethylation involving 170 genes enriched for immune-related function such as those involved in type I interferon signaling pathways or in negative regulation of viral genome replication. We mostly identified epigenetic signals at genes previously implicated in other SADs, for example MX1, PARP9, DDX60, or IFI44L, for which we also observed that MCTD patients exhibit higher DNA methylation variability compared with controls, suggesting that these sites might be involved in plastic immune responses that are relevant to the disease. Through methylation quantitative trait locus (meQTL) analysis we identified widespread local genetic effects influencing DNA methylation variability at MCTD-associated sites. Interestingly, for IRF7, IFI44 genes, and the HLA region we have evidence that they could be exerting a genetic risk on MCTD mediated through DNA methylation changes. Comparison of MCTD-associated epigenome with patients diagnosed with SLE, or Sjögren's Syndrome, reveals a common interferon-related epigenetic signature, however we find substantial epigenetic differences when compared with patients diagnosed with rheumatoid arthritis and systemic sclerosis. Furthermore, we show that MCTD-associated CpGs are potential epigenetic biomarkers with high diagnostic value. Our study serves to reveal new genes and pathways involved in MCTD, to illustrate the important role of epigenetic modifications in MCTD pathology, in mediating the interaction between different genetic and environmental MCTD risk factors, and as potential biomarkers of SADs.

Analysis of the Effect of Concentrations of Four Whitening Products in Cover Transmissivity of Mediterranean Greenhouses.

The present work analyses the traditional method of applying whitening products on Mediterranean greenhouses. Four commercial whitening products (agricultural solar protectors, ASPs), applied at four doses, were compared with a non-whitened cover. The traditional product "Blanco de España" with 99% calcium carbonate (CaCO3) and other three products with 97% CaCO3 that incorporate adhesives were tested. The use of adhesives in ASP did not influence the effect of the different products on the inside temperature, and at the same dose all four products show a similar behaviour. The findings support the maximum dose recommended by other authors of 0.50 kg L-1 (50/100), above which the transmissivity of the greenhouse cover decreases by over 50%. The effect of ASP on the transmissivity of the cover depends principally on the dose applied, but also on the climatic conditions (solar radiation, cloud cover, etc.) and on the time of year (solar elevation). The habitual use of a constant dose throughout the year does not seem to be the most adequate. Recommended doses should vary according to the time of year and the desired degree of transmissivity reduction. The adhesive components are shown to provide a high degree of protection against heavy rain. The study recommends a standardised method of ASP application, establishing a method that allows the grower to verify the concentration of the product that will remain on the greenhouse cover.

Mitochondrial DNA haplogroups influence the risk of aortic stenosis.

AIM: The underlying pathophysiologic mechanisms of aortic stenosis are not clear. Mitochondrial dysfunction plays a role in many pathological conditions including cardiac diseases. We aimed to analyze the mitochondrial DNA haplogroups in a group of patients undergoing valve replacement surgery due to severe aortic stenosis. METHODS: Mitochondrial DNA haplogroups were assessed in 176 patients with severe aortic stenosis and 308 control subjects. Cardiovascular risk factors and demographics were similar in both groups. RESULTS: Patients carrying haplogroup Uk had a lower risk of developing aortic stenosis, especially compared to patients carrying haplogroup H (odds ratio = 0.507; 95% confidence interval: 0.270-0.952, p = 0.035). CONCLUSIONS: Mitochondrial DNA haplogroups could be involved in the development of severe aortic stenosis. Specifically, haplogroup H could be a risk factor and Uk a protective factor for severe aortic stenosis in a population from Spain.

Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies.

PURPOSE OF REVIEW: DNA methylation has emerged as an important contributing factor in the pathogenesis of systemic lupus erythematosus (SLE). Here, we describe the DNA methylation patterns identified in SLE and how these epigenetic changes can influence disease susceptibility, clinical heterogeneity, and disease flares. RECENT FINDINGS: Several genome-wide DNA methylation studies have been recently completed in SLE. Important observations include robust demethylation of interferon-regulated genes, which is consistent across all cell types studied to date, and is independent of disease activity. This interferon epigenetic signature was shown to precede interferon transcription signature in SLE, suggesting it might be an early event in the disease process. Recent studies also revealed DNA methylation changes specific for renal and skin involvement in SLE, providing a proof of principle for a value of DNA methylation studies in exploring mechanisms of specific disease manifestations, and potentially as prognostic biomarkers. Inherited ethnicity-specific DNA methylation patterns have also been shown to possibly contribute to differences in SLE susceptibility between populations. Finally, a recent study revealed that DNA methylation levels at IFI44L can accurately distinguish SLE patients from healthy controls, and from patients with other autoimmune diseases, promising to be the first epigenetic diagnostic marker for SLE. Genome-wide DNA methylation studies in SLE have provided novel insights into disease pathogenesis, clinical heterogeneity, and disease flares. Further studies promise to reveal novel diagnostic, prognostic, and therapeutic targets for SLE.

Omics studies: their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases.

Omics studies of systemic autoimmune diseases (SADs) in general, and SLE in particular, have delivered isolated information from transcriptome, epigenome, genome, cytokine and metabolome analyses. Such analyses have resulted in the identification of disease susceptibility genes and the description of IFN expression signatures, allowing extensive insight into the mechanisms of disease and the development of new therapies. Access to such technologies allows the recognition of patterns of disease at a pathway level, thereby, to reclassify SLE and other SADs and to develop new therapeutics from a personalized perspective. The use of omic information allows the discovery of correlative patterns involving drugs not currently suspected to be of value in SADs. In this review, we summarize the omics findings for SLE and propose ways of using the data for the identification of new biomarkers, finding new drugs and reclassifying patients not only with SLE, but also with other SADs.