C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.

The identification of genes that confer either extension of lifespan or accelerate age-related decline was a step forward in understanding the mechanisms of ageing and revealed that it is partially controlled by genetics and transcriptional programs. Here we discovered that the human DNA sequence C16ORF70 encoded for a protein, named MYTHO (Macroautophagy and YouTH Optimizer), which controls life- and health-span. MYTHO protein is conserved from C. elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the ortholog myt-1 gene in C. elegans dramatically shortened lifespan and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy ageing.

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.

Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated. Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed. Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively. Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

Circulating tumor DNA as a biomarker for predicting progression-free survival and overall survival in patients with epithelial ovarian cancer: a systematic review and meta-analysis.

OBJECTIVES: Circulating tumor DNA (ctDNA) is emerging as a potential prognostic biomarker in multiple tumor types. However, despite the many studies available on small series of patients with ovarian cancer, a recent systematic review and meta-analysis is lacking. The objective of this study was to determine the association of ctDNA with progression-free-survival and overall survival in patients with epithelial ovarian cancer. METHODS: An electronic search was conducted using PubMed (MEDLINE), Embase, CENTRAL (Cochrane Library), and CINAHL-Complete from January 2000 to September 15, 2023. To be included in the analysis the studies had to meet the following pre-specified inclusion criteria: (1) evaluable ctDNA; (2) progression-free-survival and overall survival reported as hazard ratio (HR); and (3) the patient population had epithelial ovarian cancer at the time of ctDNA detection. We evaluated the association of ctDNA with progression-free survival and overall survival. Secondary outcomes focused on sub-group analysis of genomic alterations and international Federation of Gynecology and Obstetrics (FIGO) stage. RESULTS: A total of 26 studies reporting on 1696 patients with epithelial ovarian cancer were included. The overall concordance rate between plasma-based and tissue-based analyses was approximately 62%. We found that a high level of ctDNA in epithelial ovarian cancer was associated with worse progression-free survival (HR 5.31, 95% CI 2.14 to 13.17, p<0.001) and overall survival (HR 2.98, 95% CI 1.86 to 4.76, p<0.0001). The sub-group analysis showed a greater than threefold increase in the risk of relapse in patients with positive HOXA9 meth-ctDNA (HR 3.84, 95% CI 1.57 to 9.41, p=0.003). CONCLUSIONS: ctDNA was significantly associated with worse progression-free survival and overall survival in patients with epithelial ovarian cancer. Further prospective studies are needed. PROSPERO REGISTRATION NUMBER: CRD42023469390.

Downregulation of PLIN2 in human dermal fibroblasts impairs mitochondrial function in an age-dependent fashion and induces cell senescence via GDF15.

Perilipin 2 (PLIN2) is a lipid droplet (LD)-coating protein playing important roles in lipid homeostasis and suppression of lipotoxicity in different tissues and cell types. Recently, a role for PLIN2 in supporting mitochondrial function has emerged. PLIN2 dysregulation is involved in many metabolic disorders and age-related diseases. However, the exact consequences of PLIN2 dysregulation are not yet completely understood. In this study, we knocked down (KD) PLIN2 in primary human dermal fibroblasts (hDFs) from young (mean age 29 years) and old (mean age 71 years) healthy donors. We have found that PLIN2 KD caused a decline of mitochondrial function only in hDFs from young donors, while mitochondria of hDFs from old donors (that are already partially impaired) did not significantly worsen upon PLIN2 KD. This mitochondrial impairment is associated with the increased expression of the stress-related mitokine growth differentiation factor 15 (GDF15) and the induction of cell senescence. Interestingly, the simultaneous KD of PLIN2 and GDF15 abrogated the induction of cell senescence, suggesting that the increase in GDF15 is the mediator of this phenomenon. Moreover, GDF15 KD caused a profound alteration of gene expression, as observed by RNA-Seq analysis. After a more stringent analysis, this alteration remained statistically significant only in hDFs from young subjects, further supporting the idea that cells from old and young donors react differently when undergoing manipulation of either PLIN2 or GDF15 genes, with the latter being likely a downstream mediator of the former.

The effect of cleat position on foot pain in cyclists.

Amateur or non-competitive cycling is one of the most popular and growing sports, and the repetitive nature of this sport, combined with a cleat position that is too far forward, often leads to peripheral ischemia or pressure, which can cause pain at the metatarsal level due to the nerve and vascular structures present at this level, according to several authors. This clinical series describes the work done to reduce pain in 21 cyclists who reported foot pain/discomfort exclusively during pedaling. To exclude different causes of pain, other than the position of the cleat, the cyclists received biomechanical assessments using an indoor bike smart trainer and a 2D motion capture system. The pain was found to be associated with the incorrect positioning of the shoe cleats, which were generally positioned at the level of the phalanges and, according to our hypothesis, in a significantly forward position. Our intervention was to move the cleat back under the metatarsal head in all the cyclists examined. After five cycling sessions, feedback showed significant improvements. The authors were aware of some limitations, such as the small number of subjects studied, the different types of cleats used by different cyclists, and the lack of information on cadence. However, the overall data collected during the study showed a significant improvement of 5 points on the Numeric Pain Rating Scale (NPRS) after treatment. This clinical series supports the hypothesis that cleat retraction improves foot pain in cyclists, but further studies are needed to better characterize and understand the mechanism underlying the development of pain. More methodologically sound studies are needed. The current clinical series is the first of its kind to describe an initial method of reducing metatarsal pain in cyclists.

In trials of physiotherapy for chronic low back pain, clinical relevance is rarely interpreted, with great heterogeneity in the frameworks and thresholds used: a meta-research study.

QUESTIONS: How do authors of randomised controlled trials (RCTs) interpret the clinical relevance of the effects of physiotherapy interventions compared with no intervention on pain intensity, physical function and time to recovery in people with chronic low back pain (CLBP)? How can the clinical relevance be re-interpreted based on the available smallest worthwhile effect (SWE) threshold for this comparison? Are the studies in this field adequately powered? DESIGN: Cross-sectional meta-research study. PARTICIPANTS: People with CLBP. OUTCOME MEASURES: Pain intensity, physical function and time to recovery. RESULTS: This review included 23 RCTs with 1,645 participants. Twenty-two and 18 studies were included in the analysis of pain intensity and physical function, respectively. No studies investigated time to recovery. Sixteen studies reported varying thresholds to interpret clinical relevance for physical function and pain intensity. Discrepancies between interpretation using the minimal important difference and SWE values were observed in five studies. Study power ranged from 9% to 98%, with only four studies having a power > 80%. CONCLUSION: Little attention is given to the interpretation of clinical relevance in RCTs comparing physiotherapy with no intervention in CLBP, with great heterogeneity in the frameworks and thresholds used. Future trials should inform patients and clinicians on whether the effect of an intervention is large enough to be worthwhile, using a reliable and comprehensive approach like available SWE estimates. REGISTRATION: medRxiv https://doi.org/10.1101/2022.12.14.22283454.

The Uptake of the Core Outcome Set for Non-Specific Low Back Pain Clinical Trials is Poor: A Meta-Epidemiological Study of Trial Registrations.

We conducted a meta-epidemiological study on all non-specific low back pain (NSLBP) trial registrations on the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We aimed to 1) assess the uptake of the core outcome set (COS) for NSLBP in clinical trials; 2) assess the uptake of the core outcome measurement set for NSLBP in clinical trials; and 3) determine whether specific study characteristics are associated with the COS uptake. After applying the relevant filters for the condition, study type, and phase of the trial, 240 registry entries were included in this study. Only 50 (20.8%) entries showed a full COS uptake, and this rate did not increase over time. Most registry entries that planned to measure physical functioning (n = 152) used the Roland-Morris Disability Questionnaire (n = 74; 48.7%); a small percentage used the numeric rating scale (n = 60; 27.3%) or Short Form-12 (n = 5; 8.3%) if they planned to measure pain intensity (n = 220) or health-related quality of life (n = 60), respectively. Only the planned sample size (OR = 1.02; 95% CI = 1.01, 1.03) showed a significant but small association with COS uptake. The uptake of the COS for NSLBP is poor. Only 21% of the randomized controlled trials aimed to measure all COS domains in their study registration and COS uptake is not increased over time. Great heterogeneity in measurement instruments was also observed, revealing poor core outcome measurement set uptake. PERSPECTIVE: The Core Outcome Set (COS) for non-specific low back pain was published more than 20 years ago. We evaluated whether trial registrations are using this set of outcomes when testing interventions for low back pain. Full uptake was found only in 21% of the sample, and this is not increasing over time. Researchers should use the COS to ensure that trials measure relevant outcomes consistently.

Safety of misoprostol vs dinoprostone for induction of labor: A systematic review and meta-analysis.

OBJECTIVE: Pharmacological agents such as prostaglandins (dinoprostone and misoprostol) are commonly used to reduce the duration of labor and promote vaginal delivery. However, key safety considerations with its use include an increased risk of uterine rupture, tachysystole and hyperstimulation of pregnant women, which could potentially lead to a non-reassuring fetal heart rate and to fetal hypoxemia. The aim of this systematic review was to assess maternal and fetal outcomes between misoprostol group (PGE1) and dinoprostone group (PGE2) STUDY DESIGN: We search on MEDLINE (PubMed), CINHAL (EBSCOhost), EMBASE, Scopus (Ovid), CENTRAL (January 1, 1998, to December 31, 2022). Patients were eligible if they presented at greater than 36 weeks gestation with an indication for induction of labor and a single live cephalic fetus. We conducted a meta-analysis of data for both primary (cesarean section rate, instrumental deliveries rate, tachysystole, uterine rupture, post-partum haemorrage; chorionamiositis) and secondary outcomes (Apgar at 5 min <7, meconium-stained liquor, NICU admission, infant death) using odds-ratio (OR) as a measure of effect-size. Risk of bias assessment was performed with RoB-I. We performed statistical analyses using Cochrane RevMan version 5.4 software. RESULTS: We found 39 RCTs comparing the outcomes of interest between misoprostol and dinoprostone. The pooled effect showed no statistically significant difference between the two groups in terms of cesarean section rate [OR: 0.94; 95% CI 0.84-1.05], instrumental deliveries rate [OR: 1.04; 95% CI: 0.90-1.19; p = 0.62], tachysystole [OR: 1.21; 95% CI: 0.91-1.60; p = 0.19], post-partum hemorrhage [OR: 0.85; 95% CI: 0.62-1.15p = 0.30], chorioamnionitis [OR: 0.94; 95% CI: 0.76-1.17p = 0.59], Apgar at 5 min < 7 [OR: 0.83; 95% CI: 0.61-1.12, p = 0.21], meconium-stained liquor [OR: 1.11; 95% CI: 0.97-1.27p = 0.59], NICU admission group [OR: 0.91; 95% CI: 0.77-1.09], infant death [OR: 0.57; 95% CI: 0.22-1.44]. After performing a sub-group analysis based on the type of prostaglandins administrations (oral, vaginal gel, vaginal pessary), results did not change substantially. CONCLUSIONS: This systematic review and meta-analysis demonstrate that misoprostol and dinoprostone appear to have a similar safety profile.

Bias in the measurement of the outcome is associated with effect sizes in randomized clinical trials on exercise therapy for chronic low back pain: a meta-epidemiological study.

OBJECTIVES: To explore the relationships between the risk of bias and treatment effect estimates for exercise therapy interventions on pain intensity and physical functioning outcomes in randomized controlled trials (RCTs) involving patients with chronic low back pain. STUDY DESIGN AND SETTING: A cross-sectional meta-epidemiological study of the 230 RCTs (31,674 participants) in the 2021 'Exercise therapy for chronic low back pain' Cochrane Review were included. Study design characteristics, sample size, prospective trial registration, flowchart information, interventions, and comparisons were extracted. Independent pairs of reviewers assessed the risk of bias using the Cochrane Risk of Bias 2 tool. RESULTS: The metaregression included 220 (pain intensity) and 203 (physical functioning) effect sizes. Unadjusted and adjusted metaregression models showed no significant associations between the bias domains and pain intensity effect sizes. Only domain 'bias in the measurement of the outcome' was significantly associated with physical functioning (standardized mean difference: -0.40, 95% confidence interval: -0.77 to -0.02) when adjusted for flowchart reported (yes/no), prospective trial registration, sample size, and comparator type. CONCLUSION: The risk of bias in the measurement of the outcome could lead to slight overestimates of the effect size for physical functioning. Clinicians should consider this when they read and assess RCT results in this field. We encourage metaresearchers to replicate our findings using a consistent approach for evaluating the risk of bias (i.e., the RoB 2 tool) in other musculoskeletal conditions and interventions to investigate their generalizability.

Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective.

According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.

Benefits and Harms of Spinal Manipulative Therapy for Treating Recent and Persistent Nonspecific Neck Pain: A Systematic Review With Meta-analysis.

OBJECTIVE: We aimed to estimate the benefits and harms of cervical spinal manipulative therapy (SMT) for treating neck pain. DESIGN: Intervention systematic review with meta-analysis of randomized controlled trials (RCTs). LITERATURE SEARCH: We searched the MEDLINE, Cochrane CENTRAL, Embase, CINAHL, PEDro, Chiropractic Literature Index bibliographic databases, and grey literature sources, up to June 6, 2022. STUDY SELECTION CRITERIA: RCTs evaluating SMT compared to guideline-recommended and nonrecommended interventions, sham SMT, and no intervention for adults with neck pain were eligible for our systematic review. Prespecified outcomes included pain, range of motion, disability, health-related quality of life. DATA SYNTHESIS: Random-effects meta-analysis for clinically homogenous RCTs at short-term and long-term outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 Tool. We used the Grading of Recommendations, Assessment, Development, and Evaluations approach to judge the certainty of evidence. RESULTS: We included 28 RCTs. There was very low to low certainty evidence that SMT was more effective than recommended interventions for improving pain at short term (standardized mean difference [SMD], 0.66; 95% confidence interval [CI]: 0.35, 0.97) and long term (SMD, 0.73; 95% CI: 0.31, 1.16), and for reducing disability at short-term (SMD, 0.95; 95% CI: 0.48, 1.42) and long term (SMD, 0.65; 95% CI: 0.23, 1.06). Transient side effects only were found (eg, muscle soreness). CONCLUSION: There was very low certainty evidence supporting cervical SMT as an intervention to reduce pain and improve disability in people with neck pain. J Orthop Sports Phys Ther 2023;53(9):510-528. Epub: 10 August 2023. doi:10.2519/jospt.2023.11708.

The interpretation of clinical relevance in randomised clinical trials in patients with chronic low back pain: protocol for a meta-research study.

Chronic low back pain (cLBP) is one of the leading worldwide causes of disability. The smallest worthwhile effect (SWE) parameter has been proposed to find a threshold of clinical relevance. Specific values of the SWE have been calculated in patients with cLBP for pain intensity, physical functioning and time to recovery for physiotherapy compared with no intervention. Our objectives are 1) To evaluate how authors have interpreted the clinical relevance of the effect of physiotherapy compared to no-intervention on pain, physical functioning and time to recovery; 2) To reinterpret the clinical relevance of these between-group differences based on the available SWE estimates; 3) To evaluate, for descriptive purposes, whether the studies are adequately powered or underpowered considering the published SWE values and a power threshold of 80%. A systematic search in Medline, PEDro, Embase and Cochrane CENTRAL will be conducted. We will search for RCT investigating the effectiveness of physiotherapy as compared to no interventions in people with cLBP. We will compare the authors' interpretation of results for clinical relevance with their results to determine if they meet their a-priori definitions. Then, we will perform a re-interpretation of the between-group differences based on SWE values published for cLBP.

Long-term human spaceflight and inflammaging: Does it promote aging?

Spaceflight and its associated stressors, such as microgravity, radiation exposure, confinement, circadian derailment and disruptive workloads represent an unprecedented type of exposome that is entirely novel from an evolutionary stand point. Within this perspective, we aimed to review the effects of prolonged spaceflight on immune-neuroendocrine systems, brain and brain-gut axis, cardiovascular system and musculoskeletal apparatus, highlighting in particular the similarities with an accelerated aging process. In particular, spaceflight-induced muscle atrophy/sarcopenia and bone loss, vascular and metabolic changes, hyper and hypo reaction of innate and adaptive immune system appear to be modifications shared with the aging process. Most of these modifications are mediated by molecular events that include oxidative and mitochondrial stress, autophagy, DNA damage repair and telomere length alteration, among others, which directly or indirectly converge on the activation of an inflammatory response. According to the inflammaging theory of aging, such an inflammatory response could be a driver of an acceleration of the normal, physiological rate of aging and it is likely that all the systemic modifications in turn lead to an increase of inflammaging in a sort of vicious cycle. The most updated countermeasures to fight these modifications will be also discussed in the light of their possible application not only for astronauts' benefit, but also for older adults on the ground.

Effectiveness and safety of COVID-19 vaccine in pregnant women: A systematic review with meta-analysis.

BACKGROUND: There are limited data regarding COVID-19 vaccination during pregnancy. OBJECTIVES: To evaluate the effects of COVID-19 vaccination received during pregnancy on SARS-CoV-2 infection, COVID-19-related hospitalisation, COVID-19-related intensive care unit (ICU) admission and maternal-fetal complications. SEARCH STRATEGY: MEDLINE, CINHAL, Embase, Scopus and CENTRAL databases, as well as ClinicalTrials.gov, reference lists, related articles and grey literature sources. SELECTION CRITERIA: Randomised controlled trials, non-randomised studies of interventions, pregnant women, COVID-19 vaccination during pregnancy. DATA COLLECTION AND ANALYSIS: Study selection, risk-of-bias assessment, data extraction and assessment of the certainty of evidence using the GRADE method were performed independently by two authors. Meta-analyses were performed using Cochrane RevMan 5.4. PROSPERO registration number: CRD42022308849. MAIN RESULTS: We included 14 observational studies (362 353 women). The administration of a COVID-19 vaccine during pregnancy resulted in a statistically significant reduction in SARS-CoV-2 infection (OR 0.46, 95% CI 0.28-0.76) and COVID-19-related hospitalisation (OR 0.41, 95% CI 0.33-0.51). The effect appeared to be greater in fully vaccinated women, for both infection (OR 0.31, 95% CI 0.16-0.59) and hospitalisation (OR 0.15, 95% CI 0.10-0.21). However, the certainty of evidence was very low. The difference in COVID-19-related ICU admission between vaccinated and unvaccinated individuals did not reach statistical significance (OR 0.58, 95% CI 0.13-2.58). Finally, there were no statistically significant differences in any of the maternal-fetal complications considered in the included studies. CONCLUSIONS: COVID-19 vaccination administered during pregnancy seems to reduce SARS-CoV-2 infection and COVID-19-related hospitalisation, with no significant effects on maternal-fetal complications.

PFD-SENTINEL: Development of a screening tool for pelvic floor dysfunction in female athletes through an international Delphi consensus.

To develop a screening tool for pelvic floor dysfunction (PFD) in female athletes for use by sports medicine clinicians (eg, musculoskeletal/sports physiotherapists, sports and exercise medicine physicians), which guides referral to a PFD specialist (eg, pelvic floor/women's health physiotherapist, gynaecologist, urogynaecologist, urologist).Between February and April 2022, an international two-round modified Delphi study was conducted to assess expert opinion on which symptoms, risk factors and clinical and sports-related characteristics (items) should be included in a screening tool. We defined consensus a priori as >67% response agreement to pass each round.41 and 34 experts participated in rounds 1 and 2, respectively. Overall, seven general statements were endorsed as relevant by most participants highlighting the importance of screening for PFD in female athletes. Through consensus, the panel developed the Pelvic Floor Dysfunction-ScrEeNing Tool IN fEmale athLetes (PFD-SENTINEL) and agreed to a cluster of PFD symptoms (n=5) and items (risk factors, clinical and sports-related characteristics; n=28) that should prompt specialist care. A clinical algorithm was also created: a direct referral is recommended when at least one symptom or 14 items are reported. If these thresholds are not reached, continuous monitoring of the athlete's health is indicated.Despite increasing awareness and clinical relevance, barriers to identify PFD in female athletes are still present. The PFD-SENTINEL is a new resource for sports medicine clinicians who regularly assess female athletes and represents the first step towards early PFD identification and management. Further studies to validate the tool are needed.

A Targeted Epigenetic Clock for the Prediction of Biological Age.

Epigenetic clocks were initially developed to track chronological age, but accumulating evidence indicates that they can also predict biological age. They are usually based on the analysis of DNA methylation by genome-wide methods, but targeted approaches, based on the assessment of a small number of CpG sites, are advisable in several settings. In this study, we developed a targeted epigenetic clock purposely optimized for the measurement of biological age. The clock includes six genomic regions mapping in ELOVL2, NHLRC1, AIM2, EDARADD, SIRT7 and TFAP2E genes, selected from a re-analysis of existing microarray data, whose DNA methylation is measured by EpiTYPER assay. In healthy subjects (n = 278), epigenetic age calculated using the targeted clock was highly correlated with chronological age (Spearman correlation = 0.89). Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of increased (persons with Down syndrome, n = 62) and decreased (centenarians, n = 106; centenarians' offspring, n = 143; nutritional intervention in elderly, n = 233) biological age, respectively. These results support the potential of our targeted epigenetic clock as a new marker of biological age and open its evaluation in large cohorts to further promote the assessment of biological age in healthcare practice.

Adherence to the PRISMA statement and its association with risk of bias in systematic reviews published in rehabilitation journals: A meta-research study.

BACKGROUND: Systematic reviews (SRs) and meta-analyses are essential resources for the clinicians. They allow to evaluate the strengths and the weaknesses of the evidence to support clinical decision-making if they are adequately reported. Little is known in the rehabilitation field about the completeness of reporting of SRs and its relationship with the risk of bias (ROB). OBJECTIVES: Primary: 1) To evaluate the completeness of reporting of systematic reviews (SRs) published in rehabilitation journals by evaluating their adherence to the PRISMA 2009 checklist, 2) To investigate the relationship between ROB and completeness of reporting. Secondary: To study the association between completeness of reporting and journals and study characteristics. METHODS: A random sample of 200 SRs published between 2011 and 2020 in 68 rehabilitation journals was indexed under the "rehabilitation" category in the InCites database. Two independent reviewers evaluated adherence to the PRISMA checklist and assessed ROB using the ROBIS tool. Overall adherence and adherence to each PRISMA item and section were calculated. Regression analyses investigated the association between completeness of reporting, ROB, and other characteristics (impact factor, publication options, publication year, and study protocol registration). RESULTS: The mean overall PRISMA adherence across the 200 studies considered was 61.4%. Regression analyses show that having a high overall ROB is a significant predictor of lower adherence (B=-7.1%; 95%CI -12.1, -2.0). Studies published in fourth quartile journals displayed a lower overall adherence (B= -7.2%; 95%CI -13.2, -1.3) than those published in first quartile journals; the overall adherence increased (B= 11.9%; 95%CI 5.9, 18.0) if the SR protocol was registered. No association between adherence, publication options, and publication year was found. CONCLUSION: Reporting completeness in rehabilitation SRs is suboptimal and is associated with ROB, impact factor, and study registration. Authors of SRs should improve adherence to the PRISMA guideline, and journal editors should implement strategies to optimize the completeness of reporting.

DNA Methylation Analysis of Ribosomal DNA in Adults With Down Syndrome.

Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21, and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far. In this study, we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls. We further evaluated the expression of the precursor of ribosomal RNAs (RNA45S) in peripheral blood mononuclear cells (PBMCs) from the same subjects. We found that the rDNA promoter tends to be hypermethylated in DS concerning the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) showed a significantly lower intra-individual diversity in the DS group, which at the same time was characterized by a higher interindividual variability. Finally, we showed that RNA45S expression is lower in adults with DS. Collectively, our results suggest a rearrangement of the epigenetic profile of rDNA in DS, possibly to compensate for the extranumerary rDNA copies. Future studies should assess whether the regulation of ribosome biogenesis can contribute to the pathogenesis of DS and explain the clinical heterogeneity characteristic of the syndrome.

Completeness of Reporting Is Suboptimal in Randomized Controlled Trials Published in Rehabilitation Journals, With Trials With Low Risk of Bias Displaying Better Reporting: A Meta-research Study.

OBJECTIVE: Primary: To evaluate the completeness of reporting of randomized controlled trials (RCTs) published in rehabilitation journals through the evaluation of the adherence to the Consolidated Standards of Reporting Trials (CONSORT) checklist and investigate the relationship between reporting and risk of bias (ROB). Secondary: To study the association between completeness of reporting and the characteristics of studies and journals. DATA SOURCES: A random sample of 200 RCTs published between 2011 and 2020 in 68 rehabilitation journals indexed under the "rehabilitation" category in the InCites Journal Citation Report. STUDY SELECTION: One reviewer evaluated the completeness of reporting operationalized as the adherence to the CONSORT checklist. Two independent reviewers evaluated the ROB using the Cochrane risk-of-bias 2.0 tool. DATA EXTRACTION: Overall adherence and adherence to each CONSORT section were calculated. Regression analyses investigated the association between completeness of reporting, ROB, and other characteristics (quartile range, publication modalities, study protocol registration). DATA SYNTHESIS: The mean overall CONSORT adherence across studies was 65%. Studies with high ROB have less adherence than those with low ROB (-5.5%; CI, -10.9 to 0.0). There was a 10.2% (% CI, 6.2-14.3) increase in adherence if the RCT protocol was registered. Studies published in first quartile journals displayed an overall adherence of 11.7% (% CI 17.1-6.4) higher than those published in the fourth quartile. CONCLUSIONS: Reporting completeness is still suboptimal and is associated with ROB, journal impact ranking, and registration of the study protocol. Trial authors should improve adherence to the CONSORT guideline, and journal editors should adopt new strategies to improve the reporting.