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.

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.

Expression pattern of perilipins in human brain during aging and in Alzheimer's disease.

AIMS: Perilipins are conserved proteins that decorate intracellular lipid droplets and are essential for lipid metabolism. To date, there is limited knowledge on their expression in human brain or their involvement in brain aging and neurodegeneration. The aim of this study was to characterise the expression levels of perilipins (Plin1-Plin5) in different cerebral areas from subjects of different age, with or without signs of neurodegeneration. METHODS: We performed real-time RT-PCR, western blotting, immunohistochemistry and confocal microscopy analyses in autoptic brain samples of frontal and temporal cortex, cerebellum and hippocampus from subjects ranging from 33 to 104 years of age, with or without histological signs of neurodegeneration. To test the possible relationship between Plins and inflammation, correlation analysis with IL-6 expression was also performed. RESULTS: Plin2, Plin3 and Plin5, but not Plin1 and Plin4, are expressed in the considered brain areas with different intensities. Plin2 appears to be expressed more in grey matter, particularly in neurons in all the areas analysed, whereas Plin3 and Plin5 appear to be expressed more in white matter. Plin3 seems to be expressed more in astrocytes. Only Plin2 expression is higher in old subjects and patients with early tauopathy or Alzheimer's disease and is associated with IL-6 expression. CONCLUSIONS: Perilipins are expressed in human brain but only Plin2 appears to be modulated with age and neurodegeneration and linked to an inflammatory state. We propose that the accumulation of lipid droplets decorated with Plin2 occurs during brain aging and that this accumulation may be an early marker and initial step of inflammation and neurodegeneration.

What is known from the existing literature about the available interventions for pelvic floor dysfunction among female athletes? A scoping review.

BACKGROUND: Female athletes may be at higher risk of developing pelvic floor dysfunction (PFD). However, despite the great number of epidemiologic studies, the interventions have not been standardized. AIM: The present scoping review aimed to map and summarize the literature to identify the available interventions for PFD among female athletes. METHODS: Seven databases were searched up to May 2021. Studies considering female athletes practising sports at any performance level with any type of PFD were eligible for inclusion. Any clinical intervention and any context were considered. No language, study design, and publication type restrictions were applied. Additional studies were identified through gray literature and the reference lists of articles included. The results were presented numerically and thematically. RESULTS: From 2625 initial records, 35 studies met inclusion criteria. The majority of articles were narrative reviews, considering athletes with urinary incontinence practising multiple or high-impact sports. Authors discussed a wide range of interventions: preventive (n = 8); conservative (n = 35), pharmacological (n = 12), and surgical (n = 10). In particular, the Pelvic Floor Muscle Training was considered in 30 studies. CONCLUSIONS: This is the first scoping review to provide a comprehensive overview of the topic. Besides the great number of available interventions, specific programs and randomized controlled clinical trials for female athletes are still limited. Findings highlighted evident gaps in the primary research confirming that the current management is based on expert opinion. This review may be useful for the overall management, and it may represent a starting point for future research.

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.

Sport and pelvic floor dysfunction in male and female athletes: A scoping review.

AIMS: The aims of the present scoping review were to systematically map and summarize findings to identify any study that reported epidemiological data on pelvic floor dysfunction (PFD) among male and female athletes. METHODS: Six medical databases were searched up to March 2020. No language, study design, and publication type restrictions were applied. Additional studies were identified through gray literature and the reference lists of articles were screened. The results were presented numerically and thematically. RESULTS: A total of 4358 records were identified with an initial search. A hundred studies met the criteria for inclusion. The number of studies published annually increased over the years. Cross-sectional studies (n = 62), urinary incontinence (n = 64), multiple sports (n = 58), and female athletes (n = 83) are the most investigated study design, condition, sport, and population, respectively. Only 12 studies explored PFD in the male population. Authors focused selectively on elite athletes in 21 studies. CONCLUSIONS: This is the first scoping review to provide a comprehensive overview of the topic. The major gaps in the literature include studies focused on male participants, other PFD (e.g., anal incontinence, pelvic organ prolapse, and pelvic pain), with appropriate study design. This review may be useful to raise awareness of the issue among clinicians and stakeholders in sport and it may represent a starting point for future research.

Completeness of exercise reporting among randomized controlled trials on pelvic floor muscle training for women with pelvic organ prolapse: A systematic review.

AIMS: This systematic review aimed to assess the completeness of exercise reporting in randomized controlled trials (RCTs) on pelvic floor muscle training (PFMT) for women with pelvic organ prolapse (POP). METHODS: MEDLINE, Cochrane Central, CINHAL, Embase, SCOPUS, and PEDro databases were searched up to October 2020. Full-text RCTs comparing PFMT to any type of intervention among women with any type and stage of POP were eligible for inclusion. Completeness of intervention was evaluated with t20he template for intervention description and replication (TIDieR) and the consensus on exercise reporting template (CERT). Inter-rater agreement for each item of the tools was calculated. RESULTS: Twenty-six RCTs were included. None of the studies completely reported all intervention descriptors. On average 57.1% (6.8 ± 2.4; out of 12) of the overall TIDieR items and 35.3% (6.7 ± 2.9; out of 19) of the CERT were well described. In particular, 7 and 5 items were completely reported more than 50% of the time for the TIDieR and CERT, respectively. Frequent shortcomings were the undetailed reporting of information regarding tailoring and modifications of exercises and their adherence. Detailed descriptions of exercise repetitions to enable replication were missing in 53.8%. According to the CERT, only 11.5% of the RCTs sufficiently described the main providers' characteristics. CONCLUSION: The completeness of PFMT reporting for women with POP is still below desirable standards and it is insufficient to ensure transferability into practice. The present results may add relevant knowledge and contribute to improving adequate reporting of exercise.

Italian physiotherapists' knowledge of and adherence to osteoarthritis clinical practice guidelines: a cross-sectional study.

INTRODUCTION: Implementation of clinical practice guidelines (CPGs) to manage musculoskeletal conditions among physiotherapists appears suboptimal. Osteoarthritis is one of the most disabling conditions worldwide and several studies showed a lack of knowledge of and adherence to osteoarthritis CPGs in physiotherapists' clinical practice. However, those studies are not conclusive, as they examine the knowledge of and adherence to CPGs only in isolation, or only by focussing on a single treatment. Thus, analysis of the knowledge of and adherence to CPGs in the same sample would allow for a better understanding of the evidence-to-practice gap, which, if unaddressed, can lead to suboptimal care for these patients. This study aims at assessing Italian physiotherapists' evidence-to-practice gap in osteoarthritis CPGs. METHODS: An online survey divided into two sections investigating knowledge of and adherence to CPGs was developed based on three high-quality, recent and relevant CPGs. In the first section, participants had to express their agreement with 24 CPG statements through a 1 (completely disagree) to 5 (completely agree) scale. We defined a ≥ 70% agreement with a statement as consensus. In the second section, participants were shown a clinical case, with different interventions to choose from. Participants were classified as 'Delivering' (all recommended interventions selected), 'Partially Delivering' (some recommended interventions missing) and 'Non-Delivering' (at least one non-recommended interventions selected) the recommended intervention, depending on chosen interventions. RESULTS: 822 physiotherapists (mean age (SD): 35.8 (13.3); female 47%) completed the survey between June and July 2020. In the first section, consensus was achieved for 13/24 statements. In the second section, 25% of the participants were classified as 'Delivering', 22% as 'Partially Delivering' and 53% as 'Non-Delivering'. CONCLUSIONS: Our findings revealed an adequate level of knowledge of osteoarthritis CPGs regarding the importance of exercise and education. However, an adequate level of adherence has yet to be reached, since many physiotherapists did not advise weight reduction, but rest from physical activity, and often included secondary treatments (e.g. manual therapy) supported by low-level evidence. These results identify an evidence-to-practice gap, which may lead to non-evidence based practice behaviours for the management of patients with osteoarthritis.

Recovery from 6-month spaceflight at the International Space Station: muscle-related stress into a proinflammatory setting.

The Sarcolab pilot study of 2 crewmembers, investigated before and after a 6-mo International Space Station mission, has demonstrated the substantial muscle wasting and weakness, along with disruption of muscle's oxidative metabolism. The present work aimed at evaluating the pro/anti-inflammatory status in the same 2 crewmembers (A, B). Blood circulating (c-)microRNAs (miRs), c-proteasome, c-mitochondrial DNA, and cytokines were assessed by real-time quantitative PCR or ELISA tests. Time series analysis was performed ( i.e., before flight and after landing) at 1 and 15 d of recovery (R+1 and R+15, respectively). C-biomarkers were compared with an age-matched control population and with 2-dimensional proteomic analysis of the 2 crewmembers' muscle biopsies. Striking differences were observed between the 2 crewmembers at R+1, in terms of inflamma-miRs (c-miRs-21-5p, -126-3p, and -146a-5p), muscle specific (myo)-miR-206, c-proteasome, and IL-6/leptin, thus making the 2 astronauts dissimilar to each other. Final recovery levels of c-proteasome, c-inflamma-miRs, and c-myo-miR-206 were not reverted to the baseline values in crewmember A. In both crewmembers, myo-miR-206 changed significantly after recovery. Muscle biopsy of astronaut A showed an impressive 80% increase of α-1-antitrypsin, a target of miR-126-3p. These results point to a strong stress response induced by spaceflight involving muscle tissue and the proinflammatory setting, where inflamma-miRs and myo-miR-206 mediate the systemic recovery phase after landing.-Capri, M., Morsiani, C., Santoro, A., Moriggi, M., Conte, M., Martucci, M., Bellavista, E., Fabbri, C., Giampieri, E., Albracht, K., Flück, M., Ruoss, S., Brocca, L., Canepari, M., Longa, E., Di Giulio, I., Bottinelli, R., Cerretelli, P., Salvioli, S., Gelfi, C., Franceschi, C., Narici, M., Rittweger, J. Recovery from 6-month spaceflight at the International Space Station: muscle-related stress into a proinflammatory setting.

Down Syndrome, Ageing and Epigenetics.

During the past decades, life expectancy of subjects with Down syndrome (DS) has greatly improved, but age-specific mortality rates are still important and DS subjects are characterized by an acceleration of the ageing process, which affects particularly the immune and central nervous systems. In this chapter, we will first review the characteristics of the ageing phenomenon in brain and in immune system in DS and we will then discuss the biological hallmarks of ageing in this specific population. Finally, we will also consider in detail the knowledge on epigenetics in DS, particularly DNA methylation.

Lamins are rapamycin targets that impact human longevity: a study in centenarians.

The dynamic organisation of the cell nucleus is profoundly modified during growth, development and senescence as a result of changes in chromatin arrangement and gene transcription. A plethora of data suggests that the nuclear lamina is a key player in chromatin dynamics and argues in favour of a major involvement of prelamin A in fundamental mechanisms regulating cellular senescence and organism ageing. As the best model to analyse the role of prelamin A in normal ageing, we used cells from centenarian subjects. We show that prelamin A is accumulated in fibroblasts from centenarians owing to downregulation of its specific endoprotease ZMPSTE24, whereas other nuclear envelope constituents are mostly unaffected and cells do not enter senescence. Accumulation of prelamin A in nuclei of cells from centenarians elicits loss of heterochromatin, as well as recruitment of the inactive form of 53BP1, associated with rapid response to oxidative stress. These effects, including the prelamin-A-mediated increase of nuclear 53BP1, can be reproduced by rapamycin treatment of cells from younger individuals. These data identify prelamin A and 53BP1 as new targets of rapamycin that are associated with human longevity. We propose that the reported mechanisms safeguard healthy ageing in humans through adaptation of the nuclear environment to stress stimuli.

Quantification of mitochondrial reactive oxygen species in living cells by using multi-laser polychromatic flow cytometry.

Reactive oxygen species (ROS) are constantly produced in cells, mainly by mitochondria, as a consequence of aerobic respiration. Most ROS derive from superoxide, which is rapidly converted to hydrogen peroxide. ROS are involved in the regulation of several physiological and pathological processes, and the possibility to measure them simultaneously is needed, when the redox status of the cells is modified by experimental/biological conditions. Flow cytometry is the main technology that generates multiple information at the single cell level in a high-throughput manner, and gives rapid and quantitative measurements of different ROS with high sensitivity and reproducibility. Here, we describe a novel approach to detect simultaneously mitochondrial hydrogen peroxide and mitochondrial superoxide in living cells. The staining has been performed by using the fluorescent dyes MitoSOX Red Mitochondrial Superoxide Indicator, Mitochondria Peroxy Yellow 1, Annexin-V Pacific Blue conjugate, TO-PRO-3 iodide, anti-CD4-APC-Cy7 and -CD8-Pacific Orange mAbs. We used this approach to quantify mitochondrial ROS in CD4+ and CD8+ T cells form patients affected by Down syndrome and age- and sex-matched healthy donors. © 2016 International Society for Advancement of Cytometry.

Plasma N-Glycome Signature of Down Syndrome.

In recent years, plasma N-glycans have emerged as biomarkers for health and disease. Here, we studied N-glycomic changes in Down Syndrome (DS). Because of the progeroid phenotype of DS, we focused on the dissection of syndrome- and aging-associated glycomic changes, as well as the interaction thereof. We analyzed the plasma N-glycome of 76 DS persons, 37 siblings (DSS), and 42 mothers (DSM) of DS persons by DNA-sequencer-aided, fluorophore-assisted-carbohydrate-electrophoresis, as well as by matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS). The results showed an overall decrease of galactosylation and α2,3 sialylation, a concomitant increase of the level of fucosylated N-glycans as well as of monogalactosylated diantennary N-glycans in DS, while the GlycoAgeTest and the ratio of the two core-fucosylated, monogalactosylated diantennary isomers (galactose positioned on α1,6 arm versus α1,3 arm) were the strongest DS discriminators. Hypogalactosylation is a characteristic of both DS and aging of control individuals. A decrease in α2,3-sialylated species is also common to DS and aging of controls. However, regarding to α2,6-sialylated tri- and tetragalactosylated N-glycan species, we found those to be lowered in DS but showed an increase with age in the same persons, while these glycans were not affected by aging in control individuals. In conclusion, we identified specific glycomic changes associated with DS, aging in DS, as well as aging in controls, identifying glycomic features in line with accelerated aging in DS. Notably, our data demonstrate an aging phenotype in DS which only in part overlaps with aging in controls but reveals DS-specificity.

Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for "inflamm-aging".

Mitochondrial components, including mitochondrial DNA (mtDNA), when released extracellularly, can act as "damage-associated molecular pattern" (DAMP) agents and cause inflammation. As many elderly people are characterized by a low-grade, chronic inflammatory status defined "inflamm-aging," we evaluated if circulating mtDNA can contribute to this phenomenon. Eight hundred and thirty-one Caucasian subjects were enrolled in the study, including 429 siblings aged 90-104 (90+ siblings). mtDNA plasma levels increased gradually after the fifth decade of life. In 90+ subjects, mtDNA values of two members of the same sibling relationship were directly correlated, suggesting a role for familiar/genetic background in controlling the levels of circulating mtDNA. The subjects with the highest mtDNA plasma levels had the highest amounts of TNF-α, IL-6, RANTES, and IL-1ra; the subjects with the lowest mtDNA levels had the lowest levels of the same cytokines. In vitro stimulation of monocytes with mtDNA concentrations similar to the highest levels observed in vivo resulted in an increased production of TNF-α, suggesting that mtDNA can modulate the production of proinflammatory cytokines. Our findings therefore show that circulating mtDNA increases with age, and can significantly contribute to the maintenance of the low-grade, chronic inflammation observed in elderly people.

αvß6- and αvß8-integrins serve as interchangeable receptors for HSV gH/gL to promote endocytosis and activation of membrane fusion.

Herpes simplex virus (HSV)--and herpesviruses in general--encode for a multipartite entry/fusion apparatus. In HSV it consists of the HSV-specific glycoprotein D (gD), and three additional glycoproteins, gH/gL and gB, conserved across the Herpesviridae family and responsible for the execution of fusion. According to the current model, upon receptor binding, gD propagates the activation to gH/gL and to gB in a cascade fashion. Questions remain about how the cascade of activation is controlled and how it is synchronized with virion endocytosis, to avoid premature activation and exhaustion of the glycoproteins. We considered the possibility that such control might be carried out by as yet unknown receptors. Indeed, receptors for HSV gB, but not for gH/gL, have been described. In other members of the Herpesviridae family, such as Epstein-Barr virus, integrin receptors bind gH/gL and trigger conformational changes in the glycoproteins. We report that αvß6- and αvß8-integrins serve as receptors for HSV entry into experimental models of keratinocytes and other epithelial and neuronal cells. Evidence rests on loss of function experiments, in which integrins were blocked by antibodies or silenced, and gain of function experiments in which αvß6-integrin was expressed in integrin-negative cells. αvß6- and αvß8-integrins acted independently and are thus interchangeable. Both bind gH/gL with high affinity. The interaction profoundly affects the route of HSV entry and directs the virus to acidic endosomes. In the case of αvß8, but not αvß6-integrin, the portal of entry is located at lipid microdomains and requires dynamin 2. Thus, a major role of αvß6- or αvß8-integrin in HSV infection appears to be to function as gH/gL receptors and to promote virus endocytosis. We propose that placing the gH/gL activation under the integrin trigger point enables HSV to synchronize virion endocytosis with the cascade of glycoprotein activation that culminates in execution of fusion.

Differential expression of perilipin 2 and 5 in human skeletal muscle during aging and their association with atrophy-related genes.

Sarcopenia, the progressive loss of muscle mass and strength, is a phenomenon characterizing human aging whose etiology is still not clear. While there is increasing evidence for the influence of inter-muscular adipose tissue infiltration in the development of sarcopenia, much less is known about a possible role for intra-muscular triglycerides (IMTG). IMTG accumulate in form of lipid droplets decorated by proteins such as Perilipins (Plins). In skeletal muscle the most abundant are Plin2 and Plin5. In this study we compared the expression of these two Plins in Vastus lateralis muscle samples of subjects of different age, both healthy donors (HD) and patients with limited lower limb mobility (LLMI). These latter are characterized by a condition of chronic physical inactivity. Plin2 expression resulted higher in old age for both HD and LLMI patients, while Plin5 slightly decreased only in LLMI patients. Moreover, in these patients, only Plin2 was associated with the decrease of muscle strength and the expression of factors related to muscle atrophy (MuRF1, Atrogin and p53). An increase in Plin2 and a concomitant decrease of Plin5 was also observed when we considered animal model of disuse-induced muscle atrophy. As a whole, these data indicate that Plin2 and Plin5 have a different expression pattern during muscle aging and inactivity, and only Plin2 appears to be associated with functional alterations of the muscle.

The nucleolar size is associated to the methylation status of ribosomal DNA in breast carcinomas.

BACKGROUND: There is a body of evidence that shows a link between tumorigenesis and ribosome biogenesis. The precursor of mature 18S, 28S and 5.8S ribosomal RNAs is transcribed from the ribosomal DNA gene (rDNA), which exists as 300-400 copies in the human diploid genome. Approximately one half of these copies are epigenetically silenced, but the exact role of epigenetic regulation on ribosome biogenesis is not completely understood. In this study we analyzed the methylation profiles of the rDNA promoter and of the 5' regions of 18S and 28S in breast cancer. METHODS: We analyzed rDNA methylation in 68 breast cancer tissues of which the normal counterpart was partially available (45/68 samples) using the MassARRAY EpiTYPER assay, a sensitive and quantitative method with single base resolution. RESULTS: We found that rDNA locus tended to be hypermethylated in tumor compared to matched normal breast tissues and that the DNA methylation level of several CpG units within the rDNA locus was associated to nuclear grade and to nucleolar size of tumor tissues. In addition we identified a subgroup of samples in which large nucleoli were associated with very limited or absent rDNA hypermethylation in tumor respect to matched normal tissue. CONCLUSIONS: In conclusion, we suggest that rDNA is an important target of epigenetic regulation in breast tumors and that rDNA methylation level is associated to nucleolar size.

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.