10-Item Physical Function Scale (PF-10) as a Sarcopenia Screening Tool for Patients on Hemodialysis.

OBJECTIVE: Screening tools for the assessment of sarcopenia in clinical practice are greatly needed. Routinely, some dialysis centers assess quality of life through the 36-Item Short Form Survey (SF-36), which include 10 questions about physical function. Thus, we investigated the accuracy of the 10-Item Physical Function scale (PF-10) to identify sarcopenia among patients on hemodialysis. METHODS: A cross-sectional, multicenter study that included adult patients on hemodialysis. The revised European Working Group on Sarcopenia in Older People was used to diagnose sarcopenia. The 10 questions about daily activities from the SF-36 questionnaire were used to appoint the PF-10, where the final score could range from 10 to 30, and the lower the worse the physical function. The PF-10 accuracy to identify confirmed sarcopenia (low muscle strength + low muscle mass) was assessed through a receiver operating characteristic (ROC) curve and the cut-off was calculated using the Youden index. RESULTS: One hundred and eighty-five patients were included (median age, 59 years; 45% female). Prevalence of confirmed sarcopenia was 31.4%. The median PF-10 score was 23 (interquartile range: 10-30) and a significant association with all sarcopenia measurements was found (all P < 0.05). The best cut-off calculated from the ROC curve was ≤ 26 points (area under the curve = 0.69, 95% confidence interval 0.61-0.77) with sensitivity and specificity of 96.6% and 71.0%, respectively. Moreover, patients with ≤ 26 points (n=133, 72%) had a higher prevalence of low muscle strength by handgrip (53 vs. 19%; P<0.001) and five-time sit-to-stand (41 vs. 10%; P<0.001), low gait speed (44 vs. 19%; P=0.002), confirmed sarcopenia (39 vs. 11%; P<0.001), and severe sarcopenia (26 vs. 4%; P=0.001), but not low muscle mass (49 vs. 35%; P=0.08), in comparison with those > 26 points (n=52, 28%). CONCLUSION: The 10-Item Physical Function Scale (PF-10) may be a useful physical dysfunction and sarcopenia screening tool in patients on hemodialysis. A PF-10 threshold of around 26 points appeared to display the fairest accuracy for diagnosing sarcopenia.

Design and methodology of the SARCopenia trajectories and associations with adverse clinical outcomes in patients on HemoDialysis: the SARC-HD study.

BACKGROUND: Sarcopenia has been associated with adverse outcomes in patients with chronic kidney disease (CKD), particularly in those undergoing hemodialysis (HD). However, the trajectories across sarcopenia stages, their determinants, and associations with adverse clinical outcomes have yet to be comprehensively examined. METHODS: The SARC-HD is a multicenter, observational prospective cohort study designed to comprehensively investigate sarcopenia in patients on HD. Eligibility criteria include adult patients undergoing HD for ≥ 3 months. The primary objective is to investigate the trajectories of sarcopenia stages and their potential determinants. Secondary objectives include evaluating the association between sarcopenia and adverse clinical outcomes (i.e., falls, hospitalization, and mortality). Sarcopenia risk will be assessed by the SARC-F and SARC-CalF questionnaire. Sarcopenia traits (i.e., low muscle strength, low muscle mass, and low physical performance) will be defined according to the revised European Working Group on Sarcopenia in Older People and will be assessed at baseline and after 12 follow-up months. Patients will be followed-up at 3 monthly intervals for adverse clinical outcomes during 24 months. DISCUSSION: Collectively, we expect to provide relevant clinical findings for healthcare professionals from nephrology on the association between sarcopenia screening tools (i.e., SARC-F and SARC-CalF) with objective sarcopenia measurements, as well as to investigate predictors of trajectories across sarcopenia stages, and the impact of sarcopenia on adverse clinical outcomes. Hence, our ambition is that the data acquired from SARC-HD study will provide novel and valuable evidence to support an adequate screening and management of sarcopenia in patients on HD.

Effects of Exercise on Inflammatory Markers in Individuals with Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Individuals with chronic kidney disease (CKD) have a systemic inflammatory state. We assessed the effects of exercise on inflammatory markers in individuals with CKD. An electronic search was conducted, including MEDLINE. Experimental clinical trials that investigated the effects of exercise on inflammatory markers in individuals with CKD at all stages were included. Meta-analyses were conducted using the random-effects model and standard mean difference (SMD). Subgroup analyses were performed for resistance, aerobic, and combined exercise interventions. Twenty-nine studies were included in the meta-analyses. Exercise interventions showed significant reductions in C-reactive protein (CRP) (SMD: -0.23; 95% CI: -0.39 to -0.06), interleukin (IL)-6 (SMD: -0.35; 95% CI: -0.57, -0.14), and tumor necrosis factor-alpha (TNF-α) (SMD: -0.63, 95% CI: -1.01, -0.25) when compared with the controls. IL-10 levels significantly increased (SMD: 0.66, 95% CI: 0.09, 1.23) with exercise interventions. Resistance interventions significantly decreased CRP (SMD: -0.39, 95% CI: -0.69, -0.09) and TNF-α (SMD: -0.72, 95% CI: -1.20, -0.23) levels, while increasing IL-10 levels (SMD: 0.57, 95% CI: 0.04, 1.09). Aerobic interventions only significantly reduced IL-6 levels (SMD: -0.26, 95% CI: -0.51, -0.01). No significant changes in any inflammatory markers were observed with combined exercise interventions. Exercise interventions are effective as an anti-inflammatory therapy in individuals with CKD compared to usual care control groups. Resistance interventions seem to promote greater anti-inflammatory effects.

Intradialytic resistance training for short daily hemodialysis patients as part of the clinical routine: a quasi-experimental study.

Background and purpose: Hemodialysis patients have chronic systemic inflammation, musculoskeletal impairments, and body composition changes from several factors and exercise may attenuate. We evaluated the effects of an intradialytic resistance training program on body composition, physical function, and inflammatory markers in patients under short daily hemodialysis treatment. Materials and methods: A quasi-experimental study in clinical routine was conducted over eight months. Measures of physical function (handgrip strength, five-time sit-to-stand, timed-up and go, and gait speed), body composition (by bioelectrical impedance), and inflammatory markers (interleukin [IL]-1 beta, IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor-α) were assessed at baseline as well as at four and eight months past continued intervention. Patients underwent two intradialytic resistance training sessions per week supervised by exercise professionals. Results: A total of 18 patients (62 ± 14 years; 55.6% ≥ 60 years; 44% female) were included. Significant increases in body mass index and basal metabolic rate were found at four and eight months compared to baseline. For physical function, timed-up and go performance improved at four and eight months compared to baseline. The other body composition and physical function measures, as well as all inflammatory markers, did not significantly change over time. Conclusion: A supervised intradialytic resistance training program for patients on short daily hemodialysis treatment, as part of the clinical routine, may induce modest changes in body mass index, basal metabolic rate, and timed-up and go performance.

Implementing a resistance training programme for patients on short daily haemodialysis: A feasibility study.

BACKGROUND: Kidney failure patients receiving haemodialysis experience protein-energy wasting, muscle mass loss and physical function impairment. Intradialytic exercise interventions seem to modify these features, but they are often not implemented as a clinical routine. OBJECTIVE: To investigate the feasibility of implementing a supervised intradialytic resistance training programme as a clinical routine for patients receiving short daily haemodialysis. DESIGN: A prospective longitudinal study. PARTICIPANTS: Eighteen patients in a supervised intradialytic resistance training programme for 8 months. MEASUREMENTS: It consisted of a warm-up, lower- and upper-limb resistance exercises and a cool-down. Patients performed the resistance training during the first half of haemodialysis, twice a week, supervised by exercise physiologists and physiotherapists. The feasibility was assessed by the total and partial adherences, the reasons for refusing or for not exercising and the intradialytic complications. RESULTS: From a total of 953 potential exercise sessions, 759 were performed, with a 79.6% adherence rate. In the first 9 weeks, the adherence rate was 86.6% and the lowest rate was in the 19-27 weeks (73.5%). The main intradialytic complication during exercise sessions was hypotension (n = 31; 4.1%). The highest number of complications was reported during the first 9 weeks (n = 27; 9.1%). The main reasons for refusing or for not performing the intradialytic exercise sessions were clinical complications previous to exercise time (n = 63; 32.5%) and self-reported indisposition (n = 62; 32.0%). CONCLUSIONS: The intradialytic resistance training programme, supervised by exercise physiologists and physiotherapists, had very low complications, achieved a high long-term adherence rate and showed to be feasible as a clinical routine for patients receiving short daily haemodialysis.

Thromboelastometry demonstrates endogenous coagulation activation in nonsevere and severe COVID-19 patients and has applicability as a decision algorithm for intervention.

In patients with severe forms of COVID-19, thromboelastometry has been reported to display a hypercoagulant pattern. However, an algorithm to differentiate severe COVID-19 patients from nonsevere patients and healthy controls based on thromboelastometry parameters has not been developed. Forty-one patients over 18 years of age with positive qRT-PCR for SARS-CoV-2 were classified according to the severity of the disease: nonsevere (NS, n = 20) or severe (S, n = 21). A healthy control (HC, n = 9) group was also examined. Blood samples from all participants were tested by extrinsic (EXTEM), intrinsic (INTEM), non-activated (NATEM) and functional assessment of fibrinogen (FIBTEM) assays of thromboelastometry. The thrombodynamic potential index (TPI) was also calculated. Severe COVID-19 patients exhibited a thromboelastometry profile with clear hypercoagulability, which was significantly different from the NS and HC groups. Nonsevere COVID-19 cases showed a trend to thrombotic pole. The NATEM test suggested that nonsevere and severe COVID-19 patients presented endogenous coagulation activation (reduced clotting time and clot formation time). TPI data were significantly different between the NS and S groups. The maximum clot firmness profile obtained by FIBTEM showed moderate/elevated accuracy to differentiate severe patients from NS and HC. A decision tree algorithm based on the FIBTEM-MCF profile was proposed to differentiate S from HC and NS. Thromboelastometric parameters are a useful tool to differentiate the coagulation profile of nonsevere and severe COVID-19 patients for therapeutic intervention purposes.

The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial.

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

Serum levels of interleukin-2 differ between prostate cancer and benign prostatic hyperplasia / Níveis séricos de interleucina-2 diferem entre câncer de próstata e hiperplasia benigna da próstata

ABSTRACT Objective Investigation onthe systemic inflammatory profile ofpatients affected by prostate cancer (PCa) or prostatic hyperplasia (BPH) may contribute to characterize the pathological profile as well as enable identification of markers and promote alternatives for appropriate, less invasive treatments. Methods This research compared serum levels of 10 classic inflammatory mediators among patients aged 50 years or older affected by PCa or BPH. For this, clinical, biochemical, metabolic, anthropometric and inflammatory aspects of each patient was considered. Results From the statistical analysis, a weakpositive correlation (r = 0.16) between IL-2 with serum total PSA values was found. In addition, median serum IL-2 values were three times higher in patients with PCa compared to BPH patients. Conclusion By interpretation of current literature, we hypothesize that the activity of infiltratedtype M1 macrophages and activated cytotoxic cells in the neoplasm milieu might explain this increase of IL-2 as part of anendogenous anti-neoplastic response.

RESUMO Objetivo A investigação do perfil inflamatório sistêmico de pacientes acometidos por câncer de próstata (CaP) ou hiperplasia prostática (HPB) pode contribuir para caracterizar o perfil patológico, bem como possibilitar a identificação de marcadores e promover alternativas de tratamentos adequados e menos invasivos. Métodos Esta pesquisa comparou os níveis séricos de 10 mediadores inflamatórios clássicos em pacientes com 50 anos ou mais afetados por CaP ou HPB. Para tanto, foram considerados os aspectos clínicos, bioquímicos, metabólicos, antropométricos e inflamatórios de cada paciente. Resultados A partir da análise estatística, foi encontrada umacorrelação positiva fraca (r = 0,16) entre IL-2 com os valores de PSA total sé o. Além disso, os valores medianos de IL-2 no soro foram três vezes maiores em pacientes com CaP em comparação com pacientes com HPB. Conclusão Pela interpretação da literatura atual, hipotetizamos que a atividade de macrófagos do tipo M1 infiltrados e células citotóxicas ativadas no meio da neoplasia pode explicar esse aumento de IL-2 como parte de uma resposta antineoplásica endógena.

Mapping Salivary Proteases in Sjögren's Syndrome Patients Reveals Overexpression of Dipeptidyl Peptidase-4/CD26.

Sjögren's Syndrome (SS) is an autoimmune exocrinopathy characterized by the progressive damage of salivary and lacrimal glands associated with lymphocytic infiltration. Identifying new non-invasive biomarkers for SS diagnosis remains a challenge, and alterations in saliva composition reported in patients turn this fluid into a source of potential biomarkers. Among these, proteases are promising candidates since they are involved in several key physio-pathological processes. This study evaluated differentially expressed proteases in SS individuals' saliva using synthetic fluorogenic substrates, zymography, ELISA, and proteomic approaches. Here we reported, for the first time, increased activity of the serine protease dipeptidyl peptidase-4/CD26 (DPP4/CD26) in pSS saliva, the expression level of which was corroborated by ELISA assay. Gelatin zymograms showed that metalloproteinase proteolytic band profiles differed significantly in intensity between control and SS groups. Focusing on matrix metalloproteinase-9 (MMP9) expression, an increased tendency in pSS saliva (p = 0.0527) was observed compared to the control group. Samples of control, pSS, and sSS were analyzed by mass spectrometry to reveal a general panorama of proteases in saliva. Forty-eight protein groups of proteases were identified, among which were the serine proteases cathepsin G (CTSG), neutrophil elastase (ELANE), myeloblastin (PRTN3), MMP9 and several protease inhibitors. This work paves the way for proteases to be explored in the future as biomarkers, emphasizing DPP4 by its association in several autoimmune and inflammatory diseases. Besides its proteolytic role, DPP4/CD26 acts as a cell surface receptor, signal transduction mediator, adhesion and costimulatory protein involved in T lymphocytes activation.

Defective Allele of the Neuronal Nitric Oxide Synthase Gene Increases Insulin Resistance During Acute Phase of Myocardial Infarction.

BACKGROUND: Glycemic disorders are strong predictors of mortality in ST-elevation myocardial infarction (STEMI) patients, and disruption in nitric oxide (NO) production is associated with insulin-resistant states. We evaluated whether a defective allele of the neuronal nitric oxide synthase (nNOS) gene (NOS1) might influence insulin response and blood-glucose balance during the acute phase of STEMI and if post-infarction total plasma-NO levels and vasodilation scores varied across nNOS genotypes. METHODS: Consecutive patients with STEMI (n=354) underwent clinical evaluations and genotyping for the promoter variation rs41279104. In-hospital clinical and blood evaluations were performed at admission and five days after STEMI, with glycemic, insulinemic, and disposition indices assessed at the same times. Flow-mediated dilation (FMD) was assessed by reactive hyperemia on the 30th day. RESULTS: Homozygotes for the defective allele (A) showed lower glycemia and insulin sensitivity on day 1 while showing the highest ß-cell function and no changes in the circulating NO pool, which is compatible with hyperresponsive ß cells counteracting the inherent glucose-resistant state of AA patients. At day 5, glycemic scores had shifted to indicate greater insulin sensitivity among A homozygotes, paralleled by a significant yet poor increase in NO bioavailability compared to that among G carriers. All in all, defective homozygotes showed greater insulin resistance at admission that had reversed by 5 days after STEMI. Even so, A carriers developed lower FMD scores compared to G homozygotes after the acute phase. CONCLUSION: A defective nNOS allele (and due decline in NO production) seemed to elicit a hyperinsulinemia response to compensate for an insulin-resistant state during the acute phase of STEMI and to be associated with poor endothelial function after the acute phase.

Zopiclone to treat insomnia in older adults: A systematic review.

Considering the global increase in use of Z-drugs to treat insomnia, the study objective was to conduct a systematic review on the efficacy and safety of zopiclone to treat sleep disorders in older adults compared to other sedative-hypnotics, to placebo or to non-pharmacological interventions. The literature search for original reports - clinical trials, cohort studies and cross-sectional, observational investigations - was done in eleven databases and web search engines followed PRISMA guidelines, and methodological quality was assessed using the Risk of Bias tool in the Cochrane Reviewers' Handbook. The search resulted in 12 randomized, placebo-controlled clinical trials along with 2 open studies and 2 observational reports. Overall, the studies suggest that zopiclone is effective to treat insomnia by reducing sleep latency, nocturnal awakenings and wake time after sleep onset while increasing total sleep time, with probable effects on sleep architecture. Zopiclone was found to be fairly tolerated, to induce a low rate of adverse events with non-severe impact on psychomotor or cognitive performance and to produce no major harm to the overall well-being and daily living abilities. However, the quality of most studies was classified as low or unclear. Though the studies available support benefits from zopiclone use, there is still a need for further evidence on long-term effects, tolerability and safety in the treatment of older adults by means of high-quality trials.

Molecular and Cellular Biomarkers of COVID-19 Prognosis: Protocol for the Prospective Cohort TARGET Study.

BACKGROUND: Since the beginning of the COVID-19 pandemic, the world's attention has been focused on better understanding the relation between the human host and the SARS-CoV-2 virus, as its action has led to hundreds of thousands of deaths. OBJECTIVE: In this context, we decided to study certain consequences of the abundant cytokine release over the innate and adaptive immune systems, inflammation, and hemostasis, comparing mild and severe forms of COVID-19. METHODS: To accomplish these aims, we will analyze demographic characteristics, biochemical tests, immune biomarkers, leukocyte phenotyping, immunoglobulin profile, hormonal release (cortisol and prolactin), gene expression, thromboelastometry, neutralizing antibodies, metabolic profile, and neutrophil function (reactive oxygen species production, neutrophil extracellular trap production, phagocytosis, migration, gene expression, and proteomics). A total of 200 reverse transcription polymerase chain reaction-confirmed patients will be enrolled and divided into two groups: mild/moderate or severe/critical forms of COVID-19. Blood samples will be collected at different times: at inclusion and after 9 and 18 days, with an additional 3-day sample for severe patients. We believe that this information will provide more knowledge for future studies that will provide more robust and useful clinical information that may allow for better decisions at the front lines of health care. RESULTS: The recruitment began in June 2020 and is still in progress. It is expected to continue until February 2021. Data analysis is scheduled to start after all data have been collected. The coagulation study branch is complete and is already in the analysis phase. CONCLUSIONS: This study is original in terms of the different parameters analyzed in the same sample of patients with COVID-19. The project, which is currently in the data collection phase, was approved by the Brazilian Committee of Ethics in Human Research (CAAE 30846920.7.0000.0008). TRIAL REGISTRATION: Brazilian Registry of Clinical Trials RBR-62zdkk; https://ensaiosclinicos.gov.br/rg/RBR-62zdkk. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24211.

Influence of the ACTN3 Genotype and the Exercise Intensity on the Respiratory Exchange Ratio and Excess Oxygen Consumption After Exercise.

ABSTRACT: de L. Corrêa, H, Ribeiro, HS, Maya, ÁTD, Neves, RP, de Moraes, MR, Lima, RM, Nóbrega, OT, and Ferreira, AP. Influence of the ACTN3 genotype and the exercise intensity on the respiratory exchange ratio and excess oxygen consumption after exercise. J Strength Cond Res 35(5): 1380-1388, 2021-This study aimed to assess the respiratory exchange ratio (RER) and excess postexercise oxygen consumption (EPOC) after high-intensity interval training and continuous moderate-intensity aerobic training in accordance with the ACTN3 genotype. A cross-sectional study with 30 physically active individuals who participated in 3 experimental sessions, as follows: a high-intensity interval aerobic exercise, for 3 minutes at 115% anaerobic threshold, with 90 seconds of passive recovery; a continuous moderate-intensity aerobic exercise at 85% anaerobic threshold; and a control session. Respiratory exchange ratio and V̇o2 were obtained through an indirect, calorimetry-based gas analysis method, using a breath-by-breath approach, assessed at baseline, during the trials, and at 1, 2, 3, and 4 hours after exercise. We found that lower postexercise RER values were observed only in subjects with the X allele, in both the high- and the moderate-intensity training protocols. Homozygous RR subjects showed no differences in postexercise RER compared with the scores at the control day. After both sessions of exercise, EPOC levels were higher compared with scores at the control day for 2 hours among X allele carriers, and only in the first hour among RR homozygous. Thus, the RER and EPOC presented different responses after moderate and intense exercise according to the ACTN3 genotype. Moreover, individuals with the X allele of the ACTN3 gene show a higher oxidation of fats in the postexercise period.

Intradialytic isometric handgrip exercise does not cause hemodynamic instability: A randomized, cross-over, pilot study.

Hemodialysis (HD) patients experience hemodynamic instability and intradialytic exercise seems to attenuate it. This study aimed to verify the acute hemodynamic response to different intradialytic handgrip exercise intensities in HD patients. In a randomized, cross-over, experimental pilot study, eight patients completed two experimental sessions and one control in random order: (a) regular HD; (b) low-intensity isometric handgrip exercise; and (c) moderate-intensity isometric handgrip exercise. BP and heart rate variability were recorded immediately before and every 15 minutes. Isometric handgrip exercise protocols, regardless of the intensity, did not lead to significant changes in hemodynamic stability, nor when compared to the control condition (P > .05). The systolic BP and double product significantly increased immediately after the moderate-intensity protocol (122.0 ± 15.9 vs 131.3 ± 19.8, P < .05; 9094.7 ± 1705.7 vs 9783.0 ± 1947.9, P < .05, respectively) but returned to the pre-exercise values 10 minutes later. We conclude that intradialytic isometric handgrip exercise does not induce hemodynamic instability at low and moderate intensities.

Genome-wide profiling and predicted significance of post-mortem brain microRNA in Alzheimer's disease.

BACKGROUND: MicroRNAs (miRNAs) emerged as regulatory elements, with up to 70 % of all miRNAs found in the brain, playing key roles in the onset of Alzheimer's disease (AD). OBJECTIVE: to broadly assess the expression levels of miRNAs in post-mortem brain (PMB) samples of individuals deceased with or without AD. METHODS: A high-throughput microarray platform was used to sketch miRNA samples isolated from superior and middle temporal gyrus of A+T+ AD cases, compared to samples from age- and sex-matched AD-devoid donors, all pulled from the University of São Paulo's Brain Biobank. The miRNAs identified by microarray were subjected to validation with specific qRT-PCR assays employing independent PMB samples. RESULTS: The analyses yielded 6 miRNAs differentially expressed (miR-30e_3p; miR-365b_5p; miR-664_3p; miR-1202; miR-4286; miR-4449), and their interplay with specific AD-related genes and signaling pathways was explored using bioinformatics analyses (including the KEGG package, mirPath v.3). In the end, 3 miRNAs, 7 target genes and 11 pathways were found closely interrelated and implicated with the AD pathophysiology. CONCLUSION: A dysregulation on a subset of these miRNAs appear to affect a range of genes (notably PTEN) and pathways (emphasis to PI3K-AKT) so to provide grounds for neuronal death by apoptotic signaling, autophagy and/or oxidative damage.

The conundrum of human immune system "senescence".

There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as "immunosenescence". But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.

Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework.

At a recent symposium on aging biology, a debate was held as to whether or not we know what biological aging is. Most of the participants were struck not only by the lack of consensus on this core question, but also on many basic tenets of the field. Accordingly, we undertook a systematic survey of our 71 participants on key questions that were raised during the debate and symposium, eliciting 37 responses. The results confirmed the impression from the symposium: there is marked disagreement on the most fundamental questions in the field, and little consensus on anything other than the heterogeneous nature of aging processes. Areas of major disagreement included what participants viewed as the essence of aging, when it begins, whether aging is programmed or not, whether we currently have a good understanding of aging mechanisms, whether aging is or will be quantifiable, whether aging will be treatable, and whether many non-aging species exist. These disagreements lay bare the urgent need for a more unified and cross-disciplinary paradigm in the biology of aging that will clarify both areas of agreement and disagreement, allowing research to proceed more efficiently. We suggest directions to encourage the emergence of such a paradigm.

More than a quarter century of the most prescribed sleeping pill: Systematic review of zolpidem use by older adults.

Zolpidem is widely used to treat insomnia of older adults despite that few randomized controlled studies were conducted in this group. We systematically reviewed the relevant literature on efficacy/effectiveness and safety of zolpidem use by elderly individuals in relevant databases completed with a manual search of key journals. Studies were required to include individuals aged ≥60 years under intervention with zolpidem compared to placebo or other hypnosedatives. Outcomes were either objectively- or subjectively-assessed improvements in specific sleep parameters and safety for clinical use. The 31 reports selected for review were mostly of low-quality. The evidence suggests that zolpidem is useful typically by reducing sleep latency and episodes of wake after sleep onset, and increasing total sleep time and sleep efficiency. Regarding safety and tolerability, analyses suggest a low risk of daytime sleepiness and of deleterious effects on memory or psychomotor performance, provided that recommended dosage and precautions are followed. Few retrospective studies associate zolpidem use with risk of falls, fractures, dementia, cancer, and stroke. Zolpidem appears effective at lower doses and for short-term treatment among the elderly. Rigorous, new clinical trials are warranted to further document the specific effects of zolpidem in older individuals.

Circulating miR-34a and Bone Mineral Density of Brazilian Very-Old Adults.

The human aging is marked by several body changes, including in bone mineral density (BMD). Research shows that microRNAs are important modulators of bone metabolism. The present research aims to analyze the whole blood concentration of 10 selected microRNAs (miRs) and their association with absolute and relative scores of BMD in specific osseous site of Brazilian very-old adults. Forty noninstitutionalized and apparently healthy, very old (≥80 years) outpatients were eligible for research. Anthropometry, biochemistry, and densitometry measurements were performed along with coronary artery calcification (CAC) scores and tested across total circulating levels of microRNAs. As expected, the relative BMD scores for the lumbosacral region (L1 to S5) and for the femoral head and neck observed in the sample denote weakened bone architecture, compatible with prevalent osteopenia and osteoporosis. In this context, one single significant association was found, and negatively implicated the miR-34a-5p with both absolute (ß = -0.36, P=0.001 for BMD) and relative (ß = -0.43, P=0.001 for T-score) densitometry indexes of the femoral head (adjusted to sex and physical activity practice), but not with the other sites. No difference in total blood concentrations of the miRs was found according to CAC scores. Our findings indicate greater circulating levels for miR-34a-5p among very-old adults who display the lowest scores of BMD, being a finding consistent with a modest contribution of the miR (along with co-variables) to the mineralization of that site. Attesting clinical relevance of our findings demands forthcoming studies.

Evidence for a contribution of the APOE (but not the ACE) gene to the sleep profile of non-demented elderly adults.

This study aims to investigate alleles of the human apolipoprotein E (APOE) and of the angiotensin-converting enzyme (ACE) genes as risk factors for poor quality of sleep in elderly individuals with no major cognitive decline. This cross-sectional, analytical study was conducted with 163 participants aged 75 years in average and 85% female. Sociodemographic, anthropometric and clinical data were gathered, and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth scale, with patient followed for years prior to these evaluations to rule out onset of major mental disorders. Genotyping of classic polymorphic sites for the ApoE (rs429358 and rs7412) and the ACE (rs4646994) genes used peripheral DNA. A total of 63% of the subjects reported poor quality of sleep assessed by the PSQI whereas 54 (33%) reported daytime sleepiness through the Epworth scale. A significant correlation was observed between APOE and PSQI, with a greater frequency of the poor nighttime sleep quality phenotype among ε2 carriers, whereas no correlation was found among any of the sleep scores and the ACE genotypes. Thus, we suggest a correlation between APOE alleles and scale-assessed sleep quality scores in older adults, with no implications for ACE alleles, in a context devoid of cognitive impairment.