Progressive resistance training for concomitant increases in muscle strength and bone mineral density in older adults: A systematic review and meta-analysis

Background: Older adults experience considerable muscle and bone loss that are closely interconnected. The efficacy of progressive resistance training programs to concurrently reverse/slow the age-related decline in muscle strength and bone mineral density (BMD) in older adults remains unclear. Objectives: We aimed to quantify concomitant changes in lower-body muscle strength and BMD in older adults following a progressive resistance training program and to determine how these changes are influenced by mode (resistance only vs. combined resistance and weight-bearing exercises), frequency, volume, load, and program length. Methods: MEDLINE/PubMed and Embase databases were searched for articles published in English before 1 June, 2021. Randomized controlled trials reporting changes in leg press or knee extension one repetition maximum and femur/hip or lumbar spine BMD following progressive resistance training in men and/or women ≥ 65 years of age were included. A random-effects meta-analysis and meta-regression determined the effects of resistance training and the individual training characteristics on the percent change (∆%) in muscle strength (standardized mean difference) and BMD (mean difference). The quality of the evidence was assessed using the Cochrane risk-of-bias tool (version 2.0) and Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. Results: Seven hundred and eighty studies were identified and 14 were included. Progressive resistance training increased muscle strength (∆ standardized mean difference = 1.1%; 95% confidence interval 0.73, 1.47; p ≤ 0.001) and femur/hip BMD (∆ mean difference = 2.77%; 95% confidence interval 0.44, 5.10; p = 0.02), but not BMD of the lumbar spine (∆ mean difference = 1.60%; 95% confidence interval − 1.44, 4.63; p = 0.30). The certainty for improvement was greater for muscle strength compared with BMD, evidenced by less heterogeneity (I2 = 78.1% vs 98.6%) and a higher overall quality of evidence. No training characteristic significantly affected both outcomes (p \u3e 0.05), although concomitant increases in strength and BMD were favored by higher training frequencies, increases in strength were favored by resistance only and higher volumes, and increases in BMD were favored by combined resistance plus weight-bearing exercises, lower volumes, and higher loads. Conclusions: Progressive resistance training programs concomitantly increase lower-limb muscle strength and femur/hip bone mineral density in older adults, with greater certainty for strength improvement. Thus, to maximize the efficacy of progressive resistance training programs to concurrently prevent muscle and bone loss in older adults, it is recommended to incorporate training characteristics more likely to improve BMD

PRIME-HF: Novel Exercise for Older Patients with Heart Failure. A Pilot Randomized Controlled Study

OBJECTIVES: To test the hypothesis that (1) older patients with heart failure (HF) can tolerate COMBined moderate-intensity aerobic and resistance training (COMBO), and (2) 4 weeks of Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) before 4 weeks of COMBO will improve aerobic capacity and muscle strength to a greater extent than 8 weeks of COMBO. DESIGN: Prospective randomized parallel open-label blinded end point. SETTING: Single-site Australian metropolitan hospital. PARTICIPANTS: Nineteen adults (72.8 ± 8.4 years of age) with heart failure with reduced ejection fraction (HFrEF). INTERVENTION: Participants were randomized to 4 weeks of PRIME or COMBO (phase 1). All participants subsequently completed 4 weeks of COMBO (phase 2). Sessions were twice a week for 60 minutes. PRIME is a low-mass, high-repetition regime (40% one-repetition maximum [1RM], eight strength exercises, 5 minutes each). COMBO training involved combined aerobic (40%-60% of peak aerobic capacity [VO2peak ], up to 20 minutes) and resistance training (50-70% 1RM, eight exercises, two sets of 10 repetitions). MEASUREMENTS: We measured VO2peak , VO2 at anaerobic threshold (AT), and muscle voluntary contraction (MVC). RESULTS: The PRIME group significantly increased VO2peak after 8 weeks (2.4 mL/kg/min; 95% confidence interval [CI] = .7-4.1; P = .004), whereas the COMBO group showed minimal change (.2; 95% CI -1.5 to 1.8). This produced a large between-group effect size of 1.0. VO2 at AT increased in the PRIME group (1.6 mL/kg/min; 95% CI .0-3.2) but not in the COMBO group (-1.2; 95% CI -2.9 to .4), producing a large between-group effect size. Total MVC increased significantly in both groups in comparison with baseline; however, the change was larger in the COMBO group (effect size = .6). CONCLUSION: Traditional exercise approaches (COMBO) and PRIME improved strength. Only PRIME training produced statistically and clinically significant improvements to aerobic capacity. Taken together, these findings support the hypothesis that PRIME may have potential advantages for older patients with HFrEF and could be a possible alternative exercise modality

Bleeding Severity in Percutaneous Coronary Intervention (PCI) and Its Impact on Short-Term Clinical Outcomes

Bleeding severity in patients undergoing percutaneous coronary intervention (PCI), defined by the Bleeding Academic Research Consortium (BARC), portends adverse prognosis. We analysed data from 37,866 Australian patients undergoing PCI enrolled in the Victorian Cardiac Outcomes Registry (VCOR), and investigated the association between increasing BARC severity and in-hospital and 30-day major adverse cardiac and cerebrovascular events (MACCE) (a composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularisation, or stroke). Independent predictors associated with major bleeding (BARC groups 3&5), and MACCE were also assessed. There was a stepwise increase in in-hospital and 30-day MACCE with greater severity of bleeding. Independent predictors of bleeding included female sex (Odds Ratio (OR) 1.34), age (OR 1.02), fibrinolytic therapy (OR 1.77), femoral access (OR 1.51), and ticagrelor (OR 1.42), all significant at the p < 0.001 level. Following adjustment of clinically important variables, BARC 3&5 bleeds (OR 4.37) were still predictive of cumulative in-hospital and 30-day MACCE. In conclusion, major bleeding is an uncommon but potentially fatal PCI complication and was independently associated with greater MACCE rates. Efforts to mitigate the occurrence of bleeding, including radial access and judicious use of potent antiplatelet therapies, may ameliorate the risk of short-term adverse clinical outcomes

Cholinergic signaling influences the expression of immune checkpoint inhibitors, PD-L1 and PD-L2, and tumor hallmarks in human colorectal cancer tissues and cell lines

Background: Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host’s immune system. Cancer cells synthesize and secrete acetylcholine (ACh), acting as an autocrine or paracrine hormone to promote their proliferation, differentiation, and migration. Methods: We correlated the expression of PD-L1, PD-L2, cholinergic muscarinic receptor 3 (M3R), alpha 7 nicotinic receptor (α7nAChR), and choline acetyltransferase (ChAT) in colorectal cancer (CRC) tissues with the stage of disease, gender, age, risk, and patient survival. The effects of a muscarinic receptor blocker, atropine, and a selective M3R blocker, 4-DAMP, on the expression of immunosuppressive and cholinergic markers were evaluated in human CRC (LIM-2405, HT-29) cells. Results: Increased expression of PD-L1, M3R, and ChAT at stages III-IV was associated with a high risk of CRC and poor survival outcomes independent of patients’ gender and age. α7nAChR and PD-L2 were not changed at any CRC stages. Atropine and 4-DAMP suppressed the proliferation and migration of human CRC cells, induced apoptosis, and decreased PD-L1, PD-L2, and M3R expression in CRC cells via inhibition of EGFR and phosphorylation of ERK. Conclusions: The expression of immunosuppressive and cholinergic markers may increase the risk of recurrence of CRC. These markers might be used in determining prognosis and treatment regimens for CRC patients. Blocking cholinergic signaling may be a potential therapeutic for CRC through anti-proliferation and anti-migration via inhibition of EGFR and phosphorylation of ERK. These effects allow the immune system to recognize and eliminate cancer cells

Antiepileptic effects of lacosamide loaded polymers implanted subdurally in GAERS

The current experiment investigated the ability of coaxial electrospun poly(D,L-lactide-co-glycolide) (PLGA) biodegradable polymer implants loaded with the antiepileptic drugs (AED) lacosamide to reduce seizures following implantation above the motor cortex in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). In this prospective, randomized, masked experiments, GAERS underwent surgery for implantation of skull electrodes (n = 6), skull electrodes and blank polymers (n = 6), or skull electrodes and lacosamide loaded polymers (n = 6). Thirty-minute electroencephalogram (EEG) recordings were started at day 7 after surgery and continued for eight weeks. The number of SWDs and mean duration of one SWD were compared week-by-week between the three groups. There was no difference in the number of SWDs between any of the groups. However, the mean duration of one SWD was significantly lower in the lacosamide polymer group for up to 7 weeks when compared to the control group (0.004 \u3c p \u3c 0.038). The mean duration of one seizure was also lower at weeks 3, 5, 6, and 7 when compared to the blank polymer group (p = 0.016, 0.037, 0.025, and 0.025, resp.). We have demonstrated that AED loaded PLGA polymer sheets implanted on the surface of the cortex could affect seizure activity in GAERS for a sustained period

Higher Levels of Circulating Osteoprogenitor Cells Are Associated With Higher Bone Mineral Density and Lean Mass in Older Adults: A Cross-Sectional Study

ABSTRACT Circulating osteo progenitor (COP) cells are a heterogeneous population of cells that circulate within the peripheral blood with characteristics of the bone marrow mesenchymal stem and progenitor pool. Little is known about the behavior of this cell population in humans. The aim of this study was to identify whether a relationship exists between COP cells (as a percentage of the peripheral blood monocytic cells) and musculoskeletal morphometry and to identify if COP have potential clinical utility as a biomarker for osteoporosis. We recruited 57 older adults (median age: 69 years; IQR: 65, 75 years) living independently in the community and performed cross‐sectional analysis to identify associations between the percentage of COP cells and body composition parameters, and through receiver operating characteristic analysis, we evaluated their ability to act as a biomarker of osteoporosis. COP cells were moderately associated with whole‐body bone mineral density (BMD) (r = 0.323, p = 0.014) and bone mineral content (BMC) (r = 0.387, p = 0.003), neck of femur BMD (r = 0.473, p < 0.001), and BMC (r = 0.461, p < 0.001) as well as appendicular lean mass (ALM) (p = 0.038) and male sex (p = 0.044) in univariable analysis. In multivariable analysis controlling for age, gender, height, and weight, COP cells remained strongly associated with neck of femur BMD (p = 0.001) and content (p = 0.003). COP cells were also a good predictor of osteoporosis (dual‐energy X‐ray absorptiometry [DXA] T‐score < −2.5) at the neck of femur (cutoff: 0.4%; sensitivity: 100%; specificity 79%) and total body (cutoff: 0.35%; sensitivity: 80%; specificity: 81%). This study shows strong relationships between bone parameters and COP cell number and male sex. They also have potential as a biomarker of osteoporosis, which may provide a new tool for advanced detection and screening in clinical settings. Future larger evaluation studies should verify the cutoffs for biomarker use, and further explore the relationship between COP cells and muscle. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

Fractures in indigenous compared to non-indigenous populations: a systematic review of rates and aetiology

BackgroundCompared to non-indigenous populations, indigenous populations experience disproportionately greater morbidity, and a reduced life expectancy; however, conflicting data exist regarding whether a higher risk of fracture is experienced by either population. We systematically evaluate evidence for whether differences in fracture rates at any skeletal site exist between indigenous and non-indigenous populations of any age, and to identify potential risk factors that might explain these differences.MethodsOn 31 August 2016 we conducted a comprehensive computer-aided search of peer-reviewed literature without date limits. We searched PubMed, OVID, MEDLINE, CINAHL, EMBASE, and reference lists of relevant publications. The protocol for this systematic review is registered in PROSPERO, the International Prospective Register of systematic reviews (CRD42016043215). Using the World Health Organization reference population as standard, hip fracture incidence rates were re-standardized for comparability between countries.ResultsOur search yielded 3227 articles; 283 potentially eligible articles were cross-referenced against predetermined criteria, leaving 27 articles for final inclusion. Differences in hip fracture rates appeared as continent-specific, with lower rates observed for indigenous persons in all countries except for Canada and Australia where the opposite was observed. Indigenous persons consistently had higher rates of trauma-related fractures; the highest were observed in Australia where craniofacial fracture rates were 22-times greater for indigenous compared to non-indigenous women. After adjustment for socio-demographic and clinical risk factors, approximately a three-fold greater risk of osteoporotic fracture and five-fold greater risk of craniofacial fractures was observed for indigenous compared to non-indigenous persons; diabetes, substance abuse, comorbidity, lower income, locality, and fracture history were independently associated with an increased risk of fracture.ConclusionsThe observed paucity of data and suggestion of continent-specific differences indicate an urgent need for further research regarding indigenous status and fracture epidemiology and aetiology. Our findings also have implications for communities, governments and healthcare professionals to enhance the prevention of trauma-related fractures in indigenous persons, and an increased focus on modifiable lifestyle behaviours to prevent osteoporotic fractures in all populations

Effect of 6 months of hybrid closed-loop insulin delivery in adults with type 1 diabetes: a randomised controlled trial protocol

INTRODUCTION: Manual determination of insulin dosing largely fails to optimise glucose control in type 1 diabetes. Automated insulin delivery via closed-loop systems has improved glucose control in short-term studies. The objective of the present study is to determine the effectiveness of 6 months\u27 closed-loop compared with manually determined insulin dosing on time-in-target glucose range in adults with type 1 diabetes. METHODS AND ANALYSIS: This open-label, seven-centre, randomised controlled parallel group clinical trial will compare home-based hybrid closed-loop versus standard diabetes therapy in Australia. Adults aged &ge;25 years with type 1 diabetes using intensive insulin therapy (via multiple daily injections or insulin pump, total enrolment target n=120) will undertake a run-in period including diabetes and carbohydrate-counting education, clinical optimisation and baseline data collection. Participants will then be randomised 1:1 either to 26 weeks of MiniMed 670G hybrid closed-loop system therapy (Medtronic, Northridge, CA, USA) or continuation of their current diabetes therapy. The hybrid closed-loop system delivers insulin automatically to address basal requirements and correct to target glucose level, while bolus doses for meals require user initiation and carbohydrate estimation. Analysis will be intention to treat, with the primary outcome time in continuous glucose monitoring (CGM) target range (3.9-10.0&thinsp;mmol/L) during the final 3 weeks of intervention. Secondary outcomes include: other CGM parameters, HbA1c, severe hypoglycaemia, psychosocial well-being, sleep, cognition, electrocardiography, costs, quality of life, biomarkers of vascular health and hybrid closed-loop system performance. Semistructured interviews will assess the expectations and experiences of a subgroup of hybrid closed-loop users. ETHICS AND DISSEMINATION: The study has Human Research Ethics Committee approval. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results will be disseminated at scientific conferences and via peer-reviewed publications