Evidence-based definition of hypoprolactinemia in European men aged 40-86 years: the European male ageing study.

Empirical evidence for a low normal or reference interval for serum prolactin (PRL) is lacking for men, while the implications of very low PRL levels for human health have never been studied. A clinical state of "PRL deficiency" has not been defined except in relation to lactation. Using data from the European Male Ageing Study (EMAS), we analyzed the distribution of PRL in 3,369 community-dwelling European men, aged 40-80 years at phase-1 and free from acute illnesses. In total, 2,948 and 2,644 PRL samples were collected during phase-1 and phase-2 (3 to 5.7 years later). All samples were analysed in the same centre with the same assay. After excluding individuals with known pituitary diseases, PRL ≥ 35 ng/ml, and PRL-altering drugs including antipsychotic agents, selective serotonin reuptake inhibitors, or dopamine agonists, 5,086 data points (2,845 in phase-1 and 2,241 in phase-2) were available for analysis. The results showed that PRL declined minimally with age (slope = -0.02) and did not correlate with BMI. The positively skewed PRL distribution was log-transformed to a symmetrical distribution (skewness reduced from 13.3 to 0.015). Using two-sigma empirical rule (2[]SD about the mean), a threshold at 2.5% of the lower end of the distribution was shown to correspond to a PRL value of 2.98ng/ml. With reference to individuals with PRL levels of 5-34.9 ng/ml (event rate = 6.3%), the adjusted risk of developing type 2 diabetes increased progressively in those with PRL levels of 3-4.9 ng/ml: event rate = 9.3%, OR (95% CI) 1.59 (0.93-2.71), and more so with PRL levels of 0.3-2.9 ng/ml: event rate = 22.7%, OR 5.45 (1.78-16.62). There was also an increasing trend in prediabetes and diabetes based on fasting blood glucose levels was observed with lower categories of PRL. However, PRL levels were not associated with cancer, cardiovascular diseases, depressive symptoms or mortality. Our findings suggest that a PRL level below 3 ng/ml (64 mlU/l) significantly identifies European men with a clinically-important outcome (of type 2 diabetes), offering a lower reference-value for research and clinical practice.

Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer's disease and other forms of dementia.

Sarcopenia has been associated with adverse health outcomes, including cognitive dysfunction. However, its specific interrelationship with neurocognitive disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD) or other types of dementia has not been thoroughly explored. This meta-analysis aims to summarize the existing evidence on this interrelationship. This systematic review was pre-registered on PROSPERO (CRD42022366309) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Databases, including PubMed, Embase, CINAHL, Scopus, Web of Science, PEDro, SPORTDiscus and the Cochrane Central Register of Controlled Trials, and the data registry ClinicalTrials.gov were searched from inception to 8 June 2023. Observational studies (cross-sectional and cohort) and interventional studies reporting on the association and prevalence of sarcopenia in MCI, AD or other types of dementia in adults ≥50 years were included. For the meta-analysis, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of sarcopenia with the neurocognitive disorders using random-effects/fixed-effects models. Subgroup analyses were performed to identify potential sources of heterogeneity. A total of 77 studies consisting of 92 058 subjects were finally included in the qualitative analysis (71 cross-sectional, 4 cohort and 2 interventional studies). Studies were heterogeneous, using different diagnostic criteria to define both sarcopenia and cognitive status. The majority of studies (n = 38) included Asian community-dwelling older adults. Most studies investigated the association of sarcopenia with AD (33/77) and MCI (32/77). For studies focusing on other forms of dementia, two studies included Lewy body dementia and one study included Parkinson's dementia, whereas the remaining studies did not specify dementia aetiology (n = 21). Three cohort studies explored the association between sarcopenia and incident MCI, whereas only one cohort study explored the association between dementia and incident sarcopenia. Two interventional studies investigated whether an exercise programme could prevent the progression of sarcopenia in older adults with dementia or AD. The information for the meta-analysis was extracted from 26 studies. Sarcopenia was significantly associated with MCI (pooled OR = 1.58, 95% CI 1.42-1.76) (n = 14), AD (pooled OR = 2.97, 95% CI 2.15-4.08) (n = 3) and non-AD dementia (pooled OR = 1.68, 95% CI 1.09-2.58) (n = 9). The significance and magnitude of the associations differed in subgroup analyses by study design, population, definition of sarcopenia or used tool to measure cognitive status. This meta-analysis showed that sarcopenia is significantly associated with MCI, AD and other types of dementia. These findings suggest the importance of early screening and prevention of sarcopenia in older people with cognitive dysfunction, although further longitudinal research is needed to clarify the causal relationship.

Prevalence and trends in polypharmacy and excessive polypharmacy: a retrospective national database analysis (2012-2021).

BACKGROUND: Polypharmacy is a growing concern, impacting patient safety and healthcare costs. Monitoring its prevalence and temporal trends is essential for effective healthcare management. AIM: This study aimed to determine prevalence and trends of polypharmacy and excessive polypharmacy in Belgium. METHOD: Utilizing a federal claims database, medication data were analyzed from 2012 to 2021. Polypharmacy (≥ 5 medications) and excessive polypharmacy (≥ 10 medications) were evaluated, with prevalence calculated per 1000 inhabitants, and reported per year, age group and region. Linear regression estimated the impact of age and year on polypharmacy prevalence. RESULTS: In 2021, polypharmacy and excessive polypharmacy were reported in 135/1000 and 31/1000 Belgians respectively. Prevalence of both increased steadily from 2012 to 2021, with excessive polypharmacy rising more prominently. Among adults aged ≥ 65 years, prevalence rates were higher, with polypharmacy at 434/1000 and excessive polypharmacy at 106/1000. Regional variations were observed, with prevalence highest in the Walloons region. Patient age and year (2012-2021) were associated with both polypharmacy and excessive polypharmacy (p < 0.001). CONCLUSION: We observed increases in polypharmacy and excessive polypharmacy over a decade in Belgium, particularly among older adults. Efforts to monitor, manage, and optimize medication use are imperative to ensure safe and effective healthcare delivery.

Optimizing pharmacotherapy and deprescribing strategies in older adults living with multimorbidity and polypharmacy: EuGMS SIG on pharmacology position paper.

Inappropriate polypharmacy is highly prevalent among older adults and presents a significant healthcare concern. Conducting medication reviews and implementing deprescribing strategies in multimorbid older adults with polypharmacy are an inherently complex and challenging task. Recognizing this, the Special Interest Group on Pharmacology of the European Geriatric Medicine Society has compiled evidence on medication review and deprescribing in older adults and has formulated recommendations to enhance appropriate prescribing practices. The current evidence supports the need for a comprehensive and widespread transformation in education, guidelines, research, advocacy, and policy to improve the management of polypharmacy in older individuals. Furthermore, incorporating deprescribing as a routine aspect of care for the ageing population is crucial. We emphasize the importance of involving geriatricians and experts in geriatric pharmacology in driving, and actively participating in this transformative process. By doing so, we can work towards achieving optimal medication use and enhancing the well-being of older adults in the generations to come.

Predictors for unplanned hospital admissions in community dwelling adults: A dynamic cohort study.

BACKGROUND: Polypharmacy and inappropriate medication use are associated with unplanned hospital admissions. Targeted interventions might reduce the hospitalization risk. Yet, it remains unclear which patient profiles derive the largest benefit from such interventions. OBJECTIVE: The aim of this study was to determine independent risk factors, among which polypharmacy, for unplanned hospital admissions in a cohort of community dwelling adults. METHODS: A retrospective study was performed using a large general practice registry and an insurance database in Flanders, Belgium. Community dwelling adults aged 40 years or older with data for 2013-2015 were included. The index date was the last general practitioner contact in 2014. Determinants were collected during the preceding year. Unplanned hospital admissions were determined during the year after the index date. Univariable logistic regression models were fitted on each risk factor for an unplanned hospital admission as the primary outcome. Two multivariable models were derived. RESULTS: In total, 40411 patients were included and 2126 (5.26%) experienced an unplanned hospital admission. Mean age was 58.3 (±12.3) years. The two models identified the following determinants for an unplanned hospital admission: excessive polypharmacy, older age, male sex, number of comorbidities, atrial fibrillation, chronic obstructive pulmonary disease or stroke, low hemoglobin, use of hypnotics, antipsychotics, antidepressants or antiepileptics and prior hospital and general practitioner visits. Prior hospital visits was the largest determinant. CONCLUSIONS: In our study we identified and confirmed the presence of known determinants for unplanned hospital admissions in community dwelling adults, most of which align with a geriatric phenotype. Our findings can inform the allocation of interventions aiming to reduce unplanned hospital admissions.

Physiologically based pharmacokinetic (PBPK) modelling of oral drug absorption in older adults - an AGePOP review.

The older population consisting of persons aged 65 years or older is the fastest-growing population group and also the major consumer of pharmaceutical products. Due to the heterogenous ageing process, this age group shows high interindividual variability in the dose-exposure-response relationship and, thus, a prediction of drug safety and efficacy is challenging. Although physiologically based pharmacokinetic (PBPK) modelling is a well-established tool to inform and confirm drug dosing strategies during drug development for special population groups, age-related changes in absorption are poorly accounted for in current PBPK models. The purpose of this review is to summarise the current state-of-knowledge in terms of physiological changes with increasing age that can influence the oral absorption of dosage forms. The capacity of common PBPK platforms to incorporate these changes and describe the older population is also discussed, as well as the implications of extrinsic factors such as drug-drug interactions associated with polypharmacy on the model development process. The future potential of this field will rely on addressing the gaps identified in this article, which can subsequently supplement in-vitro and in-vivo data for more robust decision-making on the adequacy of the formulation for use in older adults and inform pharmacotherapy.

Erector spinae plane block for postoperative analgesia in robotically-assisted coronary artery bypass surgery: Results of a randomized placebo-controlled trial.

STUDY OBJECTIVE: To investigate if an erector spinae plane (ESP) block decreases postoperative opioid consumption, pain and postoperative nausea and vomiting in patients undergoing robotically-assisted minimally invasive direct coronary artery bypass surgery (RAMIDCAB). DESIGN: A single-center, double-blind, prospective, randomized, placebo-controlled trial. SETTING: Postoperative period; operating room, post-anesthesia care unit (PACU) and hospital ward in a university hospital. PATIENTS: Sixty-four patients undergoing RAMIDCAB surgery via left-sided mini-thoracotomy and enrolled in the institutional enhanced recovery after cardiac surgery program. INTERVENTIONS: At the end of surgery, patients received an ESP catheter at vertebra T5 under ultrasound guidance and were randomized to the administration of either ropivacaine 0.5% (loading dose of 30 ml and three additional doses of 20 ml each, interspersed with a 6 h interval) or normal saline 0.9% (with an identical administration scheme). In addition, patients received multimodal analgesia including acetaminophen, dexamethasone and patient-controlled analgesia with morphine. Following the final ESP bolus and before catheter removal, the position of the catheter was re-evaluated by ultrasound. Patients, investigators and medical personnel were blinded for the group allocation during the entire trial. MEASUREMENTS: Primary outcome was cumulative morphine consumption during the first 24 h after extubation. Secondary outcomes included location and severity of pain, presence/extent of sensory block, duration of postoperative ventilation and hospital length of stay. Safety outcomes comprised the incidence of adverse events. MAIN RESULTS: Median (IQR) 24-h morphine consumption was not different between the intervention- and control-groups, 67 mg (35-84) versus 71 mg (52-90) (p = 0.25), respectively. Likewise, no differences were detected in secondary and safety endpoints. CONCLUSIONS: Following RAMIDCAB surgery, adding an ESP block to a standard multimodal analgesia regimen did not reduce opioid consumption and pain scores.

Are inflammatory markers associated with sarcopenia-related traits in older adults with sarcopenia? - A cross-sectional analysis of the ENHANce study.

AIMS: To explore the relationship between inflammatory markers and sarcopenia-related traits in sarcopenic older adults. METHODS: Baseline data of the ongoing Exercise and Nutrition for Healthy AgeiNg (ENHANce) study were used for a secondary, exploratory, cross-sectional analysis. ENHANce is a 5-armed triple blinded randomized controlled trial, in older adults (>65y) with sarcopenia defined according to the revised criteria of the European Working Group of Sarcopenia in Older People (EWGSOP2) aiming to assess the effect of combined anabolic interventions (protein supplement, omega-3 supplement and physical exercise) on physical performance, compared to single/placebo interventions. Inflammatory markers C-reactive protein (hs-CRP), albumin, interleukin-1ß (IL-1ß), IL-6, IL-8, and tumour necrosis factor-α (TNF-α) were assessed at baseline. Spearman's rho (ρ) correlation coefficients were calculated to associate these inflammatory markers with baseline sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass [aLM], gait speed, Short Physical Performance Battery), physical activity (step count) and quality of life (SF-36, SarQoL). RESULTS: We included 40 sarcopenic subjects (15 men/25 women, age 77.1 ± 6.8 years). Contrary to expectations, the pro-inflammatory IL-1ß correlated positively with handgrip strength (ρ: 0.376; p = 0.024) and IL-6 with aLM (ρ: 0.334; p = 0.0433). IL-6 inversely correlated with step count (ρ:-0.358; p = 0.048). Subgroup analysis revealed important gender differences. IL-8 inversely correlated with handgrip strength in women (ρ: -0.425; p = 0.034) but not in men. In contrast, pro-inflammatory cytokines CRP (ρ: -0.615; p = 0.019), IL-6 (ρ: -0.604; p = 0.029) and TNF-α (ρ: -0.615; p = 0.025) inversely correlated with the SF-36 physical component score in men but not in women. CONCLUSION: Although Inflammageing might play a role in sarcopenia-related traits, this exploratory study highlights an important role of gender. Future research should take this into account when elucidating the Inflammageing-sarcopenia interplay.

Sarcopenia-defining parameters, but not sarcopenia, are associated with cognitive domains in middle-aged and older European men.

BACKGROUND: Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men. METHODS: This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40-79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey-Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3 years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders. RESULTS: In the whole cohort (n = 3233), ROCF-Copy (ß = 0.016; P < 0.05), ROCF-Recall (ß = 0.010; P < 0.05), CTRM (ß = 0.015; P < 0.05), DSST score (ß = 0.032; P < 0.05) and fluid cognition (ß = 0.036; P < 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (n = 456), ROCF-Copy (ß = 1.008; P < 0.05), ROCF-Recall (ß = 0.908; P < 0.05) and fluid cognition (ß = 1.482; P < 0.05) were associated with HGS. ROCF-Copy (ß = 0.394; P < 0.05), ROCF-Recall (ß = 0.316; P < 0.05), DSST (ß = 0.393; P < 0.05) and fluid cognition (ß = 0.765; P < 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analysis showed that low ROCF-Copy score at baseline was associated with an increase in CST in men ≥70 years (ß = -0.599; P < 0.05). In addition, a decrease in ROCF-Recall was associated with a decrease in GS, and a decrease in DSST was associated with an increase in CST (ß = 0.155; P < 0.0001, ß = -0.595; P < 0.001, respectively) in persons with the highest change in both cognition and muscle function. CONCLUSIONS: Sarcopenia was not associated with cognitive performance in this population, whereas several components of sarcopenia were associated with domain-specific cognitive performance. Longitudinally, baseline and change in subdomains of cognition predicted change in muscle function in specific subgroups.

Efficacy of erector spinae plane block for minimally invasive mitral valve surgery: Results of a double-blind, prospective randomized placebo-controlled trial.

STUDY OBJECTIVE: To investigate if an erector spinae plane (ESP) block decreases postoperative opioid consumption, pain and postoperative nausea and vomiting in patients undergoing minimally invasive mitral valve surgery (MIMVS). DESIGN: A single-center, double-blind, prospective, randomized, placebo-controlled trial. SETTING: Postoperative period; operating room, post-anesthesia care unit (PACU) and hospital ward in a university hospital. PATIENTS: Seventy-two patients undergoing video-assisted thoracoscopic MIMVS via right-sided mini-thoracotomy and enrolled in the institutional enhanced recovery after cardiac surgery program. INTERVENTIONS: At the end of surgery, all patients received an ESP catheter at vertebra T5 under ultrasound guidance and were randomized to the administration of either ropivacaine 0.5% (loading of dose 30 ml and three additional doses of 20 ml with a 6 h interval) or normal saline 0.9% (with an identical administration scheme). In addition, patients received multimodal postoperative analgesia including dexamethasone, acetaminophen and patient-controlled intravenous analgesia with morphine. Following the final ESP bolus and before catheter removal, the position of the catheter was re-evaluated by ultrasound. Patients, investigators and medical personnel were blinded for the group allocation during the entire trial. MEASUREMENTS: Primary outcome was cumulative morphine consumption during the first 24 h after extubation. Secondary outcomes included severity of pain, presence/extent of sensory block, duration of postoperative ventilation and hospital length of stay. Safety outcomes comprised the incidence of adverse events. MAIN RESULTS: Median (IQR) 24-h morphine consumption was not different between the intervention- and control-group, 41 mg (30-55) versus 37 mg (29-50) (p = 0.70), respectively. Likewise, no differences were detected for secondary and safety endpoints. CONCLUSIONS: Following MIMVS, adding an ESP block to a standard multimodal analgesia regimen did not reduce opioid consumption and pain scores.

Postoperative delirium and quality of life after transcatheter and surgical aortic valve replacement: A prospective observational study.

OBJECTIVE: In older patients, postoperative delirium is a frequently occurring complication after surgical aortic valve replacement, leading to an excess in postoperative morbidity and mortality. It remains controversial whether transcatheter aortic valve implantation and minimally invasive surgical aortic valve replacement can reduce the risk of postoperative delirium. This study aimed to compare the incidence of postoperative delirium after transcatheter aortic valve implantation and surgical aortic valve replacement and the impact on long-term outcomes. METHODS: Between September 2018 and January 2020, we conducted an observational, prospective cohort study in patients aged 70 years or more undergoing transcatheter aortic valve implantation or surgical aortic valve replacement. The primary end point was the incidence of in-hospital postoperative delirium during 5 postoperative days assessed with the Confusion Assessment Method. Secondary end points included perioperative inflammation, postoperative complications, health status (EuroQol 5-dimensional questionnaire 5 levels), and mortality up to 6 months. Transcatheter aortic valve implantation and surgical aortic valve replacement were compared using propensity weighting to account for important baseline differences (European System for Cardiac Operative Risk Evaluation II, age, and frailty). RESULTS: We included 250 patients with a mean (standard deviation) age of 80 (±5.8) years and a European System for Cardiac Operative Risk Evaluation score of 5 (±4.7). In the propensity-weighted analysis, those undergoing surgical aortic valve replacement (N = 166) had a higher incidence of postoperative delirium compared with transcatheter aortic valve implantation (N = 84) (51% vs 15%: P < .0001). Furthermore, patients undergoing surgical aortic valve replacement experienced more inflammation, a greater depth of anesthesia, and more intraoperative hypotension. After surgical aortic valve replacement, 41% of patients experienced an improved health status compared with 12% after transcatheter aortic valve implantation (P < .0001). No outcome differences were noted within the surgical aortic valve replacement groups. CONCLUSIONS: Transcatheter aortic valve implantation is associated with a lower risk for postoperative delirium. Nevertheless, patients undergoing surgical aortic valve replacement experience the greatest improvement in quality of life. Heart teams should consider these outcomes in shared decision-making in the choice of transcatheter aortic valve implantation or surgical aortic valve replacement.

The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort.

Background: Insulin-like peptide 3 (INSL3) is a constitutive hormone secreted in men by the mature Leydig cells of the testes. It is an accurate biomarker for Leydig cell functional capacity, reflecting their total cell number and differentiation status. Objectives: To determine the ability of INSL3 to predict hypogonadism and age-related morbidity using the EMAS cohort of older community-dwelling men. Materials & methods: Circulating INSL3 was assessed in the EMAS cohort and its cross-sectional and longitudinal relationships to hypogonadism, here defined by testosterone (T) <10.5nmol/l, and a range of age-related morbidities determined by correlation and regression analysis. Results & discussion: While INSL3 is an accurate measure of primary hypogonadism, secondary and compensated hypogonadism also indicate reduced levels of INSL3, implying that testicular hypogonadism does not improve even when LH levels are increased, and that ageing-related hypogonadism may combine both primary and secondary features. Unadjusted, serum INSL3, like calculated free testosterone (cFT), LH, or the T/LH ratio reflects hypogonadal status and is associated with reduced sexual function, bone mineral density, and physical activity, as well as increased occurrence of hypertension, cardiovascular disease, cancer, and diabetes. Using multiple regression analysis to adjust for a range of hormonal, anthropometric, and lifestyle factors, this relationship is lost for all morbidities, except for reduced bone mineral density, implying that INSL3 and/or its specific receptor, RXFP2, may be causally involved in promoting healthy bone metabolism. Elevated INSL3 also associates with hypertension and cardiovascular disease. When unadjusted, INSL3 in phase 1 of the EMAS study was assessed for its association with morbidity in phase 2 (mean 4.3 years later); INSL3 significantly predicts 7 out of 9 morbidity categories, behaving as well as cFT in this regard. In contrast, total T was predictive in only 3 of the 9 categories. Conclusion: Together with its low within-individual variance, these findings suggest that assessing INSL3 in men could offer important insight into the later development of disease in the elderly.

Association between improved compliance with enhanced recovery after cardiac surgery guidelines and postoperative outcomes: A retrospective study.

OBJECTIVE: Enhanced recovery after cardiac surgery is a multidisciplinary clinical care pathway that relies on a bundle of interventions, aiming to reduce the stress response to surgery and promote early recovery of organ function. In 2011, our institution introduced an institutional enhanced recovery after cardiac surgery program focusing on 9 central interventions, which have been expanded during the past decade by additional interventions now considered standard of care. After the recent publication of the enhanced recovery after cardiac surgery guidelines, we evaluated the relation between the compliance with these enhanced recovery after cardiac surgery guidelines and postoperative outcomes. METHODS: All patients enrolled in our enhanced recovery after cardiac surgery program in 2019 were included in this retrospective single-center audit. The primary outcome was compliance with 23 enhanced recovery after cardiac surgery guidelines. Secondary outcomes included occurrence of at least 1 postoperative complication and hospital length of stay. RESULTS: A total of 356 patients were included in this study. Compliance with the enhanced recovery after cardiac surgery guidelines was 64%. Postoperatively, 51% of the patients experienced at least 1 complication and had a median hospital length of stay of 6 days. Multivariable analysis showed that an increased compliance (per 10%) with the enhanced recovery after cardiac surgery guidelines was associated with a lower risk for any complication (odds ratio, 0.60; 95% confidence interval, 0.46-0.79; P = .0003) and a higher probability of earlier hospital discharge (hazard ratio, 1.25; 95% confidence interval, 1.10-1.43; P = .0008). CONCLUSIONS: This audit revealed a correlation between increased compliance with enhanced recovery after cardiac surgery guidelines and a reduction of postoperative complications and hospital length of stay. Future trials are needed to establish evidence-based recommendations for each separate intervention of the enhanced recovery after cardiac surgery guidelines and to create a minimum core-set of enhanced recovery after cardiac surgery interventions.

Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort.

BACKGROUND: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell-produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin-like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes. OBJECTIVES: To characterize insulin-like peptide 3 as a biomarker to assess gonadal status in aging men. METHODS AND MATERIALS: A large European multicenter (European Male Aging Study) cohort of community-dwelling men was analyzed to determine how insulin-like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters. RESULTS AND DISCUSSION: Insulin-like peptide 3 declines cross-sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin-like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin-like peptide 3 is negatively dependent on luteinizing hormone and sex hormone-binding globulin and positively dependent on follicle-stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin-like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin-like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European-wide reference range for insulin-like peptide 3 (95% confidence interval) adjusted for increasing age. CONCLUSION: Insulin-like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin-dependent short-term regulation and within-individual variation in testosterone.

Reproductive hormone levels, androgen receptor CAG repeat length and their longitudinal relationships with decline in cognitive subdomains in men: The European Male Ageing Study.

OBJECTIVE: It has been proposed that endogenous sex hormone levels may present a modifiable risk factor for cognitive decline. However, the evidence for effects of sex steroids on cognitive ageing is conflicting. We therefore investigated associations between endogenous hormone levels, androgen receptor CAG repeat length, and cognitive domains including visuoconstructional abilities, visual memory, and processing speed in a large-scale longitudinal study of middle-aged and older men. METHODS: Men aged 40-79 years from the European Male Ageing Study (EMAS) underwent cognitive assessments and measurements of hormone levels at baseline and follow-up (mean = 4.4 years, SD ± 0.3 years). Hormone levels measured included total and calculated free testosterone and estradiol, dihydrotestosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulphate and sex hormone-binding globulin. Cognitive function was assessed using the Rey-Osterrieth Complex Figure Copy and Recall, the Camden Topographical Recognition Memory and the Digit Symbol Substitution Test. Multivariate linear regressions were used to examine associations between baseline and change hormone levels, androgen receptor CAG repeat length, and cognitive decline. RESULTS: Statistical analyses included 1,827 and 1,423 participants for models investigating relationships of cognition with hormone levels and CAG repeat length, respectively. In age-adjusted models, we found a significant association of higher baseline free testosterone (ß=-0.001, p=0.005) and dihydrotestosterone levels (ß=-0.065, p=0.003) with greater decline on Rey-Osterrieth Complex Figure Recall over time. However, these effects were no longer significant following adjustment for centre, health, and lifestyle factors. No relationships were observed between any other baseline hormone levels, change in hormone levels, or androgen receptor CAG repeat length with cognitive decline in the measured domains. CONCLUSIONS: In this large-scale prospective study there was no evidence for an association between endogenous sex hormone levels or CAG repeat length and cognitive ageing in men. These data suggest that sex steroid levels do not affect visuospatial function, visual memory, or processing speed in middle-aged and older men.

SARC-F Is Inaccurate to Identify Geriatric Rehabilitation Inpatients at Risk for Sarcopenia: RESORT.

INTRODUCTION: Sarcopenia is highly prevalent in geriatric rehabilitation inpatients; screening using the Strength, Assistance in walking, Rise from a chair, Climb stairs, Falls history questionnaire (SARC-F) has been recommended. This study assessed the diagnostic accuracy of the SARC-F in identifying sarcopenia according to the European Working Group on Sarcopenia in Older People (EWGSOP), EWGSOP2, and Asian Working Group for Sarcopenia (AWGS) definitions in geriatric rehabilitation inpatients. METHODS: REStOring health of acutely unwell adulTs (RESORT) is an observational, longitudinal cohort of geriatric rehabilitation inpatients. The SARC-F was completed for 2 time-points, status at preadmission (1 month before admission) and at admission; a score ≥4 was considered at risk for sarcopenia. Muscle mass (bioelectrical impedance analysis), handgrip strength (handheld dynamometry), and gait speed (4-m walk test) were measured at admission. Diagnostic accuracy was determined by sensitivity, specificity, and area under the curve (AUC). RESULTS: The sarcopenia prevalence (n = 290, median age 84.0 years [IQR 79.0-89.0], 56.9% female) was 40.3% (EWGSOP1), 25.4% (EWGSOP2), and 38.8% (AWGS). For preadmission and admission status, respectively, the SARC-F identified 67.9 and 82.1% (EWGSOP), 66.0 and 81.0% (EWGSOP2), and 67.5 and 81.6% (AWGS) inpatients at risk for sarcopenia. The SARC-F showed fair sensitivity (67-74%), poor specificity (32-37%), and poor AUC (0.411-0.474) to identify inpatients at risk for sarcopenia at preadmission status, and fair-good sensitivity (79-84%), poor specificity (17-20%), and poor AUC (0.401-0.432) to identify inpatients at risk for sarcopenia at admission, according to EWGSOP, EWGSOP2, and AWGS definitions. CONCLUSION: The SARC-F showed poor diagnostic accuracy in identifying sarcopenia in geriatric rehabilitation inpatients. Assessment of sarcopenia is recommended without screening.

Aging Men With Insufficient Vitamin D Have a Higher Mortality Risk: No Added Value of its Free Fractions or Active Form.

CONTEXT: Low total 25-hydroxyvitamin D (25(OH)D) has been associated with mortality. Whether vitamin D in its free form or 1,25-dihydroxyvitamin D (1,25(OH)2D), provide any additional information is unclear. OBJECTIVE: To determine what level of 25(OH)D is predictive for mortality and if free 25(OH)D or 1,25(OH) 2 D concentrations have any added value. METHODS: This prospective cohort comprised 1915 community-dwelling men, aged 40 to 79 years. Intervention included determination of association of total and free 25(OH)D and 1,25(OH) 2 D concentrations with survival status. Vitamin D results were grouped into quintiles. For total 25(OH)D, specific cutoff values were also applied. Cox proportional hazard models were used adjusted for center, body mass index, smoking, alcohol, physical activity, season of blood sample, kidney function, and number of comorbidities. RESULTS: A total of 469 (23.5%) men died during a mean follow-up of 12.3 ±â€…3.4 years. Compared to those with normal vitamin D values (> 30 µg/L), men with a total 25(OH)D of less than 20 µg/L had an increased mortality (hazard ratio [HR] 2.03 [95% CI, 1.39-2.96]; P < .001). Likewise, men in the lowest 3 free 25(OH)D quintiles (< 4.43 ng/L) had a higher mortality risk compared to the highest quintile (HR 2.09 [95% CI, 1.34-3.25]; P < .01). Mortality risks were similar across all 1,25(OH)2D and vitamin D binding protein quintiles. CONCLUSION: Aging men with vitamin D deficiency have a 2-fold increased mortality risk. Determinations of either the free fractions of vitamin D or measurement of its active form offer no additional information on mortality risks.

Inflammatory markers are associated with quality of life, physical activity, and gait speed but not sarcopenia in aged men (40-79 years).

BACKGROUND: Age-related chronic low-grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia-defining parameters, quality of life (QoL), and physical activity in middle-aged and older men. METHODS: Men aged 40-79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003-2005) and again after a median follow-up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high-sensitive C-reactive protein (hs-CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF-36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole-body dual X-ray absorptiometry) and strength. In this subgroup, cross-sectional associations between baseline inflammatory markers and sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking. RESULTS: At baseline, hs-CRP and WBC were negatively associated with PASE score (hs-CRP: ß = -7.920, P < 0.001; and WBC: ß = -4.552, P < 0.001) and the physical component score of SF-36 (hs-CRP: ß = -1.025, P < 0.001; and WBC: ß = -0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (ß = -0.013; P = 0.025), quadriceps isometric 90° (ß = -5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (ß = -5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow-up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia-defining parameters between baseline and follow-up. CONCLUSIONS: In middle-aged and older men, hs-CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs-CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60-79 years). Baseline inflammatory markers (hs-CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia.

Erector spinae plane block for minimally invasive mitral valve surgery: a double-blind, prospective, randomised placebo-controlled trial-a study protocol.

INTRODUCTION: In the context of enhanced recovery after cardiac surgery, surgical techniques for mitral valve surgery have witnessed substantial modifications, from approaching the heart using open approaches with traditional sternotomy to thoracoscopic access via minithoracotomy. After cardiac surgery, acute postoperative pain is frequent and caused by surgical incision and retraction. Perioperative analgesia in cardiac surgery still relies mainly on opioids. Although neuraxial techniques could be a valuable non-opioid-based analgesia regimen, they can be associated with devastating complications in situations with (iatrogenic) coagulation abnormalities. Only two randomised clinical trials describe the erector spinae plane (ESP) block to provide sufficient postoperative analgesia following cardiac surgery with median sternotomy. Regarding postoperative analgesia after cardiac surgery with a minithoracotomy approach, adequately designed trials are still lacking. We, therefore, designed a double-blind, placebo-controlled trial to prove the hypothesis that the ESP block reduces opioid consumption in patients undergoing minimally invasive mitral valve surgery (MIMVS). METHODS AND ANALYSIS: Sixty-four patients undergoing MIMVS will be included in this double-blind, prospective, placebo-controlled trial. Patients will be randomised to receive an ESP block with a catheter with either intermittent ropivacaine 0.5% (ropi group) or normal saline 0.9% (placebo group). Both groups will receive patient-controlled intravenous analgesia with morphine following extubation. Primary endpoint is the 24-hour cumulative morphine consumption after extubation. Multiple secondary endpoints will be evaluated. ETHICS AND DISSEMINATION: The study is approved by the ethics committee of the University Hospitals Leuven, the Clinical Trials Centre of the University Hospitals Leuven and the 'Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten'. Dissemination of the study results will be via scientific papers. TRIAL REGISTRATION NUMBER: EudraCT identifier: 2019-001125-27.

Polypharmacy and excessive polypharmacy in community-dwelling middle aged and aged adults between 2011 and 2015.

AIMS: We aimed to assess the prevalence, components and evolution of polypharmacy and to evaluate risk factors associated with polypharmacy. METHODS: A retrospective dynamic cohort study was performed, using a primary healthcare database comprising Flemish community-dwelling adults aged ≥40 years between 2011 and 2015. Polypharmacy and excessive polypharmacy were defined as the use of 5-9 or minimum 10 different medications during 1 year, respectively. Temporal changes were analysed using an autoregressive error model. Risk factors for polypharmacy were evaluated using logistic regression. RESULTS: In total, 68 426 patients were included in the analysis. The prevalence of polypharmacy was 29.5% and 16.1% for excessive polypharmacy in 2015. The age-standardised prevalence rate of patients using minimum five medications increased with 1.3% per year (95% confidence interval (CI): 0.1968-2.4279). The mean number of unplanned hospital admissions was 0.07 (standard deviation (SD) 0.33) for polypharmacy patients and 0.19 (SD 0.53) for excessive polypharmacy patients. Four risk factors were found to be significantly correlated with polypharmacy: age (odds ratio (OR) 1.015; 95% CI: 1.013-1.017), female gender (OR 1.161; 95% CI: 1.108-1.216), number of chronic diseases (OR 1.126; 95% CI: 1.114-1.139) and number of general practitioner contacts (OR 1.283; 95% CI: 1.274-1.292). CONCLUSION: The prevalence of polypharmacy increased between 2011 and 2015. Polypharmacy and excessive polypharmacy patients appeared to differ based on our observations of characteristics, drug therapy and outcomes. Age, female gender, number of chronic diseases and number of general practitioner contacts were associated with polypharmacy.