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.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

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.

Education mediating the associations between early life factors and frailty: a cross-sectional study of the UK Biobank.

OBJECTIVES: Exposures in utero and during infancy may impact the development of diseases later in life. They may be linked with development of frailty, although the mechanism is unclear. This study aims to determine the associations between early life risk factors and development of frailty among middle-aged and older adults as well as potential pathways via education, for any observed association. DESIGN: A cross-sectional study. SETTINGS: This study used data from UK Biobank, a large population-based cohort. PARTICIPANTS: 502 489 individuals aged 37-73 years were included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Early life factors in this study included being breast fed as a baby, maternal smoking, birth weight, the presence of perinatal diseases, birth month and birth place (in or outside the UK). We developed a frailty index comprising 49 deficits. We used generalised structural equation modelling to examine the associations between early life factors and development of frailty and whether any observed association was mediated via educational attainment. RESULTS: A history of breast feeding and normal birth weight were associated with a lower frailty index while maternal smoking, the occurrence of perinatal diseases and birth month with a longer day length were associated with a higher frailty index. Educational level mediated the relationship between these early life factors and frailty index. CONCLUSIONS: This study highlights that biological and social risk occurring at different stages of life are related to the variations in frailty index in later life and suggests opportunities for prevention across the life course.

Household wealth, neighbourhood deprivation and frailty amongst middle-aged and older adults in England: a longitudinal analysis over 15 years (2002-2017).

BACKGROUND: frailty is a condition of reduced function and health due to ageing processes and is associated with a higher risk of falls, hospitalisation, disability and mortality. OBJECTIVE: to determine the relationship between household wealth and neighbourhood deprivation with frailty status, independently of demographic factors, educational attainment and health behaviours. DESIGN: population-based cohort study. SETTING: communities in England. SUBJECTS: in total 17,438 adults aged 50+ from the English Longitudinal Study of Ageing. METHODS: multilevel mixed-effects ordered logistic regression was used in this study. Frailty was measured using a frailty index. We defined small geographic areas (neighbourhoods) using English Lower layer Super Output Areas. Neighbourhood deprivation was measured by the English Index of Multiple Deprivation, grouped into quintiles. Health behaviours included in this study are smoking and frequency of alcohol consumption. RESULTS: the proportion of respondents who were prefrail and frail were 33.8% [95% confidence interval (CI) 33.0-34.6%] and 11.7 (11.1-12.2)%, respectively. Participants in the lowest wealth quintile and living in the most deprived neighbourhood quintile had 1.3 (95% CI = 1.2-1.3) and 2.2 (95% CI = 2.1-2.4) times higher odds of being prefrail and frail, respectively, than the wealthiest participants living in the least deprived neighbourhoods Living in more deprived neighbourhood and poorer wealth was associated with an increased risk of becoming frail. Those inequalities did not change over time. CONCLUSIONS: in this population-based sample, living in a deprived area or having low wealth was associated with frailty in middle-aged and older adults. This relationship was independent of the effects of individual demographic characteristics and health behaviours.

Patient and healthcare provider experience and perceptions of a preoperative rehabilitation class for lumbar discectomy: A qualitative study.

BACKGROUND: Lumbar disc disease is a leading cause of low back pain. Lumbar discectomy (LD) may be indicated if symptoms are not managed conservatively. Rehabilitation has traditionally been delivered postoperatively; however, there is increasing delivery preoperatively. There are few data concerning perceptions and experiences of preoperative rehabilitation. Exploring experiences of preoperative rehabilitation may help in the development and delivery of effective care for patients. OBJECTIVES: To develop an understanding of patient and healthcare provider (HCP) experiences, perspectives and preferences of preoperative LD rehabilitation, including why patients do not attend. DESIGN: A qualitative interpretive approach using focus groups and individual interviews. METHODS: Data were collected from; a) patients listed for surgery and attended the preoperative rehabilitation (October 2019 to March 2020), b) patients listed for surgery but did not attend rehabilitation, and c) HCPs involved in the delivery of rehabilitation. Data were transcribed verbatim and analysed using thematic analysis. RESULTS/FINDINGS: Twenty participants were included, twelve patients and eight HCPs. The preoperative class was a valuable service for both patients and HCPs. It provided a solution to staffing and time pressures. It provided the required education and exercise content helping the patients along their surgery pathway. Travel distance, transportation links, parking difficulty and cost, lack of knowledge about the class aims, and previous negative experiences were barriers to patient attendance. CONCLUSIONS: For most patients and HCPs, the preoperative class was valuable. Addressing the challenges and barriers could improve attendance. Future research should focus on management of patient expectations and preferences preoperatively.

The impact of frailty on patient-reported outcomes following hip and knee arthroplasty.

AIM: to determine the impact of frailty on patient-reported outcomes following hip and knee arthroplasty. METHODS: we used linked primary and secondary care electronic health records. Frailty was assessed using the electronic frailty index (categorised: fit, mild, moderate, severe frailty). We determined the association between frailty category and post-operative Oxford hip/knee score (OHS/OKS) using Tobit regression. We calculated the proportion of patients in each frailty category who achieved the minimally important change (MIC) in OHS (≥8 points) and OKS (≥7 points) and the proportion who reported a successful outcome (hip/knee problems either 'much better' or 'a little better' following surgery). RESULTS: About 42,512 people who had a hip arthroplasty and 49,208 who had a knee arthroplasty contributed data. In a Tobit model adjusted for pre-operative OHS/OKS, age, sex and quintile of index of multiple deprivation, increasing frailty was associated with decreasing post-operative OHS and OKS, respectively, ß-coefficient (95% CI) in severely frail versus fit, -6.97 (-7.44, -6.49) and - 5.88 (-6.28, -5.47). The proportion of people who achieved the MIC in OHS and OKS, respectively, decreased from 92 and 86% among fit individuals to 84 and 78% among those with severe frailty. Patient-reported success following hip and knee arthroplasty, respectively, decreased from 97 and 93% among fit individuals to 90 and 83% among those with severe frailty. CONCLUSION: frailty adversely impacts on patient-reported outcomes following hip and knee arthroplasty. However, even among those with severe frailty, the large majority achieved the MIC in OHS/OKS and reported a successful outcome.

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.

The impact of frailty on short-term mortality following primary total hip and knee arthroplasty due to osteoarthritis.

BACKGROUND: We determined the association between frailty and short-term mortality following total hip and knee arthroplasty (THA/TKA) for osteoarthritis and also the impact of THA/TKA on short-term mortality compared with a control population. METHODS: Frailty was assessed using a frailty index (categorised: fit, mild, moderate, severe frailty). The association between frailty and short-term mortality following THA/TKA was assessed using Cox regression. Mortality following THA/TKA was also compared with a control population with osteoarthritis but no previous THA/TKA, matched on year of birth, sex and quintile of index of multiple deprivation. RESULTS: A total of 103,563 cases who had a THA, 125,367 who had a TKA and matched controls contributed. Among those who had surgery, mortality increased with increasing frailty; adjusted hazard ratio (HR) (95% CI) at 30 days in severely frail versus fit: following THA, 2.85 (1.84, 4.39) and following TKA, 2.14 (1.29, 3.53). The predicted probability of 30-day mortality following THA/TKA varied by age, sex and frailty: following THA, from 0.05% among fit women aged 60-64 years to 6.55% among men with severe frailty aged ≥90 years. All-cause 30-day mortality was increased in fit cases following THA and TKA, respectively, versus fit controls (adjusted HR (95% CI), 1.60 (1.15, 2.21) and 2.98 (1.81, 4.89)), though not among cases with mild, moderate or severe frailty versus controls in the same frailty category. CONCLUSION: Short-term mortality increased with increasing frailty following THA/TKA. Comparison of mortality among cases and controls may be affected by a 'healthy surgery' selection effect.

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.

Physical therapy of patients undergoing first-time lumbar discectomy: a survey of current UK practice.

BACKGROUND: The type, timing, and extent of provision of rehabilitation for lumbar discectomy patients in the UK are currently unknown. The aim of this study was to determine the provision and type of rehabilitation for patients undergoing lumbar discectomy in UK neurosurgical centers. METHOD: Physical therapists involved in treating lumbar discectomy patients in UK neurosurgery centers were invited to complete an online survey that asked about the type, timing (preop, postop), and rehabilitation content for patients undergoing lumbar discectomy. RESULTS: Seventeen UK neurosurgery centers completed the survey. Twelve (36%) responded from the 33 centers targeted as well as an additional five private centers. All participating centers provided a rehabilitation service for lumbar discectomy patients. Rehabilitation was provided preoperatively in n = 6 (35%) centers, postoperatively as an inpatient in all centers, and postoperatively as an outpatient in n = 14 (82%) centers. Factors that influenced the decision to provide rehabilitation included both external and internal or patient-related factors. Preoperative rehabilitation focused mainly on education, whilst postoperative outpatient rehabilitation focused more on exercises. Rehabilitation consistently included mobility, functional task training, and exercise prescription. CONCLUSIONS: Whilst all neurosurgical centers in this survey provided some form of rehabilitation for patients undergoing LD surgery, the approach remains inconsistent. Rehabilitation was delivered most frequently postoperatively, with one in three centers providing it preoperatively. Rehabilitation content also varied depending on when it was provided. Further research is needed to determine the optimum timing, contents, and target of rehabilitation for patients undergoing LD surgery.

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.

Magnetic Resonance Imaging-Assessed Subchondral Cysts and Incident Knee Pain and Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: To examine whether knee subchondral cysts, measured on magnetic resonance imaging (MRI), are associated with incident knee osteoarthritis (OA) outcomes. METHODS: We used longitudinal data from the Multicenter Osteoarthritis Study, a community-based cohort of subjects with risk factors for knee OA. Participants without a history of knee surgery and/or inflammatory arthritis (i.e., rheumatoid arthritis and gout) were followed up for 84 months for the following incident outcomes: 1) radiographic knee OA (Kellgren/Lawrence grade ≥2), 2) symptomatic radiographic knee OA (radiographic knee OA and frequent knee pain), and 3) frequent knee pain (with or without radiographic knee OA). In a subset of participants, subchondral cysts were scored on baseline MRIs of 1 knee. Multiple logistic regression, with adjustment for participant characteristics and other baseline knee MRI findings, was used to assess whether subchondral cysts were predictive of incident outcomes. RESULTS: Among the participants with knees eligible for analyses of outcomes over 84 months, incident radiographic knee OA occurred in 22.8% of knees with no baseline radiographic knee OA, symptomatic radiographic knee OA occurred in 17.0% of knees with no baseline symptomatic radiographic knee OA, and frequent knee pain (with or without radiographic knee OA) occurred in 28.8% of knees with no baseline radiographic knee OA and 43.7% of knees with baseline radiographic knee OA. With adjustment for age, sex, and body mass index, the presence of subchondral cysts was not associated with incident radiographic knee OA but was associated with increased odds of incident symptomatic radiographic knee OA (odds ratio 1.92 [95% confidence interval 1.16-3.19]) and increased odds of incident frequent knee pain in those who had radiographic knee OA at baseline (odds ratio 2.11 [95% confidence interval 0.87-5.12]). Stronger and significant associations were observed for outcomes based on consistent reports of frequent knee pain within ~1 month of the study visit. CONCLUSION: Subchondral cysts are likely to be a secondary phenomenon, rather than a primary trigger, of radiographic knee OA, and may predict symptoms in knees with existing disease.

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.

The association between lower socioeconomic position and functional limitations is partially mediated by obesity in older adults with symptomatic knee osteoarthritis: Findings from the English Longitudinal Study of Ageing.

Objective: To assess the longitudinal associations of socioeconomic position (SEP) with functional limitations and knee joint replacement surgery (JRS) in people with symptomatic knee osteoarthritis (OA), and whether body mass index (BMI) mediated these relationships. Methods: Data came from the English Longitudinal Study of Ageing, a national longitudinal panel study of adults aged ≥50 years. A total of 1,499 participants (62.3% female; mean age 66.5 (standard deviation (SD) 9.4) years; 47.4% obese) self-reporting an OA diagnosis and knee pain, with at least one BMI measurement were included. Mixed effect models estimated longitudinal associations of each SEP variable (education, occupation, income, wealth and deprivation index) and obesity (BMI ≥30.0 kg/m2) with repeated measures of functional limitations. Cox regression analyses estimated associations between SEP indicators and obesity at baseline and risk of knee JRS at follow-up. Structural equation modeling estimated any mediating effects of BMI on these relationships. Results: Lower SEP and obesity at baseline were associated with increased odds of functional limitations in people with knee OA [e.g., difficulty walking 100 yards: no qualification vs. degree adjOR 4.33 (95% CI 2.20, 8.55) and obesity vs. no obesity adjOR 3.06 (95% CI 2.14, 4.37); similar associations were found for the other SEP indicators]. A small proportion of the association between lower SEP and functional limitations could be explained by BMI (6.2-12.5%). Those with lower income, lower wealth and higher deprivation were less likely to have knee JRS [e.g., adjHR most vs. least deprived 0.37 (95% CI 0.19, 0.73)]; however, no clear association was found for education and occupation. Obesity was associated with increased hazards of having knee JRS [adjHR 1.87 (95% CI 1.32, 2.66)]. As the direction of the associations for SEP and obesity with knee JRS were in opposite directions, no mediation analyses were performed. Conclusions: Lower SEP was associated with increased odds of functional limitations but lower hazards of knee JRS among people with knee OA, potentially indicating underutilization of JRS in those with lower SEP. Obesity partially mediated the relationship between lower SEP and increased odds of functional limitations, suggesting adiposity as a potential interventional target.

The effect of uncemented acetabular liner geometry and lip size on the risk of revision for instability or loosening : a study on 202,511 primary hip arthroplasties from the National Joint Registry.

AIMS: The aim of this study was to determine if uncemented acetabular polyethylene (PE) liner geometry, and lip size, influenced the risk of revision for instability or loosening. METHODS: A total of 202,511 primary total hip arthroplasties (THAs) with uncemented acetabular components were identified from the National Joint Registry (NJR) dataset between 2003 and 2017. The effect of liner geometry on the risk of revision for instability or loosening was investigated using competing risk regression analyses adjusting for age, sex, American Society of Anesthesiologists grade, indication, side, institution type, surgeon grade, surgical approach, head size, and polyethylene crosslinking. Stratified analyses by surgical approach were performed, including pairwise comparisons of liner geometries. RESULTS: The distribution of liner geometries were neutral (39.4%; 79,822), 10° (34.5%; 69,894), 15° (21.6%; 43,722), offset reorientating (2.8%; 5705), offset neutral (0.9%; 1,767), and 20° (0.8%; 1,601). There were 690 (0.34%) revisions for instability. Compared to neutral liners, the adjusted subhazard ratios of revision for instability were: 10°, 0.64 (p < 0.001); 15°, 0.48 (p < 0.001); and offset reorientating, 1.6 (p = 0.010). No association was found with other geometries. 10° and 15° liners had a time-dependent lower risk of revision for instability within the first 1.2 years. In posterior approaches, 10° and 15° liners had a lower risk of revision for instability, with no significant difference between them. The protective effect of lipped over neutral liners was not observed in laterally approached THAs. There were 604 (0.3%) revisions for loosening, but no association between liner geometry and revision for loosening was found. CONCLUSION: This registry-based study confirms a lower risk of revision for instability in posterior approach THAs with 10° or 15° lipped liners compared to neutral liners, but no significant difference between these lip sizes. A higher revision risk is seen with offset reorientating liners. The benefit of lipped geometries against revision for instability was not seen in laterally approached THAs. Liner geometry does not seem to influence the risk of revision for loosening. Cite this article: Bone Joint J 2021;103-B(12):1774-1782.

The effect of cemented acetabular component geometry on the risk of revision for instability or loosening : a study of 224,874 primary hip arthroplasties from the National Joint Registry.

AIMS: To determine if primary cemented acetabular component geometry (long posterior wall (LPW), hooded, or offset reorientating) influences the risk of revision total hip arthroplasty (THA) for instability or loosening. METHODS: The National Joint Registry (NJR) dataset was analyzed for primary THAs performed between 2003 and 2017. A cohort of 224,874 cemented acetabular components were included. The effect of acetabular component geometry on the risk of revision for instability or for loosening was investigated using log-binomial regression adjusting for age, sex, American Society of Anesthesiologists grade, indication, side, institution type, operating surgeon grade, surgical approach, polyethylene crosslinking, and prosthetic head size. A competing risk survival analysis was performed with the competing risks being revision for other indications or death. RESULTS: The distribution of acetabular component geometries was: LPW 81.2%; hooded 18.7%; and offset reorientating 0.1%. There were 3,313 (1.5%) revision THAs performed, of which 815 (0.4%) were for instability and 838 (0.4%) were for loosening. Compared to the LPW group, the adjusted subhazard ratio of revision for instability in the hooded group was 2.31 (p < 0.001) and 4.12 (p = 0.047) in the offset reorientating group. Likewise, the subhazard ratio of revision for loosening was 2.65 (p < 0.001) in the hooded group and 13.61 (p < 0.001) in the offset reorientating group. A time-varying subhazard ratio of revision for instability (hooded vs LPW) was found, being greatest within the first three months. CONCLUSION: This registry-based study confirms a significantly higher risk of revision after cemented THA for instability and for loosening when a hooded or offset reorientating acetabular component is used, compared to a LPW component. Further research is required to clarify if certain patients benefit from the use of hooded or offset reorientating components, but we recommend caution when using such components in routine clinical practice. Cite this article: Bone Joint J 2021;103-B(11):1669-1677.

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.

Assessment of bone marrow oedema-like lesions using MRI in patellofemoral knee osteoarthritis: comparison of different MRI pulse sequences.

OBJECTIVE: To compare bone marrow oedema-like lesion (BML) volume in subjects with symptomatic patellofemoral (PF) knee osteoarthritis (OA) using four different MRI sequences and to determine reliability of BML volume assessment using these sequences and their correlation with pain. METHODS: 76 males and females (mean age 55.8 years) with symptomatic patellofemoral knee OA had 1.5 T MRI scans. PD fat suppressed (FS), STIR, contrast-enhanced (CE) T1W FS, and 3D T1W fast field echo (FFE) sequences were obtained. All sequences were assessed by one reader, including repeat assessment of 15 knees using manual segmentation and the measurements were compared. We used random-effects panel linear regression to look for differences in the log-transformed BML volume (due to positive skew in the BML volume distribution) between sequences and to determine associations between BML volumes and knee pain. RESULTS: 58 subjects had PF BMLs present on at least one sequence. Median BML volume measured using T1W FFE sequence was significantly smaller (224.7 mm3, interquartile range [IQR] 82.50-607.95) than the other three sequences. BML volume was greatest on the CE sequence (1129.8 mm3, IQR 467.28-3166.02). Compared to CE sequence, BML volumes were slightly lower when assessed using PDFS (proportional difference = 0.79; 95% confidence interval [CI] 0.62, 1.01) and STIR sequences (proportional difference = 0.85; 95% CI 0.67, 1.08). There were strong correlations between BML volume on PDFS, STIR, and CE T1W FS sequences (ρs = 0.98). Correlations were lower between these three sequences and T1W FFE (ρs = 0.80-0.81). Intraclass correlation coefficients were excellent for proton density fat-suppressed, short-tau inversion recovery, and CE T1W FS sequences (0.991-0.995), while the ICC for T1W FFE was good at 0.88. We found no significant association between BML volumes assessed using any of the sequences and knee pain. CONCLUSION: T1W FFE sequences were less reliable and measured considerably smaller BML volume compared to other sequences. BML volume was larger when assessed using the contrast enhanced T1W FS though not statistically significantly different from BMLs when assessed using PDFS and STIR sequences. ADVANCES IN KNOWLEDGE: This is the first study to assess BMLs by four different MRI pulse sequences on the same data set, including different fluid sensitive sequences and gradient echo type sequence.