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).

Insulin-like peptide 3 (INSL3) as an indicator of leydig cell insufficiency (LCI) in Middle-aged and older men with hypogonadism: reference range and threshold.

Insulin-like peptide 3 (INSL3) is a circulating biomarker for Leydig cell functional capacity in men, also indicating Leydig Cell Insufficiency (LCI) and potential primary hypogonadism. Using results from large cohort studies we explore sources of biological and technical variance, and establish a reference range for adult men. It is constitutively secreted with little within-individual variation and reflects testicular capacity to produce testosterone. The main INSL3 assays available indicate good concordance with low technical variance; there is no effect of ethnicity. INSL3 declines with age from 35 years at about 15% per decade. Like low calculated free testosterone, and to a lesser extent low total testosterone, reduced INSL3 is significantly associated with increasing age-related morbidity, including lower overall sexual function, reflecting LCI. Consequently, low INSL3 (≤0.4 ng/ml; ca. <2 SD from the population mean) might serve as an additional biochemical marker in the assessment of functional hypogonadism (late-onset hypogonadism, LOH) where testosterone is in the borderline low range. Excluding individuals with low LCI (INSL3 ≤ 0.4 ng/ml) leads to an age-independent (> 35 years) reference range (serum) for INSL3 in the eugonadal population of 0.4 - 2.3 ng/ml, with low INSL3 prospectively identifying individuals at risk of increased future morbidity.

Experiences of postmenopausal osteoporosis: a narrative review.

PURPOSE: A narrative review was conducted to identify, critically appraise, and synthesise primary research on the lived experiences of postmenopausal women with osteoporosis. MATERIALS AND METHODS: A systematic search of qualitative studies published between January 1960 and August 2021 was conducted across seven databases. The selected qualitative studies reported the lived experiences of postmenopausal women with osteoporosis, both with and without a history of fragility fractures. RESULTS: A total of 17 publications (n = 334) were identified. These results suggest that osteoporosis and fragility fractures significantly affected postmenopausal women's lives. They reported difficulties in carrying out daily activities due to pain and change in their routines to cope with health problems. Some women were satisfied with the information provided by healthcare professionals. Their medicine adherence was also determined by their belief in the importance of their scheduled treatment for osteoporosis. CONCLUSION: Qualitative studies that explored the lived experiences of postmenopausal women with osteoporosis can provide important insights into the impact of the disease on women's lives and potential pathways for improving care and management.Implications for rehabilitationOsteoporosis and fragility fractures affect the quality of life of postmenopausal women worldwide.The provision of targeted and tailored health information for postmenopausal women with osteoporosis is paramount in improving their health literacy and aiding in the long-term management of their bone health.What is already knownOsteoporosis and related fragility fractures are common, affecting more than 200 million people worldwide, including three million people in the UK.Osteoporotic fractures have significant clinical and public health impacts.What this study addsOsteoporosis, particularly fragility fractures, has a significant impact on the lives of postmenopausal women, including pain and functional impairment.Women's belief in the importance of their scheduled treatment plays a significant role in their concordance with the prescribed medications for osteoporosis.Provision of targeted health information for postmenopausal women with osteoporosis is key to their involvement in decision-making and disease management.

Does testosterone influence the association between sleep and frailty in men: results from the European Male Aging Study.

BACKGROUND: Previous studies have suggested an association between sleep disturbance and frailty. The mechanism is unknown, although it has been suggested that hormonal factors may play a role. METHODS: The aim was to determine the association between sleep duration, sleep quality and frailty, and to determine whether testosterone influenced this association. Males aged 40-79 years were recruited from eight European centres to the European Male Aging Study (EMAS). Subjects completed an interviewer-assisted questionnaire including questions regarding sleep quality and duration. Sleep quality was scored 0-20 and categorised as 0-4, 5-9, 10-14, and 15-20, with higher scores indicating poorer quality. A 39-component frailty index (FI) was constructed. Total testosterone levels were measured. The association between sleep duration, sleep quality and the FI was assessed using negative binomial regression, with adjustment for putative confounders including testosterone level. RESULTS: Two thousand three hundred ninety-three participants contributed data to the analysis. The mean age was 63.3 years and mean sleep duration was 7.01 h. The mean frailty index was 0.15. Mean testosterone levels declined with decreasing sleep quality. After adjustment, compared to those with a sleep score of 0-4, the FI was 57% (95% CI 38%, 78%) higher among those with a sleep score of 15-20. After adjustment compared to those with normal sleep duration (6-9 h), those with a short (< 6 h) and long (≥ 9 h) sleep duration had a 16% (95% CI 6%, 28%) and 11% (95% CI 0%, 23%) higher FI, respectively. Adjustment for testosterone did not influence the strength of either association. CONCLUSION: Frailty is associated with impaired sleep quality and sleep duration. The association cannot, however, be explained by variation in testosterone levels.

Variation in UK fracture liaison service consultation conduct and content before and during the COVID pandemic: results from the iFraP-D UK survey.

We conducted a survey of FLSs' consultation conduct and content which identified marked variation in whether FLS HCPs discussed osteoporosis medicine with patients. A review of service pro formas showed more content related to 'investigating' and 'intervening' than to 'informing'. We propose an expanded FLS typology and model FLS pro forma. PURPOSE: To investigate the nature of direct patient contact in fracture liaison service (FLS) delivery, examine the use and content of pro formas to guide information eliciting and sharing in FLS consultations, and determine service changes which were implemented as a result of the COVID-19 pandemic. METHODS: An electronic survey of UK FLS healthcare practitioners (HCPs) was distributed through clinical networks, social media, and other professional networks. Participants were asked to upload service pro formas used to guide consultation content. Documentary analysis findings were mapped to UK FLS clinical standards. RESULTS: Forty-seven HCPs responded, providing data on 39 UK FLSs, over half of all 74 FLSs reporting to FLS-database. Results showed variation in which HCP made clinical decisions, whether medicines were discussed with patients or not, and in prescribing practice. Services were variably affected by COVID, with most reporting a move to more remote consulting. The documentary analysis of eight service pro formas showed that these contained more content related to 'investigating' and 'intervening', with fewer pro formas prompting the clinician to offer information and support (e.g., about coping with pain). Based on our findings we propose an expanded FLS typology and have developed a model FLS pro forma. CONCLUSION: There is marked variation in the delivery of services and content of consultations in UK FLSs including discussion about osteoporosis medications. Clinical standards for FLSs should clarify the roles of primary and secondary HCPs and the importance of holistic approaches to patient care.

Number of CAG repeats and mortality in middle aged and older men.

DESIGN: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. PATIENTS AND MEASUREMENTS: Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). RESULTS: One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. CONCLUSIONS: Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

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).

Impact of postmenopausal osteoporosis on the lives of Omani women and the use of cultural and religious practises to relieve pain: A hermeneutic phenomenological study.

INTRODUCTION: Osteoporosis is a significant clinical and public health concern worldwide. Despite the impact of this condition on women's lives, most studies have focused on its clinical manifestations, drug efficacy, and medical treatment. Furthermore, most studies have been conducted in the West. This study aimed to uncover the personal experiences of postmenopausal Omani women living with osteoporosis. METHODS: In this interpretive phenomenological study, a purposive sample of 15 postmenopausal Omani women with osteoporosis was recruited from primary and secondary care facilities in Muscat, Oman. Semi-structured one-to-one interviews were conducted via Zoom and telephone because of coronavirus disease 2019 restrictions. The interviews were audio-recorded, and the Ajjawi and Higgs framework was used to analyse the data thematically. RESULTS: The following key themes were constructed from the interviews: the impact of osteoporosis on religious practices, cultural and social life, and financial status, and the benefits derived from religious and cultural practices and rituals, including Muslim prayer, recitation of Quranic verses, and herbal remedies to cope with osteoporosis-related pain and suffering. CONCLUSION: Osteoporosis and fragility fractures have a significant impact on the religious, cultural, and financial lives of postmenopausal Omani women with osteoporosis. Muslim prayers, recitation of Quranic verses, and herbal remedies are coping strategies for pain in this population. PATIENT OR PUBLIC CONTRIBUTION: Postmenopausal Omani women with osteoporosis participated in this study through interviews and contributed their lived experiences. Orthopaedic doctors helped recruit patients with postmenopausal osteoporosis.

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.

Day-to-day variability of knee pain and the relationship with physical activity in people with knee osteoarthritis: an observational, feasibility study using consumer smartwatches.

OBJECTIVE: To assess the feasibility of using smartwatches in people with knee osteoarthritis (OA) to determine the day-to-day variability of pain and the relationship between daily pain and step count. DESIGN: Observational, feasibility study. SETTING: In July 2017, the study was advertised in newspapers, magazines and, on social media. Participants had to be living/willing to travel to Manchester. Recruitment was in September 2017 and data collection was completed in January 2018. PARTICIPANTS: 26 participants aged>50 years with self-diagnosed symptomatic knee OA were recruited. OUTCOME MEASURES: Participants were provided with a consumer cellular smartwatch with a bespoke app that triggered a series of daily questions including two times per day questions about level of knee pain and one time per month question from the pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The smartwatch also recorded daily step counts. RESULTS: Of the 25 participants, 13 were men and their mean age was 65 years (standard deviation (SD) 8 years). The smartwatch app was successful in simultaneously assessing and recording data on knee pain and step count in real time. Knee pain was categorised into sustained high/low or fluctuating levels, but there was considerable day-to-day variation within these categories. Levels of knee pain in general correlated with pain assessed by KOOS. Those with sustained high/low levels of pain had a similar daily step count average (mean 3754 (SD 2524)/4307 (SD 2992)), but those with fluctuating pain had much lower step count levels (mean 2064 (SD 1716)). CONCLUSIONS: Smartwatches can be used to assess pain and physical activity in knee OA. Larger studies may help inform a better understanding of causal links between physical activity patterns and pain. In time, this could inform development of personalised physical activity recommendations for people with knee OA.

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.

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.

Development, validation and performance of laboratory frailty indices: A scoping review.

INTRODUCTION: Frailty is a syndrome characterised by decline in functional ability and increasing vulnerability to disease and associated with adverse outcomes. Several established methods exist for assessing frailty. This scoping review aims to characterise the development and validation of frailty indices based on laboratory test results (FI-Lab) and to assess their utility. METHODS: Studies were included in the review if they included data concerning the development and/or testing an FI-Lab using the deficit accumulation method. Studies were identified using PubMed/MEDLINE, Embase (Elsevier), OpenGrey and Google Scholar from 2010 to 2021. Two reviewers independently screened all abstracts, and those that met the inclusion criteria were reviewed in detail. Data extracted included details about the study characteristics, number, type and coding of laboratory variables included, validation, and outcomes. A narrative synthesis of the available evidence was adopted. RESULTS: The search yielded 915 articles, of which 29 studies were included. In general, 89% of studies were conducted after 2016 and 51% in a hospital-based setting. The number of variables included in FI-Labs ranged from 13 to 77, and 51% included some non-laboratory variables in their indices, with pulse and blood pressure being the most frequent. The validity of FI-Lab was demonstrated through change with age, correlation with established frailty indices and association with adverse health outcomes. The most frequent outcome studied was mortality (79% of the studies), with FI-Lab associated with increased mortality in all but one. Other outcomes studied included self-reported health, institutionalisation, and activities of daily living. The effect of combining the FI-Lab with a non-laboratory-based FI was assessed in 7 studies with a marginal increase in predictive ability. CONCLUSION: Frailty indices constructed based on the assessment of laboratory variables, appear to be a valid measure of frailty and robust to the choice of variables included.

A prospective analysis examining frailty remission and the association with future falls risk in older adults in England.

BACKGROUND: Previous research has shown older adults experience dynamic changes in frailty status. This study aimed to determine the occurrence of sustained frailty remission and how remission is associated with falls risk. METHODS: Participants who contributed data to the analysis were in the English Longitudinal Study of Ageing from Waves 1 to 8 (2002-2017). Frailty was defined across waves using the frailty index and categorised into robust, pre-frail and frail. We classified participants who improved their frailty category from Wave 1 (2002) to Wave 2 (2004) and sustained/improved category again into Wave 3 (2006) and compared them with those who were either robust or frail across Waves 1-3. Cox proportional hazard modelling was used to determine the risk of incident falls reported at Waves 4-8, with results expressed as hazard ratios and 95% confidence intervals. RESULTS: Of 2,564 participants, 389 (15·2%) improved frailty category and sustained this during Waves 2-3, 1,489 (58·1%) remained robust and 686 (26·8%) remained frail during Waves 1-3. During the 10-year period (Waves 4-8), a total of 549 participants reported a fall. Compared with those who remained frail during Waves 1-3, those who with sustained frailty remission had a lower risk of future falls (HR 0·41; 95% CI = 0·36-0·45). CONCLUSIONS: Frailty remission is possible and can be sustained across 5 years. There is a lower risk of future falls in those who sustain frailty remission compared with those who remain frail.

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.

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.

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.

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.