Prevalence, factors and quality of life associated with frailty and pre-frailty in middle-aged and older adults living with HIV in Zimbabwe: A cross-sectional study.

OBJECTIVES: We investigated associations between HIV, frailty and health-related quality of life (HRQoL). METHODS: This cross-sectional study recruited men and women aged ≥40 years in Zimbabwe. A researcher collected clinical and HRQoL data, and performed physical assessments and HIV testing. Frailty was defined using five criteria: unintentional weight loss, exhaustion, low physical activity, low gait speed, low handgrip strength. The presence of three or more criteria defined frailty, one to two pre-frailty, and zero non-frail. Data analysis used adjusted regression modelling. RESULTS: Of 1034 adults (mean ± SD, 62.0 ± 14.0 years), 21.6% (n = 223) were living with HIV: 93.3% knew their status, of whom 96.2% were on antiretroviral therapy (ART) and 89.7% of these had a viral load <50 copies/mL. Mean age at HIV diagnosis was 44.6 ± 10.4 years (only 8.1% were ≥70 years), people had been living with HIV for 9.8 ± 5.0 years and had been on ART for 9.4 ± 5.2 years. Overall, HIV was not associated with frailty: adjusted odds ratio (aOR) was 0.99 [95% confidence interval (CI): 0.42-2.33] for frailty versus non-frailty. However, each 5 years lived with HIV was associated with twice the odds of frailty/pre-frailty (aOR = 2.03, 95% CI: 1.03-4.13), independent of age and ART duration. Furthermore, each 5 years of ART use was associated with 60% lower odds of frailty/pre-frailty (aOR = 0.39, 95% CI: 0.19-0.78), independent of age and years lived with HIV. Older age, minimal education and poverty were associated with frailty. Frailty was associated with lower HRQoL in people both with and without HIV. CONCLUSION: Reduced survival and good viral suppression may explain the lack of association between HIV and frailty. Early ART initiation could reduce future risk of frailty.

The impact of HIV infection on skeletal maturity in peripubertal children in Zimbabwe: a cross-sectional study.

INTRODUCTION: HIV infection and its treatment compromises skeletal development (growth and maturation). Skeletal maturity is assessed as bone age (BA) on hand and wrist radiographs. BA younger than chronological age (CA) indicates delayed development. We conducted a cross-sectional study to determine differences between BA and CA (i.e., skeletal maturity deviation [SMD]), and risk factors associated with SMD in peripubertal children with and without HIV established on antiretroviral therapy (ART) including use of tenofovir disoproxil fumarate (TDF). METHODS: Children with HIV taking ART for at least two years and a comparison group of HIV-negative children, aged 8-16 years and frequency-matched by age and sex, were recruited from HIV clinics and local schools in the same catchment area, in Harare, Zimbabwe. BA was assessed from non-dominant hand-wrist radiographs using the Tanner Whitehouse 3 method. Negative SMD values correspond to delayed development, i.e., BA younger than CA. Multivariable linear regression models determined factors associated with SMD overall, and in children with HIV. RESULTS: In total, 534 participants (54% males) were included; by design CA was similar in males and females, whether living with or without HIV. Mean (SD) SMD was more negative in CWH than in HIV-negative children in both males [-1.4(1.4) vs. -0.4(1.1) years] and females [-1.1(1.3) vs. -0.0(1.2) years]. HIV infection and weight-for-age Z-score<-2 were associated with more negative SMD in both males and females after adjusting for socio-economic status, orphanhood, pubertal stage, and calcium intake. Age at ART initiation was associated with SMD in both males and females with those starting ART later more delayed: starting ART aged 4-8 years 1.14 (-1.84, -0.43), or over 8 years 1.47 (-2.30, -0.65) (p-value for trend < 0.001). Similar non-significant trends were seen in males. TDF exposure TDF exposure whether < 4years or ≥ 4 years was not associated with delayed development. CONCLUSION: Perinatally-acquired HIV infection and being underweight were independently associated with delayed skeletal maturation in both males and females. Starting ART later was independently associated with skeletal maturation delay in CWH. Given the known effects of delayed development on later health, it is important to find interventions to ensure healthy weight gain through early years and in CWH to initiate ART as early as possible.

Adjusting expected deaths for mortality displacement during the COVID-19 pandemic: a model based counterfactual approach at the level of individuals.

BACKGROUND: Near-real time surveillance of excess mortality has been an essential tool during the COVID-19 pandemic. It remains critical for monitoring mortality as the pandemic wanes, to detect fluctuations in the death rate associated both with the longer-term impact of the pandemic (e.g. infection, containment measures and reduced service provision by the health and other systems) and the responses that followed (e.g. curtailment of containment measures, vaccination and the response of health and other systems to backlogs). Following the relaxing of social distancing regimes and reduction in the availability of testing, across many countries, it becomes critical to measure the impact of COVID-19 infection. However, prolonged periods of mortality in excess of the expected across entire populations has raised doubts over the validity of using unadjusted historic estimates of mortality to calculate the expected numbers of deaths that form the baseline for computing numbers of excess deaths because many individuals died earlier than they would otherwise have done: i.e. their mortality was displaced earlier in time to occur during the pandemic rather than when historic rates predicted. This is also often termed "harvesting" in the literature. METHODS: We present a novel Cox-regression-based methodology using time-dependent covariates to estimate the profile of the increased risk of death across time in individuals who contracted COVID-19 among a population of hip fracture patients in England (N = 98,365). We use these hazards to simulate a distribution of survival times, in the presence of a COVID-19 positive test, and then calculate survival times based on hazard rates without a positive test and use the difference between the medians of these distributions to estimate the number of days a death has been displaced. This methodology is applied at the individual level, rather than the population level to provide a better understanding of the impact of a positive COVID-19 test on the mortality of groups with different vulnerabilities conferred by sociodemographic and health characteristics. Finally, we apply the mortality displacement estimates to adjust estimates of excess mortality using a "ball and urn" model. RESULTS: Among the exemplar population we present an end-to-end application of our methodology to estimate the extent of mortality displacement. A greater proportion of older, male and frailer individuals were subject to significant displacement while the magnitude of displacement was higher in younger females and in individuals with lower frailty: groups who, in the absence of COVID-19, should have had a substantial life expectancy. CONCLUSION: Our results indicate that calculating the expected number of deaths following the first wave of the pandemic in England based solely on historical trends results in an overestimate, and excess mortality will therefore be underestimated. Our findings, using this exemplar dataset are conditional on having experienced a hip fracture, which is not generalisable to the general population. Fractures that impede mobility in the weeks that follow the accident/surgery considerably shorten life expectancy and are in themselves markers of significant frailty. It is therefore important to apply these novel methods to the general population, among whom we anticipate strong patterns in mortality displacement - both in its length and prevalence - by age, sex, frailty and types of comorbidities. This counterfactual method may also be used to investigate a wider range of disruptive population health events. This has important implications for public health monitoring and the interpretation of public health data in England and globally.

Call to action: a five nations consensus on the use of intravenous zoledronate after hip fracture.

Currently in the UK and Ireland, after a hip fracture most patients do not receive bone protection medication to reduce the risk of refracture. Yet randomised controlled trial data specifically examining patients with hip fracture have shown that intravenous zoledronate reduces refracture risk by a third. Despite this evidence, use of intravenous zoledronate is highly variable following a hip fracture; many hospitals are providing this treatment, whilst most are currently not. A range of clinical uncertainties, doubts over the evidence base and practical concerns are cited as reasons. This paper discusses these concerns and provides guidance from expert consensus, aiming to assist orthogeriatricians, pharmacists and health services managers establish local protocols to deliver this highly clinically and cost-effective treatment to patients before they leave hospital, in order to reduce costly re-fractures in this frail population.

Disparities in the Prevalence of Osteoporosis and Osteopenia in Men and Women Living in Sub-Saharan Africa, the UK, and the USA.

PURPOSE: To review the rising prevalence of osteopenia and osteoporosis in sub-Saharan Africa and the challenges this poses to governments and healthcare services. Using existing studies, we compare the prevalence of osteopenia and osteoporosis in men and women from sub-Saharan Africa to US and UK cohorts. Context-specific disparities in healthcare are discussed particularly the challenges in diagnosis and treatment of osteoporosis. RECENT FINDINGS: There are few epidemiological data describing the burden of osteoporosis in sub-Saharan Africa. In the studies and cohorts presented here, osteoporosis prevalence varies by sex, country and area of residence, but is generally higher in African populations, than has previously been appreciated. Risk factors contributing to poorer bone health include HIV, malnutrition and "inflammaging." Reprioritization towards care of ageing populations is urgently required. Equitable access to implementable preventative strategies, diagnostic services, treatments and pathways of care for bone health (for example embedded within HIV services) need now to be recognized and addressed by policy makers.

Menopausal symptoms by HIV status and association with health-related quality of life among women in Zimbabwe: a cross-sectional study.

BACKGROUND: The scale-up of antiretroviral therapy programmes has resulted in increased life expectancy of people with HIV in Africa. Little is known of the menopausal experiences of African women, including those living with HIV. We aimed to determine the prevalence and severity of self-reported menopause symptoms in women at different stages of menopause transition, by HIV status, and evaluate how symptoms are related to health-related quality of life (HRQoL). We further sought to understand factors associated with menopause symptoms. METHODS: A cross-sectional study recruited women resident in Harare, Zimbabwe, sampled by age group (40-44/45-49/50-54/55-60 years) and HIV status. Women recruited from public-sector HIV clinics identified two similarly aged female friends (irrespective of HIV status) with phone access. Socio-demographic and medical details were recorded and women staged as pre-, peri- or post-menopause. The Menopausal Rating Scale II (MRS), which classified symptom severity, was compared between those with and without HIV. Linear and logistic regression determined factors associated with menopause symptoms, and associations between symptoms and HRQoL. RESULTS: The 378 women recruited (193[51.1%] with HIV), had a mean (SD) age of 49.3 (5.7) years; 173 (45.8%), 51 (13.5%) and 154 (40.7%) were pre-, peri and post-menopausal respectively. Women with HIV reported more moderate (24.9% vs. 18.1%) and severe (9.7% vs. 2.6%) menopause symptoms than women without HIV. Peri-menopausal women with HIV reported higher MRS scores than those pre- and post-menopausal, whereas in HIV negative women menopausal stage was not associated with MRS score (interaction p-value = 0.014). With increasing severity of menopause symptoms, lower mean HRQoL scores were observed. HIV (OR 2.02[95% CI 1.28, 3.21]), mood disorders (8.80[2.77, 28.0]), ≥ 2 falls/year (4.29[1.18, 15.6]), early menarche (2.33[1.22, 4.48]), alcohol consumption (2.16[1.01, 4.62]), food insecurity (1.93[1.14, 3.26]) and unemployment (1.56[0.99, 2.46]), were all associated with moderate/severe menopause symptoms. No woman reported use of menopausal hormone therapy. CONCLUSIONS: Menopausal symptoms are common and negatively impact HRQoL. HIV infection is associated with more severe menopause symptoms, as are several modifiable factors, including unemployment, alcohol consumption, and food insecurity. Findings highlight an unmet health need in ageing women in Zimbabwean, especially among those living with HIV.

Patients' recovery of mobility and return to original residence after hip fracture are associated with multiple modifiable components of hospital service organisation: the REDUCE record-linkage cohort study in England and Wales.

BACKGROUND: Hip fractures are devastating injuries causing disability, dependence, and institutionalisation, yet hospital care is highly variable. This study aimed to determine hospital organisational factors associated with recovery of mobility and change in patient residence after hip fracture. METHODS: A cohort of patients aged 60 + years in England and Wales, who sustained a hip fracture from 2016 to 2019 was examined. Patient-level Hospital Episodes Statistics, National Hip Fracture Database, and mortality records were linked to 101 factors derived from 18 hospital-level organisational metrics. After adjustment for patient case-mix, multilevel models were used to identify organisational factors associated with patient residence at discharge, and mobility and residence at 120 days after hip fracture. RESULTS: Across 172 hospitals, 165,350 patients survived to discharge, of whom 163,230 (99%) had post-hospital discharge destination recorded. 18,323 (11%) died within 120 days. Among 147,027 survivors, 58,344 (40%) across 143 hospitals had their residence recorded, and 56,959 (39%) across 140 hospitals had their mobility recorded, at 120 days. Nineteen organisational factors independently predicted residence on hospital discharge e.g., return to original residence was 31% (95% confidence interval, CI:17-43%) more likely if the anaesthetic lead for hip fracture had time allocated in their job plan, and 8-13% more likely if hip fracture service clinical governance meetings were attended by an orthopaedic surgeon, physiotherapist or anaesthetist. Seven organisational factors independently predicted residence at 120 days. Patients returning to their pre-fracture residence was 26% (95%CI:4-42%) more likely if hospitals had a dedicated hip fracture ward, and 20% (95%CI:8-30%) more likely if treatment plans were proactively discussed with patients and families on admission. Seventeen organisational factors predicted mobility at 120 days. More patients re-attained their pre-fracture mobility in hospitals where (i) care involved an orthogeriatrician (15% [95%CI:1-28%] improvement), (ii) general anaesthesia was usually accompanied by a nerve block (7% [95%CI:1-12%], and (iii) bedside haemoglobin testing was routine in theatre recovery (13% [95%CI:6-20%]). CONCLUSIONS: Multiple, potentially modifiable, organisational factors are associated with patient outcomes up to 120 days after a hip fracture, these factors if causal should be targeted by service improvement initiatives to reduce variability, improve hospital hip fracture care, and maximise patient independence.

Incidence and number of fragility fractures of the hip in South Africa: estimated projections from 2020 to 2050.

Sub-Saharan Africa is undergoing rapid population ageing and better understanding of the burden of musculoskeletal conditions is needed. We have estimated a large increase in the burden of hip fractures for South Africa over the coming decades. These findings should support preparation of hip fracture services to meet this demand. INTRODUCTION: A better understanding of the burden of fragility fractures in sub-Saharan Africa is needed to inform healthcare planning. We aimed to use recent hip fracture incidence data from South Africa (SA) to estimate the future burden of hip fracture for the country over the next three decades. METHODS: Hip fracture incidence data within the Gauteng, KwaZulu-Natal and Western Cape provinces of SA were obtained from patients aged ≥ 40 years with a radiograph-confirmed hip fracture in one of 94 included hospitals. Age-, sex- and ethnicity-specific incidence rates were generated using the 2011 SA census population for the study areas. Incidence rates were standardised to United Nations (UN) population projections, for the years 2020, 2030, 2040 and 2050, and absolute numbers of hip fractures derived. RESULTS: The 2767 hip fracture patients studied had mean (SD) age 73.7 (12.7) years; 69% were female. Estimated age- and ethnicity-standardised incidence rates (per 100,000 person-years) for the overall SA population in 2020 were 81.2 for females and 43.1 for males. Overall projected incidence rates were discernibly higher by the year 2040 and increased further by the year 2050 (109.0 and 54.1 for females and males, respectively). Estimates of the overall annual number of hip fractures for SA increased from approximately 11,000 in 2020 to approximately 26,400 by 2050. CONCLUSION: The hip fracture burden for SA is expected to more than double over the next 30 years. Significant investment in fracture prevention services and inpatient fracture care is likely to be needed to meet this demand.

Role of the Microbiome in Regulating Bone Metabolism and Susceptibility to Osteoporosis.

The human microbiota functions at the interface between diet, medication-use, lifestyle, host immune development and health. It is therefore closely aligned with many of the recognised modifiable factors that influence bone mass accrual in the young, and bone maintenance and skeletal decline in older populations. While understanding of the relationship between micro-organisms and bone health is still in its infancy, two decades of broader microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and pathogenesis of osteoporosis as well as its prevention and treatment. Pre-clinical research has demonstrated biological interactions between the microbiome and bone metabolism. Furthermore, observational studies and randomized clinical trials have indicated that therapeutic manipulation of the microbiota by oral administration of probiotics may influence bone turnover and prevent bone loss in humans. In this paper, we summarize the content, discussion and conclusions of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in October, 2020. We provide a detailed review of the literature examining the relationship between the microbiota and bone health in animal models and in humans, as well as formulating the agenda for key research priorities required to advance this field. We also underscore the potential pitfalls in this research field that should be avoided and provide methodological recommendations to facilitate bridging the gap from promising concept to a potential cause and intervention target for osteoporosis.

New national osteoporosis guidance-implications for geriatricians.

Fragility fractures are painful, debilitating, often life-changing and accounted for an estimated 2.4% of pre-pandemic health care spending in the UK. Those who are older, frail and multimorbid have the highest fracture risk and therefore the most to gain from anti-osteoporosis treatments to reduce this risk. Currently, an unacceptable treatment gap exists between those eligible for and those who receive treatment. This commentary discusses the major changes to the new, National Institute for Health and Care Excellence accredited, UK National Osteoporosis Guideline Group (NOGG) guidance (published March 2022) most relevant to the management of older people's bone health. Changes include intervention thresholds; using fracture probabilities from FRAX; for patients too frail to undergo DXA; greater emphasis on vertebral fracture detection and the use of intravenous zoledronate as a first-line anti-osteoporosis therapy; the new concept of 'very high fracture risk' which should prompt consideration of use of parenteral anti-osteoporosis therapy; new guidance regarding anabolic treatment options; concerns regarding denosumab cessation; and the urgent need to get patients with a fragility fracture onto treatment to reduce re-fracture risk with follow-up to check tolerance and ensure adherence.

Predictors of returning home after hip fracture: a prospective cohort study using the UK National Hip Fracture Database (NHFD).

INTRODUCTION: our objective was to describe trends in returning home after hospitalisation for hip fracture and identify predictive factors of this important patient-focussed outcome. METHODS: a cohort of hip fracture patients from England and Wales (2018-2019) resident in their own home pre-admission were analysed to identify patient and service factors associated with returning home after hospital discharge, and with living in their own home at 120 days. Geographical variation was also analysed. RESULTS: analysis of returning home at discharge included 87,797 patients; 57,104 (65%) were discharged home. Patient factors associated with lower likelihood of discharge home included cognitive impairment (odds ratio (OR) 0.60 [95% CI: 0.57, 0.62]), malnutrition (OR 0.81 [0.76, 0.86]), being at risk of malnutrition (OR 0.81 [0.78, 0.85]) and experiencing delay to surgery due to reversal of anti-coagulant medication (OR 0.84 [0.77, 0.92]). Corresponding service factors included surgery delay due to hospital logistical reasons (OR 0.91 [0.87, 0.95]) and early morning admission between 4:00 and 7:59 am (OR 0.83 [0.78, 0.89]). Nerve block prior to arrival at the operating theatre was associated with higher likelihood of discharge home (OR 1.07 [1.03, 1.11]). Most of these associations were stronger when analysing the outcome 'living in their own home at 120 days', in which two out of 11 geographic regions were found to have significantly more patients returning home. CONCLUSION: we identify numerous modifiable factors associated with short-term and medium-term return to own home after hip fracture, in addition to significant geographical variation. These findings should support improvements to care and inform future research.

Multiple hospital organisational factors are associated with adverse patient outcomes post-hip fracture in England and Wales: the REDUCE record-linkage cohort study.

OBJECTIVES: Despite established standards and guidelines, substantial variation remains in the delivery of hip fracture care across the United Kingdom. We aimed to determine which hospital-level organisational factors predict adverse patient outcomes in the months following hip fracture. METHODS: We examined a national record-linkage cohort of 178,757 patients aged ≥60 years who sustained a hip fracture in England and Wales in 2016-19. Patient-level hospital admissions datasets, National Hip Fracture Database and mortality data were linked to metrics from 18 hospital-level organisational-level audits and reports. Multilevel models identified organisational factors, independent of patient case-mix, associated with three patient outcomes: length of hospital stay (LOS), 30-day all-cause mortality and emergency 30-day readmission. RESULTS: Across hospitals mean LOS ranged from 12 to 41.9 days, mean 30-day mortality from 3.7 to 10.4% and mean readmission rates from 3.7 to 30.3%, overall means were 21.4 days, 7.3% and 15.3%, respectively. In all, 22 organisational factors were independently associated with LOS; e.g. a hospital's ability to mobilise >90% of patients promptly after surgery predicted a 2-day shorter LOS (95% confidence interval [CI]: 1.2-2.6). Ten organisational factors were independently associated with 30-day mortality; e.g. discussion of patient experience feedback at clinical governance meetings and provision of prompt surgery to >80% of patients were each associated with 10% lower mortality (95%CI: 5-15%). Nine organisational factors were independently associated with readmissions; e.g. readmissions were 17% lower if hospitals reported how soon community therapy would start after discharge (95%CI: 9-24%). CONCLUSIONS: Receipt of hip fracture care should be reliable and equitable across the country. We have identified multiple, potentially modifiable, organisational factors associated with important patient outcomes following hip fracture.

Osteosarcopenia: where osteoporosis and sarcopenia collide.

The coexistence of osteoporosis and sarcopenia has been recently considered in some groups as a syndrome termed 'osteosarcopenia'. Osteoporosis describes low bone mass and deterioration of the micro-architecture of the bone, whereas sarcopenia is the loss of muscle mass, strength and function. With an ageing population the prevalence of both conditions is likely to increase substantially over the coming decades and is associated with significant personal and societal burden. The sequelae for an individual suffering from both conditions together include a greater risk of falls, fractures, institutionalization and mortality. The aetiology of 'osteosarcopenia' is multifactorial with several factors linking muscle and bone function, including genetics, age, inflammation and obesity. Several biochemical pathways have been identified that are facilitating the development of several promising therapeutic agents, which target both muscle and bone. In the current review we outline the epidemiology, pathogenesis and clinical consequences of 'osteosarcopenia' and explore current and potential future management strategies.

Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis.

OBJECTIVES: How insulin-like growth factor-1 (IGF-1) is related to OA is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian randomization (MR) to determine causality. METHODS: Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using Hospital Episode Statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score as an instrument. Multivariable MR included BMI as an additional exposure (instrumented by BMI genetic risk score). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample MR (2SMR) using summary statistics from Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) (IGF-1, N = 30 884) and the recent genome-wide association study meta-analysis (N = 455 221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). RESULTS: A total of 332 092 adults in UK Biobank had complete data. Their mean (s.d.) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand OA [odds ratio per doubling = 0.87 (95% CI 0.82, 0.93)], and an increased odds of hip OA [1.04 (1.01, 1.07)], but was unrelated to knee OA [0.99 (0.96, 1.01)]. Using 1SMR, we found strong evidence for an increased risk of hip [odds ratio per s.d. increase = 1.57 (1.21, 2.01)] and knee [1.30 (1.07, 1.58)] OA with increasing IGF-1 concentration. By contrast, we found no evidence for a causal effect of IGF-1 concentration on hand OA [0.98 (0.57, 1.70)]. Results were consistent when estimated using 2SMR and in multivariable MR analyses accounting for BMI. CONCLUSION: We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Orthopaedic physiotherapists' perceptions of mechanisms for observed variation in the implementation of physiotherapy practices in the early postoperative phase after hip fracture: a UK qualitative study.

OBJECTIVE: to explore physiotherapists' perceptions of mechanisms to explain observed variation in early postoperative practice after hip fracture surgery demonstrated in a national audit. METHODS: a qualitative semi-structured interview study of 21 physiotherapists working on orthopaedic wards at seven hospitals with different durations of physiotherapy during a recent audit. Thematic analysis of interviews drawing on Normalisation Process Theory to aid interpretation of findings. RESULTS: four themes were identified: achieving protocolised and personalised care; patient and carer engagement; multidisciplinary team engagement across the care continuum and strategies for service improvement. Most expressed variation from protocol was legitimate when driven by what is deemed clinically appropriate for a given patient. This tailored approach was deemed essential to optimise patient and carer engagement. Participants reported inconsistent degrees of engagement from the multidisciplinary team attributing this to competing workload priorities, interpreting 'postoperative physiotherapy' as a single professional activity rather than a care delivery approach, plus lack of integration between hospital and community care. All participants recognised changes needed at both structural and process levels to improve their services. CONCLUSION: physiotherapists highlighted an inherent conflict between their intention to deliver protocolised care and allowing for an individual patient-tailored approach. This conflict has implications for how audit results should be interpreted, how future clinical guidelines are written and how physiotherapists are trained. Physiotherapists also described additional factors explaining variation in practice, which may be addressed through increased engagement of the multidisciplinary team and resources for additional staffing and advanced clinical roles.

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population.

OBJECTIVE: Bone turnover, which regulates bone mass, may exert metabolic consequences, particularly on markers of glucose metabolism and adiposity. To better understand these relationships, we examined cross-sectional associations between bone turnover markers (BTMs) and metabolic traits in a population with high bone mass (HBM, BMD Z-score ≥+3.2). DESIGN: ß-C-terminal telopeptide of type-I collagen (ß-CTX), procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin were assessed by electrochemiluminescence immunoassays. Metabolic traits, including lipids and glycolysis-related metabolites, were measured using nuclear magnetic resonance spectroscopy. Associations of BTMs with metabolic traits were assessed using generalized estimating equation linear regression, accounting for within-family correlation, adjusting for potential confounders (age, sex, height, weight, menopause, bisphosphonate and oral glucocorticoid use). RESULTS: A total of 198 adults with HBM had complete data, mean [SD] age 61.6 [13.7] years; 77% were female. Of 23 summary metabolic traits, citrate was positively related to all BTMs: adjusted ßß-CTX  = 0.050 (95% CI 0.024, 0.076), P = 1.71 × 10-4 , ßosteocalcin  = 6.54 × 10-4 (1.87 × 10-4 , 0.001), P = .006 and ßP1NP  = 2.40 × 10-4 (6.49 × 10-5 , 4.14 × 10-4 ), P = .007 (ß = increase in citrate (mmol/L) per 1 µg/L BTM increase). Inverse relationships of ß-CTX (ß = -0.276 [-0.434, -0.118], P = 6.03 × 10-4 ) and osteocalcin (-0.004 [-0.007, -0.001], P = .020) with triglycerides were also identified. We explored the generalizability of these associations in 3664 perimenopausal women (age 47.9 [4.4] years) from a UK family cohort. We confirmed a positive, albeit lower magnitude, association between ß-CTX and citrate (adjusted ßwomen  = 0.020 [0.013, 0.026], P = 1.95 × 10-9 ) and an inverse association of similar magnitude between ß-CTX and triglycerides (ß = -0.354 [-0.471, -0.237], P = 3.03 × 10-9 ). CONCLUSIONS: Bone resorption is positively related to circulating citrate and inversely related to triglycerides. Further studies are justified to determine whether plasma citrate or triglyceride concentrations are altered by factors known to modulate bone resorption, such as bisphosphonates.

Age at puberty and accelerometer-measured physical activity: Findings from two independent UK cohorts.

BACKGROUND: It is unclear if puberty timing influences future physical activity (PA). AIM: To investigate the association of puberty timing with PA across adolescence and adulthood. SUBJECTS AND METHODS: Data were from two British cohorts. Participants from an adolescent birth cohort (females = 2349, males = 1720) prospectively reported age at menarche and voice break and had PA recorded by Actigraph accelerometers at ages 14 years and 16 years. A cohort of middle-aged and older adults (40-70 years; females = 48,282; males = 36,112) recalled their age at puberty and had PA (mean acceleration; mg) measured by AxivityAX3 accelerometers. RESULTS: After adjustment for age, education, smoking and BMI, per 1-year older age at menarche was associated with higher mean counts/minute at age 14 years (0.07 SD counts/minute; 95% CI = 0.04-0.11) with associations attenuated at age 16 years (0.02; -0.03-0.07). Differences in mean acceleration per older year at menarche were close to the null in women aged 40-49 years (0.02 mg; 0.01-0.03), 50-59 years (0.01; 0.00-0.02) and 60-70 years (0.01; 0.00-0.01). Age at voice break and PA associations were close to the null in both cohorts. CONCLUSION: We found a positive association between puberty timing and PA in females which weakened at older ages and limited evidence of an association at any age in males.

Disability, social functioning and school inclusion among older children and adolescents living with HIV in Zimbabwe.

OBJECTIVE: Increasing numbers of children with HIV are surviving to adolescence and encountering multiple clinical and social consequences of long-standing HIV infection. We aimed to investigate the association between HIV and disability, social functioning and school inclusion among 6- to 16-year-olds in Zimbabwe. METHODS: HIV-infected children receiving antiretroviral therapy from a public-sector HIV clinic and HIV-uninfected children attending primary care clinics in the same catchment area were recruited. Standardised questionnaires were used to collect socio-demographic, social functioning and disability data. Multivariable logistic regression was used to assess the relationship between HIV status and disability and functioning. RESULTS: We recruited 202 HIV-infected and 285 HIV-uninfected children. There was no difference in age and gender between the two groups, but a higher proportion of HIV-infected children were orphaned. The prevalence of any disability was higher in HIV-infected than uninfected children (37.6% vs. 18.5%, P < 0.001). HIV-infected children were more likely to report anxiety (adjusted odds ratio (aOR) 4.4; 95% CI 2.4, 8.1), low mood (aOR 4.2; 2.1, 8.4) and difficulty forming friendships (aOR 14.8; 1.9, 116.6) than uninfected children. Children with HIV also reported more missed school days, repeating a school year and social exclusion in class. These associations remained apparent when comparing children with HIV and disability to those with HIV but no disabilities. CONCLUSIONS: Children with HIV commonly experience disabilities, and this is associated with social and educational exclusion. Rehabilitation and support services are needed to facilitate educational attainment and social participation in this group.

Model of multidisciplinary teamwork in hip fracture care: a qualitative interview study.

OBJECTIVES: Hip fractures are common injuries in older age with high mortality requiring multidisciplinary clinical care. Despite guidance, there is considerable variation in hip fracture services and patient outcomes; furthermore, little is known about how successful multidisciplinary working can be enabled. This study aimed to characterise professionals' views about the core components of multidisciplinary teamwork in hip fracture care. DESIGN: The study comprised qualitative interviews with healthcare professionals delivering hip fracture care. Interviews were audio recorded, transcribed and analysed abductively: material was coded inductively and grouped into higher level concepts informed by theories and frameworks relating to teamwork. SETTING: Four hospitals in England. PARTICIPANTS: Participants were 40 healthcare professionals including orthopaedic surgeons, orthogeriatricians, physiotherapists and service managers. RESULTS: Results identified four components of successful multidisciplinary teamwork: (1) defined roles and responsibilities, (2) information transfer processes, (3) shared goals and (4) collaborative leadership. These were underpinned by a single concept: shared responsibility. Defined roles and responsibilities were promoted through formal care pathways, reinforced through induction and training with clear job plans outlining tasks. Information transfer processes facilitated timely information exchange to appropriate individuals. Well-defined common purpose was hindered by complex interdisciplinary professional relationships, particularly between orthogeriatric and orthopaedic staff, and encouraged through multidisciplinary team meetings and training. Clinical service leads were integral to bridging interdisciplinary boundaries. Mutual trust and respect were based on recognition of the value of different professional groups. Teamwork depended on formal clinical leads with facilitative and motivational roles, and on hospital leadership that created an environment supporting collaboration. Shared responsibility for patients was encouraged by joint orthopaedic and orthogeriatric care models. Staff shared responsibility by assisting colleagues when needed. CONCLUSIONS: Shared responsibility across the multidisciplinary team is fundamental to delivery of hip fracture care. Findings will inform development of clinical practice recommendations and training to build teamworking competencies.