Life course longitudinal growth and risk of knee osteoarthritis at age 53 years: evidence from the 1946 British birth cohort study

Objective: To examine the relationship between height gain across childhood and adolescence with knee osteoarthritis in the MRC National Survey of Health and Development (NSHD). / Materials and methods: Data are from 3035 male and female participants of the NSHD. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at ages 20 years. Associations between (1) height at each age (2) height gain during specific life periods (3) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and knee osteoarthritis at 53 years were tested. / Results: In sex-adjusted models, estimated associations between taller height and decreased odds of knee osteoarthritis at age 53 years were small at all ages - the largest associations were an OR of knee osteoarthritis of 0.9 per 5 cm increase in height at age 4, (95% CI 0.7–1.1) and an OR of 0.9 per 5 cm increase in height, (95% CI 0.8–1.0) at age 6. No associations were found between height gain during specific life periods or the SITAR growth curve variables and odds of knee osteoarthritis. / Conclusions: There was limited evidence to suggest that taller height in childhood is associated with decreased odds of knee osteoarthritis at age 53 years in this cohort. This work enhances our understanding of osteoarthritis predisposition and the contribution of life course height to this

Clinical and cost-effectiveness analysis of an open label, single-centre, randomised trial of spinal cord stimulation (SCS) versus percutaneous myocardial laser revascularisation (PMR) in patients with refractory angina pectoris: The SPiRiT trial.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Patients with refractory angina have significant morbidity. This study aimed to compare two of the treatment options, Spinal Cord Stimulation (SCS) and Percutaneous Myocardial Laser Revascularisation (PMR) in terms of clinical outcomes and cost-effectiveness. METHODS: Eligible patients were randomised to PMR or SCS and followed up for exercise tolerance time (ETT), Canadian Cardiovascular Society (CCS) classification and the quality of life measures SF-36, Seattle Angina Questionnaire and the EuroQoL at 3, 12 and 24 months. Utilities were calculated using the EQ-5D and these and costs were compared between groups. The incremental cost-effectiveness ratio (ICER) per QALY for SCS compared to PMR was also calculated. RESULTS: At 24 months post-randomisation, patients that had SCS and PMR had similar ETT (mean difference 0.05, 95% CI -2.08, 2.18, p = 0.96) and there was no difference in CCS classification or quality of life outcomes. The difference in overall mean costs when comparing SCS to PMR was GBP5,520 (95% CI GBP1,966 to GBP8,613; p < 0.01) and the ICER of using SCS was GBP46,000 per QALY. CONCLUSION: Outcomes after SCS did not differ appreciably from those after PMR, with the former procedure being less cost-effective as currently applied. Larger studies could clarify which patients would most benefit from SCS, potentially increasing cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09648950.Published versio

Using Super-Imposition by Translation And Rotation (SITAR) to relate pubertal growth to bone health in later life: the Medical Research Council (MRC) National Survey of Health and Development.

BACKGROUND: To explore associations between pubertal growth and later bone health in a cohort with infrequent measurements, using another cohort with more frequent measurements to support the modelling, data from the Medical Research Council (MRC) National Survey of Health and Development (2-26 years, 4901/30 004 subjects/measurements) and the Avon Longitudinal Study of Parents And Children (ALSPAC) (5-20 years) (10 896/74 120) were related to National Survey of Health and Development (NSHD) bone health outcomes at 60-64 years. METHODS: NSHD data were analysed using Super-Imposition by Translation And Rotation (SITAR) growth curve analysis, either alone or jointly with ALSPAC data. Improved estimation of pubertal growth parameters of size, tempo and velocity was assessed by changes in model fit and correlations with contemporary measures of pubertal timing. Bone outcomes of radius [trabecular volumetric bone mineral density (vBMD) and diaphysis cross-sectional area (CSA)] were regressed on the SITAR parameters, adjusted for current body size. RESULTS: The NSHD SITAR parameters were better estimated in conjunction with ALSPAC, i.e. more strongly correlated with pubertal timing. Trabecular vBMD was associated with early height tempo, whereas diaphysis CSA was related to weight size, early tempo and slow velocity, the bone outcomes being around 15% higher for the better vs worse growth pattern. CONCLUSIONS: By pooling NSHD and ALSPAC data, SITAR more accurately summarized pubertal growth and weight gain in NSHD, and in turn demonstrated notable associations between pubertal timing and later bone outcomes. These associations give insight into the importance of the pubertal period for future skeletal health and osteoporosis risk.NSHD: The authors are grateful to NSHD study members who took part in the clinic data collection for their continuing support. We thank members of the NSHD scientific and data collection teams at the following centres: MRC Unit for Lifelong Health and Ageing; Wellcome Trust (WT) Clinical Research Facility (CRF) Manchester; WTCRF and Medical Physics at the Western General Hospital in Edinburgh; WTCRF and Department of Nuclear Medicine at University Hospital Birmingham; WTCRF and the Department of Nuclear Medicine at University College London Hospital; CRF and the Department of Medical Physics at the University Hospital of Wales; CRF and Twin Research Unit at St Thomas’ Hospital London. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The research was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Oxford Univeristy Press

The effect of phase chemistry on the extent of strengthening mechanisms in model Ni-Cr-Al-Ti-Mo based superalloys

The exceptional mechanical properties of polycrystalline nickel-based superalloys arise through various concurrent strengthening mechanisms. Whilst these mechanisms are generally understood, consensus has yet to be established on the precise contribution of each to the overall alloy strength. Furthermore, changes in alloy chemistry influence several different mechanisms, making the assessment of individual alloying elements complex. In this study, a series of model quinary Ni-based superalloys has been investigated to systematically study the effect of varying Mo content on the contributing strengthening mechanisms. Using microstructural data, the yield strength was modelled by summing the individual effects of solid solution in both the γ and γ ' phases, coherency, grain boundary and precipitation strengthening. The total predicted yield stress increased with Mo content despite the diminishing contribution of precipitation strengthening. It is shown that solid solution strengthening of the ordered γ' precipitate phase is a key contributor to the overall strength, and that variations in composition between the tertiary and secondary γ ' lead to significant changes in mechanical properties that should be accounted for in models of alloy strength.Funding was provided by the EPSRC/Rolls-Royce Strategic Partnership under EP/M005607/1 and EP/H022309/1. The Oxford Atom Probe facility was funded by the EPSRC under EP/M022803/1. E. I. Galindo-Nava would like to acknowledge the Royal Academy of Engineering for his fellowship funding. Neutron diffraction beam time was supported through the Canadian Neutron Beam Centre under Experiment number 1258

White matter abnormalities in active elite adult rugby players

The recognition, diagnosis and management of mild traumatic brain injuries are difficult and confusing. It is unclear how the severity and number of injuries sustained relate to brain injuries, such as diffuse axonal injury, diffuse vascular injury and progressive neurodegeneration. Advances in neuroimaging techniques enable the investigation of neuropathologies associated with acute and long-term effects of injury. Head injuries are the most commonly reported injury seen during professional rugby. There is increased vigilance for the immediate effects of these injuries in matches, but there has been surprisingly little research investigating the longer-term effects of rugby participation. Here, we present a longitudinal observational study investigating the relationship of exposure to rugby participation and sub-acute head injuries in professional adult male and female rugby union and league players using advanced MRI. Diffusion tensor imaging and susceptibility weighted imaging was used to assess white matter structure and evidence of axonal and diffuse vascular injury. We also studied changes in brain structure over time using Jacobian Determinant statistics extracted from serial volumetric imaging. We tested 41 male and 3 female adult elite rugby players, of whom 21 attended study visits after a head injury, alongside 32 non-sporting controls, 15 non-collision-sport athletic controls and 16 longitudinally assessed controls. Eighteen rugby players participated in the longitudinal arm of the study, with a second visit at least 6 months after their first scan. Neuroimaging evidence of either axonal injury or diffuse vascular injury was present in 23% (10/44) of players. In the non-acutely injured group of rugby players, abnormalities of fractional anisotropy and other diffusion measures were seen. In contrast, non-collision-sport athletic controls were not classified as showing abnormalities. A group level contrast also showed evidence of sub-acute injury using diffusion tensor imaging in rugby players. Examination of longitudinal imaging revealed unexpected reductions in white matter volume in the elite rugby players studied. These changes were not related to self-reported head injury history or neuropsychological test scores and might indicate excess neurodegeneration in white matter tracts affected by injury. Taken together, our findings suggest an association of participation in elite adult rugby with changes in brain structure. Further well-designed large-scale studies are needed to understand the impact of both repeated sports-related head impacts and head injuries on brain structure, and to clarify whether the abnormalities we have observed are related to an increased risk of neurodegenerative disease and impaired neurocognitive function following elite rugby participation

The effect of Ni:Co ratio on the elemental phase partitioning in γ-γ′ Ni-Co-Al-Ti-Cr alloys

Atom probe tomography has been used to characterise the effect of varying Ni:Co ratio on elemental phase partitioning at 800 °C in γ-γ′ alloys derived from the Ni-Co-Al-Ti-Cr system. In all alloys tested, Al and Ti were found to partition preferentially to the γ′ phase, whereas Co and Cr partitioned preferentially to the γ phase. However, above a critical Co content (~19 at.%), the extent of partitioning of Al and Ti to the γ′ phase reduced. Conversely, Cr partitioned more strongly to the γ phase with Co additions of up to ~19 at.%, above which this preferential segregation was less pronounced. This non-monotonic trend of elemental partitioning behaviour with increasing Co concentration was attributed to a transition in the chemistry of the L1$_2$ γ′ phase from Ni$_3$(Ti, Al) to (Ni, Co)$_3$(Ti, Al) and thus to a change in its solute solubility.This work was supported by the Rolls-Royce EPSRC Strategic Partnership under EP/H022309/1 and EP/M005607/1, by the University of Michigan College of Engineering (funding) and by the Michigan Center for Materials Characterization (instruments)

An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital

Pneumocystis jirovecii pneumonia (PCP) is associated with high mortality in immunocompromised patients without human immunodeficiency virus infection. However, chemoprophylaxis is highly effective. In patients with solid tumours or haematologic malignancy, several risk factors for developing PCP have been identified, predominantly corticosteroid therapy. The aims of this study were to identify the potentially preventable cases of PCP in patients receiving corticosteroid therapy at a tertiary care cancer centre and to estimate the frequency of utilisation of chemoprophylaxis in these patients. Two retrospective reviews were performed. Over a 10-year period, 14 cases of PCP were identified: no cases were attributable to failed chemoprophylaxis, drug allergy or intolerance. During a 6-month period, 73 patients received high-dose corticosteroid therapy (⩾25 mg prednisolone or ⩾4 mg dexamethasone daily) for ⩾4 weeks. Of these, 22 (30%) had haematologic malignancy, and 51 (70%) had solid tumours. Fewer patients with solid tumours received prophylaxis compared to patients with haematologic malignancy (3.9 vs 63.6%, P<0.0001). Guidelines for PCP chemoprophylaxis in patients with haematologic malignancy or solid tumours who receive corticosteroid therapy are proposed. Successful primary prevention of PCP in this population will require a multifaceted approach targeting the suboptimal prescribing patterns for chemoprophylaxis

Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study

Objectives: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson’s disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. Methods: We prospectively recruited patients with PD in the Tracking Parkinson’s study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. Results: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher’s disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. Conclusions: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD. Clinical trial registration: NCT02881099; Results

Menopause, reproductive life, hormone replacement therapy and bone phenotype at age 60-64: a British birth cohort

CONTEXT: Previous studies of menopausal age and length of reproductive life on bone are limited by retrospective reproductive histories, being cross sectional, or lacking gold standard bone technologies, or information on hormone replacement therapy (HRT) or surgical treatment. OBJECTIVE: To investigate age at menopause, length of reproductive life and HRT use in relation to volumetric and areal bone mineral density (vBMD, aBMD), bone size and strength in women aged 60-64. DESIGN: A birth cohort study followed for 64 years with prospective measures of age at menarche and menopause and monthly HRT histories. SETTING: England, Scotland, Wales Participants: 848 women with known type of menopause and bone measures at 60-64 years Main outcome measures: Peripheral quantitative computed tomography (pQCT) measurements of the distal radius total and trabecular vBMD; diaphyseal radius total and medullary cross sectional area, cortical vBMD and polar strength strain index (SSI); dual energy x-ray absorptiometry (DXA) measurments of aBMD at the lumbar spine and total hip. RESULTS: A ten year increase in age at natural (but not surgical) menopause was associated with 8.2% (95% CI: 1.3,15.1%, p=.02) greater trabecular vBMD and a 6.0% (95% CI 0.51,11.5%, p=.03) greater total vBMD; findings were similar for length of reproductive life. A ten year difference in HRT use was associated with a 6.0% (95% CI 2.6%,9.3%, p<.001) greater polar SSI and a 0.9% (95% CI 0.4%, 1.5%, p=.001) greater cortical vBMD. These estimates changed little on adjustment. Estimates for aBMD were consistent with those for pQCT. CONCLUSIONS: The positive effects on trabecular vBMD of later natural menopause and longer reproductive life persisted into early old age. HRT use was associated with greater radius cortical vBMD and polar SSI, and spine aBMD