MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Risk of severe COVID-19 in patients with inflammatory rheumatic diseases treated with immunosuppressive therapy in Scotland.

OBJECTIVE: To investigate the association of severe coronavirus disease 2019 (COVID-19) in patients with inflammatory rheumatic diseases (IRDs) treated with immunosuppressive drugs. METHOD: A list of 4633 patients on targeted - biological or targeted synthetic - DMARDs in March 2020 was linked to a case-control study that includes all cases of COVID-19 in Scotland. RESULTS: By 22 November 2021, 433 of the 4633 patients treated with targeted DMARDS had been diagnosed with COVID-19, of whom 58 had been hospitalized. With all those in the population not on DMARDs as the reference category, the rate ratio for hospitalized COVID-19 associated with DMARD treatment was 2.14 [95% confidence interval (CI) 2.02-2.26] in those on conventional synthetic (cs) DMARDs, 2.01 (95% CI 1.38-2.91) in those on tumour necrosis factor (TNF) inhibitors as the only targeted agent, and 3.83 (95% CI 2.65-5.56) in those on other targeted DMARDs. Among those on csDMARDs, rate ratios for hospitalized COVID-19 were lowest at 1.66 (95% CI 1.51-1.82) in those on methotrexate and highest at 5.4 (95% CI 4.4-6.7) in those on glucocorticoids at an average dose > 10 mg/day prednisolone equivalent. CONCLUSION: The risk of hospitalized COVID-19 is elevated in IRD patients treated with immunosuppressive drugs compared with the general population. Of these drugs, methotrexate, hydroxychloroquine, and TNF inhibitors carry the lowest risk. The highest risk is associated with prednisolone. A larger study is needed to estimate reliably the risks associated with each class of targeted DMARD.

In-vivo analysis of Protec™ and ß-glucan supplementation on innate immune performance and intestinal health of rainbow trout.

Functional diets are often given to fish during key stages to improve health through the interaction of the feed components with the host intestine. The additional factors added in these diets are known to modulate the immune response and as such may also offer protection against pathogenic challenges. The present study was undertaken to evaluate whether ß-glucan supplementation for 6 weeks can alter the magnitude of immune response to immunological challenges and subsequently offer an improved innate immune response to bacterial challenge in rainbow trout. Two experimental diets were used to study these effects: a basic commercial diet supplemented with ß-glucan and a commercially available functional diet (Protec™) that has ß-glucan as a functional component in addition to other components were compared to a basic commercial control diet. No significant differences were observed in biometric data. Histological analysis revealed a significantly greater number of goblet cells in the fish fed Protec™ and ß-glucan diets compared to those fed a control diet. Cell marker gene expression of distal intestine leucocytes indicated higher expression of T- and B-cells marker genes to both the ß-glucan containing diets in comparison to control. The Protec™ diet demonstrated modulation of innate immune markers after 6 weeks of feeding with key antimicrobial genes (SAA, HAMP, IL-1ß and TNFα) showing significant increases compared to the other diets. After stimulation with both PAMPs and an immune challenge with A. salmonicida fish fed the ß-glucan diet and the Protec™ exhibited modulation of the innate immune response. An immune challenge with A. salmonicida was carried out to identify if dietary composition led to differences in the innate immune response of rainbow trout. Modulation of the magnitude of response in some immune genes (SAA, IL-1ß and HAMP) was observed in both the distal intestine and head kidney in the Protec™ and ß-glucan fed fish compared to those fed the control diet.

Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Immune responses to prebiotics in farmed salmonid fish: How transcriptomic approaches help interpret responses.

Within aquaculture, prebiotics are composed of complex carbohydrate molecules that cannot be digested by the fish directly but are metabolised by the microbial communities within the host gut, with the desire that "healthy" bacterial species are promoted with subsequently improved performance of the fish, there are likely some direct responses of intestinal cells to these dietary components. The sources and processing of prebiotics, which fall under the overarching theme of "functional feeds" are highly varied between species and types of prebiotics administered. How these feeds exert their effect, and the host responses are hard to determine, but new technologies and the development of high-throughput technologies (omics) are enabling the mechanisms and methods of action to be further understood. The recent advances in the availability of 'omics' technologies with the transition from single gene assays to microarray and RNA-seq in fish health have enabled novel functional ingredients to be analysed. This review will focus on recent studies on targeted gene expression and 'omics' technologies to characterize immune responses. Comparisons between the immunomodulatory effect of different prebiotics have been made and specific examples of how transcriptomics techniques have been used to identify immune responses to prebiotics are given.

High-pressure developments for resonant X-ray scattering experiments at I16.

An experimental setup to perform high-pressure resonant X-ray scattering (RXS) experiments at low temperature on I16 at Diamond Light Source is presented. The setup consists of a membrane-driven diamond anvil cell, a panoramic dome and an optical system that allows pressure to be measured in situ using the ruby fluorescence method. The membrane cell, inspired by the Merrill-Bassett design, presents an asymmetric layout in order to operate in a back-scattering geometry, with a panoramic aperture of 100° in the top and a bottom half dedicated to the regulation and measurement of pressure. It is specially designed to be mounted on the cold finger of a 4 K closed-cycle cryostat and actuated at low-temperature by pumping helium into the gas membrane. The main parts of the body are machined from a CuBe alloy (BERYLCO 25) and, when assembled, it presents an approximate height of 20-21 mm and fits into a 57 mm diameter. This system allows different materials to be probed using RXS in a range of temperatures between 30 and 300 K and has been tested up to 20 GPa using anvils with a culet diameter of 500 µm under quasi-cryogenic conditions. Detailed descriptions of different parts of the setup, operation and the developed methodology are provided here, along with some preliminary experimental results.

Birth preparation acupuncture for normalising birth: An analysis of NHS service routine data and proof of concept.

A number of studies show that acupuncture may help with labour and delivery. An NHS maternity acupuncture service providing birth preparation acupuncture has assessed its routine hospital maternity annual data from 2014 to 2016 to see what effect it had on labour and delivery outcomes. The data from this service was analysed and women who had birth preparation acupuncture were compared with those who did not receive it. Maternal age, parity and socio-economic status were considered confounders and were adjusted for in the analysis. Women who received acupuncture had more normal births (less surgical births) [OR 0.76 (0.64, 0.91)], required less intrapartum analgesia [OR 0.74 (0.63, 0.86)], fewer components of an induction of labour [OR 0.74 (0.61, 0.91)] and a reduced length of a hospital stay [OR 0.91 (0.87, 0.95)]. The patients highly valued the availability of acupuncture within the maternity service as it enhanced their patient journey.Impact statementWhat is already known on this subject? Numerous studies provide evidence for the effects of acupuncture in normalising pregnancy and birth. These effects include musculoskeletal preparation of the pelvis, cervical ripening, enhancing endogenous oxytocin release, and analgesic properties.What do the results of this study add? Our analysis shows that women who received birth preparation acupuncture had fewer surgical births, required less intrapartum analgesia, less components of induction of labour and had a reduced length of hospital stay, supporting the use of maternity acupuncture in normalising birth outcomes.What are the implications of these findings for clinical practice and/or further research? The findings show that acupuncture, by potentially normalising birth, may lead to reductions in costs of service. Further, additional research is required to see whether acupuncture is cost effective and could have an adjunctive role as a complementary therapy for improving birth outcomes and a woman's experience of childbirth.

Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials.

OBJECTIVES: The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. METHODS: We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96. RESULTS: We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001). CONCLUSIONS: Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.

Detection of cholesteatoma: High-resolution DWI using RS-EPI and parallel imaging at 3 tesla.

The purpose of this study is to evaluate the impact of RS-EPI-DWI in the detection of cholesteatoma and to compare with single-shot echo-planar DWI (SS-EPI-DWI). Diffusion-weighted and apparent diffusion-coefficient (ADC) images were obtained using RS-EPI and SS-EPI techniques in 30 patients. Presence of cholesteatoma (3 point scale), amount of artefacts (4 point scale), visibility (4 point scale), and ADC values of the lesions were assessed. The results of both techniques were compared with each other and gold-standard (GS) test results. Lesion visibility and presence of artefact scores of RS-EPI-DWI group were significantly different from those of the SS-EPI group. RS-EPI-DWI images had fewer artefacts and higher visibility scores. The sensitivity, specificity, negative/positive-predictive, and overall-agreement values of RS-EPI-DWI technique were 100%, 78%, 100%, 74%, and 87%; respectively. These values for SS-EPI-DWI technique were 91%, 60%, 88%, 67%, and 75%; respectively. Also, these values were higher on axial plane than coronal plane images for ADC measurements. Based on gold-standard test findings, agreement values were good (κ=0.74) for RS-EPI-DWI and moderate for SS-EP-DWI (κ=0.50) techniques (P<0.001 for both). The RS-EPI-DWI technique allows a higher spatial-resolution and this technique is less susceptible to artefacts when compared with SS-EPI technique.

The safety and efficacy of benzbromarone in gout in Aotearoa New Zealand.

BACKGROUND: Benzbromarone is a potent uricosuric but is not widely available due to concerns about hepatotoxicity. In Aotearoa New Zealand, benzbromarone has been available since April 2013, subject to funding restrictions, for patients with inadequate urate-lowering response or intolerance to allopurinol and probenecid. AIM: To assess the safety and efficacy of benzbromarone in a real-life setting. METHODS: All patients who received funding for benzbromarone from 1 April 2013 to 30 September 2014 were identified. Prescribers were sent a questionnaire for each individual. Information on demographics, efficacy of previous urate-lowering drugs and reasons for discontinuation were collected. Specific information about the dose, effect on serum urate, adverse effects and liver function tests after commencing benzbromarone was recorded. RESULTS: Completed questionnaires were returned for 123 of 164 (75%) patients. Mean (SD) serum urate prior to benzbromarone was 0.57 (0.12) mmol/L, and estimated glomerular filtration rate was 50.3 (22.8) mL/min/1.73 m(2) . The median dose of benzbromarone was 100 mg/day (25-200 mg/day). Six months after commencing benzbromarone, mean (SD) serum urate was 0.35 (0.12) mmol/L. Benzbromarone-related adverse events included rash (n = 4), diarrhoea (n = 9), nausea (n = 6) and urate stones (n = 3). Liver function test abnormalities were uncommon and tended to be mild. There were 14 patient deaths; none was considered related to benzbromarone. Allopurinol had been prescribed prior to benzbromarone in 117 of 123 patients; median maximum allopurinol dose was 200 mg/day (range 25-600 mg/day), and 19% patients received allopurinol >300 mg/day. CONCLUSION: Benzbromarone provides useful urate-lowering efficacy and does not appear unsafe in patients with gout. Urate-lowering therapy prescribing requires further optimisation.

The Impact of EBV Status on Characteristics and Outcomes of Posttransplantation Lymphoproliferative Disorder.

We examined the associations of Epstein-Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 (58 [33%] EBV-negative; 118 [67%] EBV-positive). The proportion of EBV-negative cases increased over time from 10% (1990-1995) to 48% (2008-2013) (p < 0.001). EBV-negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high-risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV-positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV-negative versus EBV-positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV-negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV-negative PTLD.

Vacancy defects and monopole dynamics in oxygen-deficient pyrochlores.

The idea of magnetic monopoles in spin ice has enjoyed much success at intermediate temperatures, but at low temperatures a description in terms of monopole dynamics alone is insufficient. Recently, numerical simulations were used to argue that magnetic impurities account for this discrepancy by introducing a magnetic equivalent of residual resistance in the system. Here we propose that oxygen deficiency is the leading cause of magnetic impurities in as-grown samples, and we determine the defect structure and magnetism in Y2Ti2O7-δ using diffuse neutron scattering and magnetization measurements. These defects are eliminated by oxygen annealing. The introduction of oxygen vacancies causes Ti(4+) to transform to magnetic Ti(3+) with quenched orbital magnetism, but the concentration is anomalously low. In the spin-ice material Dy2Ti2O7 we find that the same oxygen-vacancy defects suppress moments on neighbouring rare-earth sites, and that these magnetic distortions markedly slow down the long-time monopole dynamics at sub-Kelvin temperatures.

[Application of brain diffusion-weighted imaging performed using readout segmentation of long variable echo trains].

We report the preliminary use of the readout segmentation of long variable echo trains(RESOLVE)sequence, a novel magnetic resonance(MR)scanning technique based on a readout segmented echo planar imaging(EPI)strategy. RESOLVE enables high-resolution diffusion-weighted imaging(DWI)by minimizing susceptibility distortions and T2* blurring. The software for this sequence was provided by Siemens AG, Germany. Previously, we determined appropriate sequence parameters to obtain sufficiently high-resolution images through phantom studies. Then, we applied the sequence to some clinical cases with neurological disorders and analyzed the RESOLVE-DWI data with diffusion tensor imaging(DTI)techniques. In this article, we report clinical application of the RESOLVE sequence in two cases, one with cerebellar infarction and one with an intracranial epidermoid cyst. In both cases, RESOLVE-DWI clearly exposed structures that were obscured or severely distorted by artifacts on usual single-shot EPI-DWI. DTI analyses for RESOLVE-DWI data provided detailed information about fiber tracts and cranial nerves.

The clinical features, management and prognostic effects of pathological fractures in a multicenter series of 373 patients with diffuse large B-cell lymphoma of the bone.

BACKGROUND: Pathological fractures (PFs) occur in 10%-20% of patients with diffuse large B-cell lymphoma (DLBCL) of the bone. The clinical features and the effects of this severe complication on management and prognosis have not been previously analyzed in a large series. PATIENTS AND METHODS: The effects of PF on management and prognosis were reviewed in an international retrospective series of 373 patients with newly diagnosed bone DLBCL, comparing 78 patients with PF at presentation (group 'PF-BL') and 295 patients without PF ('controls'). RESULTS: At a median follow-up of 53 months (range 3-246), PF-BL patients exhibited lower rates of overall response (ORR, 78% versus 85%; P = 0.17), 5-year progression-free survival (PFS, 53 ± 6% versus 61 ± 3%; P = 0.02) and 5-year overall survival (OS, 54 ± 6% versus 68 ± 3%, P = 0.008) than controls. Initial surgical stabilization of the PF did not change therapeutic outcome (5-year OS: 45 ± 9% versus 54 ± 10%; P = 0.20). PF-BL patients referred to irradiation of the fractured bone before chemotherapy exhibited a significantly poorer outcome than patients managed with the inverse sequence (ORR: 52% versus 92%, P = 0.0005; 5-year OS: 22 ± 14% versus 64 ± 9%, P = 0.007). Multivariate analysis confirmed the independent association between PF and worse survival and the negative effect of radiotherapy as initial therapy. CONCLUSION: Fracture is an independent, adverse prognostic event in patients with bone DLBCL. Anthracycline-based chemotherapy followed by radiotherapy seems to be the better treatment sequence. Initial fracture stabilization does not seem to improve outcome; it should be used to improve patient's quality of life only if chemotherapy delays can be avoided.

Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review.

Aromatase inhibitors (AIs) decrease the production of oestrogen, decreasing stimulation of hormone receptor-positive breast cancer. Theoretically, AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. We performed a systematic review to assess the effect of obesity on AI efficacy in breast cancer treatment. The review followed PRISMA guidelines. Studies included were interventional or observational studies with comparison groups, of postmenopausal women with hormone receptor-positive breast cancer on treatment with an AI, alone or in combination with other drugs, in which body mass index or another measure of obesity was recorded. Studies in all languages were included; if published as an abstract only, authors were contacted for further information. Outcome measures included overall survival, disease-free survival or time to progressive disease, survival from the start of therapy, mortality measures, local or distant recurrence of primary cancer and time to recurrence. Of 2,344 citations identified from five databases, eight studies met the criteria for inclusion; three randomised controlled trials and five retrospective cohort studies. Due to variability in study factors, it was not possible to perform a quantitative meta-analysis. However, the systematic review showed a trend towards a negative effect of obesity on AI efficacy. There is evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive breast cancer, but the size of the effect cannot be assessed. More information is needed before clinical recommendations are made.

Suppression of thermal conductivity by rattling modes in thermoelectric sodium cobaltate.

The need for both high electrical conductivity and low thermal conductivity creates a design conflict for thermoelectric systems, leading to the consideration of materials with complicated crystal structures. Rattling of ions in cages results in low thermal conductivity, but understanding the mechanism through studies of the phonon dispersion using momentum-resolved spectroscopy is made difficult by the complexity of the unit cells. We have performed inelastic X-ray and neutron scattering experiments that are in remarkable agreement with our first-principles density-functional calculations of the phonon dispersion for thermoelectric Na(0.8)CoO2, which has a large-period superstructure. We have directly observed an Einstein-like rattling mode at low energy, involving large anharmonic displacements of the sodium ions inside multi-vacancy clusters. These rattling modes suppress the thermal conductivity by a factor of six compared with vacancy-free NaCoO2. Our results will guide the design of the next generation of materials for applications in solid-state refrigerators and power recovery.

Oxygen cost of walking, physical activity, and sedentary behaviours in rheumatoid arthritis.

OBJECTIVES: To evaluate the oxygen cost of gait and measure physical activity profiles, including time spent sedentary, in people with rheumatoid arthritis (RA) and matched controls. METHOD: We recruited 19 people with RA and 19 controls matched for age, sex, and body mass index (BMI). Demographic details and clinical characteristics of the RA population were recorded. Oxygen uptake per metre walked (oxygen cost) was measured in the laboratory using a portable gas analyser. Activity profiles including the number of steps per day, time spent sedentary (sitting or lying down), and intensity of walking were recorded over 5 days using an activity monitor, from which physical activity was classified by intensity categories. Levels of pain, fatigue, anxiety, and depression were recorded. RESULTS: People with RA walked with a slower self-selected gait speed (p < 0.001) than controls but there was no difference in the oxygen cost of walking (p = 0.992) between the groups. People with RA took fewer steps (p < 0.001), had increased sedentary time (p = 0.029) and lower time walking at cadences commensurate with moderate to vigorous physical activity (MVPA) compared to controls (p < 0.001). Pain, fatigue, and depression were higher in the RA group (all p < 0.001). CONCLUSIONS: The oxygen cost of walking in this cohort of people with RA was similar to that of matched controls but there was an increase in time spent sedentary and a reduction in time spent at cadences commensurate with MVPA. Clinical symptoms such as depression, pain, and fatigue may explain the changes in activity/sedentary behaviours in people with RA and require further investigation.

Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender.

BACKGROUND AND AIMS: We describe the novel anatomical distribution of exostoses in patients with hereditary multiple exostoses according to their gender and genotype. METHODS AND RESULTS: A prospective database of 143 patients from 65 families with hereditary multiple exostoses was compiled. Patient demographics, genotype and number of exostoses according to anatomical site were recorded. The hand was affected by the greatest proportion of exostoses for both EXT1 (19%) and EXT2 (14%) genotypes and was the most prevalent site for exostoses in patients with an EXT1 genotype (92%). Patients with an EXT1 genotype had a significantly greater number of exostoses compared to those with an EXT2 genotype (2680 vs. 1828, p = 0.006); however, this was only significantly different for 10 of the 19 anatomical regions examined. Male patients with an EXT1 genotype had a significantly (p < 0.05) greater number of exostoses affecting their hands, distal radius, proximal humerus, scapular and ribs compared to female patients with the same genotype and males with an EXT2 genotype. CONCLUSION: The anatomical distribution of exostoses varies according to genotype and gender; however, the reason for this difference is not clear and may relate to different biochemical pathways.

Risk of cancer following primary total hip replacement or primary resurfacing arthroplasty of the hip: a retrospective cohort study in Scotland.

BACKGROUND: Release and dispersion of particles arising from corrosion and wear of total hip arthroplasty (THA) components has raised concerns about a possible increased risk of cancer. Concerns have been heightened by a recent revival in the use of metal-on-metal (MoM) hip prostheses. METHODS: From a linked database of hospital discharge, cancer registration, and mortality records, we selected a cohort of patients who underwent primary THA (1990-2009) or primary resurfacing arthroplasty (mainly 2000-2009) in Scotland, with follow-up to the end of 2010. Available operation codes did not enable us to distinguish MoM THAs. Indirectly standardised incidence ratios (SIRs) were calculated for selected cancers with standardisation for age, sex, deprivation, and calendar period. RESULTS: The study cohort included 71 990 patients yielding 547 001 person-years at risk (PYAR) and 13 946 cancers diagnosed during follow-up. For the total period of observation combined, the risks of all cancers (SIR: 1.05; 95% CI: confidence interval 1.04-1.07), prostate cancer (SIR: 1.07; 95% CI: 1.01-1.14), and multiple myeloma (SIR: 1.22; 95% CI: 1.06-1.41) were increased. These modest increases in risk emerged in the context of effectively multiple tests of statistical significance, and may reflect inadequate adjustment for confounding factors. For 1317 patients undergoing primary resurfacing arthroplasty between 2000 and 2009 (PYAR=5698), the SIR for all cancers (n=39) was 1.23 (95% CI: 0.87-1.68). CONCLUSION: In the context of previous research, these results do not suggest a major cause for concern. However, the duration of follow-up of patients receiving recently introduced, new-generation MoM prostheses is too short to rule out a genuinely increased risk of cancer entirely.

The relationship between environmental variables and response of cotton to nematicides.

Nematicide/irrigation rate trials were conducted in Texas (TX) in 2009 and 2010 in cotton grown at three irrigation rates, where irrigation rate (base (B), B - 33%, B + 33%) was the main plot and treatment (untreated check, aldicarb, and nematicide seed treatment (NST) and NST + aldicarb) were the subplots. Aldicarb improved cotton lint yield with the base (medium) irrigation rate over the untreated check, but not at the B - 33% and B + 33% irrigation rates. In a second evaluation, 20 tests conducted over 7 yr at the same field in TX and 12 tests conducted over 6 yr at the same field in Alabama (AL) were examined for impact of environmental variables (EV) on the response to NST (containing thiodicarb or abamectin), aldicarb, a nontreated check (CK), insecticide seed treatment (TX only), and a combination of NST + aldicarb + oxamyl (NST/A/O, AL only) on root galls (TX only), early season nematode eggs (AL only), and yield (both sites). Galls/root system were lower with aldicarb-treated plots, than for the CK- or NST-treated plots. As water (irrigation plus rain) in May increased, galls/root system increased for CK or insecticide-only-treated plots, and decreased for NST- and aldicarb-treated plots, suggesting efficacy of nematicides was strongly improved by adequate soil moisture. Nematode reproduction was not affected by EV in either location, though yield was negatively affected by root-knot nematode eggs in AL at 60 d. Yield in both AL and TX was negatively related to temperature parameters and positively related to water parameters. With the addition of EV in TX, chemical treatments went from not significantly different in the absence of EV to aldicarb-treated plots having higher yields than nonnematicide-treated plots in the presence of EV. In AL, NST/A/O-treated plots yielded similar to aldicarb and better than CK or NST in the absence of EV and had significantly higher yields than all other treatments in the presence of most EV.