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BACKGROUND: Excess reactive oxygen species generated by NADPH oxidase 2 (Nox2) in response to ethanol exposure mediate aspects of skeletal toxicity including increased osteoclast differentiation and activity. Because perturbation of chondrocyte differentiation in the growth plate by ethanol could be prevented by dietary antioxidants, we hypothesized that Nox2 in the growth plate was involved in ethanol-associated reductions in longitudinal bone growth. METHODS: Nox2 conditional knockout mice were generated, where the essential catalytic subunit of Nox2, cytochrome B-245 beta chain (Cybb), is deleted in chondrocytes using a Cre-Lox model with Cre expressed from the collagen 2a1 promoter (Col2a1-Cre). Wild-type and Cre-Lox mice were fed an ethanol Lieber-DeCarli-based diet or pair-fed a control diet for 8 weeks. RESULTS: Ethanol treatment significantly reduced the number of proliferating chondrocytes in the growth plate, enhanced bone marrow adiposity, shortened femurs, reduced body length, reduced cortical bone volume, and decreased mRNA levels of a number of osteoblast and chondrocyte genes. Conditional knockout of Nox2 enzymatic activity in chondrocytes did not consistently prevent any ethanol effects. Rather, knockout mice had fewer proliferating chondrocytes than wild-type mice in both the ethanol- and control-fed animals. Additional analysis of tibia samples from Nox4 knockout mice showed that loss of Nox4 activity also reduced the number of proliferating chondrocytes and altered chondrocyte size in the growth plate. CONCLUSIONS: Although Nox enzymatic activity regulates growth plate development, ethanol-associated disruption of the growth plate morphology is independent of ethanol-mediated increases in Nox2 activity.

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California has a large population of people experiencing homelessness (PEH) that is characterised by a high proportion of people who are unsheltered and chronically homeless. PEH are at increased risk of communicable diseases due to multiple, intersecting factors, including increased exposures, comorbid conditions including substance use disorder and mental illness and lack of access to hygiene and healthcare facilities. Data available for several communicable diseases show that PEH in California experiences an increased burden of communicable diseases compared to people not experiencing homelessness. Public health agencies face unique challenges in serving this population. Efforts to reduce homelessness, increase access to health care for PEH, enhance data availability and strengthen partnerships among agencies serving PEH can help reduce the disparity in communicable disease burden faced by PEH.

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SETTING: Tuberculosis (TB) cases in California, USA, occur predominantly among foreign-born persons, many of whom have abnormal chest radiographs (CXRs) on overseas medical examination. These persons are recommended for follow-up TB evaluation upon arrival in the United States. OBJECTIVE: To estimate the increased TB risk associated with abnormal vs. normal domestic CXRs among individuals arriving with abnormal overseas CXRs. DESIGN: Cox regression analyses of 35 633 foreign-born persons aged 15 years who arrived in California during 1999-2012 with abnormal overseas CXRs and were free of imported active TB. Domestic CXRs were conducted during post-arrival evaluation. Subsequent cases through 2014 were identified from California's TB registry. RESULTS: A total of 121 (0.3%) arrivers developed TB disease. Progression rates were respectively 63.6 (95%CI 50.8-76.4) and 25.4 (95% CI 15.7-35.2) cases/100 000 person-years among persons with abnormal and normal domestic CXRs. Relative to arrivers with normal domestic CXRs, those with abnormal domestic CXRs had an elevated disease risk during the first 4 years after immigration; this increased risk was greatest during the first year (hazard ratio 2.9, 95%CI 1.8-4.8). CONCLUSION: Among arrivers with abnormal overseas CXRs, those with abnormal CXRs upon domestic evaluation have an elevated disease risk and represent an important target group for preventive treatment.

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BACKGROUND: Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent periods of ischaemia in a tissue or organ remote from the heart. The mechanisms of this effect are incompletely understood. We hypothesised that RIPC might enhance coronary vasodilatation by an endothelium-dependent mechanism. METHODS: We performed a prospective, randomised, sham-controlled, blinded clinical trial. Patients with stable coronary artery disease (CAD) undergoing elective invasive management were prospectively enrolled, and randomised to RIPC or sham (1:1) prior to angiography. Endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses (10-6, 10-5, 10-4mol/l). Venous blood was sampled pre- and post-RIPC or sham, and analysed for circulating markers of endothelial function. Coronary luminal diameter was assessed by quantitative coronary angiography. The primary outcome was the between-group difference in the mean percentage change in coronary luminal diameter following the maximal acetylcholine dose (Clinicaltrials.gov identifier: NCT02666235). RESULTS: 75 patients were enrolled. Following angiography, 60 patients (mean±SD age 57.5±8.5years; 80% male) were eligible and completed the protocol (n=30 RIPC, n=30 sham). The mean percentage change in coronary luminal diameter was -13.3±22.3% and -2.0±17.2% in the sham and RIPC groups respectively (difference 11.32%, 95%CI: 1.2- 21.4, p=0.032). This remained significant when age and sex were included as covariates (difference 11.01%, 95%CI: 1.01- 21.0, p=0.035). There were no between-group differences in endothelial-independent vasodilation, ECG parameters or circulating markers of endothelial function. CONCLUSIONS: RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion. This endothelium-dependent mechanism may contribute to the cardioprotective effects of RIPC.

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Chromosome microarrays are an essential tool for investigation of copy number changes in children with congenital anomalies and intellectual deficit. Attempts to standardise microarray testing have focused on establishing technical and clinical quality criteria, however external quality assessment programs are still needed. We report on a microarray proficiency testing program for Australasian laboratories. Quality metrics evaluated included analytical accuracy, result interpretation, report completeness, and laboratory performance data: sample numbers, success and abnormality rate and reporting times. Between 2009 and 2014 nine samples were dispatched with variable results for analytical accuracy (30-100%), correct interpretation (32-96%), and report completeness (30-92%). Laboratory performance data (2007-2014) showed an overall mean success rate of 99.2% and abnormality rate of 23.6%. Reporting times decreased from >90 days to <30 days for normal results and from >102 days to <35 days for abnormal results. Data trends showed a positive correlation with improvement for all these quality metrics, however only 'report completeness' and reporting times reached statistical significance. Whether the overall improvement in laboratory performance was due to participation in this program, or from accumulated laboratory experience over time, is not clear. Either way, the outcome is likely to assist referring clinicians and improve patient care.

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In 2004 the WHO estimated that 64 million people worldwide suffered from chronic obstructive pulmonary disease (COPD), with 3 million dying from related complications in 2005. Although many patients go undiagnosed, the number of people with the disease continues to increase, and by 2030 it is thought it will be the third most common cause of death in the world. With no cure for COPD, treatment of symptoms increased the European health bill by USD 10 million last year and the market is thought to increase to approximately USD 37.7 million by 2030. These staggering numbers were presented by Frank Thielman (Novartis Pharma) as he opened SMi's Seventh Annual COPD Conference in London, U.K. The meeting gathered experts and scientific pioneers in the respiratory area to discuss developments in known and new therapies, devices and diagnosis, including biomarker models to gain greater disease understanding. This report covers highlights from the 2-day meeting.

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SETTING: Distal sensory polyneuropathy (DSP) may manifest in human immunodeficiency virus (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur in response to isoniazid (INH); this can be prevented by pyridoxine supplementation. N-acetyltransferase 2 (NAT2) polymorphisms influence drug acetylation and possibly the risk for INH-associated DSP. OBJECTIVE: To investigate the relationship between previous/current TB, pyridoxine deficiency and DSP in HIV-infected individuals enrolled in a government-sponsored HIV programme. DESIGN: Neuropathy assessments were performed among 159 adults pre-ART and 12 and 24 weeks thereafter. DSP was defined as ⩾1 neuropathic symptom and sign. NAT2 genotypes predicted acetylation phenotype. Serum pyridoxine levels (PLP) were quantified at baseline and week 12. RESULTS: DSP was present in 16% of individuals pre-ART and was associated with previous/current TB (P = 0.020). Over 50% were pyridoxine deficient (PLP < 25 nmol/l), despite supplementation with vitamin B complex supplements (2-4 mg/day pyridoxine). Those with a history of TB and pre-ART DSP were more likely to be pyridoxine deficient (P = 0.029), and slow/intermediate NAT2 phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21% of the participants. PLP levels remained low after ART, particularly among those with prior TB, but without an association between DSP or NAT2 phenotypes. CONCLUSION: Adequate pyridoxine supplementation before ART initiation should be prioritised, particularly in those with a history of TB or current TB.

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Group B streptococcus (GBS) is an increasing cause of disease in adults. We present long-term trends in incidence of overall infections and identify characteristics of patients with GBS cellulitis, bone and joint infections. Active, population-based surveillance was conducted from 1995-2012 in three California counties and the data were analysed retrospectively. All cases had isolation of GBS from a normally sterile site. Cases of cellulitis were classified based on clinical diagnosis. GBS bone or joint infection was defined as isolation of GBS from a bone or joint or a diagnosis of osteomyelitis or septic arthritis. Medical charts were reviewed for demographic and clinical information. There were 3917 cases of GBS; the incidence of disease increased from 5·8 to 8·3 cases/100 000 persons (P < 0·001) from 1995 to 2012. In adults aged ⩾40 years, the overall incidence of GBS increased from 8·5 to 14·2 cases/100 000 (P < 0·001) persons during the study period. The incidence of cellulitis increased from 1·6 to 3·8 cases/100 000 (P < 0·001), bone infection increased from 0·7 to 2·6 cases/100 000 (P < 0·001), and the incidence of joint infection remained approximately constant at an average rate of 1·0 case/100 000. The highest incidence rates were observed in men, persons aged ⩾80 years, non-Hispanic blacks and Hispanics. Diabetes was the most common underlying condition (51·2% cellulitis cases, 76·3% bone infections, 29·8% joint infections).

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UNLABELLED: This study explored the distribution of vertebral fractures in hip fracture patients. Unlike patients with intertrochanteric fractures, those with subcapital fractures were less likely to have vertebral fractures in the T4-T10 region of the spine. The dissimilar distribution of vertebral fractures among patients with intertrochanteric and subcapital fractures may indicate different underlying etiologies. INTRODUCTION: There are two main types of hip fractures: intertrochanteric and subcapital. Both types can have associated vertebral fractures. In this study, we explored the distribution of vertebral fractures in the two hip fracture populations. METHODS: This was a retrospective analysis of a convenience sample of 120 patients: 40 with subcapital fractures and vertebral fractures, 40 with intertrochanteric fractures and vertebral fractures, and 40 with vertebral fractures only. Based on Genant's semiquantitative assessment method of radiographic images, the distribution and severity of each patient's vertebral fractures were explored [1]. RESULTS: Patients with subcapital fractures had significantly fewer total vertebral fractures (93 vs. 144, p = 0.005; 93 vs. 127, p = 0.019), vertebral fractures from T4 to T10 (41 vs. 81, p = 0.005; 41 vs. 64, p = 0.042), and vertebral fractures at the T7-T8 peak (11 vs. 31, p = 0.002; 11 vs. 30, p = 0.003) than patients with intertrochanteric fractures and those with vertebral fractures alone, respectively, and they were more likely to have only one vertebral fracture (15 vs. 3, p < 0.001; 15 vs. 2, p < 0.001). The number of vertebral fractures from T11 to L4 and at the T12-L1 peak did not differ among the groups. The numbers of fractures at each vertebral level was significantly correlated only between those with intertrochanteric fractures and those with vertebral fractures alone (r = 0.65, p = 0.009). CONCLUSION: The distribution of vertebral fractures among patients with subcapital fractures differed from the other fracture groups, which may indicate that subcapital fractures and some lumbar fractures have a different underlying etiology than intertrochanteric fractures and thoracic (T4-T10) fractures.

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CEO and President Adrian Adams described Auxilium Pharmaceuticals as "the same as a Big Pharma company, only smaller." This 'specialty biopharmaceutical company' has transformed itself in the last 6 to 9 months to become the "leading men's healthcare franchise with a broad and diverse product portfolio." All of this has led to a very busy 2013, which began with the USD 600 million acquisition (Q2) and integration of Actient Pharmaceuticals, the licensing of avanafil (Stendra™) for erectile dysfunction and ended with the approval of collagenase Clostridium histolyticum (Xiaflex®) in Peyronie's disease. From a portfolio of 2 products at the beginning of 2013, Auxilium ended the year with 12.

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OBJECTIVE: To investigate the exercise barriers, facilitators and preferences of a mixed sample of cancer survivors as well as fatigue levels, quality of life (QoL) and the frequency and intensity of exercise that cancer survivors typically engage in. METHODS: An anonymous, postal questionnaire-survey with a convenience sample of 975 cancer survivors was used. Standardised measures were used to establish fatigue (Multidimensional Fatigue Symptom Inventory-Short Form), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30), exercise frequency and intensity (Leisure Score Index). RESULTS: A 52.3% response rate (n = 456) was achieved. A total of 76.0% were female, with stage I (18.3%) or stage II (21.0%) breast cancer (64.4%), and 62.3% were ≥ 3 years post treatment. A total of 73.5% reported fatigue with 57.2% experiencing fatigue on a daily basis. A total of 68.1% had never been given any advice on how to manage fatigue. A total of 9.4% reported to engage in strenuous physical activity, 43.5% in moderate physical activity and 65.5% in mild physical activity. Respondents experienced difficulties with emotional, cognitive and social functioning and the symptoms of fatigue, insomnia and pain. Barriers that interfered with exercise 'often/very often' were mainly related to respondents' health and environmental factors. A total of 50.2% were interested in exercise and 52.5% felt able to exercise. Exercise facilitators, preferences and motivators provide some insight into cancer survivors' needs in terms of becoming more physically active. CONCLUSIONS: Although cancer survivors continue to experience fatigue and QoL issues long after treatment completion, over half are willing and feel able to participate in exercise. Exercise barriers were mainly health related or environmental issues, however, the main barriers reported were those that had the potential to be alleviated by exercise.

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BACKGROUND: This study aims to assess current practices of Canadian physicians providing botulinum toxin-A (BoNT-A) treatments for children with hypertonia and to contrast these with international "best practice" recommendations, in order to identify practice variability and opportunities for knowledge translation. METHODS: Thirteen Canadian physicians assembled to develop and analyze results of a cross-sectional electronic survey, sent to 50 physicians across Canada. RESULTS: Seventy-eight percent (39/50) of physicians completed the survey. The most frequently identified assessment tools were Gross Motor Function Classification System, Modified Tardieu Scale and neurological examination. Goal-setting tools were infrequently utilized. Common indications for BoNT-A injections and the muscles injected were identified. Significant variability was identified in using BoNT-A for hip displacement associated with hypertonia. The most frequent adverse event reported was localized weakness; 54% reporting this "occasionally" and 15% "frequently". Generalized weakness, fatigue, ptosis, diplopia, dysphagia, aspiration, respiratory distress, dysphonia and urinary incontinence were reported rarely or never. For dosage, 52% identified 16 Units/kg body weight of Botox® as maximum. A majority (64%) reported a maximum 400 Units for injection at one time. For localization, electrical stimulation and ultrasound were used infrequently (38% and 19% respectively). Distraction was the most frequently used pain-management technique (64%). CONCLUSIONS: Canadian physicians generally adhere to international best practices when using BoNT-A to treat paediatric hypertonia. Two knowledge-translation opportunities were identified: use of individualized goal setting prior to BoNT-A and enhancing localization techniques. Physicians reported a good safety profile of BoNT-A in children.

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OBJECTIVES: To evaluate the reliability and validity of a children's carers' feedback tool, to explore the feasibility of delivering this nationally and to determine acceptability to doctors of this assessment. PARTICIPANTS: 122 UK paediatricians on the specialist register undertaking outpatient consultations. DESIGN: Participants were each sent 50 forms for distribution to carers. Mean scores for each question, and for the overall pilot cohort were returned to participants with verbatim free text comments. Participating paediatricians' views were sought before and after receiving feedback. RESULTS: 122 doctors returned 4415 forms (mean 36 per doctor). All doctors scored highly with scores across all returned forms having a median of 4.58 (IQ range 0.17) where the maximum score was 5. Differences were observed between scores from female compared to male carers (p<0.05), from consultations rated by carer and child compared to carer alone (p<0.05) and from carers who had previously met the doctor compared to those in their first consultation (p<0.001). 'White' doctors received higher ratings than 'non-white' doctors (p<0.05) and white patients rated both white doctors and non-white doctors more highly than non-white patients (p<0.01). A minimum of 25 consultations rated by children's carers are needed for acceptable reliability. 93.9% of participants would be happy to be assessed in this way for the purposes of revalidation. CONCLUSIONS: National delivery of a valid and reliable method of carer feedback is feasible. The scores received and acceptability in these self-selected doctors was high. Confounding variables may influence feedback, so guidance on interpretation may be needed.

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SETTING: Importation of infectious tuberculosis (TB) threatens TB control in California and the United States. OBJECTIVE: To assess the effectiveness of an enhanced pre-immigration screening and treatment protocol to prevent the importation of infectious TB. DESIGN: Retrospective analysis of immigrants ≥ 15 years of age with TB suspect classifications who were screened for TB in their countries of origin before (pre-intervention cohort) and after (post-intervention cohort) implementation of enhanced pre-immigration screening. Enhanced pre-immigration screening added sputum cultures to the existing screening system based on sputum smears for persons with abnormal chest radiographs. RESULTS: The pre- and post-intervention cohorts included respectively 2049 and 1430 immigrants. The occurrence of tuberculosis ≤ 6 months after US arrival in this population decreased following the intervention, from 4.2% (86 cases) to 1.5% (22 cases, P < 0.001). Among pre-intervention cohort cases, 14% were sputum acid-fast bacilli (AFB) smear-positive and 81% were sputum culture-positive for TB, compared with 5% sputum AFB smear-positive (P = 0.46) and 68% sputum culture-positive (P = 0.18) among the post-intervention cohort cases. CONCLUSION: The enhanced pre-immigration screening was associated with a decline in the proportion of immigrants with TB suspect classifications identified with TB within 6 months of arrival in the United States. Continued state and national surveillance is critical to monitor the effectiveness of the revised pre-immigration screening as it is implemented in additional countries.

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Tuberculosis (TB) is increasing in incidence in certain parts of the world, particularly where there is a co-epidemic of human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS), and it is associated with a significant degree of morbidity and mortality. One of the most common complications of anti-tuberculosis treatment is the development of a painful isoniazid (INH) associated polyneuropathy (PN), which is preventable with adequate pyridoxine supplementation. As PN is also the most frequent neurological complication associated with HIV infection, subjects who are HIV and TB co-infected may be at increased risk of developing PN. In this review, we explore current knowledge of anti-tuberculosis drug associated PN focusing on INH and its relationship to pyridoxine, as well as the additional impact of antiretroviral treatment and TB-HIV co-infection. It is evident that guidelines established for the prevention and treatment of this problem differ between industrialised and developing countries, and that further research is needed to define the optimum dosing of pyridoxine supplementation in populations where there is a significant burden of TB and HIV.

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STUDY DESIGN: A retrospective review of acute spinal cord injury patients having assisted ventilation on or after admission between 1981 and 2005. OBJECTIVE: To assess survival after acute ventilatory support. SETTING: Northwest Regional Spinal Injuries Centre, Southport, England. METHODS: Causes of death were ascertained from the Office of National Statistics. Kaplan-Meier analysis of survival was calculated according to ventilator-wean status at discharge. Risk factors were obtained by Cox regression analysis. RESULTS: Over 50% of deaths in weaned and ventilated patients were respiratory in origin. The mean survival of weaned patients in the age group 31-45 was 19.3 compared with 10.5 years for ventilated patients (P=0.047). Those under 30 survived a further 22.1 and 18.4 years (P=0.31), while those over 45 lived for 11.0 and 8.3 years (P=0.50), values for weaned and ventilated patients, respectively. The survival advantage for weaned patients in the middle age group was less evident when the 1-year survivors were compared. The mean survival time of younger patients with diaphragm pacing was 1.8 years longer than those on mechanical ventilation (P=0.142). The variables with significant hazard ratios were any comorbidity (3.07); mechanical ventilation on discharge (2.26); and older age at injury, (3.1). CONCLUSIONS: The survival time for patients with high tetraplegia on long-term ventilation compares with other datasets and older patients have a proportionately greater loss in life expectancy. Self-ventilating patients with tetraplegia remain at considerable risk from respiratory death and consideration needs to be given to more effective preventative measures.

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The Economic and Social Research Council (ESRC)-funded Data Management through e-Social Sciences (DAMES) project is investigating, as one of its four research themes, how research into depression, self-harm and suicide may be enhanced through the adoption of e-Science infrastructures and techniques. In this paper, we explore the challenges in supporting such research infrastructures and describe the distributed and heterogeneous datasets that need to be provisioned to support such research. We describe and demonstrate the application of an advanced user and security-driven infrastructure that has been developed specifically to meet these challenges in an on-going study into depression, self-harm and suicide.

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