Work and Retirement Among Women: The Health and Employment After Fifty Study.

BACKGROUND: Women increasingly work beyond age 50+ but their occupational health is under-researched. AIMS: To investigate what jobs older contemporary women do, when they exit their jobs and what factors predict job exit. METHODS: Data came from the Health and Employment After Fifty cohort, which recruited women aged 50-64 at baseline in 2013-14 and has followed them up annually collecting: demographic, lifestyle and work information. Exits from employment were mapped longitudinally over five follow-ups. Time-to-first event Cox regression analyses were used to identify risk factors for job exit. RESULTS: At baseline, 4436 women participated, 64% of whom were working. The proportions of women working at 50-54, 55-60 and over 60 years were 86%, 79% and 38%, respectively. Amongst all women, after adjustment for age, managing comfortably financially and not coping with the mental demands of the job were associated with exit. Risk factors for job exit differed in the age bands: 50-54; 55-59 and >60 years, reflecting socio-economic status, markers of health (musculoskeletal pain and poor self-rated health) and work factors (under-appreciation, job dissatisfaction, temporary/permanent contracts, coping with work's physical demands). CONCLUSIONS: Factors contributing to exit from work among older women differ by age group, after controlling for perceived financial position, age and mental demands of the job. A number of work characteristics predict job exit and suggest that employers can play an important role in supporting women to continue working until older ages. Identification and treatment of musculoskeletal pain could also enable work amongst older women.

First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from part B of the JAVELIN Merkel 200 study.

BACKGROUND: Results from the JAVELIN Merkel 200 study led to the approval of avelumab [an anti-programmed death-ligand 1 (PD-L1) antibody] for the treatment of metastatic Merkel cell carcinoma (mMCC) in multiple countries and its inclusion in the treatment guidelines as a preferred or recommended therapy in this setting. Here, we report 4-year follow-up results from the cohort of patients with mMCC who received avelumab as first-line treatment. PATIENTS AND METHODS: In part B of JAVELIN Merkel 200, a single-arm, open-label, phase II study, patients with mMCC who had not received prior systemic therapy for metastatic disease received avelumab 10 mg/kg via intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term overall survival (OS), patient disposition, and subsequent treatment were analyzed. RESULTS: In total, 116 patients received first-line avelumab. At the data cutoff (2 February 2022), the median follow-up was 54.3 months (range 48.0-69.7 months). Seven patients (6.0%) remained on treatment and an additional 21 patients remained in follow-up (18.1%); 72 patients (62.1%) had died. The median OS was 20.3 months [95% confidence interval (CI) 12.4-42.0 months], with a 4-year OS rate of 38% (95% CI 29% to 47%). In patients with PD-L1+ or PD-L1- tumors, the 4-year OS rate was 48% (95% CI 26% to 67%) and 35% (95% CI 25% to 45%), respectively. In total, 48 patients (41.4%) received poststudy anticancer drug therapy, most commonly etoposide (20.7%), carboplatin (19.0%), and avelumab (12.1%). CONCLUSIONS: Avelumab first-line monotherapy in patients with mMCC resulted in meaningful long-term OS, which compared favorably with historical studies of first-line chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.

Assessing the environmental benefit of palladium-based single-atom heterogeneous catalysts for Sonogashira coupling.

The Pd-Cu catalysed Sonogashira coupling of terminal alkynes and aryl halides is a cornerstone synthetic strategy for C-C bond formation. Homogeneous organometallic systems conventionally applied are typically not reusable and require efficient downstream Pd removal steps for product purification, making it challenging to fully recover the precious metal. A holistic cradle-to-gate life cycle assessment (LCA) unveils that process footprint can be improved up to two orders of magnitude from repeated catalyst reuse. New classes of heterogeneous catalysts based on isolated metal atoms (single-atom catalysts, SACs) demonstrate promising potential to synergise the benefits of solid and molecular catalysts for efficient Pd utilisation. Here we show that using Pd atoms anchored on nitrogen-doped carbon permits full recovery of the metal and reuse of the catalyst over multiple cycles. A hybrid process using the Pd-SAC with a homogeneous CuI cocatalyst is more effective than a fully heterogeneous analogue based on a bimetallic Pd-Cu SAC, which deactivates severely due to copper leaching. In some scenarios, the LCA-based metrics demonstrate the footprint of the hybrid homogeneous-heterogeneous catalytic process is leaner than the purely homogeneous counterpart already upon single reuse. Combining LCA with experimental evaluation will be a useful guide to the implementation of solid, reusable catalysts for sustainable organic transformations.

Morbidities among older workers and work exit: the HEAF cohort.

BACKGROUND: Governments need people to work to older ages, but the prevalence of chronic disease and comorbidity increases with age and impacts work ability. AIMS: To investigate the effects of objective health diagnoses on exit from paid work amongst older workers. METHODS: Health and Employment After Fifty (HEAF) is a population cohort of adults aged 50-64 years recruited from English GP practices which contribute to the Clinical Practice Research Datalink (CPRD). Participants have completed questionnaires about health and work at baseline and annually for 2 years: their responses were linked with their objective health diagnoses from the CPRD and data analysed using Cox regression. RESULTS: Of 4888 HEAF participants ever in paid work, 580 (25%) men and 642 (25%) women exited employment, 277 of them mainly or partly for a health reason (health-related job loss (HRJL)). Amongst HEAF participants who remained in work (n = 3666) or who exited work but not for health reasons (n = 945), there was a similar prevalence of background health conditions. In men and women, HRJL was associated with inflammatory arthritis, sleep disorders, common mental health conditions and musculoskeletal pain. There were however gender differences: widespread pain and lower limb osteoarthritis were associated with HRJL in women but hypertension and cardiovascular disease in men. CONCLUSIONS: Improved diagnosis and management of common conditions might be expected to increase working lives. Workplace well-being interventions targeting obesity and increasing mobility might contribute to extended working lives. Employers of predominantly female, as compared with male workforces may need different strategies to retain older workers.

Shift work amongst older UK workers and job exit.

BACKGROUND: Night/shift work may be increasing but there are few data about the prevalence amongst older workers. With governments encouraging people to work to older ages, it is important to know how feasible night/shift work is for them and whether there are any adverse health consequences. AIMS: Amongst current older workers (aged 50-64 years), to explore the prevalence of night/shift working and evaluate its health impacts and sustainability over 4 years of follow-up. METHODS: Data from the Health and Employment After Fifty cohort were used to describe the demographic, job and health characteristics of men and women undertaking night/shift work. Longitudinal data were used to examine the number and nature of exits annually thereafter. RESULTS: Amongst the 5409 working at baseline, 32% reported night/shift work in sectors which differed by sex. Night/shift workers were more likely to be: current smokers; doing physically demanding work; struggling to cope at work; dissatisfied with their hours; depressed; sleeping poorly; rating their health poorly. Women whose job involves night work were more likely to exit the workforce over 4 years. CONCLUSIONS: Almost one in three contemporary UK older workers report night/shift work. We found some evidence of adverse impacts on health, sleep and well-being and higher rates of job exit amongst women. More research is needed but night/shift work may be challenging to sustain for older workers and could have health consequences.

Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. PATIENTS AND METHODS: In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. RESULTS: In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1- tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). CONCLUSION: Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.

The Italian Society for Rheumatology recommendations for the management of axial spondyloarthritis.

Over the last few years, the landscape of treatments for axial spondyloarthritis (SpA) has been rapidly evolving, urging international scientific societies to draft or update existing clinical practice guidelines (CPGs) on the management of axial SpA. The Italian Society for Rheumatology (SIR) committed to provide revised and adapted evidence- and expert-based recommendations for the management of patients with axial SpA in Italy. A systematic approach to the adaptation of existing CPGs - the ADAPTE methodology - was adopted to obtain updated recommendations suitable for the Italian context. A systematic literature search was performed in Medline and Embase databases to find international CPGs and consensus statements with recommendations for the management of axial SpA published in the previous five years. A working group composed of rheumatologists with proven experience in the management of axial SpA and methodologists identified the key research questions which guided study selection and data extraction. Guideline quality was assessed using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The Italian recommendations were developed by endorsing or adapting and rewording some existing recommendations. The draft of the recommendations was sent to a multidisciplinary group of external reviewers for comment and rating. Six original CPGs were selected and used to create this SIR CPG, which includes a final set of 14 recommendations covering the management of patients with axial SpA across the following domains: assessment, pharmacological and non-pharmacological treatment, and follow-up. The dissemination and implementation of these SIR recommendations are expected to support an evidencebased clinical approach to the management of patients with axial SpA in Italy.

Differential relationships between parent-child DXA and pQCT bone measures: Results from the Southampton Women's Survey.

AIM: To investigate the associations between indices of bone health in childhood and corresponding parental measures. METHODS: The Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (ß-coefficients (95%CI) unit/unit for each bone measure). RESULTS: Data were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (ß = 0.26 g·cm-2/g·cm-2 (0.21,0.32)) and father-child aBMD (ß = 0.16 g·cm-2/g·cm-2 (0.11,0.21)), P-difference in ß = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (ß = 0.33 mm2/mm2 (0.17,0.48)), but little evidence of a father-offspring association (ß = -0.06 mm2/mm2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (ß = 0.48 mg·cm-3/mg·cm-3 (0.15,0.82)) than mothers (ß = 0.27 mg·cm-3/mg·cm-3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height. CONCLUSIONS: Whilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects. SUMMARY: In an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships.

Clinical phenotypes of Behçet's syndrome in a large cohort of Italian patients: focus on gender differences.

Objective: The aim of this study was to investigate the clinical phenotypes of Italian patients with Behçet's syndrome (BS) according to gender. BS is a rare chronic multisystemic disorder with a wide spectrum of clinical manifestations. Human leucocyte antigen (HLA)-B51, gender, and ethnicity have been suggested as factors that could influence the clinical manifestations in BS patients. To date, few data assessing gender differences in Italian BS patients are available in the literature.Method: We retrospectively evaluated a group of Italian patients seen consecutively at our dedicated tertiary centre from 1 January 2000 to 31 May 2018. Demographics, clinical features during follow-up, and HLA status were obtained from a review of medical records and analysed in male and female groups.Results: In total, 285 [168 male (M) and 117 female (F)] patients were eligible for the study. Males had papulopustolar lesions, posterior uveitis, and deep venous thrombosis more often than females (83.3% M vs 46.2% F, 36.9% M vs 18.8% F, and 8.3% M vs 0.9% F, respectively; p < 0.01). Erythema nodosum (59.0% F vs 41.1% M; p < 0.01) and arthralgia (52.1% F vs 31.6% M; p < 0.01) were more frequent in females. No differences were found in HLA-B51 status (59.2% M vs 59.0% F).Conclusion: In our Italian cohort, BS was slightly more prevalent in males. Some gender-related differences were observed when comparing male and female cohorts. The data also confirmed that BS tends to be less aggressive in Italian female patients.

Impact of the first Covid-19 pandemic wave on first episode psychosis in Milan, italy.

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic appears to increase risk for mental illness, either directly due to inflammation caused by the virus or indirectly due to related psychosocial stress, resulting in the development of both anxious-depressive and psychotic symptoms. The purpose of the present study was to assess the frequency and characteristics of all patients with First Episodes Psychosis (FEP) without COVID-19 infection hospitalized in the first four months since lockdown in Milan. We recruited sixty-two patients hospitalized between March 8 to July 8, 2020 versus those first  hospitalized in the same period in 2019. The two subgroups were compared for sociodemographic variables and clinical characteristics of the episodes. Patients with FEP in 2020 were significantly older than patients with FEP in 2021, and presented with significantly less substances abuse. Interestingly, patients presenting with FEP in 2020 were significantly older than patients with FEP in 2019. These data are compatible with the greater vulnerability to stressful factors during the pandemic, as well as with the greater concern regarding a possible COVID-19 infection producing brain damage causing the FEP.

Placental volume at 11 weeks is associated with offspring bone mass at birth and in later childhood: Findings from the Southampton Women's Survey.

OBJECTIVES: To investigate associations between placental volume (PV) at 11 weeks' gestation and offspring bone outcomes at birth, 6 years and 8 years. METHODS: 3D ultrasound scanning was used to assess 11 week PV in a subset (n = 236) of the Southampton Women's Survey (a prospective mother-offspring cohort). Maternal anthropometric measures and lifestyle information were obtained pre-pregnancy and at 11 weeks' gestation. Offspring dual-energy x-ray absorptiometry scanning was performed within 2 weeks postnatally and at 6 and 8 years. Linear regression was used to assess associations between PV and bone outcomes, adjusting for offspring age at DXA and sex, and maternal age, height, smoking status, walking speed and triceps skinfold thickness. ß are SD change in bone outcome per SD change in PV. RESULTS: In adjusted models, 11 week PV was positively associated with bone area (BA) at all time points, with evidence of persisting associations with increasing childhood age (birth: n = 80, ß = 0.23 [95%CI = 0.03, 0.42], 6 years: n = 110, ß = 0.17 [-0.01, 0.36], 8 years: n = 85, ß = 0.13 [-0.09, 0.36]). Similar associations between 11 week PV and bone mineral content (BMC) were observed. Associations with size-corrected bone mineral content were weaker at birth but strengthened in later childhood (birth: n = 78, ß = 0.07 [-0.21, 0.35], 6 years: n = 107, ß = 0.13 [-0.08, 0.34], 8 years: n = 71, ß = 0.19 [-0.05, 0.43]). CONCLUSIONS: 11 week PV is associated with DXA bone measures at birth, with evidence of persisting associations into later childhood. Further work is required to elucidate the contributions of placental morphology and function to gestational influences on skeletal development.

COVID-19 and associations with frailty and multimorbidity: a prospective analysis of UK Biobank participants.

BACKGROUND: Frailty and multimorbidity have been suggested as risk factors for severe COVID-19 disease. AIMS: We investigated, in the UK Biobank, whether frailty and multimorbidity were associated with risk of hospitalisation with COVID-19. METHODS: 502,640 participants aged 40-69 years at baseline (54-79 years at COVID-19 testing) were recruited across UK during 2006-10. A modified assessment of frailty using Fried's classification was generated from baseline data. COVID-19 test results (England) were available for 16/03/2020-01/06/2020, mostly taken in hospital settings. Logistic regression was used to discern associations between frailty, multimorbidity and COVID-19 diagnoses, after adjusting for sex, age, BMI, ethnicity, education, smoking and number of comorbidity groupings, comparing COVID-19 positive, COVID-19 negative and non-tested groups. RESULTS: 4510 participants were tested for COVID-19 (positive = 1326, negative = 3184). 497,996 participants were not tested. Compared to the non-tested group, after adjustment, COVID-19 positive participants were more likely to be frail (OR = 1.4 [95%CI = 1.1, 1.8]), report slow walking speed (OR = 1.3 [1.1, 1.6]), report two or more falls in the past year (OR = 1.3 [1.0, 1.5]) and be multimorbid (≥ 4 comorbidity groupings vs 0-1: OR = 1.9 [1.5, 2.3]). However, similar strength of associations were apparent when comparing COVID-19 negative and non-tested groups. However, frailty and multimorbidity were not associated with COVID-19 diagnoses, when comparing COVID-19 positive and COVID-19 negative participants. DISCUSSION AND CONCLUSIONS: Frailty and multimorbidity do not appear to aid risk stratification, in terms of positive versus negative results of COVID-19 testing. Investigation of the prognostic value of these markers for adverse clinical sequelae following COVID-19 disease is urgently needed.

Quality indicators for hyperthermia treatment: Italian survey analysis.

AIM: Nowadays, no Quality Indicators (QI) have been proposed for Hyperthermia treatments. Starting from radiotherapy experience, the aim of this work is to adapt radiotherapy indicators to Hyperthermia and to propose a new specific set of QI in Hyperthermia field. MATERIAL AND METHODS: At first, radiotherapy quality indicators published in literature have been adapted to hyperthermia setting. Moreover, new specific indicators for the treatment of hyperthermia have been defined. To obtain the standard reference values of quality indicators, a questionnaire was sent to 7 Italian hyperthermia Institutes with a list of questions on physical and clinical hyperthermia treatment in order to highlight the different therapeutic approaches. RESULTS: Three structure, five process and two outcome QI were selected. It has been possible to adapt seven indicators from radiotherapy, while three indicators have been defined as new specific indicators for hyperthermia. Average values used as standard reference values have been obtained and proposed. CONCLUSION: The survey performed on 7 Italian centres allowed to derive the standard reference value for each indicator. The proposed indicators are available to be investigated and applied by a larger number of Institutes in which hyperthermia treatment is performed in order to monitor the operational procedures and to confirm or modify the reference standard value derived for each indicator.

Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages.

BACKGROUND: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. RESULTS: No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. CONCLUSIONS: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688).

Job stress and post-retirement health in the Hertfordshire Cohort Study.

BACKGROUND: Job demand-control (DC) and effort-reward imbalance (ERI) are two commonly used measures of work stress which are independently associated with health. AIMS: To test the hypothesis that DC and ERI have different and cumulative effects on health. METHODS: DC and ERI were assessed in the Hertfordshire Cohort Study. The characteristics and occupations of men and women reporting either or both work stresses were compared and the interaction of these with health status were explored. RESULTS: Complete data were available for 1021 men and 753 women, reporting on their most recent or current job. A total of 647 (63%) men and 444 (59%) women reported neither work stress, while 103 (10%) men and 78 (10%) women reported both. Patterns of ERI and DC, alone and in combination, were different by type of occupation and by gender. Men reporting both work stresses (as compared with neither) were more likely to be single. Reported ERI with DC in the most recent or current job was associated with: poorer SF-36 physical function scores (OR 2.3 [95% CI 1.5-3.7] for men; OR 2.0 [95% CI 1.2-3.6] for women) and mental health scores (OR 2.8 [95% CI 1.8-4.4] for men; OR 3.1 [95% CI 1.8-5.3] for women). Moreover, average grip strength was 1.7 kg (95% CI 0.2-3.3) lower among men who described both work stresses. CONCLUSION: DC and ERI are two models of the psychosocial workplace environment which offer different but cumulative insight into the impacts of work on an individual's psychological and physical health, particularly in a population sample.

ERAP1 molecular characterization: Identification of a de novo allelic variant.

The novel ERAP1 allelic variant is a missense polymorphism leading to the Arg53Pro substitution.

Prior fragility fracture and risk of incident ischaemic cardiovascular events: results from UK Biobank.

In the large UK Biobank population-based cohort, we found that amongst men, but not women, prior fragility fracture was associated with increased risk of admission with ischaemic heart disease. INTRODUCTION: We aimed to investigate the relationship between prior fracture and risk of incident ischaemic cardiovascular events in a UK population-based cohort. METHODS: UK Biobank is a large prospective cohort comprising 502,637 men and women aged 40-69 years, with detailed baseline assessment. History of fracture was self-reported, and details of hospital admissions for ischaemic heart disease (IHD) (ICD-10:I20-I25) were obtained through linkage to UK Hospital Episode Statistics. Cox proportional hazards models were used to investigate the prospective relationships between prior fracture and hospital admission for men and women, controlling for age, BMI, smoking, alcohol, educational level, physical activity, systolic blood pressure, calcium and vitamin D use, ankle spacing-width, heel BUA and HRT use (women). RESULTS: Amongst men, a fragility fracture (hip, spine, wrist or arm fracture resulting from a simple fall) within the previous 5 years was associated with a 35% increased risk of IHD admission (fully adjusted HR 1.35; 95%CI 1.00, 1.82; p = 0.047), with the relationship predominantly driven by wrist fractures. Associations with hospitalisation for angina in men were similar in age-adjusted models [HR1.54; 95%CI: 1.03, 2.30), p = 0.037], but did not remain statistical significant after full adjustment [HR 1.64; 95%CI: 0.88, 3.07); p = 0.121]. HRs for admission with angina were lower in women, and neither age- nor fully adjusted relationships attained statistical significance. CONCLUSIONS: Prior fragility fracture is an independent risk factor for incident ischaemic cardiovascular events in men. Further work may clarify whether this association is causal or represents shared risk factors, but these findings are likely to be of value in risk assessment of both osteoporosis and cardiovascular disease.

Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates.

Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D(KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.

Functional role of airflow-sensing hairs on the bat wing.

The wing membrane of the big brown bat (Eptesicus fuscus) is covered by a sparse grid of microscopic hairs. We showed previously that various tactile receptors (e.g., lanceolate endings and Merkel cell neurite complexes) are associated with wing-hair follicles. Furthermore, we found that depilation of these hairs decreased the maneuverability of bats in flight. In the present study, we investigated whether somatosensory signals arising from the hairs carry information about airflow parameters. Neural responses to calibrated air puffs on the wing were recorded from primary somatosensory cortex of E. fuscus Single units showed sparse, phasic, and consistently timed spikes that were insensitive to air-puff duration and magnitude. The neurons discriminated airflow from different directions, and a majority responded with highest firing rates to reverse airflow from the trailing toward the leading edge of the dorsal wing. Reverse airflow, caused by vortices, occurs commonly in slowly flying bats. Hence, the present findings suggest that cortical neurons are specialized to monitor reverse airflow, indicating laminar airflow disruption (vorticity) that potentially destabilizes flight and leads to stall. NEW & NOTEWORTHY: Bat wings are adaptive airfoils that enable demanding flight maneuvers. The bat wing is sparsely covered with sensory hairs, and wing-hair removal results in reduced flight maneuverability. Here, we report for the first time single-neuron responses recorded from primary somatosensory cortex to airflow stimulation that varied in amplitude, duration, and direction. The neurons show high sensitivity to the directionality of airflow and might act as stall detectors.

The relationship between maternal self-efficacy, compliance and outcome in a trial of vitamin D supplementation in pregnancy.

In a randomised controlled trial of vitamin D during pregnancy, we demonstrated that women with lower self-efficacy were more likely to experience practical problems with taking the trial medication and that this was associated with lower compliance and achieved 25(OH)-vitamin D concentrations. INTRODUCTION: The relationship between self-efficacy (the belief that one can carry out a behaviour), compliance with study protocol and outcome was explored within a randomised, double-blind, placebo-controlled trial of vitamin D supplementation in pregnancy. METHODS: In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial, women with circulating plasma 25(OH)-vitamin D of 25-100 nmol/l in early pregnancy were randomised to either 1000 IU cholecalciferol/day or matched placebo from 14 weeks until delivery. Circulating 25(OH)-vitamin D concentrations were assessed at 14 and 34 weeks' gestation. A sequential sub-sample completed Schwarzer's General Self-Efficacy Scale at 14 and 34 weeks and the Problematic Experiences of Therapy Scale at 34 weeks. Women were interviewed about their experiences of the trial and interview transcripts analysed thematically. RESULTS: In 203 women, those with higher self-efficacy were less likely to experience practical problems taking the study medication (odds ratio (OR) 0.81 (95 % confidence interval (CI) 0.69-0.95), p = 0.01). Over half reported practical problems associated with poorer compliance with the protocol requiring women to take the medication daily. Compliance in women who experienced practical problems was 94 % compared with 98 % for those with no problems (p < 0.001). Poorer compliance was also associated with lower concentrations of 25(OH)-D in late pregnancy in the treatment group (ß = 0.54 nmol/l (95 % CI 0.18-0.89), p = 0.003). Thematic analysis suggested common difficulties were remembering to take the medication every day and swallowing the large capsules. CONCLUSIONS: These findings suggest that differences in self-efficacy influence trial outcomes. Such information may help clinicians anticipate responses to routine vitamin D supplementation in pregnancy and identify those who may need more support to comply. TRIAL REGISTRATION: ISRCTN82927713, registered 11/04/2008.