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Abstract Background The COVID-19 pandemic has impacted the physical and mental health of people worldwide including those living with genetic conditions. Sickle cell disease (SCD) is a hematologic chronic disease that causes multisystem damage and morbidity. Individuals living with SCD have had to continue managing their care for their chronic disease while following public health measures to protect against infection with COVID-19. Promoting resilience has been posited as being psychologically protective for those living with SCD. This study examines changes in resilience over time in a SCD population in the context of the COVID-19 pandemic. Methods Ninety-seven adults living with SCD completed two parent studies: (1) The INSIGHTS Study, a cross-sectional natural history study conducted from 2014–2019 and (2) The Living with SCD in COVID-19 Pandemic Study, an online survey conducted in 2020. Changes over time in resilience, perceived stress, emotional distress, and physical and mental health were analyzed in multivariable repeated measures model. Results Results showed that the psychological resilience of our study cohort had significantly decreased (0.19, p=0.01) over time. Resilience during the pandemic was associated with better mental health and physical health and lower perceived stress and emotional distress. In addition, results showed that marital status, education level, and employment were significantly associated with the psychological resilience of study participants. Conclusion Resilience declined during the COVID-19 pandemic but was still associated with better physical and mental health outcomes. Future studies should investigate the relationship between resilience and sociodemographic factors.

Summary: The diversity of the U.S. population is currently not reflected in the genomic workforce and across the greater scientific enterprise. Although diversity and inclusion efforts have focused on increasing the number of individuals from underrepresented groups across scientific fields, structural racism remains. Thus, the cultivation and adoption of diversity as an ethos requires shifting our focus to being intentional about an institution’s character, culture, and climate. One way for this ethos to be sustained is by facilitating an intentional anti-racism approach within the field. Adopting a new perspective on diversity utilizing an anti-racism approach will support genomics researchers as we build supportive, collaborative research environments. We seek to expand critical thought in the framing of diversity in the research enterprise and propose an anti-racism approach that informs deliberate actions required to address structural racism.

The diversity of the U.S, population is currently not reflected in the genomic workforce and across the greater scientific enterprise. Although diversity and inclusion efforts have focused on increasing the number of individuals from underrepresented groups across scientific fields, structural racism remains. Thus, the cultivation and adoption of diversity as an ethos requires shifting our focus to being intentional about an institution's character, culture, and climate. One way for this ethos to be sustained is by facilitating an intentional anti-racism approach within the field. Adopting a new perspective on diversity utilizing art anti-racism approach will support genomics researchers as we build supportive, collaborative research environments. We seek to expand critical thought in the framing of diversity in the research enterprise and propose an anti-racism approach that informs deliberate actions required to address structural racism. [ABSTRACT FROM AUTHOR]

Purpose: To test a new approach to address moral distress in intensive care unit (ICU) personnel., Methods: Using principles of participatory action research, we developed an eight-step moral conflict assessment (MCA) that guides participants in describing the behaviour that they have to implement, the effects this has on them, their current coping strategies, their values in conflict, any other concerns related to the situation, what helps and hinders the situation, new coping strategies, and the effect of the preceding steps on participants. This assessment was tested with eight ICU providers in an 11-bed community ICU., Results: During three one-hour sessions, participants described their moral distress that was caused by the use of ongoing life-support for a patient who the team believed did not prefer this course of care, but whose family was requesting it. Participants experienced frustration and discouragement and coping strategies included speaking to colleagues and exercising. They felt that they were unable to take meaningful action to resolve this conflict. Values that were in conflict in the situation included beneficence and patient autonomy. Based on ranking of helping and hindering factors, the team proposed new strategies including improving consistency of care plans and educating patients' family members and ICU personnel about advance care planning and end-of-life care. After completing this assessment, participants reported less stress and a greater ability to take meaningful action, including some of the proposed new strategies., Conclusions: We found this new approach to address moral distress in ICU personnel to be feasible and a useful tool for facilitating plans for reducing moral distress., (© 2022. The Author(s).)

Background: Ageing is commonly associated with sarcopenia (SP) and osteoporosis (OP), both of which are associated with disability, impaired quality of life, and mortality. The aims of this study were to explore the relationships between SP, OP, frailty, and multimorbidity in community-dwelling older adults participating in the Hertfordshire Cohort Study (HCS) and to determine whether coexistence of OP and SP was associated with a significantly heavier health burden., Methods: At baseline, 405 participants self-reported their comorbidities. Cut-offs for low grip strength and appendicular lean mass index were used according to the EWSGOP2 criteria to define SP. OP was diagnosed when T-scores of < -2.5 were present at the femoral neck or the participant reported use of the anti-OP medications including hormone replacement therapy (HRT), raloxifene, or bisphosphonates. Frailty was defined using the standard Fried definition., Results: One hundred ninety-nine men and 206 women were included in the study. Baseline median (interquartile range) age of participants was 75.5 (73.4-77.9) years. Twenty-six (8%) and 66 (21.4%) of the participants had SP and OP, respectively. Eighty-three (20.5%) reported three or more comorbidities. The prevalence of pre-frailty and frailty in the study sample was 57.5% and 8.1%, respectively. Having SP only was strongly associated with frailty [odds ratio (OR) 8.28, 95% confidence interval (CI) 1.27, 54.03; P = 0.027] while the association between having OP alone and frailty was weaker (OR 2.57, 95% CI 0.61, 10.78; P = 0.196). The likelihood of being frail was substantially higher in the presence of coexisting SP and OP (OR 26.15, 95% CI 3.13, 218.76; P = 0.003). SP alone and OP alone were both associated with having three or more comorbidities (OR 4.71, 95% CI 1.50, 14.76; P = 0.008 and OR 2.86, 95% CI 1.32, 6.22; P = 0.008, respectively) although the coexistence of SP and OP was not significantly associated with multimorbidity (OR 3.45, 95% CI 0.59, 20.26; P = 0.171)., Conclusions: Individuals living with frailty were often osteosarcopenic. Multimorbidity was common in individuals with either SP or OP. Early identification of SP and OP not only allows implementation of treatment strategies but also presents an opportunity to mitigate frailty risk., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Concerns regarding personal, professional, administrative, and institutional implications of medical assistance in dying (MAiD) are of particular interest to palliative and hospice care providers (PHCPs), who may encounter additional moral distress and professional challenges in providing end-of-life (EOL) care in the new legislative and cultural era. Objective: To explore PHCPs' encountered challenges and resource recommendations for caring for patients considering MAiD. Design: Qualitative thematic analysis of audio-recorded semistructured interviews with PHCPs. Setting/Subjects: Multidisciplinary PHCPs in acute, community, residential, and hospice care in Vancouver, Canada, with experience supporting patients who have made MAiD inquiries or requests. Measurements: Interviews were deidentified, transcribed verbatim, and coded by four researchers using a common coding scheme. Key themes were analyzed. Results: Twenty-six PHCP participants included physicians ( n  = 7), nurses ( n  = 12), social workers ( n  = 5), and spiritual health practitioners ( n  = 2). Average interview length was 52 minutes (range 35-90). Analysis revealed four broad challenges associated with providing EOL care after MAiD legalization: (1) moral ambiguity and provider distress, (2) family distress, (3) interprofessional team conflict, and (4) impact on palliative care. Participants also recommended three types of resources to support clinicians in delivering quality EOL care to patients contemplating MAiD: (1) education and training, (2) pre- and debriefing for team members, and (3) tailored bereavement support. Conclusions: PHCPs encountered multilevel MAiD-related challenges, but noted improvement in organizational policies and coordination. Resources to enhance training, pre- and debriefing, and tailored bereavement may further support PHCPs in providing high-quality EOL care as they navigate the legislative and cultural shifts.

Background: Diet quality in older people with chronic obstructive pulmonary disease (COPD) is associated with better health and lung function. Social factors, such as social support, social networks and participation in activities, have been linked with diet quality in older age. A social network tool-GENIE (Generating Engagement in Network Involvement)-was implemented in a COPD community care context. The study aimed to assess the feasibility of the GENIE intervention to promote diet quality and other health behaviours in COPD., Methods: Twenty-two community-dwelling older adults with COPD were recruited from a local COPD service. Participants were offered usual care or the GENIE intervention. Process evaluation methods were used to assess intervention implementation, context and mechanisms of impact; these included observations of patient interactions with the intervention, documented in observational field notes and in films of a patient group discussion. Diet quality was assessed by food frequency questionnaire; 'prudent' diet scores were used to describe diet quality at baseline and at 3-month follow-up. Change in diet quality was expressed per month, from baseline to follow-up., Results: Feasibility data showed that the GENIE intervention could be implemented in this sample of community-living older people. The intervention was acceptable to clinicians and older people with COPD, especially for those with less severe disease, when facilitated appropriately and considering the levels of literacy of participants. There was no significant change in diet quality in the intervention group over the follow-up period (median change in prudent diet score per month (interquartile range (IQR), 0.03 (- 0.24-0.07)), whereas an overall fall in diet quality was observed in the control group (- 0.15 (- 0.24-0.03))., Conclusion: The process evaluation findings suggest that this intervention is feasible and acceptable to both patients and clinicians. Although the sample size achieved in this study was small, findings suggest that the intervention may have a protective effect against declines in diet quality, and other health behaviours, in an older COPD population. Findings from this feasibility study indicate that further evaluation of the GENIE intervention is warranted in a larger study, with a longer follow-up., Trial Registration: ClinicalTrials.gov, NCT02935452. NIH U.S. National Library of Medicine. Registered 17 October 2016., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Objectives: Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease which presents with polyarthritis in addition to extra-articular manifestations. Historically, studies have shown a link between RA and adverse musculoskeletal outcomes but these studies were reported before the widespread use of biologic therapies. The aim of this study was therefore to investigate associations between RA, RA medications and bone mineral density, falls and fractures, using UK Biobank data. Methods: Diagnosis of RA was made using Hospital Episode Statistics (HES) ICD-10 coding. We assessed RA relationships with estimated bone mineral density (eBMD) from heel quantitative ultrasound measurements, self-reported falls (in last year) and HES recorded fracture, adjusted for age, ethnicity, BMI, smoking status, and physical activity. Results: Of 502,543 participants, 3849 (1.4%) of women and 1643 (0.7%) of men had a diagnosis of RA. Median age of the participants was 57 years (IQR 50-63) in women and 58 (IQR 50-64) in men. RA was associated with lower eBMD (men: β -0.244, 95% CI -0.378, -0.110 p < 0.001; women: β -0.217, 95% CI -0.297, -0.138 p < 0.001) a reported fall in the last year (men: OR 1.54, 95% CI 1.26, 1.87 p < 0.001; women: OR 1.36, 95% CI 1.19, 1.56 p < 0.001) and fracture in women (OR 1.76, 95% CI 1.43, 2.16 p < 0.001). Corticosteroid therapy in men (β -0.934, 95% CI -1.565, -0.304 p = 0.004) and disease modifying anti-rheumatic drug (DMARD) use in both sexes (men: β -0.437, 95% CI -0.761, -0.112 p = 0.008; women: β -0.243, 95% CI -0.421, -0.065 p = 0.007), but not biologic therapy, were associated with a lower eBMD with RA. Conclusions: RA was associated with lower eBMD, increased falls and fracture. Corticosteroid and DMARD therapy, but not biologic therapy, were associated with lower eBMD., (Copyright © 2019 Clynes, Jameson, Prieto-Alhambra, Harvey, Cooper and Dennison.)

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations., Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis., Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included., Main Outcomes and Measures: Type 2 diabetes and glycemic traits., Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration., Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

Background: multi-morbidity is an increasing challenge in western medicine and has the potential to impact patients' quality of life, treatment options and compliance with medications. The aim of this study was to identify the early-life predictors of long-term multi-morbidity in an historical cohort, the Hertfordshire Cohort Study (HCS)., Methods: perinatal and infant health records were kept on all children born in Hertfordshire between 1931 and 1939. Participants who were still alive in 1998 were recruited to the HCS and data collected on major chronic diseases. They were subsequently followed up in the Clinical Outcomes Study (COS), and data recorded on all major illnesses since HCS, as well as current medications. Ordinal logistic regression analysed the association between early-life factors and the number of morbidities in these two surveys as well as medication count., Results: a total of 2299 participants had data in COS, 1131 (49%) were female, median age (interquartile range) at recruitment to HCS was 66 (64-68) years. Higher rates of childhood illnesses were significantly associated with future multi-morbidity (multivariate odds ratio (OR) (95% confidence interval (CI)) 1.15 (1.06, 1.25)) and higher medication counts at COS (multivariate OR (95%CI) 1.14 (1.06, 1.23))., Conclusions: children who experience more illnesses at a young age may be prone to develop multi-morbidity in later life.

Setting: The majority of Canadians' food acquisition occurs in retail stores. Retail science has become increasingly sophisticated in demonstrating how consumer environments influence population-level diet quality and health status. The retail food environment literature is new but growing rapidly in Canada, and there is a relative paucity of evidence from intervention research implemented in Canada., Intervention: The healthy corner store model is a comprehensive complex population health intervention in small retail stores, intended to transform an existing business model to a health-promoting one through intersectoral collaboration. Healthy corner store interventions typically involve conversions of existing stores with the participation of health, community, and business sector partners, addressing business fundamentals, merchandising, and consumer demand., Outcomes: This article introduces pioneering experiences with the healthy corner store intervention in Canada. First, we offer a brief overview of the state of evidence within and outside Canada. Second, we discuss three urban and one rural healthy corner store initiatives, led through partnerships among community food security organizations, public health units, academics, and business partners, in Manitoba, Ontario, and Newfoundland and Labrador. Third, we synthesize the promising practices from these local examples, including aspects of both intervention science (e.g., refinements in measuring the food environment) and community-based practice (e.g., dealing with unhealthy food items and economic impact for the retailer)., Implications: This article will synthesize practical experiences with healthy corner stores in Canada. It offers a baseline assessment of promising aspects of this intervention for health and health equity, and identifies opportunities to strengthen both science and practice in this area of retail food environment work.

As healthcare delivery becomes increasingly interprofessional, it is imperative to identify opportunities for effective collaboration and coordination of care. Drawing on a Canadian qualitative study that adopted a constant comparative method based on the grounded theory approach, we report how healthcare providers' (HCPs) personal experiences and professional roles intersect with system factors in hindering or enhancing their ability to support patients and families in planning for end-of-life (EOL) care. We used a criterion-based sampling strategy and sought HCPs who had direct experience engaging patients and families in complex healthcare decisions on: (1) initiating, withholding, or withdrawing treatment; (2) care planning; and/or (3) discharge planning. Interviews sought to understand what HCPs perceived as individual, (inter)professional, and system factors that might hinder, promote, or enhance support for patients/families. We present four major intersecting themes from in-depth interviews with 28 HCPs across acute, long-term, and community care settings that represent three barriers and one facilitator: discomfort with death and dying, confusion about role responsibility, lack of coordinated care, and importance of interprofessional teamwork. Attending to system power hierarchy, we explore interprofessional strategies to support patients' and families' care experiences and promote team-based decision-making. We recommend an interprofessional team approach to facilitate EOL decision-making across care settings and before death becomes imminent. Increasing educational initiatives and developing tools that focus on interprofessional collaboration may help HCPs to understand each other's roles and perspectives, so that they can work together to provide a more coherent and coordinated approach to EOL decision-making.

Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKβ mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKβ as a potential regulator of excessive alcohol drinking had not previously been investigated. Based on previous findings that the overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKβ would limit/decrease drinking by preventing the activation of NF-κB. We studied the systemic effects of two pharmacological inhibitors of IKKβ, TPCA-1 and sulfasalazine, on ethanol intake using continuous- and limited-access, two-bottle choice drinking tests in C57BL/6J mice. In both tests, TPCA-1 and sulfasalazine reduced ethanol intake and preference without changing total fluid intake or sweet taste preference. A virus expressing Cre recombinase was injected into the nucleus accumbens and central amygdala to selectively knock down IKKβ in mice genetically engineered with a conditional Ikkb deletion ( Ikkb F/F ). Although IKKβ was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKβ in either brain region reduced ethanol intake and preference in the continuous access two-bottle choice test without altering the preference for sucrose. Pharmacological and genetic inhibition of IKKβ decreased voluntary ethanol consumption, providing initial support for IKKβ as a potential therapeutic target for alcohol abuse.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. PPAR agonists have well-documented anti-inflammatory and neuroprotective roles in the central nervous system. Recent evidence suggests that PPAR agonists are attractive therapeutic agents for treating neurodegenerative diseases as well as addiction. However, the distribution of PPAR mRNA and protein in brain regions associated with these conditions (i.e. prefrontal cortex, nucleus accumbens, amygdala, ventral tegmental area) is not well defined. Moreover, the cell type specificity of PPARs in mouse and human brain tissue has yet to be investigated. We utilized quantitative PCR and double immunofluorescence microscopy to determine that both PPAR mRNA and protein are expressed ubiquitously throughout the adult mouse brain. We found that PPARs have unique cell type specificities that are consistent between species. PPARα was the only isotype to colocalize with all cell types in both adult mouse and adult human brain tissue. Overall, we observed a strong neuronal signature, which raises the possibility that PPAR agonists may be targeting neurons rather than glia to produce neuroprotection. Our results fill critical gaps in PPAR distribution and define novel cell type specificity profiles in the adult mouse and human brain.

The first national audit for rheumatoid and early inflammatory arthritis has benchmarked care for the first 3 months of follow-up activity from first presentation to a rheumatology service. Access to care, management of early rheumatoid arthritis and support for self care were measured against National Institute for Health and Care Excellence quality standards; impact of early arthritis and experience of care were measured using patient-reported outcome and experience measures. The results demonstrate delays in referral and accessing specialist care and the need for service improvement in treating to target, suppression of high levels of disease activity and support for self-care. Improvements in patient-reported outcomes within 3 months and high levels of overall satisfaction were reported but these results were affected by low response rates. This article presents a summary of the national data from the audit and discusses the implications for nursing practice.

Unlabelled: Clustering of factors linked with poor bone health is common in older adults and is associated with lower bone density and increased fracture risk in women., Purpose: Many factors are associated with bone mineral density, which in turn is strongly linked with risk of fragility fracture. We assessed how commonly clustering of risk factors occurs and related such clustering to bone mineral density in a population of older community-dwelling men and women., Method: This is a cross-sectional study with 498 men and 498 women aged 59 to 72 years, who were participants in the Hertfordshire Cohort Study, in whom incident fracture was recorded. Physical activity, diet quality, history of prior fracture, family history of fracture, cigarette and alcohol consumption and comorbidities were obtained through baseline questionnaire. Measurements of grip strength and bone mineral density of the lumbar spine and total femur were also taken., Results: Clustering of risk factors was common, with over 30% having two or more. In women, a graded association between the number of risk factors and low bone density was seen, and strong relationships were also seen between the number of risk factors and incident fracture; women with three or more risk factors had an adjusted hazard ratio (HR) of incident fracture of 5.98 (1.67, 21.43; p = 0.006) compared to women with no risk factors; women with two risk factors had an adjusted HR of 2.97 (1.14, 7.74; p = 0.03) and those with one, 2.28 (0.90, 5.75; p = 0.08)., Conclusion: Clustering of risk factors for poor bone health is common in community-dwelling older adults and is associated with increased risk of fracture and adverse bone health in women., Competing Interests: Compliance with ethical standards The East and North Hertfordshire Ethical Committees granted ethical approval for the study, and all participants gave written informed consent. Conflicts of interest Elaine Dennison has received speaker fees from Lilly; Cyrus Cooper has received consultancy fees/honoraria from Servier, Eli Lilly, Merck, Amgen, Novartis and Medtronic. Jean Zhang, Karen Jameson, Avan Aihie Sayer and Sian Robinson declare that they have no conflict of interest. Funding The Hertfordshire Cohort Study is funded by grants from the Medical Research Council and Arthritis Research UK.

Aims: To assess adherence to the UK's National Institute for Health and Care Excellence (NICE) guidelines for initiating and continuing glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes (T2DM)., Research Design and Methods: A retrospective cohort study of 7133 primary care patients ≥40 years with a first prescription for a GLP-1 receptor agonist following publication of NICE guideline/guidance. Patient characteristics and levels of clinical monitoring were assessed using descriptive analyses., Main Outcome Measures: Main outcomes were the proportion of patients initiating GLP-1 receptor agonists as part of NICE-recommended dual- or triple-therapy regimens; the proportions meeting NICE triple therapy initiation criteria (glycosylated hemoglobin [HbA1c] ≥7.5% and body mass index [BMI] ≥35 kg/m(2)) and the proportions continuing GLP-1 receptor agonist at 6 months according to NICE recommendations., Results: Mean age at initiating GLP-1 receptor agonists was 58.2 years (SD 9.4), BMI 38.4 kg/m(2) (SD 6.8) and HbA1c 9.2% (SD 3.2%). Overall, only 25% of patients initiated GLP-1 receptor agonists as part of a NICE-recommended regimen. Of patients initiated on a recommended triple-therapy regimen, 50% (646/1284) fulfilled both NICE HbA1c and BMI initiation criteria. Approximately 18% (32/174) of patients continuing NICE-recommended dual therapy at 6 months achieved a 1% reduction in HbA1c and 6.4% (33/515) continuing with NICE-recommended triple therapy achieved NICE's target reductions for both HbA1c and body weight. About 8% of patients continuing exenatide as triple therapy (N = 243) achieved both targets., Conclusions: Adherence to NICE guidance for initiating and continuing GLP-1 receptor agonists is low. However, lack of data on ethnicity (for assessing NICE's BMI criteria) and on contraindications and/or hypersensitivity to other diabetes medication in the treatment pathway have limited our ability to fully assess adherence to GLP-1 prescribing. Further research is warranted to better understand general practitioners' prescribing decisions given the cost of prescribing GLP-1 receptor agonists.

Purpose: Chronic heavy alcohol consumption is associated with bone density loss and increased fracture risk, while low levels of alcohol consumption have been reported as beneficial in some studies. However, studies relating alcohol consumption to bone geometry, volumetric bone mineral density (vBMD) and bone microarchitecture, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), are lacking., Methods: Here we report an analysis from the Hertfordshire Cohort Study, in which we studied associations between HR-pQCT measures at the distal radius and tibia and alcohol consumption in 376 participants (198 men and 178 women) aged 72.1-81.4 years., Results: A total of 30 (15.2%), 90 (45.5%) and 78 (39.4%) men drank minimal/none (<1 unit/week), low (≥1 unit/week and <11 units/week) and moderate/high (≥11 units/week) amounts of alcohol respectively. These figures were 74 (41.8%), 80 (45.2%) and 23 (13.0%) respectively in women for minimal/none (<1 unit/week), low (≥1 unit/week and <8 units/week) and moderate/high (≥8 units/week). At the distal radius, after adjustment for confounding factors (age, BMI, smoking status, dietary calcium intake, physical activity and socioeconomic status and years since menopause and HRT use for women), men that drank low alcohol had lower cortical thickness (p=0.038), cortical vBMD (p=0.033), and trabecular vBMD (p=0.028) and higher trabecular separation (p=0.043) than those that drank none/minimal alcohol. Similar differences were shown between minimal/none and moderate/high alcohol although these only reached statistical significance for the cortical parameters. Interestingly, after similar adjustment, women showed similar differences in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia. However, women that drank moderate/high alcohol had significantly higher trabecular vBMD (p=0.007), trabecular thickness (p=0.026), and trabecular number (p=0.042) and higher trabecular separation (p=0.026) at the distal radius than those that drank low alcohol., Conclusions: Our results suggest that alcohol consumption (low and moderate/high) may have a detrimental impact on bone health in men in both the cortical and trabecular compartments at the distal radius with similar results in women in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia suggesting that avoidance of alcohol may be beneficial for bone health., (Copyright © 2015. Published by Elsevier Inc.)

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: This study aimed to estimate the prevalence of chronic kidney disease (CKD) in the UK in 2010 and to assess prevalence, comorbidities and comedications associated with the disease over time, following inclusion of CKD in the Quality and Outcomes Framework (QOF)., Methods: This was a retrospective, longitudinal study assessing individuals with prevalent or incident CKD (identified using estimated glomerular filtration rate readings and/or Read codes) in the General Practice Research Database (GPRD) in 2010. Individuals were assessed at two time points: in 2010 and at the date of their first classification of CKD in the GPRD., Results: The prevalence of stage 3-5 CKD in 2010 was 5.9%. In patients with stage 3-5 CKD at first classification, their disease remained stable, progressed or improved by 2010 in approximately 50%, 10-15% and 25-30% of patients, respectively. Diagnoses of cardiovascular-related comorbidities (hypertension, hypercholesterolaemia, diabetes and cardiovascular disease), and treatment with antihypertensives and lipid-modifying therapy (LMT), increased with worsening disease severity. When patients were stratified by diagnosis date, the proportion of patients with stage 3-5 CKD and cardiovascular-related comorbidities decreased with time, and the relative use of LMT and antihypertensives among patients with hypercholesterolaemia and hypertension increased with time., Conclusions: Chronic kidney disease is generally stable or progressive, although more patients improve disease stage than previously assumed. Data suggest that the introduction of CKD into the QOF has increased awareness of CKD among physicians in the UK, allowing for earlier intervention and better control of CKD progression., (© 2014 John Wiley & Sons Ltd.)

Background: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk., Methods: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium., Findings: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002)., Interpretation: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study., Funding: British Heart Foundation, UK Medical Research Council, and Academy of Finland., (Copyright © 2014 Vimaleswaran et al. Open Access article distributed under the terms of CC BY. Published by .. All rights reserved.)

Objective: British clinical guidelines recommend statins as first-line lipid-modifying treatment (LMT) for patients at high risk of cardiovascular disease (CVD). We undertook an observational study to assess total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in high-risk patients who were treated with atorvastatin monotherapy by UK general practitioners., Methods: This retrospective database study included patients with a prescription for atorvastatin monotherapy between November 30, 2008, and November 30, 2011, with the index date defined as the first atorvastatin prescription during this period. Eligible high-risk patients with evidence of coronary heart disease (CHD), atherosclerotic vascular disease (AVD), diabetes mellitus (DM), or familial hypercholesterolemia (FH) were required to have ≥1 TC and LDL-C measurement between 3 and 12 months after the index date, and continuous enrollment 1 year before and 1 year after the index date. Cholesterol levels were assessed using the National Institute for Health and Care Excellence (NICE) guidelines: TC <4.0 mmol/L or LDL-C <2.0 mmol/L., Results: Of 2999 high-risk patients (60.2% men; mean [SD] age = 67.9 [10.6] years) meeting selection criteria, 23.9% 28.2%, 36.2%, and 11.6% received prescriptions for atorvastatin 10, 20, 40, and 80 mg, respectively (percentages do not sum to 100 because of rounding). Across all doses, the mean (SD) follow-up TC was 4.08 (0.80) mmol/L and LDL-C 2.08 (0.65) mmol/L. A large proportion of patients (88.8%) had TC < 5.0 mmol/L. However, only 45.8% had TC < 4.0 mmol/L, and 46.5% had LDL-C < 2.0 mmol/L. Although a larger proportion of patients with CHD/AVD + DM reached guideline-recommended lipid levels, only 63.7% of such patients had TC < 4.0 or LDL-C < 2.0 mmol/L, which are the current targets for this subgroup as recommended by NICE., Conclusions: Less than half of UK high-CVD-risk patients receiving atorvastatin monotherapy achieved guideline-recommended treatment targets for TC, and less than two-thirds of patients with CHD/AVD + DM had values below TC (4.0 mmol/L) or LDL-C (2.0 mmol/L) targets. More effective lipid-lowering strategies may be warranted to optimize cholesterol lowering and target attainment in high-risk patients. Limitations of this study include its retrospective, observational nature.

Objective: We investigated the circumstances of ezetimibe discontinuation as its prescribing had been discouraged in some publications., Research Design and Methods: Adults on stable lipid-modifying therapy (LMT) including ezetimibe, who then had >8 weeks cessation in their prescribed ezetimibe regimen (2010-2011) were identified from THIN UK primary care database. Lipid values and parallel changes to other LMT were described overall and in a sub-group with a history of diabetes, cardiovascular disease or familial hypercholesterolaemia (high-risk group)., Results: Ezetimibe therapy stopped in 7087 patients after a mean of 38 months; 67.0% were in the high-risk group. No lipid readings were recorded for 16.1% of patients in the year before and 26.2% in the year after ezetimibe stopped; 11.0% and 12.4% in the high-risk group respectively. In the prior year, 60.2% patients with any lipid reading had a total cholesterol (T-cholesterol) <5 mmol/l and 59.2% had a T-cholesterol <5 mmol/l and LDL-cholesterol <3 mmol/l. In the high-risk group, 66.8% had a T-cholesterol <5 mmol/l, 38.9% had either a T-cholesterol <4 or a LDL-cholesterol <2 mmol/l and 29.4% had reached both targets. In both populations, 42% patients had 6 months' follow-up after ezetimibe stopped with no change to other LMT. An LMT change within 8 weeks (19%) was usually a new statin while 27% overall had a further ezetimibe prescription after 8-26 weeks., Limitations: Only absolute lipid values were included, as percentage change from baseline level may not be reliable. The study included a larger proportion of patients in Scotland relative to the UK population., Conclusions: Prescribed ezetimibe often stopped without either a recent lipid value or attainment of optimal, or sometimes minimum, lipid targets. Patients did not always receive parallel intensification of other LMT or a further ezetimibe prescription within 6 months.

Aims: To estimate the prevalence of dyslipidaemias in high-risk patients new to lipid-modifying therapy (LMT), and establish the extent to which these lipid abnormalities are addressed by treatment in UK clinical practice., Methods: The PRIMULA study was a retrospective analysis, conducted using the UK General Practice Research Database. Two periods were studied as follows: a pretreatment period, defined as the 12 months before initiation of LMT (the index date), and a follow-up period of at least 12 months. Patients included in the study (n = 25,011) had dyslipidaemia with at least one abnormal lipid measurement [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) or triglycerides (TG)] in the pretreatment period. All patients were at high risk of cardiovascular events, which was defined as having a history of cardiovascular disease, a 10-year Framingham risk score higher than 20%, diabetes or hypertension, as defined by the Joint British Societies 2 guidelines., Results: At the index date, 98% of patients were initiated on statin monotherapy. After 12 months of treatment, 15.2% (sub-group range: 11.0-22.9%) of all high-risk patients had no lipid abnormalities. The proportions of patients with high TC or LDL-C levels decreased from 98.8% to 68.9%, and from 99.2% to 68.7%, respectively, over 12 months. The prevalence of high TG levels decreased from 45.0% to 26.9%, whereas that of low HDL-C levels increased, from 16.6% to 18.0%. Risk factors for cardiovascular events were not consistently associated with the likelihood of attaining optimal lipid levels., Conclusions: Despite widespread use of statins, many individuals at high risk of cardiovascular events have persistently abnormal lipid levels, with over two-thirds of patients not achieving target levels of LDL-C or TC. Management of dyslipidaemia is therefore suboptimal in this important high-risk group in UK standard practice., (© 2013 Merck Sharp & Dohme Corp. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Background: Although low-density lipoprotein cholesterol (LDL-C) is the primary lipid target for cardiovascular disease (CVD) risk reduction, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) have also emerged as risk factors. This study evaluated attainment of goal/normal lipid levels in current clinical practice among high-risk patients following lipid-modifying therapy (LMT)., Methods: Data for patients aged ≥35years and on LMT for ≥12months were identified from electronic medical records (United Kingdom and Sweden) and extracted from medical charts (Canada and Spain). High CVD risk was defined according to the Adult Treatment Panel III guidelines. An index period was defined, from January 1995-July 2008, during which patients received an initial LMT prescription. Prevalence of lipid abnormalities was assessed 12months before and after the index date. Multivariate logistic regressions evaluated predictors of attaining goal/normal lipid levels., Results: Among 12,768 high-risk patients, 75% had elevated LDL-C, 37% low HDL-C, and 30% elevated TG before LMT. Despite therapy (97% statins only), 23% had elevated LDL-C, 36% low HDL-C, 16% elevated TG, and 17% had ≥2 abnormal lipid levels. Framingham risk score >20% (Odds Ratio, 95% confidence interval: 0.37,0.31-0.43), diabetes (0.75,0.64-0.88), hypertension (1.26,1.09-1.46), current smoker (0.82,0.70-0.95) and increased body mass index (0.95,0.94-0.96) were associated with the likelihood of attaining ≥2 normal lipid levels (vs. LDL-C goal only)., Conclusion: Current approaches to lipid management improve LDL-C goal attainment; however, control of multiple lipid risk factors remains poor. Patients may benefit from more comprehensive approaches to lipid management, which treat multiple lipid abnormalities, as suggested in clinical guidelines., (© 2013.)

Introduction: sarcopenia is associated with adverse health outcomes. The aim of this study was to describe the prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) consensus definition., Methods: we applied the EWGSOP definition to 103 community-dwelling men participating in the Hertfordshire Sarcopenia Study (HSS) using both the lowest third of dual-energy X-ray absorptiometry (DXA) lean mass (LM) and the lowest third of skin-fold-based fat-free mass (FFM) as markers of low muscle mass. We also used the FFM approach among 765 male and 1,022 female participants in the Hertfordshire Cohort Study (HCS). Body size, physical performance and self-reported health were compared in participants with and without sarcopenia., Results: the prevalence of sarcopenia in HSS men (mean age 73 years) was 6.8% and 7.8% when using the lowest third of DXA LM and FFM, respectively. DXA LM and FFM were highly correlated (0.91, P < 0.001). The prevalence of sarcopenia among the HCS men and women (mean age 67 years) was 4.6% and 7.9%, respectively. HSS and HCS participants with sarcopenia were shorter, weighed less and had worse physical performance. HCS men and women with sarcopenia had poorer self-reported general health and physical functioning scores., Conclusions: this is one of the first studies to describe the prevalence of sarcopenia in UK community-dwelling older people. The EWGSOP consensus definition was of practical use for sarcopenia case finding. The next step is to use this consensus definition in other ageing cohorts and among older people in a range of health-care settings.

The FRAX(tr) algorithm uses clinical risk factors (CRF) and bone mineral density (BMD) to predict fracture risk but does not include falls history in the calculation. Using results from the Hertfordshire Cohort Study, we examined the relative contributions of CRFs, BMD and falls history to fracture prediction. We studied 2299 participants at a baseline clinic that included completion of a health questionnaire and anthropometric data. A mean of 5.5years later (range 2.9-8.8years) subjects completed a postal questionnaire detailing fall and fracture history. In a subset of 368 men and 407 women, bone densitometry was performed using a Hologic QDR 4500 instrument. There was a significantly increased risk of fracture in men and women with a previous fracture. A one standard deviation drop in femoral neck BMD was associated with a hazards ratio (HR) of incident fracture (adjusted for CRFs) of 1.92 (1.04-3.54) and 1.77 (1.16-2.71) in men and women respectively. A history of any fall since the age of 45years resulted in an unadjusted HR of fracture of 7.31 (3.78-14.14) and 8.56 (4.85-15.13) in men and women respectively. In a ROC curve analysis, the predictive capacity progressively increased as BMD and previous falls were added into an initial model using CRFs alone. Falls history is a further independent risk factor for fracture. Falls risk should be taken into consideration when assessing whether or not to commence medication for osteoporosis and should also alert the physician to the opportunity to target falls risk directly., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Meta-analysis of case-control genome-wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes., Objective: We aimed to validate association of these variants with obesity-related traits in population-based samples., Design: Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r (2)>0.8), with the odds of being overweight and obese, as well as with body mass index (BMI), percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age(2) in adults and for sex, age, age group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods., Results: We had 80% power to detect odds ratios of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P>0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (β=0.013 s.d./allele, P=0.040), but not with any of the remaining obesity-related traits (P>0.3)., Conclusion: Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.

Unlabelled: Hip fracture incidence is not known in India. This retrospective study was conducted to evaluate hip fracture incidence rates in Rohtak, a single district of North India. A total of 304 patients from this district with hip fracture were hospitalized during the calendar year 2009. The crude hip fracture rates were found to be 159 and 105 per 100,000, respectively, in women and men above the age of 50 years. Hip fracture is a significant health problem in North India., Purpose: This aims to study hip fracture incidence in Rohtak district of North India., Methods: The study was conducted in Rohtak district, Haryana state, India located 80 km north of New Delhi. All patients having hip fracture admitted in Pandit B.D. Sharma Postgraduate Institute or one of the four orthopaedic centres located in Rohtak in year 2009 were included. Total population of Rohtak for the year 2009 was used to calculate age-specific hip fracture incidence., Results: A total of 541 patients with hip fracture were hospitalized in Rohtak district in year 2009. Out of these, 304 were from Rohtak district. Hip fracture crude incidence above the age of 50 years was 129 per 100,000. The corresponding figures were 105 and 159 per 100,000 among men and women, respectively. Hip fracture incidence was similar in both sexes till age of 55 years. From age of 55 onwards, the rates were significantly higher in women., Conclusions: This is the first hip fracture incidence study from India. Hip fracture incidence rates in Rohtak district of India are intermediate between those in the industrialised world and Africa and similar to some of Asian countries such as China, Iran and South Korea. This study will help in formulating strategies for prevention of hip fracture in India.

Grip strength is a marker of sarcopenia, the age-related decline in muscle mass and function, and has been little researched in Asian populations. We aimed to describe the feasibility and acceptability of measuring grip strength in hospitalized, older people in Malaysia and to explore its range, determinants and association with length of stay. Patients admitted acutely to the geriatrics ward of a teaching hospital were consecutively recruited. Inability to consent or use the dynamometer led to exclusion. Maximum grip strength, anthropometric data, length of hospital stay, discharge destination, 3-point Barthel score, mini-mental state examination, falls history and number of co-morbidities and medications on admission were recorded. 80/153 (52%) eligible patients were recruited (52 women; age range 64-100 years). 9/153 (6%) refused to participate and 64/153 (42%) were excluded (34 too unwell, 24 unable to consent, 4 unable to use the dynamometer, 2 other reasons). 76/80 patients (95%) reported that they would undergo grip strength measurement again. Determinants were similar to those of Caucasian populations but grip strength values were lower. After adjustment for sex, age and height, stronger grip strength was associated with shorter length of stay [hazard ratio 1.05 (95% CI 1.00, 1.09; P=0.03)]. This is the first report of grip strength measurement in hospitalized older people in Malaysia. It was feasible, acceptable to participants and associated with length of stay. Further research is warranted to elucidate the normative range in different ethnic groups and explore its potential use in clinical practice in Malaysia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis., Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores)., Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

Objective: To evaluate the effect of a diabetes awareness campaign on the incidence of diabetic ketoacidosis (DKA) at the first presentation of type 1 diabetes in children (0-18 yr)., Methods: This study was a controlled population intervention study with a 2-yr baseline period and a 2-yr intervention period. Data were collected on all children presenting with their initial diagnosis of type 1 diabetes [pH, bicarbonate, base excess, blood glucose level (BGL), urea, and creatinine] at Gosford, Newcastle, and Sydney (Sydney Children's Hospital and Royal North Shore Hospital). During the intervention period, diabetes education occurred in the intervention region (Gosford). Child care centers, schools, and doctor's offices were offered education and posters about the symptoms of type 1 diabetes. Doctor's offices were given glucose and ketone testing equipment. The control regions (Newcastle and Sydney) did not receive any educational intervention or test equipment. DKA was defined as pH < 7.3 or bicarbonate < 15 mmol/L., Results: In Gosford, the proportion of children presenting in DKA decreased from 37.5% (15/40) during the 2-yr baseline period to 13.8% (4/29) during the 2-yr intervention (p < 0.03). There was no significant change in the control regions during the same time periods, 37.4% (46/123) and 38.6% (49/127), respectively. In Gosford, the average BGL at presentation was 27.5 mmol/L during the baseline and 21.2 mmol/L during the intervention (p < 0.01)., Conclusion: During the diabetes awareness campaign, the rate of DKA at initial diagnosis of type 1 diabetes in children decreased by 64%., (© 2012 John Wiley & Sons A/S.)

Sporulation in Bacillus subtilis begins with an asymmetric cell division producing two genetically identical cells with different fates. SpoIIE is a membrane protein that localizes to the polar cell division sites where it causes FtsZ to relocate from mid-cell to form polar Z-rings. Following polar septation, SpoIIE establishes compartment-specific gene expression in the smaller forespore cell by dephosphorylating the anti-sigma factor antagonist SpoIIAA, leading to the release of the RNA polymerase sigma factor σ(F) from an inhibitory complex with the anti-sigma factor SpoIIAB. SpoIIE therefore couples morphological development to differential gene expression. Here, we determined the crystal structure of the phosphatase domain of SpoIIE to 2.6 Å spacing, revealing a domain-swapped dimer. SEC-MALLS (size-exclusion chromatography with multi-angle laser light scattering) analysis however suggested a monomer as the principal form in solution. A model for the monomer was derived from the domain-swapped dimer in which 2 five-stranded β-sheets are packed against one another and flanked by α-helices in an αββα arrangement reminiscent of other PP2C-type phosphatases. A flap region that controls access of substrates to the active site in other PP2C phosphatases is diminished in SpoIIE, and this observation correlates with the presence of a single manganese ion in the active site of SpoIIE in contrast to the two or three metal ions present in other PP2C enzymes. Mapping of a catalogue of mutational data onto the structure shows a clustering of sites whose point mutation interferes with the proper coupling of asymmetric septum formation to sigma factor activation and identifies a surface involved in intramolecular signaling., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Purpose: Frequent exacerbations which are both costly and potentially life-threatening are a major concern to patients with chronic obstructive pulmonary disease (COPD), despite the availability of several treatment options. This study aimed to assess the lifetime costs and outcomes associated with alternative treatment regimens for patients with severe COPD in the UK setting., Patients and Methods: A Markov cohort model was developed to predict lifetime costs, outcomes, and cost-effectiveness of various combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), an inhaled corticosteroid (ICS), and roflumilast in a fully incremental analysis. Patients willing and able to take ICS, and those refusing or intolerant to ICS were analyzed separately. Efficacy was expressed as relative rate ratios of COPD exacerbation associated with alternative treatment regimens, taken from a mixed treatment comparison. The analysis was conducted from the UK National Health Service (NHS) perspective. Parameter uncertainty was explored using one-way and probabilistic sensitivity analysis., Results: Based on the results of the fully incremental analysis a cost-effectiveness frontier was determined, indicating those treatment regimens which represent the most cost-effective use of NHS resources. For ICS-tolerant patients the cost-effectiveness frontier suggested LAMA as initial treatment. Where patients continue to exacerbate and additional therapy is required, LAMA + LABA/ICS can be a cost-effective option, followed by LAMA + LABA/ICS + roflumilast (incremental cost-effectiveness ratio [ICER] versus LAMA + LABA/ICS: £16,566 per quality-adjusted life-year [QALY] gained). The ICER in ICS-intolerant patients, comparing LAMA + LABA + roflumilast versus LAMA + LABA, was £13,764/QALY gained. The relative rate ratio of exacerbations was identified as the primary driver of cost-effectiveness., Conclusion: The treatment algorithm recommended in UK clinical practice represents a cost-effective approach for the management of COPD. The addition of roflumilast to the standard of care regimens is a clinical and cost-effective treatment option for patients with severe COPD, who continue to exacerbate despite existing bronchodilator therapy.

Objective: The objective of the present study was to explore the association of serum vitamin D concentration and polymorphism in the vitamin D receptor (VDR), with knee pain and radiographic knee osteoarthritis (OA) among men and women in a large population-based UK cohort study., Methods: Seven hundred and eighty-seven participants in the Hertfordshire Cohort Study (399 men, 388 women; mean age 65.6±2.7 years) underwent a questionnaire on knee pain and radiographic knee examination. This study examined the association of Fok1, Cdx2 and Apa1 polymorphism in the gene for the VDR and serum 25(OH)D concentration with knee pain and radiographic knee OA by a generalized estimating equations population averaged logistic regression analysis in the Hertfordshire Cohort Study., Results: There were no associations of Fok1, Cdx2 and Apa1 polymorphisms of the VDR with knee OA except for Aa for Apa1 compared with AA [Odds ratio (OR) 0.59, 95% confidence interval (CI) 0.36-0.95, P=0.031]. While, ff for Fok1 (OR 1.60, 95% CI 1.07-2.39, P=0.022) and AA for Cdx2 polymorphism (OR 2.21, 95% CI 1.07-4.56, P=0.032) was significantly associated with higher prevalence of knee pain compared with FF for Fok1 and GG for Cdx2, respectively. None of these are statistically significant after adjusting for the three polymorphisms tested. 25(OH)D level was not significantly associated with radiographic knee OA, while, low tertile of 25(OH)D level tended to be associated with knee pain compared with high tertile of 25(OH)D level., Conclusion: The present cross-sectional study using a large-scale population from the Hertfordshire Cohort study indicated that vitamin D may be associated with pain rather than radiographic change, but the evidence for an association between vitamin D genetic variation and pain in knee OA is very weak in the present study. Further replication of our results will be required to elucidate the association of vitamin D and knee OA., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Older patients with newly diagnosed type 2 diabetes mellitus are less likely to receive antihyperglycaemic therapy compared to their younger counterparts. The purpose of this study was to assess the reasons of general practitioners (GPs) for not treating younger and older patients with newly diagnosed type 2 diabetes mellitus with antihyperglycaemic agents., Methods: In a survey conducted between November 2009 and January 2010, 358 GPs from the United Kingdom selected reasons for not initiating antihyperglycaemic therapy in younger (< 65 years) and older (≥65 years) patients with newly diagnosed type 2 diabetes mellitus and untreated with any antihyperglycaemic agent for at least six months following diagnosis. Thirty-six potential reasons were classified into four major categories: Mild hyperglycaemia, Factors related to antihyperglycaemic agents, Comorbidities and polypharmacy, and Patient-related reasons. Reasons for non-treatment were compared between younger (n = 1, 023) and older (n = 1, 005) patients., Results: Non-treatment reasons related to Mild hyperglycaemia were selected more often by GPs for both younger (88%) and older (86%) patients than those in other categories. For older patients, Factors related to antihyperglycaemic agents (46% vs. 38%) and Comorbidities and polypharmacy (33% vs. 19%), both including safety-related issues, were selected significantly (p < 0.001) more often by GPs. No between-group difference was observed for the Patient-related reasons category. The GP-reported HbA1c threshold for initiating antihyperglycaemic therapy was significantly (p < 0.001) lower for younger patients (mean ± standard deviation: 7.3% ± 0.7) compared to older patients (7.5% ± 0.9)., Conclusions: GPs selected reasons related to Mild hyperglycaemia for non-treatment of their untreated patients with newly diagnosed type 2 diabetes mellitus, despite nearly one-third of these patients having their most recent HbA1c value ≥7%. The findings further suggest that safety-related issues may influence the non-treatment of older patients with type 2 diabetes mellitus.

Childhood diabetes care may be suboptimal in resource-poor countries. A cross-sectional study of youths with diabetes aged ≤19 years attending the three major paediatric centres in Vietnam was performed. Diabetes management was documented by questionnaire. Glycated haemoglobin (HbA1c) was measured with a fingerprick blood sample. Multiple linear regression analysis was used to examine factors associated with glycaemic control. In total, 105 patients participated, comprising 93 with type 1 diabetes and 12 with neonatal diabetes. The median age was 11.5 years [interquartile range (IQR) 6.4-14.5 years] and the median duration of diabetes was 2.6 years (IQR 1.5-6.1 years). Patients with type 1 diabetes performed few blood glucose tests per month (median 8, IQR 4-30). Mean HbA1c was higher in patients with type 1 diabetes compared with neonatal diabetes (9.9% vs. 7.5%; P = 0.01). In type 1 diabetes using multivariate analysis, higher HbA1c was associated with older age (β = 0.3, 95% CI 0.2-0.4; P < 0.001), lower frequency of blood glucose monitoring (β = -0.06, 95% CI -0.10 to 0.12; P = 0.01) and use of pre-mixed insulin (β = -1.7, 95% CI -3.4 to 0.0; P = 0.05). In conclusion, international glycaemic control targets for childhood diabetes (HbA1c <7.5%) are not being achieved in Vietnam, and intensive diabetes management is rare. There is an urgent need to address barriers to achieving optimal control in this population.

Background: Small birth size may be associated with increased risk of cardiovascular diseases (CVD), whereas large birth size may predict increased risk of obesity and some cancers. The net effect of birth size on long-term mortality has only been assessed in individual studies, with conflicting results., Methods: The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines for conducting and reporting meta-analysis of observational studies were followed. We retrieved 22 studies that assessed the association between birthweight and adult mortality from all causes, CVD or cancer. The studies were systematically reviewed and those reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs) per kilogram (kg) increase in birthweight were included in generic inverse variance meta-analyses., Results: For all-cause mortality, 36,834 deaths were included and the results showed a 6% lower risk (adjusted HR = 0.94, 95% CI: 0.92-0.97) per kg higher birthweight for men and women combined. For cardiovascular mortality, the corresponding inverse association was stronger (HR = 0.88, 95% CI: 0.85-0.91). For cancer mortality, HR per kg higher birthweight was 1.13 (95% CI: 1.07-1.19) for men and 1.04 (95% CI: 0.98-1.10) for women (P(interaction) = 0.03). Residual confounding could not be eliminated, but is unlikely to account for the main findings., Conclusion: These results show an inverse but moderate association of birthweight with adult mortality from all-causes and a stronger inverse association with cardiovascular mortality. For men, higher birthweight was strongly associated with increased risk of cancer deaths. The findings suggest that birthweight can be a useful indicator of processes that influence long-term health.

Background: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background., Objective: The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight., Design: A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623); and 3) all published data (n(max) = 14,837)., Results: Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (β ± SE: -13 ± 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (β ± SE: 11 ± 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing., Conclusions: Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity.

Background: recent studies suggest that diet may affect the physical performance of older adults, but the impact of variations in the UK diet on physical performance has not been assessed., Objective: to examine relationships between diet and physical performance in community-dwelling older men and women., Setting and Participants: a total of 628 men and women aged 63-73 years who were taking part in the Hertfordshire Cohort Study., Methods: diet was assessed using an administered food frequency questionnaire; physical performance was assessed by the time taken to complete a 3-m walk, chair-rise test and one-legged balance test., Results: in women, higher intakes of the antioxidant nutrients, β-carotene and selenium, were associated with shorter 3-m walk times; higher β-carotene and vitamin C intakes were associated with shorter chair-rise times (all P < 0.05). Higher vitamin D intakes and percentage energy from protein were also associated with faster 3-m walk times (both P < 0.05), but they were not related to chair-rise time. There were no associations between any measure of dietary intake and balance in the women studied. After adjustment for the effects of confounding influences, we found no associations between diet and physical performance among men., Conclusions: these data indicate that variations in the diets of community-dwelling older women may be linked to differences in physical performance, but further work is needed to determine the role of variations in diet on physical performance and its decline with age among older adults in the UK.

Summary: This study of 22 girls with Turner syndrome (TS) demonstrates a reduction in bone mineral apparent density (BMAD) at the femoral neck along with a reduction in cortical bone density at the radius (with sparing of trabecular bone). These findings may account for the increased fracture risk noted in this population., Introduction: Increased fracture risk is a feature of TS; however, the reasons for this are unclear. Little is known regarding cortical and trabecular bone mineral density (BMD) in TS. We have addressed this by measurement of volumetric bone mineral density (vBMD) using peripheral quantitative computed tomography (pQCT)., Methods: We studied 22 females with TS and 21 females without TS; mean ages 12.7 and 12.9 years, respectively. Bone mass measurements were made by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femur and pQCT of the radius. BMAD was calculated from DXA values. We utilized published reference data to generate Z-scores for both populations., Results: The mean BMAD Z-score at the lumbar spine was not significantly different in individuals with TS compared to the controls. At the femoral neck, individuals with TS had a significantly lower BMAD Z-score compared to the controls (-1.32 vs. -0.14, p = 0.001). At the distal radius, total vBMD Z-score and trabecular vBMD Z-score were not significantly different between the TS group and controls. A significant reduction in cortical vBMD at the proximal radius was noted in the TS group however (-2.58 vs. -1.38, p = 0.02). There was also a trend towards reduced cortical thickness at this site in the TS group (Z-score -2.89 vs. -1.73, p = 0.08)., Discussion: TS is associated with reduced BMAD at the femoral neck; pQCT data suggests that cortical density is reduced with sparing of trabecular bone. This differential of cortical and trabecular BMD may predispose to fracture.

Introduction: Wrist fracture causes pain and decreased physical, social and emotional function. The International Osteoporosis Foundation has developed a specific questionnaire to assess quality of life in patients with wrist fracture. This questionnaire, including 12 questions, was validated in a multicentre study and compared with an osteoporosis-specific questionnaire (Qualeffo-41) and a generic questionnaire (EQ-5D)., Methods: The study included 105 patients with a recent wrist fracture and 74 sex- and age-matched control subjects. The questionnaire was administered as soon as possible after the fracture, at 6 weeks, 3 months, 6 months and 1 year after the fracture. Test-retest reproducibility, internal consistency and sensitivity to change were assessed., Results and Discussion: The results showed adequate repeatability and internal consistency of the International Osteoporosis Foundation (IOF) wrist fracture questionnaire. The discriminatory capacity between patients and control subjects was very high, with significant odds ratios for each question and domain. The IOF-wrist fracture questionnaire domain scores showed significant improvement after 3 and 6 months and some improvement from 6 months up to 1 year. The sensitivity to change was much higher for the IOF-wrist fracture total score than for Qualeffo-41 and EQ-5D., Conclusion: In conclusion, the IOF-wrist fracture questionnaire appears to be a reliable and responsive quality of life questionnaire.

Background: dietary patterns analysis takes account of the combined effects of foods and may be a more meaningful way of assessing dietary exposure than considering individual nutrients. Little is known about the dietary patterns of older adults in the UK., Objective: to describe the dietary patterns of a population of community-dwelling older men and women and to examine factors associated with compliance with these patterns., Setting and Participants: 3,217 men and women aged 59-73 years who were participants in the Hertfordshire Cohort Study., Methods: diet was assessed using an administered food frequency questionnaire; dietary patterns were identified using principal component analysis., Results: two dietary patterns were identified. The first was characterised by high consumption of fruit, vegetables, oily fish and wholemeal cereals ('prudent' pattern); the second was characterised by high consumption of vegetables, processed and red meat, fish and puddings ('traditional' pattern). High 'prudent' diet scores were more common in women, in men and women in non-manual classes and in non-smokers (all P < 0.05), whilst high 'traditional' diet scores were more common in men, in men and women who had partners and were associated with higher alcohol consumption (all P < 0.05)., Conclusions: we have described large variations in food consumption and nutrient intake amongst older adults that are likely to have implications for future health. The specific socio-demographic correlates of the dietary patterns provide insights into the contexts within which good and poor diets exist, and may help in the identification of opportunities for dietary intervention.