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Background: This study aimed to identify and describe links between pain medication use and self-reported pain among people aged ≥ 50 years with osteoarthritis (OA) in an Irish population, and to examine the relationships between pain, medication usage and socioeconomic and clinical characteristics., Methods: Secondary data analysis of wave 1 cross-sectional data from The Irish Longitudinal Study on Ageing (TILDA) was undertaken of 1042 people with self-reported doctor-diagnosed OA. We examined use of medications typically included in OA clinical guidelines, including non-opioid analgesics (e.g. paracetamol), topical and oral non-steroidal anti-inflammatory drugs (NSAIDs), opioids and nutraceuticals. Latent Class Analysis (LCA) was used to identify underlying clinical subgroups based on medication usage patterns, and self-reported pain severity. Multinomial logistic regression was used to explore sociodemographic and clinical characteristic links to latent class membership., Results: A total of 358 (34.4%) of the 1042 people in this analysis were taking pain medications including oral NSAIDs (17.5%), analgesics (11.4%) and opioids (8.7%). Nutraceutical (glucosamine/chondroitin) use was reported by 8.6% and topical NSAID use reported by 1.4%. Three latent classes were identified: (1) Low medication use/no pain (n = 382, 37%), (2) low medication use/moderate pain (n = 523, 50%) and (3) moderate medication use/high pain (n = 137, 13%). Poorer self-rated health and greater sleep disturbance were associated with classes 2 and 3; depressive symptoms and female gender were associated with class 2, and retirement associated with class 3., Conclusions: Whilst pain medication use varied with pain severity, different medication types reported broadly aligned with OA guidelines. The two subgroups exhibiting higher pain levels demonstrated poorer self-rated health and greater sleep disturbance., (© 2024. The Author(s).)

Existing modelling tools, developed to aid the design of efficient molecular wires and to better understand their charge-transport behaviour and mechanism, have limitations in accuracy and computational cost. Further research is required to develop faster and more precise methods that can yield information on how charge transport properties are impacted by changes in the chemical structure of a molecular wire. In this study, we report a clear semilogarithmic correlation between charge transport efficiency and nuclear magnetic resonance chemical shifts in multiple series of molecular wires, also accounting for the presence of chemical substituents. The NMR data was used to inform a simple tight-binding model that accurately captures the experimental single-molecule conductance values, especially useful in this case as more sophisticated density functional theory calculations fail due to inherent limitations. Our study demonstrates the potential of NMR spectroscopy as a valuable tool for characterising, rationalising, and gaining additional insights on the charge transport properties of single-molecule junctions., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Studies of vertebrate bone biomechanics often focus on skeletal adaptations at upper extremes of body mass, disregarding the importance of skeletal adaptations at lower extremes. Yet mammals are ancestrally small and most modern species have masses under 5 kg, so the evolution of morphology and function at small size should be prioritized for understanding how mammals subsist. We examined allometric scaling of lumbar vertebrae in the small-bodied Philippine endemic rodents known as cloud rats, which vary in mass across two orders of magnitude (15.5 g-2700 g). External vertebral dimensions scale with isometry or positive allometry, likely relating to body size and nuances in quadrupedal posture. In contrast to most mammalian trabecular bone studies, bone volume fraction and trabecular thickness scale with positive allometry and isometry, respectively. It is physiologically impossible for these trends to continue to the upper extremes of mammalian body size, and we demonstrate a fundamental difference in trabecular bone allometry between large- and small-bodied mammals. These findings have important implications for the biomechanical capabilities of mammalian bone at small body size; for the selective pressures that govern skeletal evolution in small mammals; and for the way we define 'small' and 'large' in the context of vertebrate skeletons.

Introduction: The COVID-19 pandemic has prompted governments internationally to consider strengthening their public health systems. To support the work of Ireland's Public Health Reform Expert Advisory Group, the Health Information and Quality Authority, an independent governmental agency, was asked to describe the lessons learnt regarding the public health response to COVID-19 internationally and the applicability of this response for future pandemic preparedness., Methods: Semi-structured interviews with key public health representatives from nine countries were conducted. Interviews were conducted in March and April 2022 remotely via Zoom and were recorded. Notes were taken by two researchers, and a thematic analysis undertaken., Results: Lessons learnt from the COVID-19 pandemic related to three main themes: 1) setting policy; 2) delivering public health interventions; and 3) providing effective communication. Real-time surveillance, evidence synthesis, and cross-sectoral collaboration were reported as essential for policy setting; it was noted that having these functions established prior to the pandemic would lead to a more efficient implementation in a health emergency. Delivering public health interventions such as testing, contact tracing, and vaccination were key to limiting and or mitigating the spread of the SARS-CoV-2 virus. However, a number of challenges were highlighted such as staff capacity and burnout, delays in vaccination procurement, and reduced delivery of regular healthcare services. Clear, consistent, and regular communication of the scientific evidence was key to engaging citizens with mitigation strategies. However, these communication strategies had to compete with an infodemic of information being circulated, particularly through social media., Conclusions: Overall, functions relating to policy setting, public health interventions, and communication are key to pandemic response. Ideally, these should be established in the preparedness phase so that they can be rapidly scaled-up during a pandemic., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the current practice of preconception care in the Netherlands and the perceptions of birth care professionals concerning preconception care., Methods: We have developed a digital questionnaire and conducted a cross-sectional study by distributing the questionnaire among 102 organisations: 90 primary care midwifery practices and obstetric departments of 12 hospitals in the Southwest region of the Netherlands between December 2020 and March 2021. One birth care professional per organization was asked to complete the questionnaire. Descriptive statistics were used to present the results., Findings: Respondents of eighty-three organisations (81.4 %) filled in the questionnaire, of whom 74 respondents were independent primary care midwives and 9 respondents were obstetricians. Preconception care mostly consisted of an individual consultation in which personalized health and lifestyle advice was given. Among the respondents, 44.4 % reported that the organization had a preconception care protocol. The way in which the consultation was carried out, as well as the health and lifestyle related questions asked, differed between respondents. More than 85 % of the respondents inquire about the following possible risk factors for complications: maternal illnesses, obstetric history, folic acid supplement intake, alcohol intake, smoking, substance abuse, hereditary disease, prescription medication, dietary habits, overweight, and birth defects in the family. The respondents acknowledged that preconception care should be offered to all couples who wish to become pregnant, as opposed to offering preconception care only to those with an increased risk of complications. Still, respondents do not receive many questions regarding the preconception period or requests for preconception care consultations., Key Conclusion: Birth care professionals acknowledge the need for preconception care for all couples. In the Netherlands, preconception care consists mostly of an individual consultation with recommendations for health and lifestyle advice. However, the identification of risk factors varies between birth care professionals and less than half of the respondents indicate that they have a protocol available in their practice. Furthermore, the demand of parents-to-be for preconception care is low. More research, that includes more obstetricians, is necessary to investigate if there is a difference between the care provided by primary care midwives and obstetricians., Implications for Practice: To increase the awareness and uptake of preconception care, it would be prudent to emphasize its importance to parents-to-be and professionals, and actively promote the use of widespread, standardized protocols for birth care professionals., Competing Interests: Declaration of Competing Interest None declared, (Copyright © 2023. Published by Elsevier Ltd.)

Sleep quality and sleep duration are important for children's physical and mental health. Mental health diagnoses and sleep disturbances may be interlinked. We sought to identify the methods used to assess sleep in paediatric community-based mental health programmes. A systematic review was conducted using an a priori protocol to ascertain the sleep assessment methods used in paediatric community-based mental health programmes. Children for this review were defined as any person under the age of 19. Cochrane Library, CINAHL, Web of Science, ProQuest, APA PsycInfo, and PubMed databases were searched from January 2021 to March 2022. Of the 320 records screened, 314 records were excluded. Six studies were included for analysis. A variety of validated and non-validated sleep instruments were used to measure sleep quality and a range of sleep disturbances in community health programmes for children. There were a limited number of studies associated with sleep assessment in paediatric community-based settings suggesting this is an area of research that may be understudied. Sleep questionnaires were predominately completed by parents or guardians. Further research is required to establish the most effective method for screening sleep behaviour in paediatric community mental health programmes to understand the impact of sleep in the recovery of children and adolescents with mental health disorders., (© 2023 John Wiley & Sons Australia, Ltd.)

Trabecular bone is a spongy bone tissue that serves as a scaffolding-like support inside many skeletal elements. Previous research found allometric variation in some aspects of trabecular bone architecture (TBA) and bone microstructure, whereas others scale isometrically. However, most of these studies examined very wide size and phylogenetic ranges or focused exclusively on primates or lab mice. We examined the impact of body size on TBA across a smaller size range in the mammalian clade Xenarthra (sloths, armadillos, and anteaters). We µCT-scanned the last six presacral vertebrae of 23 xenarthran specimens (body mass 120 g-35 kg). We collected ten gross-morphology measurements and seven TBA metrics and analyzed them using phylogenetic and nonphylogenetic methods. Most metrics had similar allometries to previous work. However, because ecology and phylogeny align closely in Xenarthra, the phylogenetic methods likely removed some covariance due to ecology; clarifying the impact of ecology on TBA in xenarthrans requires further work. Regressions for Folivora had high P -values and low R -squared values, indicating that the extant sloth sample either is too limited to determine patterns or that the unique way sloths load their vertebral columns causes unusually high TBA variation. The southern three-banded armadillo sits far below the regression lines, which may be related to its ability to roll into a ball. Body size, phylogeny, and ecology impact xenarthran TBA, but parsing these effects is highly complex., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

How spontaneously fluctuating functional magnetic resonance imaging (fMRI) signals in different brain regions relate to behaviour has been an open question for decades. Correlations in these signals, known as functional connectivity, can be averaged over several minutes of data to provide a stable representation of the functional network architecture for an individual. However, associations between these stable features and behavioural traits have been shown to be dominated by individual differences in anatomy. Here, using kernel learning tools, we propose methods to assess and compare the relation between time-varying functional connectivity, time-averaged functional connectivity, structural brain data, and non-imaging subject behavioural traits. We applied these methods to Human Connectome Project resting-state fMRI data to show that time-varying fMRI functional connectivity, detected at time-scales of a few seconds, has associations with some behavioural traits that are not dominated by anatomy. Despite time-averaged functional connectivity accounting for the largest proportion of variability in the fMRI signal between individuals, we found that some aspects of intelligence could only be explained by time-varying functional connectivity. The finding that time-varying fMRI functional connectivity has a unique relationship to population behavioural variability suggests that it might reflect transient neuronal communication fluctuating around a stable neural architecture., (Copyright © 2021. Published by Elsevier Inc.)

Background: Early warning systems (EWSs) are used to assist clinical judgment in the detection of acute deterioration to avoid or reduce adverse events including unanticipated cardiopulmonary arrest, admission to the intensive care unit and death. Sometimes healthcare professionals (HCPs) do not trigger the alarm and escalate for help according to the EWS protocol and it is unclear why this is the case. The aim of this qualitative evidence synthesis was to answer the question 'why do HCPs fail to escalate care according to EWS protocols?' The findings will inform the update of the National Clinical Effectiveness Committee (NCEC) National Clinical Guideline No. 1 Irish National Early Warning System (INEWS)., Methods: A systematic search of the published and grey literature was conducted (until February 2018). Data extraction and quality appraisal were conducted by two reviewers independently using standardised data extraction forms and quality appraisal tools. A thematic synthesis was conducted by two reviewers of the qualitative studies included and categorised into the barriers and facilitators of escalation. GRADE CERQual was used to assess the certainty of the evidence., Results: Eighteen studies incorporating a variety of HCPs across seven countries were included. The barriers and facilitators to the escalation of care according to EWS protocols were developed into five overarching themes: Governance, Rapid Response Team (RRT) Response, Professional Boundaries, Clinical Experience, and EWS parameters. Barriers to escalation included: Lack of Standardisation, Resources, Lack of accountability, RRT behaviours, Fear, Hierarchy, Increased Conflict, Over confidence, Lack of confidence, and Patient variability. Facilitators included: Accountability, Standardisation, Resources, RRT behaviours, Expertise, Additional support, License to escalate, Bridge across boundaries, Clinical confidence, empowerment, Clinical judgment, and a tool for detecting deterioration. These are all individual yet inter-related barriers and facilitators to escalation., Conclusions: The findings of this qualitative evidence synthesis provide insight into the real world experience of HCPs when using EWSs. This in turn has the potential to inform policy-makers and HCPs as well as hospital management about emergency response system-related issues in practice and the changes needed to address barriers and facilitators and improve patient safety and quality of care.

Teeth lie at the interface between an animal and its environment and, with some exceptions, act as a major component of resource procurement through food acquisition and processing. Therefore, the shape of a tooth is closely tied to the type of food being eaten. This tight relationship is of use to biologists describing the natural history of species and given the high instance of tooth preservation in the fossil record, is especially useful for paleontologists. However, correlating gross tooth morphology to diet is only part of the story, and much more can be learned through the study of dental biomechanics. We can explore the mechanics of how teeth work, how different shapes evolved, and the underlying forces that constrain tooth shape. This review aims to provide an overview of the research on dental biomechanics, in both mammalian and non-mammalian teeth, and to synthesize two main approaches to dental biomechanics to develop an integrative framework for classifying and evaluating dental functional morphology. This framework relates food material properties to the dynamics of food processing, in particular how teeth transfer energy to food items, and how these mechanical considerations may have shaped the evolution of tooth morphology. We also review advances in technology and new techniques that have allowed more in-depth studies of tooth form and function., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Objective: To determine if osteoarthritis (OA) progression and joint tissue-pathology associations link specific animal models to different human OA phenotypes., Design: Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA). Joint tissue histopathology was scored day-3 to week-16. Tissue-pathology associations (corrected for time and at week-16) were determined by partial correlation coefficients, and odds ratios (OR) calculated for likelihood of cartilage damage and joint inflammation by ordinal-logistic-regression., Results: Despite distinct temporal patterns of progression, by week-16 joint-wide OA pathology in DMM and AIA was equivalent. Significant pathology associations common to both models included: osteophyte size and maturity (r > 0.4); subchondral bone (SCB) sclerosis and osteophyte maturity (r > 0.25); cartilage erosion and chondrocyte hypertrophy/apoptosis (r > 0.4), SCB sclerosis (r > 0.26), osteophyte size (r > 0.3), and maturity (r > 0.32). DMM-specific associations were between cartilage proteoglycan loss and structural damage (r = 0.56), osteophyte maturity (r = 0.49), size (r = 0.45), and SCB sclerosis (r = 0.28). AIA-specific associations were between SCB sclerosis and chondrocyte hypertrophy/apoptosis (r = 0.40) and osteophyte size (r = 0.37); and synovitis with cartilage structural damage (r = 0.18). No tissue-pathology associations were common to both models at week-16. Increased likelihood of cartilage structural damage was associated with: chondrocyte hypertrophy/apoptosis (OR>1.7), and osteophyte size (OR>2.3) in both models; SCB sclerosis (OR = 2.0) and proteoglycan loss (OR = 2.4) in DMM; and synovitis (OR = 1.2) in AIA. Joint inflammation was associated positively with cartilage proteoglycan loss (OR = 1.4) and inversely with osteophyte size (OR = 0.21) in AIA only., Conclusion: This study highlights the importance of defining OA-models by initiating mechanisms and progression, not just end-stage joint-tissue pathology., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Bone loss in astronauts during spaceflight may be a risk factor for osteoporosis, fractures and renal stone formation. We previously reported that the bisphosphonate alendronate, combined with exercise that included an Advanced Resistive Exercise Device (ARED), can prevent or attenuate group mean declines in areal bone mineral density (aBMD) measured soon after ~ 6-month spaceflights aboard the International Space Station (ISS). It is unclear however if the beneficial effects on postflight aBMD were due to individual or combined effects of alendronate and ARED. Hence, 10 additional ISS astronauts were recruited who used the ARED (ARED group) without drug administration using similar measurements in the previous study, i.e., densitometry, biochemical assays and analysis of finite element (FE) models. In addition densitometry data (DXA and QCT only) were compared to published data from crewmembers (n = 14-18) flown prior to in-flight access to the ARED (Pre-ARED). Group mean changes from preflight (± SD %) were used to evaluate effects of countermeasures as sequentially modified on the ISS (i.e., Pre-ARED vs. ARED; ARED vs. Bis+ARED). Spaceflight durations were not significantly different between groups. Postflight bone density measurements were significantly reduced from preflight in the Pre-ARED group. As previously reported, combined Bis+ARED prevented declines in all DXA and QCT hip densitometry and in estimates of FE hip strengths; increased the aBMD of lumbar spine; and prevented elevations in urinary markers for bone resorption during spaceflight. ARED without alendronate partially attenuated declines in bone mass but did not suppress biomarkers for bone resorption or prevent trabecular bone loss. Resistive exercise in the ARED group did not prevent declines in hip trabecular vBMD, but prevented reductions in cortical vBMD of the femoral neck, in FE estimate of hip strength for non-linear stance (NLS) and in aBMD of the femoral neck. We conclude that a bisphosphonate, when combined with resistive exercise, enhances the preservation of bone mass because of the added suppression of bone resorption in trabecular bone compartment not evident with ARED alone., (Published by Elsevier Inc.)

The complexity and heterogeneity of patients with multimorbidity and polypharmacy renders traditional disease-oriented guidelines often inadequate and complicates clinical decision making. To address this challenge, guidelines have been developed on multimorbidity or polypharmacy. To systematically analyse their recommendations, we conducted a systematic guideline review using the Ariadne principles for managing multimorbidity as analytical framework. The information synthesis included a multistep consensus process involving 18 multidisciplinary experts from seven countries. We included eight guidelines (four each on multimorbidity and polypharmacy) and extracted about 250 recommendations. The guideline addressed (i) the identification of the target population (risk factors); (ii) the assessment of interacting conditions and treatments: medical history, clinical and psychosocial assessment including physiological status and frailty, reviews of medication and encounters with healthcare providers highlighting informational continuity; (iii) the need to incorporate patient preferences and goal setting: eliciting preferences and expectations, the process of shared decision making in relation to treatment options and the level of involvement of patients and carers; (iv) individualized management: guiding principles on optimization of treatment benefits over possible harms, treatment communication and the information content of medication/care plans; (v) monitoring and follow-up: strategies in care planning, self-management and medication-related aspects, communication with patients including safety instructions and adherence, coordination of care regarding referral and discharge management, medication appropriateness and safety concerns. The spectrum of clinical and self-management issues varied from guiding principles to specific recommendations and tools providing actionable support. The limited availability of reliable risk prediction models, feasible interventions of proven effectiveness and decision aids, and limited consensus on appropriate outcomes of care highlight major research deficits. An integrated approach to both multimorbidity and polypharmacy should be considered in future guidelines., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Aims: Attendance at structured diabetes education has been recommended internationally for all people with Type 2 diabetes. However, attendance rates are consistently low. This qualitative study aimed to explore experiences of attending and delivering Type 2 diabetes structured education programmes in Ireland and barriers and facilitators to attendance., Methods: People with Type 2 diabetes who had attended one of the three programmes delivered in Ireland and educators from the three programmes took part in semi-structured telephone interviews. Interviews were audio-taped, transcribed and analysed using inductive thematic analysis., Results: Twelve attendees and 14 educators were interviewed. Two themes were identified in relation to experiences of programme attendance and delivery: 'Structured education: addressing an unmet need' and 'The problem of non-attendance'. The third theme 'Barriers to attendance: can't go, won't go, don't know and poor system flow' outlined how practicalities of attending, lack of knowledge of the existence and benefits, and limited resources and support for education within the diabetes care pathway impacts on attendance. The final theme 'Supporting attendance: healthcare professionals and the diabetes care pathway' describes facilitators to participants' attendance and the strategies educators perceived to be important in increasing attendance., Conclusions: Healthcare professionals have an important role in improving attendance at structured diabetes education programmes. Improving attendance may require promotion by healthcare professionals and for education to be better embedded and supported within the diabetes care pathway., (© 2018 Diabetes UK.)

Background: Prescribing for patients taking multiple medicines (i.e. polypharmacy) is challenging for general practitioners (GPs). Limited evidence suggests that the integration of pharmacists into the general practice team could improve the management of these patients. The aim of this study is to develop and test an intervention involving pharmacists, working within GP practices, to optimise prescribing in Ireland, which has a mixed public and private primary healthcare system., Methods: This non-randomised pilot study will use a mixed-methods approach. Four general practices will be purposively sampled and recruited. A pharmacist will join the practice team for 6 months. They will participate in the management of repeat prescribing and undertake medication reviews (which will address high-risk prescribing and potentially inappropriate prescribing, deprescribing and cost-effective and generic prescribing) with adult patients. Pharmacists will also provide prescribing advice regarding the use of preferred drugs, undertake clinical audits, join practice team meetings and facilitate practice-based education. Throughout the 6-month intervention period, anonymised practice-level medication (e.g. medication changes) and cost data will be collected. A nested Patient Reported Outcome Measure (PROM) study will be undertaken during months 4 and 5 of the 6-month intervention period to explore the impact of the intervention in older adults (aged ≥ 65 years). For this, a sub-set of 50 patients aged ≥ 65 years with significant polypharmacy (≥ 10 repeat medicines) will be recruited from each practice and invited to a medication review with the pharmacist. PROMs and healthcare utilisation data will be collected using patient questionnaires, and a 6-week follow-up review conducted. Acceptability of the intervention will be explored using pre- and post-intervention semi-structured interviews with key stakeholders. Quantitative and qualitative data analysis will be undertaken and an economic evaluation conducted., Discussion: This non-randomised pilot study will provide evidence regarding the feasibility and potential effectiveness of general practice-based pharmacists in Ireland and provide data on whether a randomised controlled trial of this intervention is indicated. It will also provide a deeper understanding as to how a pharmacist working as part of the general practice team will affect organisational processes and professional relationships in a mixed public and private primary healthcare system., Competing Interests: Ethical approval was granted by the Irish College of General Practitioners, on 14 June 2017. Recruited practices received information about the study when first invited to participate. Information about the study will be given to eligible patient participants. It will be explained that participation is voluntary and can be terminated at any time. Written informed consent will be obtained prior to the interviews being recorded. Interview transcripts will be anonymised.Consent to publish data collected as part of this project will be attained prior to publication.The authors declare that they have no competing interests. .Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Aims: To systematically review the evidence on the costs and cost-effectiveness of self-management support interventions for people with diabetes., Background: Self-management support is the provision of education and supportive interventions to increase patients' skills and confidence in managing their health problems, potentially leading to improvements in HbA 1c levels in people with diabetes., Methods: Randomized controlled trials, observational studies or economic modelling studies were eligible for inclusion in the review. The target population was adults with diabetes. Interventions had to have a substantial component of self-management support and be compared with routine care. Study quality was evaluated using the Consensus on Health Economic Criteria and International Society of Pharmacoeconomic Outcomes Research questionnaires. A narrative review approach was used., Results: A total of 16 costing and 21 cost-effectiveness studies of a range of self-management support interventions were identified. There was reasonably consistent evidence across 22 studies evaluating education self-management support programmes suggesting these interventions are cost-effective or superior to usual care. Telemedicine-type interventions were more expensive than usual care and potentially not cost-effective. There was insufficient evidence regarding the other types of self-management interventions, including pharmacist-led and behavioural interventions. The identified studies were predominantly of poor quality, with outcomes based on short-term follow-up data and study designs at high risk of bias., Conclusions: Self-management support education programmes may be cost-effective. There was limited evidence regarding other formats of self-management support interventions. The poor quality of many of the studies undermines the evidence base regarding the economic efficiency of self-management support interventions for people with diabetes., (© 2016 Diabetes UK.)

Native insects can form novel associations with introduced invasive plants and use them as a food source. The recent introduction into eastern North America of a nonnative European vine, Vincetoxicum rossicum (Kleopow) Barbar., allows us to examine the initial response of a native chrysomelid beetle, Chrysochus auratus F., that feeds on native plants in the same family as V. rossicum (Apocynaceae). We tested C. auratus on V. rossicum and closely related or co-occurring native plants (Apocynum spp., Asclepias spp., and Solidago canadensis L.) using all life stages of the beetle in lab, garden, and field experiments. Experiments measured feeding (presence or absence and amount), survival, oviposition, and whether previous exposure to V. rossicum in the lab or field affected adult beetle feeding. Beetles fed significantly less on V. rossicum than on native Apocynum hosts. Adult beetles engaged in exploratory feeding on leaves of V. rossicum and survived up to 10 d. Females oviposited on V. rossicum, eggs hatched, and larvae fed initially on the roots; however, no larvae survived beyond second instar. Beetles collected from Apocynum cannabinum L. field sites intermixed with V. rossicum were less likely to feed on this novel nonnative host than those collected from colonies further from and less likely to be exposed to V. rossicum (>5 km). Our experimental work indicates that V. rossicum may act as an oviposition sink for C. auratus and that this native beetle has not adapted to survive on this recently introduced novel host plant., (© The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

What Is Known and Objective: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk., Methods: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib., Results and Discussion: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379-2·378), placebo (OR: 1·655: 95% CI: 1·029-2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146-4·053), and COXIBs (OR: 1·800, 95% CI: 1·217-2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396-0·857) and (OR: 0·609, 95% CI: 0·375-0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027-2·155) and (OR: 1·933, 95% CI: 1·052-3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410-0·887), (OR: 0·517, 95% CI: 0·287-0·929), and (OR: 0·509, 95% CI: 0·280-0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313-1·981), (OR: 1·572, 95% CI: 1·123-2·201) and (OR: 1·838, 95% CI: 1·323-2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658-0·986) and (OR: 0·557, 95% CI: 0.404-0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data., What Is New and Conclusion: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group., (© 2016 John Wiley & Sons Ltd.)

MEG offers dynamic and spectral resolution for resting-state connectivity which is unavailable in fMRI. However, there are a wide range of available network estimation methods for MEG, and little in the way of existing guidance on which ones to employ. In this technical note, we investigate the extent to which many popular measures of stationary connectivity are suitable for use in resting-state MEG, localising magnetic sources with a scalar beamformer. We use as empirical criteria that network measures for individual subjects should be repeatable, and that group-level connectivity estimation shows good reproducibility. Using publically-available data from the Human Connectome Project, we test the reliability of 12 network estimation techniques against these criteria. We find that the impact of magnetic field spread or spatial leakage artefact is profound, creates a major confound for many connectivity measures, and can artificially inflate measures of consistency. Among those robust to this effect, we find poor test-retest reliability in phase- or coherence-based metrics such as the phase lag index or the imaginary part of coherency. The most consistent methods for stationary connectivity estimation over all of our tests are simple amplitude envelope correlation and partial correlation measures., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Assessment and reporting of adverse events (AEs) in studies of perioperative interventions is critical given the potential for unintended and preventable iatrogenic morbidity and mortality. This focused review evaluated the quality of AE assessment and reporting in acute post-operative pain treatment trials. Since older analgesics (e.g., opioids, NSAIDs) already have a well-characterized safety profile, we concentrated on trials of pregabalin and gabapentin as a representative sample of studies where the perioperative safety profile was relatively unknown., Methods: We reviewed primary reports of trials of pregabalin and gabapentin for treatment of acute post-operative pain for: (1) adherence to the 10 recommendations from the 'CONSORT Extension for Harms,' (2) AE assessment method, (3) timing of AE assessment and reporting, and (4) assessment and reporting of AE severity., Results: We identified 31 trials of pregabalin and 59 of gabapentin. The median number of CONSORT harms recommendations that were satisfied was 7 of 10. The most common (41%) method of AE assessment was direct questioning about specific AEs by investigators. However, AE assessment method was not described in 18% of trials. AE assessments were reported for specified perioperative time points in only 24% of trials. Of greatest concern, no AE data were reported whatsoever in 8 of the included publications., Conclusions: Considerable widespread improvements are needed in AE reporting for post-operative pain treatment trials. In addition to heightened awareness among clinical investigators, mandatory journal editorial policies may further facilitate improvements in safety assessment and reporting., (© 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

When asked to perform the same task, different individuals exhibit markedly different patterns of brain activity. This variability is often attributed to volatile factors, such as task strategy or compliance. We propose that individual differences in brain responses are, to a large degree, inherent to the brain and can be predicted from task-independent measurements collected at rest. Using a large set of task conditions, spanning several behavioral domains, we train a simple model that relates task-independent measurements to task activity and evaluate the model by predicting task activation maps for unseen subjects using magnetic resonance imaging. Our model can accurately predict individual differences in brain activity and highlights a coupling between brain connectivity and function that can be captured at the level of individual subjects., (Copyright © 2016, American Association for the Advancement of Science.)

Little is known about the impact of treatment-resistant hypertension (TRH) on health-related quality of life (HrQoL). We aimed to compare HrQoL measures in adults with apparent TRH (aTRH) and non-resistant hypertension among nationally representative US Medical Expenditure Panel Survey data pooled from 2000 to 2011. Cohorts compared were adults with aTRH (⩾2 unique fills from ⩾4 antihypertensive classes during a year) versus non-resistant hypertension (those with hypertension not meeting the aTRH definition). Key outcomes were cohort differences in SF-12v2 physical component summary (PCS) and mental component summary (MCS) scores and disease-state utility using the SF-6D. Of 57 150 adults with hypertension, 2501 (4.4%) met criteria for aTRH. Persons with aTRH, compared with non-resistant hypertension, were older (mean, 68 vs 61 years), had a higher BMI (30.9 vs 29.7 kg m(-)(2)) and were more likely to be Black (20% vs 14%), but less likely to be female (46% vs 54%). Persons with aTRH, compared with non-resistant hypertension, had lower mean PCS scores (35.8 vs 43.2; P<0.0001), and utility (0.68 vs 0.74; P<0.0001), but similar MCS scores (49.1 vs 50.4). In multivariable-adjusted analyses, aTRH was associated with a 2.37 (95% CI 1.71 to 3.02) lower PCS score and 0.02 (95% CI 0.01 to 0.03) lower utility, compared with non-resistant hypertension. In conclusion, aTRH was associated with substantially lower HrQoL in physical functioning and health utility, but not in mental functioning, compared with non-resistant hypertension. The multivariable-adjusted reduction in physical functioning was similar in magnitude to previous observations comparing hypertension with no hypertension.

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

Objective: To determine the long-term effectiveness of a complex intervention in primary care aimed at improving outcomes for patients with coronary heart disease., Design: A 6-year follow-up of a cluster randomised controlled trial, which found after 18 months that both total and cardiovascular hospital admissions were significantly reduced in intervention practices (8% absolute reduction)., Setting: 48 general practices in the Republic of Ireland and Northern Ireland., Participants: 903 patients with established coronary heart disease at baseline in the original trial., Intervention: The original intervention consisted of tailored practice and patient plans; training sessions for practitioners in medication prescribing and behavioural change; and regular patient recall system. Control practices provided usual care. Following the intervention period, all supports from the research team to intervention practices ceased., Primary Outcome: hospital admissions, all cause and cardiovascular; secondary outcomes: mortality; blood pressure and cholesterol control., Results: At 6-year follow-up, data were collected from practice records of 696 patients (77%). For those who had died, we censored their data at the point of death and cause of death was established. There were no significant differences between the intervention and control practices in either total (OR 0.83 (95% CI 0.54 to 1.28)) or cardiovascular hospital admissions (OR 0.91 (95% CI 0.49 to 1.65)). We confirmed mortality status of 886 of the original 903 patients (98%). There were no significant differences in mortality (15% in intervention and 16% in control) or in the proportions of patients above target control for systolic blood pressure or total cholesterol., Conclusions: Initial significant differences in the numbers of total and cardiovascular hospital admissions were not maintained at 6 years and no differences were found in mortality or blood pressure and cholesterol control. Policymakers need to continue to assess the effectiveness of previously efficacious programmes., Trial Registration Number: Current Controlled Trials ISRCTN24081411., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Ambiguities in the source reconstruction of magnetoencephalographic (MEG) measurements can cause spurious correlations between estimated source time-courses. In this paper, we propose a symmetric orthogonalisation method to correct for these artificial correlations between a set of multiple regions of interest (ROIs). This process enables the straightforward application of network modelling methods, including partial correlation or multivariate autoregressive modelling, to infer connectomes, or functional networks, from the corrected ROIs. Here, we apply the correction to simulated MEG recordings of simple networks and to a resting-state dataset collected from eight subjects, before computing the partial correlations between power envelopes of the corrected ROItime-courses. We show accurate reconstruction of our simulated networks, and in the analysis of real MEGresting-state connectivity, we find dense bilateral connections within the motor and visual networks, together with longer-range direct fronto-parietal connections., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine minimal dose levels required for local inhibition of orthodontic relapse by recombinant OPG protein (OPG-Fc), while also determining effects of injected OPG-Fc on alveolar bone and long bone., Setting and Sample Population: The Department of Orthodontics and Pediatric Dentistry at the University of Michigan. Eighteen male Sprague Dawley rats., Materials & Methods: Maxillary molars were moved with nickel-titanium springs and then allowed to relapse in Sprague Dawley rats. Upon appliance removal, animals were injected with a single dose of 1.0 mg/kg OPG-Fc, 0.1 mg/kg OPG-Fc, or phosphate-buffered saline (vehicle) just distal to the molar teeth. Tooth movement measurements were made from stone casts, which were scanned and digitally measured. Alveolar tissues were examined by histology. Micro-computed tomography was used to quantify changes in alveolar and femur bone., Results: Local injection of OPG-Fc inhibited molar but not incisor relapse, when compared to vehicle-injected animals. No significant differences in alveolar or femur bone were seen between the three treatment groups after 24 days of relapse., Conclusions: Our results demonstrate that a single local injection of OPG-Fc effectively inhibits orthodontic relapse, with minimal systemic bone metabolic effects. Our results also show that a single injection of OPG-Fc will influence tooth movement only in teeth close to the injection site. These findings indicate that OPG-Fc has potential as a safe and effective pharmacological means to locally control osteoclasts, for uses such as maintaining anchorage during orthodontic tooth movement and preventing orthodontic relapse in humans., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

What Is Known and Objective: Fibromyalgia is a painful disease affecting 1-2% of the United States population. Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and milnacipran, are well studied and frequently used for treating this disorder. However, efficacy data are limited for the SNRI venlafaxine despite its use in nearly a quarter of patients with fibromyalgia. Accordingly, we systematically reviewed the efficacy of venlafaxine for treatment of fibromyalgia., Methods: PubMed, Web of Science and the Cochrane Database were searched using the terms 'venlafaxine' and 'fibromyalgia'. Results were classified as primary studies or review articles based on abstract review. References of review articles were evaluated to ensure no primary studies evaluating venlafaxine were overlooked. All clinical studies that investigated venlafaxine for the treatment of fibromyalgia were included and graded on strength of evidence., Results and Discussion: Five studies met the inclusion criteria, including 4 open-label cohort studies and 1 randomized, controlled trial. Study durations ranged from 6 weeks to 6 months, and study sizes ranged from 11 to 102 participants. Four of the five published studies reported improvement in at least one outcome. Generally consistent improvements were observed in pain-related outcome measures, including the Fibromyalgia Impact Questionnaire (range, 26-29% reduction; n = 2 studies), Visual Analog Scale (range, 36-45% reduction; n = 2 studies), McGill Pain Questionnaire (48% reduction; n = 1 study) and Clinical Global Impression scale (51% had significant score change; n = 1 study). However, the few studies identified were limited by small sample size, inconsistent use of outcomes and methodological concerns., What Is New and Conclusion: Studies assessing the efficacy of venlafaxine in the treatment of fibromyalgia to date have been limited by small sample size, inconsistent venlafaxine dosing, lack of placebo control and lack of blinding. In the context of these limitations, venlafaxine appears to be at least modestly effective in treating fibromyalgia. Larger randomized controlled trials are needed to further elucidate the full benefit of venlafaxine., (© 2014 John Wiley & Sons Ltd.)

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

Background: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear., Patients and Methods: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses., Results: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission., Conclusions: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Unlabelled: We assessed the potential for countermeasures to lessen the loss of bone calcium during bed rest. Subjects ingested less calcium during bed rest, and with artificial gravity, they also absorbed less calcium. With exercise, they excreted less calcium. To retain bone during bed rest, calcium intake needs to be maintained., Introduction: This study aims to assess the potential for artificial gravity (AG) and exercise (EX) to mitigate loss of bone calcium during space flight., Methods: We performed two studies: (1) a 21-day bed rest (BR) study with subjects receiving 1 h/day AG (n = 8) or no AG (n = 7) and (2) a 28-day BR study with 1 h/day resistance EX (n = 10) or no EX (n = 3). In both studies, stable isotopes of Ca were administered orally and intravenously, at baseline and after 10 days of BR, and blood, urine, and feces were sampled for up to 14 days post dosing. Tracers were measured using thermal ionization mass spectrometry. Data were analyzed by compartmental modeling., Results: Less Ca was absorbed during BR, resulting in lower Ca balance in BR+AG (-6.04 ± 3.38 mmol/day, P = 0.023). However, Ca balance did not change with BR+EX, even though absorbed Ca decreased and urinary Ca excretion increased, because endogenous excretion decreased, and there was a trend for increased bone deposition (P = 0.06). Urinary N-telopeptide excretion increased in controls during BR, but not in the EX group. Markers of bone formation were not different between treatment groups for either study. Ca intake decreased during BR (by 5.4 mmol/day in the AG study and 2.8 mmol/day in the EX study), resulting in lower absorbed Ca., Conclusions: During BR (or space flight), Ca intake needs to be maintained or even increased with countermeasures such as exercise, to enable maintenance of bone Ca.

Many signaling pathways are mediated by Shc adapter proteins that, in turn, are expressed as three isoforms with distinct functions. The p66(Shc) isoform antagonizes proliferation, regulates oxidative stress, and mediates apoptosis. It is highly expressed in the canalicular but not the later stages of mouse lung development, and its expression persists in bronchopulmonary dysplasia, a chronic disease associated with premature birth. These observations suggest that p66(Shc) has a developmental function. However, constitutive p66(Shc) deletion yields no morphological phenotype, and the structure of the Shc gene precludes its inducible deletion. To elucidate its function in lung development, we transfected p66(Shc) or nonsilencing small-interfering RNA (siRNA) into the epithelia of embryonic day 11 mouse lungs that were then cultured for 3 days and analyzed morphometrically. To assess cellular proliferation and epithelial differentiation, lung explants were immunostained and immunoblotted for p66(Shc), proliferating cell nuclear antigen (PCNA), the proximal airway differentiation antigens Clara cell 10-kDa protein (CC10) and thyroid transcription factor (TTF)-1, and the alveolar surfactant proteins (SP)-A, -B, and -C. Explants transfected with nonsilencing siRNA demonstrated specific epithelial uptake and normal morphological development relative to uninjected controls. In contrast, transfection with p66(Shc) siRNA significantly increased lumenal cross-sectional areas, decreased branching, and increased epithelial proliferation (P < 0.05 for all). Relative to controls, the expression of SP-B, SP-C, CC10, and TTF-1 was decreased by p66(Shc) knockdown. SP-A was not expressed in either control or treated lungs. These data suggest that p66(Shc) attenuates epithelial proliferation while promoting both distal and proximal epithelial maturation.

Calcium and bone metabolism remain key concerns for space travelers, and ground-based models of space flight have provided a vast literature to complement the smaller set of reports from flight studies. Increased bone resorption and largely unchanged bone formation result in the loss of calcium and bone mineral during space flight, which alters the endocrine regulation of calcium metabolism. Physical, pharmacologic, and nutritional means have been used to counteract these changes. In 2012, heavy resistance exercise plus good nutritional and vitamin D status were demonstrated to reduce loss of bone mineral density on long-duration International Space Station missions. Uncertainty continues to exist, however, as to whether the bone is as strong after flight as it was before flight and whether nutritional and exercise prescriptions can be optimized during space flight. Findings from these studies not only will help future space explorers but also will broaden our understanding of the regulation of bone and calcium homeostasis on Earth.

This review seeks to provide a current overview of musculoskeletal pain in overweight and obese children. Databases searched were Academic Search Complete, CINAHL, Medline, Proquest Health and Medical Complete, Scopus, Google Scholar, SPORTDiscuss and Trove for studies published between 1 January 2000 and 30 December 2012. We used a broad definition of children within a 3- to 18-year age range. The search strategy included the following terms: obesity, morbid obesity, overweight, pain, musculoskeletal pain, child, adolescent, chronic pain, back pain, lower back pain, knee pain, hip pain, foot pain and pelvic pain. Two authors independently assessed each record, and any disagreement was resolved by the third author. Data were analysed using a narrative thematic approach owing to the heterogeneity of reported outcome measures. Ninety-seven records were initially identified using a variety of terms associated with children, obesity and musculoskeletal pain. Ten studies were included for thematic analysis when predetermined inclusion criteria were applied. Bone deformity and dysfunction, pain reporting and the impact of children being overweight or obese on physical activity, exercise and quality of life were the three themes identified from the literature. Chronic pain, obesity and a reduction in physical functioning and activity may contribute to a cycle of weight gain that affects a child's quality of life. Future studies are required to examine the sequela of overweight and obese children experiencing chronic musculoskeletal pain.

INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support) aims to monitor and benchmark the healthiness of food environments globally. In order to assess the impact of food environments on population diets, it is necessary to monitor population diet quality between countries and over time. This paper reviews existing data sources suitable for monitoring population diet quality, and assesses their strengths and limitations. A step-wise framework is then proposed for monitoring population diet quality. Food balance sheets (FBaS), household budget and expenditure surveys (HBES) and food intake surveys are all suitable methods for assessing population diet quality. In the proposed 'minimal' approach, national trends of food and energy availability can be explored using FBaS. In the 'expanded' and 'optimal' approaches, the dietary share of ultra-processed products is measured as an indicator of energy-dense, nutrient-poor diets using HBES and food intake surveys, respectively. In addition, it is proposed that pre-defined diet quality indices are used to score diets, and some of those have been designed for application within all three monitoring approaches. However, in order to enhance the value of global efforts to monitor diet quality, data collection methods and diet quality indicators need further development work., (© 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity.)

Objectives: The aim of this systematic review was to examine the epidemiology of malpractice claims in primary care., Design: A computerised systematic literature search was conducted. Studies were included if they reported original data (≥10 cases) pertinent to malpractice claims, were based in primary care and were published in the English language. Data were synthesised using a narrative approach., Setting: Primary care., Participants: Malpractice claimants., Primary Outcome: Malpractice claim (defined as a written demand for compensation for medical injury). We recorded: medical misadventure cited in claims, missed/delayed diagnoses cited in claims, outcome of claims, prevalence of claims and compensation awarded to claimants., Results: Of the 7152 articles retrieved by electronic search, a total of 34 studies met the inclusion criteria and were included in the narrative analysis. Twenty-eight studies presented data from medical indemnity malpractice claims databases and six studies presented survey data. Fifteen studies were based in the USA, nine in the UK, seven in Australia, one in Canada and two in France. The commonest medical misadventure resulting in claims was failure to or delay in diagnosis, which represented 26-63% of all claims across included studies. Common missed or delayed diagnoses included cancer and myocardial infarction in adults and meningitis in children. Medication error represented the second commonest domain representing 5.6-20% of all claims across included studies. The prevalence of malpractice claims in primary care varied across countries. In the USA and Australia when compared with other clinical disciplines, general practice ranked in the top five specialties accounting for the most claims, representing 7.6-20% of all claims. However, the majority of claims were successfully defended., Conclusions: This review of malpractice claims in primary care highlights diagnosis and medication error as areas to be prioritised in developing educational strategies and risk management systems.

Across the world, more dairy producers are considering on-farm dairy processing to add value to the milk produced on their farms. Dairy producers may bottle milk or process their milk into cheese, ice cream, butter, yogurt, or cream. The primary objective of this research was to establish a series of sound factors or indicators of success for those considering on-farm processing. A survey was employed to collect opinions and advice from managers of on-farm processing enterprises. Surveys were distributed online (n=120), with 31 surveys returned, accounting for a 25.8% response rate. Most (64%) respondents had been involved in on-farm dairy processing for less than 10 yr. Sixty-one percent of respondents attained a positive cash flow in 1 to 3 yr. The primary products manufactured were cheese (69%), milk (59%), ice cream (31%), yogurt (25%), and butter (21%). Factors influencing the decision to start an on-farm dairy processing enterprise included commodity milk prices (61%), desire to work with the public (41%), an opportunity to promote the dairy industry (39%), a desire to maintain or expand a small family operation (29%), and product differentiation (16%). Respondents cited dealing with regulations (26%), product marketing (19%), manufacturing technicalities (19%), and securing funding (17%) as the most difficult parts of starting the business. Open-ended responses provided by the respondents of this survey were also documented to give future dairy producers advice. The most common advice to future on-farm processors was to work on realistic business plans, develop and follow realistic budgets, and observe and use market surveys within the industry. These results provide a useful array of information for future on-farm dairy processing enterprises., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Unlabelled: We report the results of alendronate ingestion plus exercise in preventing the declines in bone mass and strength and elevated levels of urinary calcium and bone resorption in astronauts during 5.5 months of spaceflight., Introduction: This investigation was an international collaboration between NASA and the JAXA space agencies to investigate the potential value of antiresorptive agents to mitigate the well-established bone changes associated with long-duration spaceflight., Methods: We report the results from seven International Space Station (ISS) astronauts who spent a mean of 5.5 months on the ISS and who took an oral dose of 70 mg of alendronate weekly starting 3 weeks before flight and continuing throughout the mission. All crewmembers had available for exercise a treadmill, cycle ergometer, and a resistance exercise device. Our assessment included densitometry of multiple bone regions using X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and assays of biomarkers of bone metabolism., Results: In addition to pre- and post-flight measurements, we compared our results to 18 astronauts who flew ISS missions and who exercised using an early model resistance exercise device, called the interim resistance exercise device, and to 11 ISS astronauts who exercised using the newer advanced resistance exercise device (ARED). Our findings indicate that the ARED provided significant attenuation of bone loss compared with the older device although post-flight decreases in the femur neck and hip remained. The combination of the ARED and bisphosphonate attenuated the expected decline in essentially all indices of altered bone physiology during spaceflight including: DXA-determined losses in bone mineral density of the spine, hip, and pelvis, QCT-determined compartmental losses in trabecular and cortical bone mass in the hip, calculated measures of fall and stance computed bone strength of the hip, elevated levels of bone resorption markers, and urinary excretion of calcium., Conclusions: The combination of exercise plus an antiresoptive drug may be useful for protecting bone health during long-duration spaceflight.

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 μg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, "downstream" inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.

The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Context: Animal models and human studies suggest that osteocytes regulate the skeleton's response to mechanical unloading in part by an increase in sclerostin. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading., Objective: We determined changes in serum sclerostin and bone turnover markers in healthy adult men undergoing controlled bed rest., Design, Setting, and Participants: Seven healthy adult men (31 ± 3 yr old) underwent 90 d of 6° head down tilt bed rest at the University of Texas Medical Branch Institute for Translational Sciences-Clinical Research Center., Outcomes: Serum sclerostin, PTH, vitamin D, bone resorption and formation markers, urinary calcium and phosphorus excretion, and 24-h pooled urinary markers of bone resorption were evaluated before bed rest [baseline (BL)] and at bed rest d 28 (BR-28), d 60 (BR-60), and d 90 (BR-90). Bone mineral density was measured at BL, BR-60, and 5 d after the end of the study (BR+5). Data are reported as mean ± SD., Results: Consistent with prior reports, bone mineral density declined significantly (1-2% per month) at weight-bearing skeletal sites. Serum sclerostin was elevated above BL at BR-28 (+29 ± 20%; P = 0.003) and BR-60 (+42 ± 31%; P < 0.001), with a lesser increase at BR-90 (+22 ± 21%; P = 0.07). Serum PTH levels were reduced at BR-28 (-17 ± 16%; P = 0.02) and BR-60 (-24 ± 14%; P = 0.03) and remained lower than BL at BR-90 (-21 ± 21%; P = 0.14), but did not reach statistical significance. Serum bone turnover markers were unchanged; however, urinary bone resorption markers and calcium were significantly elevated at all time points after bed rest (P < 0.01)., Conclusions: In healthy men subjected to controlled bed rest for 90 d, serum sclerostin increased, with a peak at 60, whereas serum PTH declined, and urinary calcium and bone resorption markers increased.

Objective: To examine 3-year quality-of-life (QOL) outcomes among United States adults with Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) antisocial personality disorder (ASPD), syndromal adult antisocial behavior without conduct disorder (CD) before age 15 [adulthood antisocial behavioral syndrome (AABS), not a DSM-IV diagnosis], or no antisocial behavioral syndrome at baseline., Method: Face-to-face interviews (n = 34 653). Psychiatric disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV Version. Health-related QOL was assessed using the Short-Form 12-Item Health Survey, version 2 (SF-12v2). Other outcomes included past-year Perceived Stress Scale-4 (PSS-4) scores, employment, receipt of Supplemental Security Income (SSI), welfare, and food stamps, and participation in social relationships., Results: Antisocial personality disorder and AABS predicted poorer employment, financial dependency, social relationship, and physical health outcomes. Relationships of antisociality to SSI and food stamp receipt and physical health scales were modified by baseline age. Both antisocial syndromes predicted higher PSS-4, AABS predicted lower SF-12v2 Vitality, and ASPD predicted lower SF-12v2 Social Functioning scores in women., Conclusion: Similar prediction of QOL by ASPD and AABS suggests limited utility of requiring CD before age 15 to diagnose ASPD. Findings underscore the need to improve prevention and treatment of antisocial syndromes., (Published 2012. This article is a US Government work and is in the public domain in the USA.)

Background/objectives: Adults often misreport dietary intake; the magnitude varies by the methods used to assess diet and classify participants. The objective was to quantify the accuracy of the Goldberg method for categorizing misreporters on a food frequency questionnaire (FFQ) and two 24-h recalls (24HRs)., Subjects/methods: We compared the Goldberg method, which uses an equation to predict total energy expenditure (TEE), with a criterion method that uses doubly labeled water (DLW), in a study of 451 men and women. Underreporting was classified using recommended cut points and calculated values. Sensitivity and specificity, positive predictive value (PPV) and negative predictive value and the area under the receiver operating characteristic curve (AUC) were calculated. Predictive models of underreporting were contrasted for the Goldberg and DLW methods., Results: AUCs were 0.974 and 0.972 on the FFQ, and 0.961 and 0.938 on the 24HR for men and women, respectively. The sensitivity of the Goldberg method was higher for the FFQ (92%) than the 24HR (50%); specificity was higher for the 24HR (99%) than the FFQ (88%); PPV was high for the 24HR (92%) and FFQ (88%). Simulation studies indicate attenuation in odds ratio estimates and reduction of power in predictive models., Conclusions: Although use of the Goldberg method may lead to bias and reduction in power in predictive models of underreporting, the method has high predictive value for both the FFQ and the 24HR. Thus, in the absence of objective measures of TEE or physical activity, the Goldberg method is a reasonable approach to characterize underreporting.

Sirex noctilio F. is an exotic woodwasp now found in eastern North America where it shares natural enemies with native woodwasps of Pinus spp. To study the extent to which native hymenopteran parasitoids and parasitic nematodes could affect woodwasp populations, 60 Pinus trees with symptoms of S. noctilio attack were felled in 2007 and 2008 in Ontario, Canada. Each tree bole was cut into 1-m sections that were placed in individual rearing tubes; emergence was monitored from May to November of the year of felling. Female S. noctilio were dissected to assess parasitism by the nematode Deladenus siricidicola Bedding. Two species of Siricidae emerged from these trees; S. noctilio, which accounted for most of the specimens collected, and S. nigricornis F. Of the three species of parasitoid that emerged, Ibalia leucospoides (Hochenwarth) was the most abundant, accounting for an overall hypothetical Siricidae parasitism rate of almost 20%. This parasitoid emerged over a similar time period as S. noctilio-between early July and early September. Except in trees >15 m in height, parasitism by I. leucospoides generally appeared uniform throughout the bole. Parasitism rates did not vary between the 2 yr, but did between sites in 1 yr. Parasitic nematodes were found in the haemocoel of about one third of S. noctilio females dissected but were never found sterilizing the eggs; none were found in S. noctilio emerging from P. resinosa. These findings suggest that I. leucospoides is currently the primary invertebrate natural enemy of S. noctilio in Ontario.

Several studies have demonstrated age-related regional differences in the magnitude of the BOLD signal using task-based fMRI. It has been suggested that functional changes reflect either compensatory or de-differentiation mechanisms, both of which assume response to a specific stimulus. Here, we have tested whether ageing affects both task-based and resting brain function, and the extent to which functional changes are mediated by reductions in grey matter (GM) volume. Two groups, of 22 healthy younger and 22 older volunteers, underwent an imaging protocol involving structural and functional MRI, both during a memory task and at rest. The two groups had similar socio-demographical characteristics and cognitive performance. Image analysis revealed both structural and functional differences. Increased BOLD signal in older relative to younger volunteers was mainly observed in the frontal lobes, both during the task and at rest. Functional changes in the frontal lobes were largely located in brain regions spared from GM loss, and adding GM covariates to the fMRI analysis did not significantly alter the group differences. Our results are consistent with the suggestion that, during normal ageing, the brain responds to neuronal loss by fine-tuning connections between spared neurons. Longitudinal studies will be necessary to fully test this hypothesis., (Copyright © 2011 Elsevier Inc. All rights reserved.)