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Surfers are prone to acute injuries as well as conditions resulting from chronic environmental exposure. Sprains, lacerations, strains, and fractures are the most common types of trauma. Injury from the rider's own surfboard may be the prevailing mechanism. Minor wound infections can be treated on an outpatient basis with ciprofloxacin or trimethoprim-sulfamethoxazole. Jellyfish stings are common and may be treated with heat application. Other treatment regimens have had mixed results. Seabather's eruption is a pruritic skin reaction caused by exposure to nematocyst-containing coelenterate larvae. Additional surfing hazards include stingrays, coral reefs, and, occasionally, sharks. Otologic sequelae of surfing include auditory exostoses, tympanic membrane rupture, and otitis externa. Sun exposure and skin cancer risk are inherent dangers of this sport. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is common in women of reproductive age and is associated with obesity. Clinical guidelines recommend weight loss, but the impact on the clinical manifestations of PCOS is unclear., Purpose: To quantify the effect of weight loss interventions on clinical features of PCOS, compared with usual care., Data Sources: MEDLINE, Embase, PsycINFO, CINAHL, Cochrane, Web of Science, and trial registries were searched from inception through June 2024., Study Selection: Randomized controlled trials comparing interventions aiming to reduce weight against usual care, including lower-intensity weight loss interventions in people with PCOS. Conversations with people with PCOS informed the outcomes., Data Extraction: Pairs of independent reviewers screened studies, extracted data, and assessed risk of bias (RoB). Outcomes included glycemic control (Homeostasis Model Assessment for Insulin Resistance [HOMA-IR], fasting insulin and glucose), hormonal markers (free androgen index [FAI] and other sex hormones), menstrual frequency, hirsutism, and PCOS-related quality of life (QoL). Pooled mean differences were obtained from random-effects meta-analysis with Knapp-Hartung adjustment., Data Synthesis: Primary analyses included 29 comparisons with 1529 participants: 13, 12, and 4 comparisons were judged as high, some, or low RoB, respectively. Twelve used behavioral interventions, 9 used glucagon-like peptide-1 (GLP1) agonists, and 8 used other weight loss medications. Weight loss interventions were associated with significantly greater improvements in HOMA-IR (mean difference, -0.45 [-0.75 to -0.15]; I 2  = 24%), FAI (mean difference, -2.03 [-3.0 to -1.07]; I 2  = 48%), and menstrual frequency (mean difference, 2.64 [0.65 to 4.63]; I 2  = 43%). There was no evidence that weight loss interventions were associated with clinically or statistically significant improvements in hirsutism, QoL, or other sex hormones, which may be due to the limited power of the available data., Limitation: There was high statistical heterogeneity in the interventions, comparators, and outcomes, largely unexplained by sensitivity and subgroup analyses., Conclusion: Weight loss interventions were associated with improvements in some important features of PCOS and should be considered as a routine treatment option for people with PCOS., Primary Funding Source: National Institute for Health and Care Research School for Primary Care Research. (PROSPERO: CRD42022367488)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3179.

Background: No single multimorbidity measure is validated for use in NHS (National Health Service) England's General Practice Extraction Service Data for Pandemic Planning and Research (GDPPR), the nationwide primary care data set created for COVID-19 pandemic research. The Cambridge Multimorbidity Score (CMMS) is a validated tool for predicting mortality risk, with 37 conditions defined by Read Codes. The GDPPR uses the more internationally used Systematized Nomenclature of Medicine clinical terms (SNOMED CT). We previously developed a modified version of the CMMS using SNOMED CT, but the number of terms for the GDPPR data set is limited making it impossible to use this version., Objective: We aimed to develop and validate a modified version of CMMS using the clinical terms available for the GDPPR., Methods: We used pseudonymized data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre (RSC), which has an extensive SNOMED CT list. From the 37 conditions in the original CMMS model, we selected conditions either with (1) high prevalence ratio (≥85%), calculated as the prevalence in the RSC data set but using the GDPPR set of SNOMED CT codes, divided by the prevalence included in the RSC SNOMED CT codes or (2) conditions with lower prevalence ratios but with high predictive value. The resulting set of conditions was included in Cox proportional hazard models to determine the 1-year mortality risk in a development data set (n=500,000) and construct a new CMMS model, following the methods for the original CMMS study, with variable reduction and parsimony, achieved by backward elimination and the Akaike information stopping criterion. Model validation involved obtaining 1-year mortality estimates for a synchronous data set (n=250,000) and 1-year and 5-year mortality estimates for an asynchronous data set (n=250,000). We compared the performance with that of the original CMMS and the modified CMMS that we previously developed using RSC data., Results: The initial model contained 22 conditions and our final model included 17 conditions. The conditions overlapped with those of the modified CMMS using the more extensive SNOMED CT list. For 1-year mortality, discrimination was high in both the derivation and validation data sets (Harrell C=0.92) and 5-year mortality was slightly lower (Harrell C=0.90). Calibration was reasonable following an adjustment for overfitting. The performance was similar to that of both the original and previous modified CMMS models., Conclusions: The new modified version of the CMMS can be used on the GDPPR, a nationwide primary care data set of 54 million people, to enable adjustment for multimorbidity in predicting mortality in people in real-world vaccine effectiveness, pandemic planning, and other research studies. It requires 17 variables to produce a comparable performance with our previous modification of CMMS to enable it to be used in routine data using SNOMED CT., (©Debasish Kar, Kathryn S Taylor, Mark Joy, Sudhir Venkatesan, Wilhelmine Meeraus, Sylvia Taylor, Sneha N Anand, Filipa Ferreira, Gavin Jamie, Xuejuan Fan, Simon de Lusignan. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.08.2024.)

The employment of antibodies as a targeted drug delivery vehicle has proven successful which is exemplified by the emergence of antibody-drug conjugates (ADCs). However, ADCs are not without their shortcomings. Improvements may be made to the ADC platform by decoupling the cytotoxic drug from the delivery vehicle and conjugating an organometallic catalyst in its place. The resulting protein-metal catalyst conjugate was designed to uncage the masked cytotoxin administered as a separate entity. Macropinocytosis of albumin by cancerous cells suggests the potential of albumin acting as the tumor-targeting delivery vehicle. Herein reported are the first preparation and demonstration of ruthenium catalysts with cyclopentadienyl and quinoline-based ligands conjugated to albumin. The effective uncaging abilities were demonstrated on allyloxy carbamate (alloc)-protected rhodamine 110 and doxorubicin, providing a promising catalytic scaffold for the advancement of selective drug delivery methods in the future.

Objectives: Despite being prioritized during initial COVID-19 vaccine rollout, vulnerable individuals at high risk of severe COVID-19 (hospitalization, intensive care unit admission, or death) remain underrepresented in vaccine effectiveness (VE) studies. The RAVEN cohort study (NCT05047822) assessed AZD1222 (ChAdOx1 nCov-19) two-dose primary series VE in vulnerable populations., Methods: Using the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub, linked to secondary care, death registration, and COVID-19 datasets in England, COVID-19 outcomes in 2021 were compared in vaccinated and unvaccinated individuals matched on age, sex, region, and multimorbidity., Results: Over 4.5 million AZD1222 recipients were matched (mean follow-up ∼5 months); 68% were ≥50 years, 57% had high multimorbidity. Overall, high VE against severe COVID-19 was demonstrated, with lower VE observed in vulnerable populations. VE against hospitalization was higher in the lowest multimorbidity quartile (91.1%; 95% CI: 90.1, 92.0) than the highest quartile (80.4%; 79.7, 81.1), and among individuals ≥65 years, higher in the 'fit' (86.2%; 84.5, 87.6) than the frailest (71.8%; 69.3, 74.2). VE against hospitalization was lowest in immunosuppressed individuals (64.6%; 60.7, 68.1)., Conclusions: Based on integrated and comprehensive UK health data, overall population-level VE with AZD1222 was high. VEs were notably lower in vulnerable groups, particularly the immunosuppressed., Competing Interests: Declaration of Competing Interest Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. KS, LC, MO, ST, SV, TM, TNT, and WM are employees of AstraZeneca and may own stock/shares. AJP was a member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization until January 2022 and remains Chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee. AJP also reports providing advice to Shionogi on COVID-19, and funding from the National Institute for Health Research (NIHR), AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, the Serum Institute of India, and the Coalition for Epidemic Preparedness Innovations (CEPI); and being a contributor to the intellectual property licensed by Oxford University Innovation to AstraZeneca. DAC reports consulting fees from Oxford University Consulting, Bristol Myers Squibb, and grants from UK Research and Innovation, Wellcome Trust, NIHR, Hong Kong ITC, AstraZeneca, and Glaxo Smith Kline (GSK); and patents held by Oxford University Innovation. JD is an employee at Momentum data and may own stocks/shares. FDRH acknowledges support as Director of the NIHR Applied Research Collaboration Oxford Thames Valley and Theme Lead of the NIHR Oxford University Hospitals Biomedical Research Centre. He also reports fees or expenses for speaking or consultancy from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb/Pfizer, and Novartis. GJ reports ownership of GSK stocks/shares and honoraria form AstraZeneca. SdeL reports advisory board membership for AstraZeneca, GSK, Sanofi, and Seqirus (fees paid to University); and receiving university research grants from AstraZeneca, GSK, Sanofi, Seqirus, and Takeda. ST reports ownership of GSK stocks/shares. UH is an employee at Oxford University and reports membership on a Janssen advisory committee, funding from Seqirus for podcasts, and research funding from Seqirus and AstraZeneca. WH resorts partial salary funding from AstraZeneca-sponsored research grants. AD, AF, DK, KST, MF, MJ, RB, RW, SNA, and XF declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: In people with heart failure (HF), a high body mass index (BMI) has been linked with better outcomes ('obesity paradox'), but there is limited evidence in community populations across long-term follow-up. We aimed to examine the association between BMI and long-term survival in patients with HF in a large primary care cohort., Methods: We included patients with incident HF aged ≥45 years from the Clinical Practice Research Datalink (2000-2017). We used Kaplan-Meier curves, Cox regression and penalised spline methods to assess the association of pre-diagnostic BMI, based on WHO classification, with all-cause mortality., Results: There were 47 531 participants with HF (median age 78.0 years (IQR 70-84), 45.8% female, 79.0% white ethnicity, median BMI 27.1 (IQR 23.9-31.0)) and 25 013 (52.6%) died during follow-up. Compared with healthy weight, people with overweight (HR 0.78, 95% CI 0.75 to 0.81, risk difference (RD) -4.1%), obesity class I (HR 0.76, 95% CI 0.73 to 0.80, RD -4.5%) and class II (HR 0.76, 95% CI 0.71 to 0.81, RD -4.5%) were at decreased risk of death, whereas people with underweight were at increased risk (HR 1.59, 95% CI 1.45 to 1.75, RD 11.2%). In those underweight, this risk was greater among men than women (p value for interaction=0.02). Class III obesity was associated with increased risk of all-cause mortality compared with overweight (HR 1.23, 95% CI 1.17 to 1.29)., Conclusion: The U-shaped relationship between BMI and long-term all-cause mortality suggests a personalised approach to identifying optimal weight may be needed for patients with HF in primary care. Underweight people have the poorest prognosis and should be recognised as high-risk., Competing Interests: Competing interests: CJT reports personal fees and non-financial support from Roche outside the submitted work. All other authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Purpose: The present work investigated dietary changes amongst individuals living with and beyond cancer (LWBC) from before to during the pandemic. To identify those at greatest risk of unhealthy changes, it was further examined whether patterns varied by sociodemographic, health-related, and COVID-19-related characteristics., Methods: This longitudinal cohort study analysed data from 716 individuals LWBC participating in the Advancing Survivorship Cancer Outcomes Trial (ASCOT). Using data provided before and during the pandemic, changes in fruit and vegetable, snack, and alcohol intake were tested using mixed-effect regression models., Results: Fruit and vegetable (95%CI: - 0.30; - 0.04) and alcohol consumption (95%CI: - 1.25; - 0.31) decreased, whilst snacking increased (95%CI: 0.19; 0.53). Women and individuals with limited social contact were more likely to reduce fruit and vegetable intake during the pandemic. Women and individuals with poorer sleep quality, limited social contact, and shielding requirements and without higher education were more likely to increase snacking during the pandemic. Individuals with poorer sleep quality, poorer mental health, and regular social contact were more likely to decrease alcohol consumption during the pandemic., Conclusions: Findings suggest decreased intake for fruit, vegetable, and alcohol consumption and increased snack intake in response to the pandemic amongst individuals LWBC. These changes appear to differ across various characteristics, suggesting the pandemic has not equally impacted everyone in this population. Findings highlight the need for targeted post-COVID strategies to support individuals LWBC most adversely affected by the pandemic, including women and socially isolated individuals. This encourages resources to be prioritised amongst these groups to prevent further negative impact of the pandemic. Whilst the findings are statistically significant, practically they appear less important. This is necessary to acknowledge when considering interventions and next steps., (© 2023. The Author(s).)

Pickering emulsions stabilized by TEMPO-oxidized chitin nanocrystals (T-ChNCs) were developed for quercetin delivery. T-ChNCs were synthesized by TEMPO oxidation chitin and systematically characterized in terms of their physicochemical properties. T-ChNCs were rod-like with a length of 279.7 ± 11.5 nm and zeta potential around -56.1 ± 1.6 mV. The Pickering emulsions were analyzed through an optical microscope and CLSM. The results showed that the emulsion had a small droplet size (972.9 ± 86.0 to 1322.3 ± 447.7 nm), a high absolute zeta potential value (-48.2 ± 0.8 to -52.9 ± 1.9 mV) and a high encapsulation efficiency (quercetin: 79.6%). The emulsion stability was measured at different levels of T-ChNCs and pH values. The droplet size and zeta potential decreased with longer storage periods. The emulsions formed by T-ChNCs retarded the release of quercetin at half rate of that of the quercetin ethanol solution. These findings indicated that T-ChNCs are a promising candidate for effectively stabilizing Pickering emulsions and controlling release of quercetin.

The COVID-19 pandemic has placed forecasting models at the forefront of health policy making. Predictions of mortality, cases and hospitalisations help governments meet planning and resource allocation challenges. In this paper, we consider the weekly forecasting of the cumulative mortality due to COVID-19 at the national and state level in the U.S. Optimal decision-making requires a forecast of a probability distribution, rather than just a single point forecast. Interval forecasts are also important, as they can support decision making and provide situational awareness. We consider the case where probabilistic forecasts have been provided by multiple forecasting teams, and we combine the forecasts to extract the wisdom of the crowd. We use a dataset that has been made publicly available from the COVID-19 Forecast Hub. A notable feature of the dataset is that the availability of forecasts from participating teams varies greatly across the 40 weeks in our study. We evaluate the accuracy of combining methods that have been previously proposed for interval forecasts and predictions of probability distributions. These include the use of the simple average, the median, and trimming methods. In addition, we propose several new weighted combining methods. Our results show that, although the median was very useful for the early weeks of the pandemic, the simple average was preferable thereafter, and that, as a history of forecast accuracy accumulates, the best results can be produced by a weighted combining method that uses weights that are inversely proportional to the historical accuracy of the individual forecasting teams., (© 2021 Elsevier B.V. All rights reserved.)

Background: Patients with ESKD treated with hemodialysis in the United States have persistently higher rates of nonadherence compared with patients in other developed countries. Nonadherence is associated with an increased risk of death and higher medical expenditure. There is an urgent need to address it with feasible, effective interventions as the prevalence of patients on hemodialysis in the United States continues to grow. However, published adherence interventions demonstrate limited long-term efficacy., Methods: We conducted a synthesis of qualitative studies on adherence to hemodialysis treatment, medications, and fluid and dietary restrictions to identify gaps in published adherence interventions, searching PubMed, CINAHL, PsychInfo, Embase, and Web of Science databases. We analyzed qualitative data with a priori codes derived from the World Health Organization's adherence framework and subsequent codes from thematic analysis., Results: We screened 1775 articles and extracted qualitative data from 12. The qualitative data revealed 20 factors unique to hemodialysis across the World Health Organization's five dimensions of adherence. In addition, two overarching themes emerged from the data: (1) adherence in the context of patients' whole lives and (2) dialysis treatment as a double-edged sword. Patient-level factors reflected in the qualitative data extended beyond knowledge about hemodialysis treatment or motivation to adhere to treatment. Patients described a profound grieving process over the loss of their "old self" that impacted adherence. They also navigated complex challenges that could be exacerbated by social determinants of health as they balanced treatment, life tasks, and social roles., Conclusions: This review adds to the growing evidence that one-size-fits-all approaches to improving adherence among patients on hemodialysis are inadequate. Adherence may improve when routine care incorporates patient context and provides ongoing support to patients and families as they navigate the logistical, physical, and psychological hardships of living with dialysis. New research is urgently needed to guide a change in course., (Copyright © 2022 by the American Society of Nephrology.)

Background: Natriuretic peptide (NP) testing is recommended for patients presenting to primary care with symptoms of chronic heart failure (HF) to prioritise referral for diagnosis., Aim: To report NP test performance at European Society of Cardiology (ESC) and National Institute for Health and Care Excellence (NICE) guideline referral thresholds., Design and Setting: Diagnostic accuracy study using linked primary and secondary care data (2004 to 2018)., Method: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NP testing for HF diagnosis was assessed., Results: In total, 229 580 patients had an NP test and 21 102 (9.2%) were diagnosed with HF within 6 months. The ESC NT-proBNP threshold ≥125 pg/mL had a sensitivity of 94.6% (95% confidence interval [CI] = 94.2 to 95.0) and specificity of 50.0% (95% CI = 49.7 to 50.3), compared with sensitivity of 81.7% (95% CI = 81.0 to 82.3) and specificity of 80.3% (95% CI = 80.0 to 80.5) for the NICE NT-proBNP ≥400 pg/mL threshold. PPVs for an NT-proBNP test were 16.4% (95% CI = 16.1 to 16.6) and 30.0% (95% CI = 29.6 to 30.5) for ESC and NICE thresholds, respectively. For both guidelines, nearly all patients with an NT-proBNP level below the threshold did not have HF (NPV: ESC 98.9%, 95% CI = 98.8 to 99.0 and NICE 97.7%, 95% CI = 97.6 to 97.8)., Conclusion: At the higher NICE chronic HF guideline NP thresholds, one in five cases are initially missed in primary care but the lower ESC thresholds require more diagnostic assessments. NP is a reliable 'rule-out' test at both cut-points. The optimal NP threshold will depend on the priorities and capacity of the healthcare system., (© The Authors.)

Adverse childhood experiences (ACEs) are linked to poorer mental health outcomes, and growing evidence implicates biological and genetic pathways from early adversity to psychopathology. However, little is known about the relationship of ACEs and their underlying biological and genetic mechanisms with older people's mental health responses to the COVID-19 pandemic. We tested the associations of ACEs, hair cortisol, C-reactive protein (CRP), and polygenic scores (PGS) with depression, anxiety, and loneliness among older adults during the COVID-19 pandemic, accounting for the potential interplay of ACEs with biological and genetic risk markers. Data were drawn from the English Longitudinal Study of Ageing, a prospective cohort study of older adults living in England. Retrospective information on ACEs were collected in 2006/7, while CRP and hair cortisol were measured at wave 6 (2012/13). Psychological distress was assessed before the pandemic (2018-19) and at two COVID-19 assessments in 2020 (June-July and November-December). Associations were tested on 2050 participants using linear/logistic regression models adjusted for pre-pandemic outcome measures and mixed-effect models to assess changes before and during the pandemic. The results showed that ACEs were associated with higher levels of depression (OR = 2.55[95%CI:1.81,3.59]) anxiety (OR = 1.84[95%CI:1.13,3.01]), and loneliness (b = 0.28[95%CI:0.14,0.42]) during the pandemic. Hair cortisol was related to an increased risk of depression (OR = 1.15[95%CI:1.04,1.26]), and CRP was associated with greater loneliness scores (b = 0.16[95%CI:0.03,0.30]). The relationship between cortisol and psychological distress was larger among participants with ACEs (e.g., OR depression  = 1.07[95%CI:1.00,1.14]). Further, individuals with high CRP experienced greater increases in feelings of loneliness from before to during the pandemic, compared to those with lower CRP levels (interaction effect=0.23; 95%CI:0.1-0.37). Individuals with 2+ ACEs experienced greater increases in depressive symptoms compared to those with none (interaction effect=2.09; 95%CI:1.1-3.98). Higher levels of hair cortisol were also related to worse changes in depressive symptoms across timepoints (interaction effect=1.84;95%CI:1.41-2.41). These results highlight the lasting impact of biosocial vulnerabilities on older adults' mental health responses to new environmental stressors. They also implicate biological mechanisms in the pathophysiology of later-life psychological distress., (© 2022. The Author(s).)

Background: A combined forecast from multiple models is typically more accurate than an individual forecast, but there are few examples of studies of combining in infectious disease forecasting. We investigated the accuracy of different ways of combining interval forecasts of weekly incident and cumulative coronavirus disease-2019 (COVID-19) mortality., Methods: We considered weekly interval forecasts, for 1- to 4-week prediction horizons, with out-of-sample periods of approximately 18 months ending on 8 January 2022, for multiple locations in the United States, using data from the COVID-19 Forecast Hub. Our comparison involved simple and more complex combining methods, including methods that involve trimming outliers or performance-based weights. Prediction accuracy was evaluated using interval scores, weighted interval scores, skill scores, ranks, and reliability diagrams., Results: The weighted inverse score and median combining methods performed best for forecasts of incident deaths. Overall, the leading inverse score method was 12% better than the mean benchmark method in forecasting the 95% interval and, considering all interval forecasts, the median was 7% better than the mean. Overall, the median was the most accurate method for forecasts of cumulative deaths. Compared to the mean, the median's accuracy was 65% better in forecasting the 95% interval, and 43% better considering all interval forecasts. For all combining methods except the median, combining forecasts from only compartmental models produced better forecasts than combining forecasts from all models., Conclusions: Combining forecasts can improve the contribution of probabilistic forecasting to health policy decision making during epidemics. The relative performance of combining methods depends on the extent of outliers and the type of models in the combination. The median combination has the advantage of being robust to outlying forecasts. Our results support the Hub's use of the median and we recommend further investigation into the use of weighted methods., Competing Interests: The authors have declared that no competing interests exist.

Background: Monitoring is the mainstay of chronic kidney disease management in primary care; however, there is little evidence about the best way to do this., Aim: To compare the effectiveness of estimated glomerular filtration rate (eGFR) derived from serum creatinine and serum cystatin C to predict renal function decline among those with a recent eGFR of 30-89 ml/min/1.73 m 2 ., Design and Setting: Observational cohort study in UK primary care., Method: Serum creatinine and serum cystatin C were both measured at seven study visits over 2 years in 750 patients aged ≥18 years with an eGFR of 30-89 ml/min/1.73 m 2 within the previous year. The primary outcome was change in eGFR derived from serum creatinine or serum cystatin C between 6 and 24 months., Results: Average change in eGFR was 0.51 ml/min/1.73 m 2 /year when estimated by serum creatinine and -2.35 ml/min/1.73 m 2 /year when estimated by serum cystatin C. The c-statistic for predicting renal decline using serum creatininederived eGFR was 0.495 (95% confidence interval [CI] = 0.471 to 0.519). The equivalent c-statistic using serum cystatin C-derived eGFR was 0.497 (95% CI = 0.468 to 0.525). Similar results were obtained when restricting analyses to those aged ≥75 or <75 years, or with eGFR ≥60 ml/min/1.73 m 2 . In those with eGFR <60 ml/min/1.73 m 2 , serum cystatin C-derived eGFR was more predictive than serum creatinine-derived eGFR for future decline in kidney function., Conclusion: In the primary analysis neither eGFR estimated from serum creatinine nor from serum cystatin C predicted future change in kidney function, partly due to small changes during 2 years. In some secondary analyses there was a suggestion that serum cystatin C was a more useful biomarker to estimate eGFR, especially in those with a baseline eGFR <60 ml/min/1.73 m 2 ., (© The Authors.)

Competing Interests: Competing interests: KRM and JKA were associate editors of BMJ Evidence Medicine at the time of submission.

Competing Interests: Competing interests: KRM and JKA were Associate Editors of BMJ Evidence Medicine at the time of submission.

In healthy young volunteers, acquisition of blood oxygen level-dependent (BOLD) magnetic resonance (MR) and muscle sympathetic nerve (MSNA) signals during simulation of obstructive or central sleep apnea identified cortical cardiovascular autonomic regions in which the BOLD signal changed synchronously with acute noradrenergic excitation. In the present work, we tested the hypothesis that such Mueller maneuvers (MM) and breath-holds (BH) would elicit greater concomitant changes in mean efferent nerve firing and BOLD signal intensity in patients with moderate to severe obstructive sleep apnea (OSA) relative to age- and sex-matched individuals with no or only mild OSA (Apnea Hypopnea Index, AHI, <15 events/h). Forty-six participants, 24 with OSA [59 ± 8 years; AHI 31 ± 18 events/h (mean ± SD); seven women] and 22 without (58 ± 11 years; AHI 7 ± 4; nine women), performed a series of three MM and three BH, in randomly assigned order, twice: during continuous recording of MSNA from the right fibular nerve and, on a separate day, during T2 ∗ -weighted echo planar functional MR imaging. MSNA at rest was greater in those with OSA (65 ± 19 vs. 48 ± 17 bursts per 100 heart beats; p < 0.01). MM and BH elicited similar heart rate, blood pressure, and MSNA responses in the two cohorts; group mean BOLD data were concordant, detecting no between-group differences in cortical autonomic region signal activities. The present findings do not support the concept that recurring episodes of cyclical apnea during sleep alter cortical or peripheral neural responsiveness to their simulation during wakefulness by volitional Mueller maneuvers or breath-holds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Taylor, Keir, Haruki, Kimmerly, Millar, Murai and Floras.)

Competing Interests: Competing interests: KRM and JA were associate editors of BMJ Evidence Medicine at the time of submission.

Laucysteinamide A ( 4 ) is a marine natural product isolated from the cyanobacterium Caldora penicillata and contains structural motifs found in promising cancer drug leads. The first total synthesis of 4 and its analogues was achieved, which also enabled a concise formal synthesis of somocystinamide A ( 3 ), a dimeric congener of 4 that previously showed extremely potent antiproliferative activities. This work provides further insights on structure-activity relationships in this class of natural products.

Competing Interests: Competing interests: KRM and JA were Associate Editors of BMJ Evidence Medicine at the time of submission.

Background: Heart failure (HF) is a chronic and common condition with a rising prevalence, especially in the elderly. Morbidity and mortality rates in people with HF are similar to those with common forms of cancer. Clinical guidelines highlight the need for more detailed prognostic information to optimise treatment and care planning for people with HF. Besides proven prognostic biomarkers and numerous newly developed prognostic models for HF clinical outcomes, no risk stratification models have been adequately established. Through a number of linked systematic reviews, we aim to assess the quality of the existing models with biomarkers in HF and summarise the evidence they present., Methods: We will search MEDLINE, EMBASE, Web of Science Core Collection, and the prognostic studies database maintained by the Cochrane Prognosis Methods Group combining sensitive published search filters, with no language restriction, from 1990 onwards. Independent pairs of reviewers will screen and extract data. Eligible studies will be those developing, validating, or updating any prognostic model with biomarkers for clinical outcomes in adults with any type of HF. Data will be extracted using a piloted form that combines published good practice guidelines for critical appraisal, data extraction, and risk of bias assessment of prediction modelling studies. Missing information on predictive performance measures will be sought by contacting authors or estimated from available information when possible. If sufficient high quality and homogeneous data are available, we will meta-analyse the predictive performance of identified models. Sources of between-study heterogeneity will be explored through meta-regression using pre-defined study-level covariates. Results will be reported narratively if study quality is deemed to be low or if the between-study heterogeneity is high. Sensitivity analyses for risk of bias impact will be performed., Discussion: This project aims to appraise and summarise the methodological conduct and predictive performance of existing clinically homogeneous HF prognostic models in separate systematic reviews.Registration: PROSPERO registration number CRD42019086990., Competing Interests: Competing interestsCT declares speaker fees from Novartis and Vifor outside the submitted work and non-financial support from Roche outside the submitted work. All other authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: The prevalence of obesity is increasing globally and this could partly explain the worldwide increase in the prevalence of atrial fibrillation (AF), as both overweight and obesity are established risk factors. However, the relationship between weight change and risk of incident AF, independent of starting weight, remains uncertain., Methods: MEDLINE, Embase, Pubmed, Web of Science, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Trials Register-clinicaltrials.gov, CINAHL and the WHO ICTRP were searched from inception to July 2018.We included randomised controlled trials and cohort studies across all healthcare settings but excluded studies of bariatric surgery. A random effects model was used to calculate pooled hazard ratios. The primary outcome was the risk of incident AF in relation to weight change., Results: Ten studies, including 108 996 people, met our inclusion criteria. For a 5% gain in weight, the incidence of AF increased by 13% (HR 1.13, 95% CI 1.04 to 1.23, I 2 =70%, n>20 411 in five studies; study size was unknown for one study). A 5% loss in body weight was not associated with a significant change in the incidence of AF (HR 1.04, 95% CI 0.94 to 1.16, I 2 =73%, n=40 704 in five studies)., Conclusions: Weight gain may increase the risk of AF, but there was no clear evidence that non-surgical weight loss altered AF incidence. Strategies to prevent weight gain in the population may reduce the global burden of AF. Given the lack of studies and methodological limitations, further research is needed., Competing Interests: Competing interests: CT reports speaker fees from Vifor and Novartis and non-financial support from Roche outside the submitted work. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objective: To evaluate the effects of drug interventions that may modify the progression of chronic kidney disease (CKD) in adults with CKD stages 3 and 4., Design: Systematic review and meta-analysis., Methods: Searching MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, International Clinical Trials Registry Platform, Health Technology Assessment, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index and Clinical Trials Register, from March 1999 to July 2018, we identified randomised controlled trials (RCTs) of drugs for hypertension, lipid modification, glycaemic control and sodium bicarbonate, compared with placebo, no drug or a drug from another class, in ≥40 adults with CKD stages 3 and/or 4, with at least 2 years of follow-up and reporting renal function (primary outcome), proteinuria, adverse events, maintenance dialysis, transplantation, cardiovascular events, cardiovascular mortality or all-cause mortality. Two reviewers independently screened citations and extracted data. For continuous outcomes, we used the ratio of means (ROM) at the end of the trial in random-effects meta-analyses. We assessed methodological quality with the Cochrane Risk of Bias Tool and confidence in the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework., Results: We included 35 RCTs and over 51 000 patients. Data were limited, and heterogeneity varied. Final renal function (estimated glomerular filtration rate) was 6% higher in those taking glycaemic control drugs (ROM 1.06, 95% CI 1.02 to 1.10, I 2 =0%, low GRADE confidence) and 4% higher in those taking lipid-modifying drugs (ROM 1.04, 95% CI 1.00 to 1.08, I 2 =88%, very low GRADE confidence). For RCTs of antihypertensive drugs, there were no significant differences in renal function. Treatment with lipid-modifying drugs led to a 36% reduction in cardiovascular disease and 26% reduction in all-cause mortality., Conclusions: Glycaemic control and lipid-modifying drugs may slow the progression of CKD, but we found no pooled evidence of benefit nor harm from antihypertensive drugs. However, given the data limitations, further research is needed to confirm these findings., Prospero Registration Number: CRD42015017501., Competing Interests: Competing interests: KST, JM, JKA and SF receive funding from the NIHR Programme for Applied Research. JYV receives funding from the NIHR Community Healthcare MIC, Nuffield Department of Primary Care Health Sciences and University of Oxford NIHR Diagnostic Evidence Co-operative (DEC). DSL receives funding from the NIHR Community Healthcare MIC. FDRH acknowledges his part-funding from the National Institute for Health Research (NIHR) School for Primary Care Research, the NIHR Collaboration for Leadership in Health Research and Care (CLAHRC) Oxford, the NIHR Oxford Biomedical Research Centre (BRC) (UHT), and the NIHR Oxford Medtech and In Vitro Diagnostics Co-operative (MIC). RP receives funding from the NIHR Oxford Biomedical Research Centre Programme, the NIHR Programme for Applied Research, the NIHR HPRU Gastrointestinal Infections Group, and the NIHR Diagnostic Evidence Co-operative (DEC)., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Respiratory syncytial virus (RSV) causes respiratory infection across the world, with infants and the elderly at particular risk of developing severe disease and death. The replication-defective chimpanzee adenovirus (PanAd3-RSV) and modified vaccinia virus Ankara (MVA-RSV) vaccines were shown to be safe and immunogenic in young healthy adults. Here we report an extension to this first-in-man vaccine trial to include healthy older adults aged 60-75 years., Methods: We evaluated the safety and immunogenicity of a single dose of MVA-RSV given by intra-muscular (IM) injection (n = 6), two doses of IM PanAd3-RSV given 4-weeks apart (n = 6), IM PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), intra-nasal (IN) spray of PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), or no vaccine (n = 6). Safety measures included all adverse events within one week of vaccination and blood monitoring. Immunogenicity measures included serum antibody responses (RSV- and PanAd3-neutralising antibody titres measured by plaque-reduction neutralisation and SEAP assays, respectively), peripheral B-cell immune responses (frequencies of F-specific IgG and IgA antibody secreting cells and memory B-cells by ex vivo and cultured dual-colour ELISpot assays respectively), and peripheral RSV-specific T-cell immune responses (frequencies of IFNγ-producing T-cells by ex vivo ELISpot and CD4+/CD8+/Tfh-like cell frequencies by ICS/FACS assay)., Results: The vaccines were safe and well tolerated. Compared with each individual baseline immunity the mean fold-changes in serum RSV-neutralising antibody, appearance and magnitude of F-specific IgG and IgA ASCs and expansion of CD4+/CD8+ IFNγ-producing T-cells in peripheral circulation were comparable to the results seen from younger healthy adults who received the same vaccine combination and dose. There were little/no IgA memory B-cell responses in younger and older adults. Expansion of IFNγ-producing T-cells was most marked in older adults following IM prime, with balanced CD4+ and CD8+ T cell responses. The RSV-specific immune responses to vaccination did not appear to be attenuated in the presence of PanAd3 (vector) neutralising antibody., Conclusions: PanAd3-RSV and MVA-RSV was safe and immunogenic in older adults and the parallel induction of RSV-specific humoral and cellular immunity merits further assessment in providing protection from severe disease., (Copyright © 2019. Published by Elsevier Ltd.)

Many children fail to comprehend what they read because they do not monitor their understanding, which requires making accurate judgements of what they know and then employing repair strategies when comprehension fails. Relying on research from learning science and cognitive and developmental psychology, we developed the Word Knowledge e-Book (WKe-Book) to improve children's calibration of their word knowledge, strategy use, and word knowledge overall; skills which are associated with reading comprehension. The WKe-Book, which is read on a tablet computer, is a choose-your-own adventure book where choices require choosing between two rare words (e.g., cogitate vs. procrastinate). Depending on the word chosen, the story follows a different plot. There are also embedded comprehension questions where students receive immediate feedback with consequences for incorrect answers, such as being sent back to reread a few pages. In a randomized controlled trial, we tested whether students ( N = 603 in 25 third through fifth grade classrooms in Arizona in the US) reading the WKe-Book would demonstrate improved word knowledge, strategy use, and word knowledge calibration. Classrooms were randomly assigned to read the WKe-Book immediately (treatment) or later (delayed-treatment control), and within classrooms, students were randomly assigned to either participate in a 15-minute weekly book club (book club treatment) or to read the WKe-Book independently with no book club (no book club control). Results revealed a significant treatment effect of the WKe-Book on students' word knowledge, word knowledge calibration, and strategy use, which predicted student performance on standardized reading comprehension and vocabulary measures. The effects were greater for students who participated in weekly book clubs compared to students in the no book club control. These findings suggest that the affordances offered by technology, which are unavailable in paper-based books, can support students' development of metacognition, including word knowledge calibration, strategy use, and word learning skills.

Hypertensive disorders during pregnancy result in substantial maternal morbidity and are a leading cause of maternal deaths worldwide. Self-monitoring of blood pressure (BP) might improve the detection and management of hypertensive disorders of pregnancy, but few data are available, including regarding appropriate thresholds. This systematic review and individual patient data analysis aimed to assess the current evidence on differences between clinic and self-monitored BP through pregnancy. MEDLINE and 10 other electronic databases were searched for articles published up to and including July 2016 using a strategy designed to capture all the literature on self-monitoring of BP during pregnancy. Investigators of included studies were contacted requesting individual patient data: self-monitored and clinic BP and demographic data. Twenty-one studies that utilized self-monitoring of BP during pregnancy were identified. Individual patient data from self-monitored and clinic readings were available from 7 plus 1 unpublished articles (8 studies; n=758) and 2 further studies published summary data. Analysis revealed a mean self-monitoring clinic difference of ≤1.2 mm Hg systolic BP throughout pregnancy although there was significant heterogeneity (difference in means, I 2 >80% throughout pregnancy). Although the overall population difference was small, levels of white coat hypertension were high, particularly toward the end of pregnancy. The available literature includes no evidence of a systematic difference between self and clinic readings, suggesting that appropriate treatment and diagnostic thresholds for self-monitoring during pregnancy would be equivalent to standard clinic thresholds.

Objective: To investigate feasibility and acceptability of self-testing for proteinuria during pregnancy., Study Design: Mixed methods approach which included: an accuracy study where pregnant women (n = 100) and healthcare professionals (n = 96) tested seven synthetic protein samples and completed a questionnaire, a feasibility study where pregnant women who were self-monitoring their blood pressure were asked to self-test for proteinuria (n = 30), and an online questionnaire about women's experiences of self-testing (n = 200)., Main Outcome Measures: Sensitivity and specificity of testing and questionnaire results., Results: There were no significant differences in the accuracy of synthetic sample testing by pregnant women (sensitivity 0.81 (95% confidence intervals (CI) 0.78-0.85), specificity 0.93 (95% CI 0.91-0.95)) and healthcare professionals: (sensitivity 0.83 (95% CI 0.79-0.86), specificity 0.92 (95% CI 0.90-0.94)). Automated readers had significantly better sensitivity (0.94 (0.91-0.97) (p ≤ .001 in each case), but worse specificity 0.78 (0.69-0.85). Similar results were gained using self-tested urine samples compared to staff-testing using a reference standard of laboratory urine protein-creatinine ratio (uPCR). Women who completed the online survey with experience of self-testing (n = 39, 20%) generally found it easy, and with support from healthcare professionals felt it improved involvement in their care and reduced anxiety., Conclusions: Self-testing for proteinuria by pregnant women had similar accuracy to healthcare professional testing and was acceptable to both groups. Self-testing of urine combined with self-monitoring of blood pressure could provide a useful adjunct to clinic-based surveillance for the detection of pre-eclampsia. Such novel strategies warrant further research., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Youth baseball is extremely popular in the United States, but it has been associated with shoulder pain and injury. The incidence of shoulder abnormalities in this athletic population has yet to be defined., Purpose: To examine abnormalities noted on magnetic resonance imaging (MRI) in the shoulders of asymptomatic Little League baseball players and to correlate these findings with the players' throwing history and physical examinations., Study Design: Case-control study; Level of evidence, 3., Methods: A total of 23 Little League baseball players aged 10 to 12 years were recruited. All players underwent a comprehensive physical examination and responded to a questionnaire addressing their playing history and any arm or shoulder pain. Bilateral shoulder MRIs were performed and read in a blinded manner by 2 radiologists. Responses on the questionnaire and physical examination findings were compared between participants with and without positive MRI findings through use of chi-square test and analysis of variance., Results: The dominant arm was 8.5 times more likely to have an abnormality on MRI compared with the nondominant arm. In all, 12 players (52%) had 17 positive MRI findings in their throwing shoulder that were not present in their nondominant shoulder. These findings included edema or widening of the proximal humeral physis (n = 5), labral tear (n = 4), partial rotator thickness tear (n = 4), acromioclavicular joint abnormality (n = 2), subacromial bursitis (n = 1), and cystic change of the greater tuberosity (n = 1). Two primary risk factors were associated with an abnormal MRI: year-round play and single-sport athletes focusing solely on baseball ( P < .05). Players with no risk factors, 1 risk factor, and both risk factors had a 25%, 71%, and 100% chance, respectively, of having an abnormal MRI. A majority of players (61%) had previously experienced shoulder pain, especially pitchers throwing curveballs and sliders ( P < .05), but this was not associated with an abnormal MRI., Conclusion: Abnormalities seen on MRI involving the shoulder are common in Little League baseball players, especially those who are single-sport athletes playing year-round., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was funded by the Rady Children’s Hospital 2016 Academic Enrichment Grant.

The sympathetic excitation elicited acutely by obstructive apnea during sleep (OSA) carries over into wakefulness. We hypothesized that OSA induces structural changes in the insula and cingulate, key central autonomic network elements with projections to brainstem sympathetic premotor regions. The aims of this study were to (1) apply two distinct but complementary methods (cortical thickness analysis [CTA] and voxel-based morphometry [VBM]) to compare insula and cingulate gray matter thickness in participants without and with OSA; (2) determine whether oxygen desaturation index (ODI) relates to cortical thickness; and (3) determine whether cortical thickness or volume in these regions predicts muscle sympathetic nerve activity (MSNA) burst incidence (BI). Overnight polysomnography, anatomical magnetic resonance imaging, and MSNA data were acquired in 41 participants with no or mild OSA (n = 19; 59 ± 2 years [Mean ± SE]; six females; apnea-hypopnea index [AHI] 7 ± 1 events per hour) or moderate-to-severe OSA (n = 22; 59 ± 2 years; five females; AHI 31 ± 4 events per hour). Between-group CTA analyses identified cortical thinning within the left dorsal posterior insula and thickening within the left mid-cingulate cortex (LMCC), whereas VBM identified thickening within bilateral thalami (all [p < .05]). CTA revealed inverse relationships between ODI and bilateral dpIC and left posterior cingulate cortex (LPCC) or precuneus thickness. Positive correlations between BI and LMCC gray matter thickness or volume were evident with both methods and between BI and left posterior thalamus volume using VBM. In OSA, the magnitude of insular thinning, although a function of hypoxia severity, does not influence MSNA, whereas cingulate and thalamic thickening relate directly to the intensity of sympathetic discharge during wakefulness., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Background: Raised blood pressure (BP) affects approximately 10% of pregnancies worldwide, and a high proportion of affected women develop pre-eclampsia. This study aimed to evaluate the feasibility of self-monitoring of BP in pregnancy in women at higher risk of pre-eclampsia., Methods: This prospective cohort study of self-monitoring BP in pregnancy was carried out in two hospital trusts in Birmingham and Oxford and thirteen primary care practices in Oxfordshire. Eligible women were those defined by the UK National Institute for Health and Care Excellence (NICE) guidelines as at higher risk of pre-eclampsia. A total of 201 participants were recruited between 12 and 16 weeks of pregnancy and were asked to take two BP readings twice daily three times a week through their pregnancy. Primary outcomes were recruitment, retention and persistence of self-monitoring. Study recruitment and retention were analysed with descriptive statistics. Survival analysis was used to evaluate the persistence of self-monitoring and the performance of self-monitoring in the early detection of gestational hypertension, compared to clinic BP monitoring. Secondary outcomes were the mean clinic and self-monitored BP readings and the performance of self-monitoring in the detection of gestational hypertension and pre-eclampsia compared to clinic BP., Results: Of 201 women recruited, 161 (80%) remained in the study at 36 weeks or to the end of their pregnancy, 162 (81%) provided any home readings suitable for analysis, 148 (74%) continued to self-monitor at 20 weeks and 107 (66%) at 36 weeks. Self-monitored readings were similar in value to contemporaneous matched clinic readings for both systolic and diastolic BP. Of the 23 who developed gestational hypertension or pre-eclampsia and self-monitored, 9 (39%) had a raised home BP prior to a raised clinic BP., Conclusions: Self-monitoring of BP in pregnancy is feasible and has potential to be useful in the early detection of gestational hypertensive disorders but maintaining self-monitoring throughout pregnancy requires support and probably enhanced training.

Background: Hypertensive disorders in pregnancy are a leading cause of maternal and fetal morbidity worldwide. Raised blood pressure (BP) affects 10% of pregnancies worldwide, of which almost half develop pre-eclampsia. The proportion of pregnant women who have risk factors for pre-eclampsia (such as pre-existing hypertension, obesity and advanced maternal age) is increasing. Pre-eclampsia can manifest itself before women experience symptoms and can develop between antenatal visits. Incentives to improve early detection of gestational hypertensive disorders are therefore strong and self-monitoring of blood pressure (SMBP) in pregnancy might be one means to achieve this, whilst improving women's involvement in antenatal care. The Blood Pressure Self-Monitoring in Pregnancy (BuMP) study aimed to evaluate the feasibility and acceptability of SMBP in pregnancy., Methods: To understand women's experiences of SMBP during pregnancy, we undertook a qualitative study embedded within the BuMP observational feasibility study. Women who were at higher risk of developing hypertension and/or pre-eclampsia were invited to take part in a study using SMBP and also invited to take part in an interview. Semi-structured interviews were conducted at the women's homes in Oxfordshire and Birmingham with women who were self-monitoring their BP as part of the BuMP feasibility study in 2014. Interviews were conducted by a qualitative researcher and transcribed verbatim. A framework approach was used for analysis., Results: Fifteen women agreed to be interviewed. Respondents reported general willingness to engage with monitoring their own BP, feeling that it could reduce anxiety around their health during pregnancy, particularly if they had previous experience of raised BP or pre-eclampsia. They felt able to incorporate self-monitoring into their weekly routines, although this was harder post-partum. Self-monitoring of BP made them more aware of the risks of hypertension and pre-eclampsia in pregnancy. Feelings of reassurance and empowerment were commonly reported by the women in our sample., Conclusions: SMBP in pregnancy was both acceptable and feasible to women in this small pilot study.

Hypertension is the leading cause of cardiovascular disease in the United States and worldwide. It also provides a useful model for team-based chronic disease management. This article describes the M.A.P. checklists: a framework to help practice teams summarize best practices for providing coordinated, evidence-based care to patients with hypertension. Consisting of three domains-Measure Accurately; Act Rapidly; and Partner With Patients, Families, and Communities-the checklists were developed by a team of clinicians, hypertension experts, and quality improvement experts through a multistep process that combined literature review, iterative feedback from a panel of internationally recognized experts, and pilot testing among a convenience sample of primary care practices in two states. In contrast to many guidelines, the M.A.P. checklists specifically target practice teams, instead of individual clinicians, and are designed to be brief, cognitively easy to consume and recall, and accessible to healthcare workers from a range of professional backgrounds., (©2017 Wiley Periodicals, Inc.)

Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea-hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea-hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index (r=0.53; P<0.001), minimum oxygen saturation (r=-0.43; P=0.002), apnea-hypopnea index (r=0.41; P=0.004), age (r=0.36; P=0.013), and body mass index (r=0.33; P=0.022) but not with oxygen desaturation index (r=0.28; P=0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted R 2 (0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea-hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals., (© 2016 American Heart Association, Inc.)

The insula (IC) and cingulate are key components of the central autonomic network and central nodes of the salience network (SN), a set of spatially distinct but temporally correlated brain regions identified with resting-state (task free) functional MRI (rsMRI). To examine the SN's involvement in sympathetic outflow, we tested the hypothesis that individual differences in intrinsic connectivity of the SN correlate positively with resting postganglionic muscle sympathetic nerve activity (MSNA) burst incidence (BI) in subjects without and with obstructive sleep apnea (OSA). Overnight polysomnography, 5-min rsMRI, and fibular MSNA recording were performed in 36 subjects (mean age 57 yr; 10 women, 26 men). Independent component analysis (ICA) of the entire cohort identified the SN as including bilateral IC, pregenual anterior cingulate cortex (pgACC), midcingulate cortex (MCC), and the temporoparietal junction (TPJ). There was a positive correlation between BI and the apnea-hypopnea index (AHI) (P < 0.001), but dual-regression analysis identified no differences in SN functional connectivity between subjects with no or mild OSA (n = 17) and moderate or severe (n = 19) OSA. Correlation analysis relating BI to the strength of connectivity within the SN revealed large (i.e., spatial extent) and strong correlations for the left IC (P < 0.001), right pgACC/MCC (P < 0.006), left TPJ (P < 0.004), thalamus (P < 0.035), and cerebellum (P < 0.013). Indexes of sleep apnea were unrelated to BI and the strength of SN connectivity. There were no relationships between BI and default or sensorimotor network connectivity. This study links connectivity within the SN to MSNA, demonstrating several of its nodes to be key sympathoexcitatory regions., (Copyright © 2016 the American Physiological Society.)

Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4(+) and CD8(+) T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease., (Copyright © 2015, American Association for the Advancement of Science.)

In addition to mean blood pressure, blood pressure variability is hypothesized to have important prognostic value in evaluating cardiovascular risk. We aimed to assess the prognostic value of blood pressure variability within 24 hours. Using MEDLINE, EMBASE and Cochrane Library to April 2013, we conducted a systematic review of prospective studies of adults, with at least one year follow-up and any day, night or 24-hour blood pressure variability measure as a predictor of one or more of the following outcomes: all-cause mortality, cardiovascular mortality, all cardiovascular events, stroke and coronary heart disease. We examined how blood pressure variability is defined and how its prognostic use is reported. We analysed relative risks adjusted for covariates including the appropriate mean blood pressure and considered the potential for meta-analysis. Our analysis of methods included 24 studies and analysis of predictions included 16 studies. There were 36 different measures of blood pressure variability and 13 definitions of night- and day-time periods. Median follow-up was 5.5 years (interquartile range 4.2-7.0). Comparing measures of dispersion, coefficient of variation was less well researched than standard deviation. Night dipping based on percentage change was the most researched measure and the only measure for which data could be meaningfully pooled. Night dipping or lower night-time blood pressure was associated with lower risk of cardiovascular events. The interpretation and use in clinical practice of 24-hour blood pressure variability, as an important prognostic indicator of cardiovascular events, is hampered by insufficient evidence and divergent methodologies. We recommend greater standardisation of methods.

Background: Endoplasmic reticulum (ER) stress and autophagy each play important roles in hepatocyte cell injury. We hypothesized that gene expression of C/EBP-homologous protein (CHOP) and the BH3 proteins Bcl2-interacting mediator of cell death (BIM) and BH3-interacting domain death agonist (BID) are involved in a complex interplay that regulates ER stress-induced autophagy and cell death., Materials and Methods: Hepatocytes were cultured from lean Zucker rats. Confluent hepatocytes were incubated with single or combined small interfering RNA for CHOP, BIM, and/or BID for 24 h providing gene inhibition. Incubation with tunicamycin (TM) for another 24 h stimulated ER stress. Quantitative real-time polymerase chain reaction determined the expression levels of CHOP, BIM, and BID. Immunostaining with microtubule-associated protein 1 light chain 3 measured autophagy activity. Trypan blue exclusion determined the cell viability., Results: TM treatment increased the messenger RNA levels of CHOP and BIM but decreased the messenger RNA levels of BID. TM increased autophagy and decreased cell viability. Individual inhibition of CHOP, BIM, or BID protected against autophagy and cell death. However, simultaneous treatment with any combination of CHOP, BIM, and BID small interfering RNAs reduced autophagy activity but increased cell death independent of ER stress induction., Conclusions: Autophagy in hepatocytes results from acute ER stress and involves interplay, at the gene expression level, of CHOP, BIM, and BID. Inhibition of any one of these individual genes during acute ER stress is protective against cell death. Conversely, inhibition of any two of the three genes results in increased nonautophagic cell death independent of ER stress induction. This study suggests interplay between CHOP, BIM, and BID expression that can be leveraged for protection against ER stress-related cell death. However, disruption of the CHOP/BH3 gene expression homeostasis is detrimental to cell survival independent of other cellular stress., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study was undertaken to perform a systematic review and meta-analysis of studies of mortality in Parkinson's disease (PD) and to investigate which factors were associated with mortality. We conducted comprehensive searches of studies reporting a ratio of mortality in PD versus controls, descriptive survival measures, or factors predicting survival; assessed study quality; and extracted relevant data. Descriptive analysis, meta-analysis, and meta-regression were performed as appropriate. Eighty-eight studies were included in the review with variable study methods and quality. Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity. Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5. Inception cohorts, measurements at longer follow-up duration, and older study recruitment year were associated with lower mortality ratios, but these findings were not robust in sensitivity analyses. Within studies, mortality ratios increased over time. No robust evidence was found that mortality has decreased after the introduction of levodopa (L-dopa). On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity. In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years. Increasing age and presence of dementia were most commonly associated with increased mortality. Parkinson's disease is associated with increased mortality, but major heterogeneity is seen in estimates of mortality, which is probably explained by variable methodology and patient selection. Individual-patient-data meta-analysis of high-quality inception studies with long-term follow-up would be the optimal way to investigate the factors influencing mortality., (© 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Bacopa monniera is a rejuvenating herb for brain cells enhancing learning and cognitive ability. In the present investigation, the ameliorative effects of Bacopa monniera were examined against lead-induced oxidative stress in different regions of rat brain. Male rats were divided into five groups: control (1000 ppm sodium acetate) and exposed (1000 ppm lead acetate) for 4 weeks; DMSA (Meso-2,3-Dimercaptosuccinic acid)-treated (90 mg/kg body weight/day); Bacopa monniera-treated (BM) (10 mg/kg body weight/day) and a combination of BM + DMSA for seven consecutive days after 4 weeks of lead exposure. After treatment, the whole brain was isolated by sacrificing rats and four regions were separated namely cerebellum, hippocampus, frontal cortex and brain stem. Results indicated a significant (p < 0.05) increase in reactive oxygen species (ROS), lipid peroxidation products (LPP) and total protein carbonyl content (TPCC) in association with tissue metal content in all the four regions of brain for exposed group compared with their respective controls. However, the lead-induced ROS, LPP, TPCC and tissue metal content were lowered on treatment with Bacopa monniera, almost reaching the control group values in all the above brain regions compared to DMSA and a combination therapy. Results suggest that Bacopa monniera can mitigate the lead induced-oxidative stress tissue specifically by pharmacologic interventions which encompass both chelation as well as antioxidant functions.