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Relative energy deficiency in sport (REDs) is a widely adopted model, originally proposed by an International Olympic Committee (IOC) expert panel in 2014 and recently updated in an IOC 2023 consensus statement. The model describes how low energy availability (LEA) causes a wide range of deleterious health and performance outcomes in athletes. With increasing frequency, sports practitioners are diagnosing athletes with "REDs," or "REDs syndrome," based largely upon symptom presentation. The purpose of this review is not to "debunk" REDs but to challenge dogmas and encourage rigorous scientific processes. We critically discuss the REDs concept and existing empirical evidence available to support the model. The consensus (IOC 2023) is that energy availability, which is at the core of REDs syndrome, is impossible to measure accurately enough in the field, and therefore, the only way to diagnose an athlete with REDs appears to be by studying symptom presentation and risk factors. However, the symptoms are rather generic, and the causes likely multifactorial. Here we discuss that (1) it is very difficult to isolate the effects of LEA from other potential causes of the same symptoms (in the laboratory but even more so in the field); (2) the model is grounded in the idea that one factor causes symptoms rather than a combination of factors adding up to the etiology. For example, the model does not allow for high allostatic load (psychophysiological "wear and tear") to explain the symptoms; (3) the REDs diagnosis is by definition biased because one is trying to prove that the correct diagnosis is REDs, by excluding other potential causes (referred to as differential diagnosis, although a differential diagnosis is supposed to find the cause, not demonstrate that it is a pre-determined cause); (4) observational/cross-sectional studies have typically been short duration (< 7 days) and do not address the long term "problematic LEA," as described in the IOC 2023 consensus statement; and (5) the evidence is not as convincing as it is sometimes believed to be (i.e., many practitioners believe REDs is well established). Very few studies can demonstrate causality between LEA and symptoms, most studies demonstrate associations and there is a worrying number of (narrative) reviews on the topic, relative to original research. Here we suggest that the athlete is best served by an unbiased approach that places health at the center, leaving open all possible explanations for the presented symptoms. Practitioners could use a checklist that addresses eight categories of potential causes and involve the relevant experts if and when needed. The Athlete Health and Readiness Checklist (AHaRC) we introduce here simply consists of tools that have already been developed by various expert/consensus statements to monitor and troubleshoot aspects of athlete health and performance issues. Isolating the purported effects of LEA from the myriad of other potential causes of REDs symptoms is experimentally challenging. This renders the REDs model somewhat immune to falsification and we may never definitively answer the question, "does REDs syndrome exist?" From a practical point of view, it is not necessary to isolate LEA as a cause because all potential areas of health and performance improvement should be identified and tackled. [ABSTRACT FROM AUTHOR]

Background: Attention Deficit-Hyperactive Disorder (ADHD) is a neurodevelopmental disorder, often persisting into adulthood. Aims: To investigate the levels of functionality and quality of life (QoL) in adult patients newly diagnosed with ADHD and to compare with those without an ADHD diagnosis. Methods: Consecutive patients who were referred to and assessed in a tertiary adult ADHD clinic enrolled in the study. Diagnosis of ADHD was based on DSM-5 criteria. Functionality was measured using the Weiss Functional Impairment Rating Scale (WFIRS) and the Global Assessment of Functioning Scale (GAF). QoL was assessed with the Adult ADHD Quality of Life Questionnaire (AAQoL). Results: Three-hundred and forty participants were recruited, 177 (52.1%) females. Of them 293 (86.2%) were newly diagnosed with ADHD. Those with ADHD had significant lower functionality as it was measured with the WFIRS and GAF, and worse QoL (AAQoL) compared to those without. In addition, a significant correlation between GAF and WFIRS was found. Conclusions: The results show that adults with ADHD have decreased functionality and worse QoL when compared against those presenting with a similar symptomatology, but no ADHD diagnosis. ADHD is not just a behavioural disorder in childhood, but a lifelong condition with accumulating problems that can lead to lower QoL and impaired functioning throughout adulthood. [ABSTRACT FROM AUTHOR]

Purpose: The significance of dental status and oral hygiene on a range of medical conditions is well-recognised. However, the correlation between periodontitis, oral bacterial dysbiosis and visceral surgical outcomes is less well established. To this end, we study sought to determine the influence of dental health and oral hygiene on the rates of postoperative complications following major visceral and transplant surgery in an exploratory, single-center, retrospective, non-interventional study. Methods: Our retrospective non-interventional study was conducted at the Department of General, Visceral, and Transplant Surgery, University Hospital Heidelberg, Germany. Patients operated on between January 2018 and December 2019 were retrospectively enrolled in the study based on inclusion (minimum age of 18 years, surgery at our Department, intensive care / IMC treatment after major surgery, availability of patient-specific preoperative dental status assessment, documentation of postoperative complications) and exclusion criteria (minor patients or legally incapacitated patients, lack of intensive care or intermediate care (IMC) monitoring, incomplete documentation of preoperative dental status, intestinal surgery with potential intraoperative contamination of the site by intestinal microbes, pre-existing preoperative infection, absence of data regarding the primary endpoints of the study). The primary study endpoint was the incidence of postoperative complications. Secondary study endpoints were: 30-day mortality, length of hospital stay, duration of intensive care stay, Incidence of infectious complications, the microbial spectrum of infectious complication. A bacteriology examination was added whenever possible (if and only if the examination was safe for the patient)for infectious complications. Results: The final patient cohort consisted of 417 patients. While dental status did not show an influence (p = 0.73) on postoperative complications, BMI (p = 0.035), age (p = 0.049) and quick (p = 0.033) were shown to be significant prognostic factors. There was significant association between oral health and the rate of infectious complications for all surgical procedures (p = 0.034), excluding transplant surgery. However, this did not result in increased 30-day mortality rates, prolonged intensive care unit treatment or an increase in the length of hospital stay (LOS) for the cohort as a whole. In contrast there was a significant correlation between the presence of oral pathogens and postoperative complications for a group as a whole (p < 0.001) and the visceral surgery subgroup (p < 0.001). Whilst this was not the case in the cohort who underwent transplant surgery, there was a correlation between oral health and LOS in this subgroup (p = 0.040). Bacterial swabs supports the link between poor oral health and infectious morbidity. Conclusions: Dental status was a significant predictor of postoperative infectious complications in this visceral surgery cohort. This study highlights the importance preoperative dental assessment and treatment prior to major surgery, particularly in the case of elective surgical procedures. Further research is required to determine the effect of oral health on surgical outcomes in order to inform future practice. Trial registration: Trial registered under the ethics-number S-082/2022 (Ethic Committee of the University Heidelberg). [ABSTRACT FROM AUTHOR]

Wire arc-directed energy deposition (WA-DED) is a promising additive manufacturing (AM) technique for building large, complex near-net-shape parts, combining high deposition rates and fully dense builds. The goal of this study was to explore the advantages of WA-DED for local property optimization by joining a high-strength nickel-based alloy with a wear-resistant cobalt-based alloy. Single-pass depositions of the IN718 Ni-based alloy on round L605 Co-based alloy stock were prepared, using a Fronius cold metal transfer (CMT) WA-DED system to achieve low heat input and clean weld passes. The influence of varying process control settings during the deposition process on the final porosity and interface integrity, as well as resultant variations in microstructure and mechanical property, were evaluated. The results indicate that the process did successfully produce crack-free, non-porous, and continuous welds. In the as-deposited condition, the weld metal showed the presence of Nb-enriched regions and phases, and variation in process control settings resulted in a change of mean precipitate size. The interface regions showed increases in hardness, likely due to precipitate strengthening during extended cooling times. Lastly, the general microstructure and mechanical properties showed relative insensitivity to changes in processing setting during WA-DED using the CMT system, allowing for greater flexibility during manufacturing. [ABSTRACT FROM AUTHOR]

Objectives: Corner metaphyseal lesions (CMLs) are specific for child abuse but challenging to detect on radiographs. The accuracy of CT for CML detection is unknown. Our aim was to compare diagnostic accuracy for CML detection on post-mortem skeletal surveys (PMSS, plain radiography) versus post-mortem CT (PMCT). Methods: A 10-year retrospective review was performed at a children's hospital for patients having PMSS, PMCT and histopathological correlation (reference standard) for suspected CMLs. Twenty-four radiologists independently reported the presence or absence of CMLs in all cases in a blinded randomised cross-over design across two rounds. Logistic regression models were used to compare accuracy between modalities. Results: Twenty CMLs were reviewed for each of the 10 subjects (200 metaphyses in all). Among them, 20 CMLs were confirmed by bone histopathology. Sensitivity for these CMLs was significantly higher for PMSS (69.6%, 95% CI 61.7 to 76.7) than PMCT (60.5%, 95% CI 51.9 to 68.6). Using PMSS for detection of CMLs would yield one extra correct diagnosis for every 11.1 (95% CI 6.6 to 37.0) fractured bones. In contrast, specificity was higher on PMCT (92.7%, 95% CI 90.3 to 94.5) than PMSS (90.5%, 95% CI 87.6 to 92.8) with an absolute difference of 2.2% (95% CI 1.0 to 3.4, p < 0.001). More fractures were reported collectively by readers on PMSS (785) than on PMCT (640). Conclusion: PMSS remains preferable to PMCT for CML evaluation. Any investigation of suspected abuse or unexplained deaths should include radiographs of the limbs to exclude CMLs. Clinical relevance statement: In order to avoid missing evidence that could indicate child abuse as a contributory cause for death in children, radiographs of the limbs should be performed to exclude CMLs, even if a PMCT is being acquired. Key Points: • Corner metaphyseal lesions (CMLs) are indicative for abuse, but challenging to detect. Skeletal surveys (i.e. radiographs) are standard practice; however, accuracy of CT is unknown. • Sensitivity for CML detection on radiographs is significantly higher than CT. • Investigation of unexplained paediatric deaths should include radiographs to exclude CMLs even if CT is also being performed. [ABSTRACT FROM AUTHOR]

Background: Mucinous appendiceal adenocarcinomas (MAA) and non-mucinous appendiceal adenocarcinomas (NMAA) demonstrate differences in rates and patterns of recurrence, which may inform the appropriate extent of surgical resection (i.e., appendectomy versus colectomy). The impact of extent of resection on disease-specific survival (DSS) for each histologic subtype was assessed. Patients and Methods: Patients with resected, non-metastatic MAA and NMAA were identified in the Surveillance, Epidemiology, and End Results database (2000–2020). Multivariable models were created to examine predictors of colectomy for each histologic subtype. DSS was calculated using Kaplan–Meier estimates and examined using Cox proportional hazards modeling. Results: Among 4674 patients (MAA: n = 1990, 42.6%; NMAA: n = 2684, 57.4%), the majority (67.8%) underwent colectomy. Among colectomy patients, the rate of nodal positivity increased with higher T-stage (MAA: T1: 4.6%, T2: 4.0%, T3: 17.1%, T4: 21.6%, p < 0.001; NMAA: T1: 6.8%, T2: 11.4%, T3: 25.6%, T4: 43.8%, p < 0.001) and higher tumor grade (MAA: well differentiated: 7.7%, moderately differentiated: 19.2%, and poorly differentiated: 31.3%; NMAA: well differentiated: 9.0%, moderately differentiated: 20.5%, and 44.4%; p < 0.001). Nodal positivity was more frequently observed in NMAA (27.6% versus 16.4%, p < 0.001). Utilization of colectomy was associated with improved DSS for NMAA patients with T2 (log rank p = 0.095) and T3 (log rank p = 0.018) tumors as well as moderately differentiated histology (log rank p = 0.006). Utilization of colectomy was not associated with improved DSS for MAA patients, which was confirmed in a multivariable model for T-stage, grade, and use of adjuvant chemotherapy [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.81–1.22]. Conclusions: Colectomy was associated with improved DSS for patients with NMAA but not MAA. Colectomy for MAA may not be required. [ABSTRACT FROM AUTHOR]

This article discusses POLR3A-related disorders, which encompass a range of clinical phenotypes beyond the classical triad of hypomyelinating leukodystrophy, hypodontia, and hypogonadotrophic hypogonadism. The case study presented focuses on a 46-year-old woman with walking difficulties, lower limb pain, weakness, and stiffness. The patient exhibited various neurological symptoms, including a waddling gait, dystonic posturing of the feet, and head tremors. The article highlights the importance of considering POLR3A-related disorders in the differential diagnosis of spastic or cerebellar ataxias in adolescents and adults. [Extracted from the article]

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.In this study, Giron et al. find that people living with chronic HIV experience accelerated aging-associated alterations in antibody glycans. These alterations, attributed to senescence enzymes, predict comorbidities and reduce the antiviral function of antibodies. [ABSTRACT FROM AUTHOR]

This study explores dissatisfaction and neutrality metrics from 12 years of a national-level undergraduate student survey. The notion of dissatisfaction is much less prevalent in the narratives surrounding student survey outcomes, and the underpinning metrics are seldom considered. This is despite an increasingly vociferous debate about 'value for money' of higher education and the positioning of students as consumers in a marketised sector. We used machine learning methods to explore over 2.7 million national survey outcomes from 154 institutions to describe year-on-year stability in the survey items that best predicted dissatisfaction and neutrality, together with their similarity to known metric predictors of satisfaction. The widely publicised annual increases in student 'satisfaction' are shown to be the result of complex reductions in the proportions of disagreement and neutrality across different survey dimensions. Due to the widespread use of survey metrics in university league tables, we create an anonymised, illustrative table to demonstrate how UK institutional rankings would have differed if dissatisfaction metrics had been the preferred focus for reporting. We conclude by debating the tensions of balancing the provision of valuable information about dissatisfaction, with perpetuating negative impacts that derive from this important subset of the survey population. [ABSTRACT FROM AUTHOR]

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure managed on intensive care units were randomised (Ketogenic n = 14, Control n = 15) into a two-centre pilot open-label trial of ketogenic versus standard enteral feeding. The primary endpoints were assessment of feasibility and safety, recruitment and retention rates and achievement of ketosis and glucose control. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis in all patients in the intervention group, with a refusal rate of 4.1% and 82.8% retention. Patients who received ketogenic feeding had fewer hypoglycaemic events (0.0% vs. 1.6%), required less exogenous international units of insulin (0 (Interquartile range 0-16) vs.78 (Interquartile range 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Ketogenic feeding was feasible and may be an intervention for addressing bioenergetic failure in critically ill patients. Clinical Trials.gov registration: NCT04101071. Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. Here the authors show ketogenic diets may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis. [ABSTRACT FROM AUTHOR]

Galactic outflows are believed to play a critical role in the evolution of galaxies by regulating their mass build-up and star formation1. Theoretical models assume bipolar shapes for the outflows that extend well into the circumgalactic medium (CGM), up to tens of kiloparsecs (kpc) perpendicular to the galaxies. They have been directly observed in the local Universe in several individual galaxies, for example, around the Milky Way and M82 (refs. 2,3). At higher redshifts, cosmological simulations of galaxy formation predict an increase in the frequency and efficiency of galactic outflows owing to the increasing star-formation activity4. Galactic outflows are usually of low gas density and low surface brightness and therefore difficult to observe in emission towards high redshifts. Here we present an ultra-deep Multi-Unit Spectroscopic Explorer (MUSE) image of the mean Mg II emission surrounding a sample of galaxies at z ≈ 1 that strongly suggests the presence of outflowing gas on physical scales of more than 10 kpc. We find a strong dependence of the detected signal on the inclination of the central galaxy, with edge-on galaxies clearly showing enhanced Mg II emission along the minor axis, whereas face-on galaxies show much weaker and more isotropic emission. We interpret these findings as supporting the idea that outflows typically have a bipolar cone geometry perpendicular to the galactic disk. We demonstrate that this CGM-scale outflow is prevalent among galaxies with stellar mass M* ≳ 109.5M⊙.An ultra-deep MUSE image of the mean Mg II emission for a sample of galaxies at redshift z ≈ 1 suggests the presence of bipolar outflows on scales of 10 kpc or more. [ABSTRACT FROM AUTHOR]

Background: A direct comparison of the cost–benefit analysis of retroperitoneoscopic adrenalectomy (RPA) versus the minimally invasive transperitoneal access (LTA) approach is currently lacking. We hypothesized that RPA is more cost effective than LTA; promising significant savings for the healthcare system in an era of ever more limited resources. Methods: We performed a monocentric retrospective observational cohort study based on data from our Endocrine Surgery Registry. Patients who were operated upon between 2019 and 2022 were included. After pair-matching, both cohorts (RPA vs. LTA) were compared for perioperative variables and treatment costs (process cost calculation), revenue and profit. Results: Two homogenous cohorts of 43 patients each (RPA vs. LTA) were identified following matching. Patient characteristics between the cohorts were comparable. In terms of both treatment-associated costs and profit, the RPA procedure was superior to LTA (costs: US$5789.99 for RPA vs. US$6617.75 for LTA, P = 0.043; profit: US$1235.59 for RPA vs. US$653.33 for LTA, P = 0.027). The duration of inpatient treatment and comorbidities significantly influenced the cost of treatment and the overall profit. Conclusions: RPA appears not only to offer benefits over LTA in terms of perioperative morbidity and length of hospital stay, but also has a superior financial cost/benefit profile. [ABSTRACT FROM AUTHOR]

In 2009, 98.0% of people with mental illness in Sierra Leone were not receiving treatment, partly due to the absence of public psychiatric facilities outside the capital. In response to this situation, the Ministry of Health and Sanitation rolled out nurse-led mental health units (MHUs) to every district. This study evaluates the barriers and facilitators to mental health service delivery in decentralised MHUs in Sierra Leone using key informant interviews and focus group discussions with 13 purposefully sampled clinical staff and senior management personnel. The interviews were audio-recorded, translated from Krio if necessary, transcribed, and analysed using manifest content analysis. The findings suggest that factors affecting nurse-led mental health service delivery include small workforce and high workload, culture and beliefs, risks, lack of safety measures and required resources, outdated policies, poor salaries, lack of funds for medication, distance, power, influence, and stigma. Factors that could facilitate nurse-led mental health services include: increasing motivation, increasing the workforce, knowledge sharing, mentorship, availability of medication, passion and modern psychiatry. The findings contribute towards understanding the challenges and opportunities faced by the recently established nurse-led decentralised mental health services across Sierra Leone, in order to address the large mental health treatment gap. We hope the findings will inform further policy and planning to improve the quality of decentralised mental healthcare. [ABSTRACT FROM AUTHOR]

Introduction: Personal protective equipment (PPE) inhibits heat dissipation and elevates heat strain. Impaired cooling with PPE warrants investigation into practical strategies to improve work capacity and mitigate exertional heat illness. Purpose: Examine physiological and subjective effects of forearm immersion (FC), fan mist (MC), and passive cooling (PC) following three intermittent treadmill bouts while wearing PPE. Methods: Twelve males (27 ± 6 years; 57.6 ± 6.2 ml/kg/min; 78.3 ± 8.1 kg; 183.1 ± 7.2 cm) performed three 50-min (10 min of 40%, 70%, 40%, 60%, 50% vVO2max) treadmill bouts in the heat (36 °C, 30% relative humidity). Thirty minutes of cooling followed each bout, using one of the three strategies per trial. Rectal temperature (Tcore), skin temperature (Tsk), heart rate (HR), heart rate recovery (HRR), rating of perceived exertion (RPE), thirst, thermal sensation (TS), and fatigue were obtained. Repeated-measures analysis of variance (condition x time) detected differences between interventions. Results: Final Tcore was similar between trials (P >.05). Cooling rates were larger in FC and MC vs PC following bout one (P <.05). HRR was greatest in FC following bouts two (P =.013) and three (P <.001). Tsk, fluid consumption, and sweat rate were similar between all trials (P >.05). TS and fatigue during bout three were lower in MC, despite similar Tcore and HR. Conclusion: Utilizing FC and MC during intermittent work in the heat with PPE yields some thermoregulatory and cardiovascular benefit, but military health and safety personnel should explore new and novel strategies to mitigate risk and maximize performance under hot conditions while wearing PPE. [ABSTRACT FROM AUTHOR]

Introduction: Studies show that the COVID-19 pandemic disproportionately affected people with diabetes and those from disadvantaged backgrounds. During the first 6 months of the UK lockdown, > 6.6 M glycated haemoglobin (HbA1c) tests were missed. We now report variability in the recovery of HbA1c testing, and its association with diabetes control and demographic characteristics. Methods: In a service evaluation, we examined HbA1c testing across ten UK sites (representing 9.9% of England's population) from January 2019 to December 2021. We compared monthly requests from April 2020 to those in the equivalent 2019 months. We examined effects of (i) HbA1c level, (ii) between-practice variability, and (iii) practice demographics. Results: In April 2020, monthly requests dropped to 7.9–18.1% of 2019 volumes. By July 2020, testing had recovered to 61.7–86.9% of 2019 levels. During April–June 2020, we observed a 5.1-fold variation in the reduction of HbA1c testing between general practices (12.4–63.8% of 2019 levels). There was evidence of limited prioritization of testing for patients with HbA1c > 86 mmol/mol during April–June 2020 (4.6% of total tests vs. 2.6% during 2019). Testing in areas with the highest social disadvantage was lower during the first lockdown (April–June 2020; trend test p < 0.001) and two subsequent periods (July–September and October–December 2020; both p < 0.001). By February 2021, testing in the highest deprivation group had a cumulative fall in testing of 34.9% of 2019 levels versus 24.6% in those in the lowest group. Conclusion: Our findings highlight that the pandemic response had a major impact on diabetes monitoring and screening. Despite limited test prioritization in the > 86 mmol/mol group, this failed to acknowledge that those in the 59–86 mmol/mol group require consistent monitoring to achieve the best outcomes. Our findings provide additional evidence that those from poorer backgrounds were disproportionately disadvantaged. Healthcare services should redress this health inequality. [ABSTRACT FROM AUTHOR]

The warm-water species, striped searobin (Prionotus evolans), has colonized Narragansett Bay (Rhode Island, USA) in recent decades. To clarify the high variability of past investigations, the aim of this study was to characterize the diet of striped searobins. Stomach contents from searobins collected throughout Narragansett Bay in 2019 were identified and analyzed. Diet varied ontogenetically, seasonally, and regionally. The ontogenetic changes in diet reflected an expansion of searobin niche breadth: all searobins ate a diet with sand shrimp; however, smaller searobins ate primarily sand shrimp, while larger searobins also consumed crustaceans and finfish. Searobin diet varied by month, but diet composition did not exhibit a singular trend. Regional variation was illustrated by a dominance of mysid shrimp in Upper-Bay searobin samples, while the Mid- and Lower-Bay samples contained larger proportions of other crustacea and sand shrimp. Their flexible diet provides strong evidence that striped searobins are adaptable generalist feeders. Searobin stomachs included nine prey species of economic importance; such predation could become more common as continued increase of habitat use of searobins in Narragansett Bay may result in greater overlap with the occurrence of vulnerable juvenile stages of economically valuable species (e.g., winter flounder). The results of this work contribute to our understanding of the evolving role of the striped searobin in food webs, particularly those in Southern New England (USA). [ABSTRACT FROM AUTHOR]

Background: More complex cases are being performed robotically. This study aims to characterize trends in robotic pancreatoduodenectomy (RPD) over time and assess opportunities for advanced trainees. Methods: Using the ACS-NSQIP database from 2014 to 2019, PD cases were characterized by operative approach (open-OPN, laparoscopic-LAP, robotic-ROB). Proficiency and postoperative outcomes were described by approach over time. Results: 24,268 PDs were identified, with the ROB approach increasing from 2.8% to 7.5%. Unplanned conversion increased over time for LAP (27.7–39.0%, p = 0.003) but was unchanged for ROB cases (14.8–14.7%, p = 0.257). Morbidity increased for OPN PD (35.5–36.8%, p = 0.041) and decreased for ROB PD (38.7–30.3%, p = 0.010). Mean LOS was lower in ROB than LAP/OPN (9.5 vs. 10.9 vs. 10.9 days, p < 0.00001). Approximately, 100 AHPBA, SSO, and ASTS fellows are being trained each year in North America; however, only about 5 RPDs are available per trainee per year which is far below that recommended to achieve proficiency. Conclusion: Over a 6-year period, a significant increase was observed in the use of RPD without a concomitant increase in conversion rates. RPD was associated with decreased morbidity and length of stay. Despite this shift, the number of cases being performed is not adequate for all fellows to achieve proficiency before graduation. [ABSTRACT FROM AUTHOR]

Eczema and asthma are allergic diseases and two of the commonest chronic conditions in high-income countries. Their co-existence with other allergic conditions is common, but little research exists on wider multimorbidity with these conditions. We set out to identify and compare clusters of multimorbidity in people with eczema or asthma and people without. Using routinely-collected primary care data from the U.K. Clinical Research Practice Datalink GOLD, we identified adults ever having eczema (or asthma), and comparison groups never having eczema (or asthma). We derived clusters of multimorbidity from hierarchical cluster analysis of Jaccard distances between pairs of diagnostic categories estimated from mixed-effects logistic regressions. We analysed 434,422 individuals with eczema (58% female, median age 47 years) and 1,333,281 individuals without (55% female, 47 years), and 517,712 individuals with asthma (53% female, 44 years) and 1,601,210 individuals without (53% female, 45 years). Age at first morbidity, sex and having eczema/asthma affected the scope of multimorbidity, with women, older age and eczema/asthma being associated with larger morbidity clusters. Injuries, digestive, nervous system and mental health disorders were more commonly seen in eczema and asthma than control clusters. People with eczema and asthma of all ages and both sexes may experience greater multimorbidity than people without eczema and asthma, including conditions not previously recognised as contributing to their disease burden. This work highlights areas where there is a critical need for research addressing the burden and drivers of multimorbidity in order to inform strategies to reduce poor health outcomes. [ABSTRACT FROM AUTHOR]

Background: More than half of paediatric radiology research presented at annual conference meetings between 2010–2012 remains unpublished. It is unclear if there are any improvements in this statistic despite some initiatives to improve awareness of the importance of evidence-based medicine. Objectives: To determine the abstract to publication rates (APRs) originating from recent paediatric radiology meetings, trends in research topics and factors associated with publication success. Materials and methods: All PubMed cited articles originating from oral presentations at European Society of Paediatric Radiology, Society for Paediatric Radiology or International Paediatric Radiology conferences between 2013–2016 were evaluated, and compared to those from previously published data from the same conferences dated 2010–2012. Publication rates, study design and topic as well as characteristics of the research group (e.g., author affiliations and number) were evaluated and compared between published and unpublished groups. Results: The APR increased to 433/937 (46%) for abstracts presented between 2013–2016, compared to 300/715 (42%) in 2010–2012 (P=0.094). The largest proportion of publications comes from academic and tertiary centres (324/433 [75%]). International collaboration increased to 49/433 (11%) from 18/300 (6%) in 2010–2012 (P=0.018). A greater proportion of work was published within 12 months of conference: 41% in 2013–2016, compared to 29% in 2010–2012 (P=0.02). Paediatric Radiology remained the most popular destination journal, publishing 167/433 (39%) articles. Conclusion: There was a slight increase over time in the proportion of abstracts that resulted in publication, yet more than half of abstracts still do not reach publication status. Further work should identify how radiologists (particularly those outside tertiary and academic centres) can be supported to share their research. [ABSTRACT FROM AUTHOR]

Naturally occurring plant cellulose, our most abundant renewable resource, consists of fibers of long polymer chains that are tightly packed in parallel arrays in either of two crystal phases collectively referred to as cellulose I. During mercerization, a process that involves treatment with sodium hydroxide, cellulose goes through a conversion to another crystal form called cellulose II, within which every other chain has remarkably changed direction. We designed a neutron diffraction experiment with deuterium labelling in order to understand how this change of cellulose chain direction is possible. Here we show that during mercerization of bacterial cellulose, chains fold back on themselves in a zigzag pattern to form crystalline anti-parallel domains. This result provides a molecular level understanding of one of the most widely used industrial processes for improving cellulosic materials. During mercerization, cellulose undergoes a conversion from form I to form II which involves change of the direction of every other cellulose chain but a clear understanding of how this change happens is lacking. Here, the authors use neutron diffraction on deuterium labelled cellulose to demonstrate that chains fold back on themselves in a zigzag pattern to form crystalline anti-parallel domains. [ABSTRACT FROM AUTHOR]

Background: Incident diabetes risk is inversely proportional to 25-hydroxyvitamin D [25(OH)D] levels among non-Hispanic white but is unclear among African American (AA) populations. Serum 25(OH)D2 may be an important component of total 25(OH)D among AA populations due to higher levels of melanin. Objective: To assess the association of serum 25(OH)D with incident diabetes among AAs and stratify by detectable 25(OH)D2. Design: Serum 25(OH)D2 and 25(OH)D3 were collected from 2000 to 2004 among AA participants in the Jackson Heart Study. A cosinor model was used to adjust for the seasonality of 25(OH)D3; 25(OH)D3 and 25(OH)D2 were combined to ascertain total 25(OH)D. Incident diabetes (fasting glucose ≥126 mg/dl, use of diabetes drugs, or HbA1c ≥6.5%) was assessed over 12 years among adults without diabetes at baseline. Participants with missing baseline covariates or diabetes follow-up were excluded. Hazard ratios (HR) were estimated using Cox modeling, adjusting for age, sex, education, occupation, smoking, physical activity, alcohol use, aldosterone, and body-mass index. Results: Among 3311 adults (mean age 53.3 years, 63% female) 584 participants developed diabetes over a median of 7.7 years. After adjustment, 25(OH)D ≥20 compared to <12 ng/ml was associated with a HR 0.78 (95% CI: 0.61, 1.00). Among participants with detectable 25(OH)D2 and 25(OH)D3 (n = 1671), 25(OH)D ≥ 20 ng/ml compared to <12 ng/ml was associated with a 35% (HR 0.65, 95% CI: 0.46, 0.91) lower risk of diabetes. Conclusions: Higher levels of 25(OH)D may be protective against the development of diabetes among AA individuals, particularly among those with detectable 25(OH)D2 and 25(OH)D3. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine if significant clinical differences exist in patient-reported outcome measures (PROMs) between PS and CR TKAs implanted using robotic-assisted technology. This was an IRB-approved retrospective study from an institutional database evaluating 214 knees in 190 patients. Inclusion criteria included: primary RA-TKA, age 22–89 at the time of surgery, preoperative coronal limb deformity within 15º of neutral alignment, and minimum 1-year follow-up. The PS cohort consisted of 103 patients with 107 RA-TKAs, whereas the CR cohort consisted of 87 patients with 107 RA-TKAs. Cohorts were compared on the basis of demographics and PROMs (KSS knee, KSS function, FJS-12, KOOS-JR, WOMAC, and 5-point satisfaction Likert scale) collected preoperatively and at 1-year follow-up. Statistical analyses comparing measures were conducted via Student's t tests for continuous data and Chi-squared analyses for categorical data. There were no significant differences identified in short-term PROMs at 1-year follow-up between cohorts (all p values > 0.05). 93.1% of patients with CR knees and 94.7% of patients with PS knees reported a satisfaction level of "very satisfied" or "satisfied". Revision arthroplasty occurred in six knees (2.8%, 3 knees in CR cohort, 3 knees in PS cohort) with no differences in overall complications between groups. The use of RA-TKA technology promoted high patient satisfaction scores within this study, independent of CR or PS implant type with no significant differences in PROMs, satisfaction, revisions, or complications between the two groups. [ABSTRACT FROM AUTHOR]

Conditional degron tags (CDTs) are a powerful tool for target validation that combines the kinetics and reversible action of pharmacological agents with the generalizability of genetic manipulation. However, successful design of a CDT fusion protein often requires a prolonged, ad hoc cycle of construct design, failure, and re-design. To address this limitation, we report here a system to rapidly compare the activity of five unique CDTs: AID/AID2, IKZF3d, dTAG, HaloTag, and SMASh. We demonstrate the utility of this system against 16 unique protein targets. We find that expression and degradation are highly dependent on the specific CDT, the construct design, and the target. None of the CDTs leads to efficient expression and/or degradation across all targets; however, our systematic approach enables the identification of at least one optimal CDT fusion for each target. To enable the adoption of CDT strategies more broadly, we have made these reagents, and a detailed protocol, available as a community resource. Conditional Degron Tags are a valuable tool to validate and study novel therapeutic targets. Here, the authors compared 5 orthogonal tags across 16 unique proteins and provide a panel of vectors for users to systematically screen the tags with their own protein of interest. [ABSTRACT FROM AUTHOR]

Animal testing has long been the cornerstone of chemical safety assessments, but fish embryo assays represent an alter­native. Omics studies allow the examination of early molecular responses of organisms to environmental stressors, but reduction of animal use within this context has been overlooked. For proteomics, there is significant disparity and vari­ability in the organismal pool size used for studies, ranging from 1-1500 embryos per replicate for zebrafish alone. However, it is unknown if varying sample pool size results in differences in protein identifications. To examine whether the detected proteome changes depend on this variable, 3 pool sizes (5, 10 or 20 embryos or larvae per replicate) were compared using the two most common fish models with an appropriate biological replicate number determined by power analysis (n = 7). Data was acquired using MSe, resulting in 1,946 and 3,172 protein groups identified (1% false discovery rate) for fathead minnow and zebrafish, respectively. Proteins were not differentially expressed among pool sizes, and no significant difference was observed among the identified protein groups. However, for the fathead minnow, a decrease in the number of identified proteins was observed with increasing pool size, while a trend towards an increase in protein identifications was observed in zebrafish between the lowest and highest pool size. Taken together, our observations suggest that a proteome characterization experiment using these fish models can achieve comparable protein identifications using pool sizes of less than 5 organisms per replicate, assuming a protein requirement of 50 μg or less. [ABSTRACT FROM AUTHOR]

Purpose: The force–velocity relationship of muscular contraction has been extensively studied. However, previous research has focussed either on isolated muscle or single-joint movements, whereas human movement consists of multi-joint movements (e.g. squatting). Therefore, the purpose of this study was to investigate the force–velocity relationship of isovelocity squatting. Methods: Fifteen male participants (24 ± 2 years, 79.8 ± 9.1 kg, 177.5 ± 6 cm) performed isovelocity squats on a novel motorised isovelocity device (Kineo Training System) at three concentric (0.25, 0.5, and 0.75 m s−1) and three eccentric velocities (− 0.25, − 0.5, and − 0.75 m s−1). Peak vertical ground reaction forces, that occurred during the isovelocity phase, were collected using dual force plates (2000 Hz) (Kistler, Switzerland). Results: The group mean squat force–velocity profile conformed to the typical in vivo profile, with peak vertical ground reaction forces during eccentric squatting being 9.5 ± 19% greater than isometric (P = 0.037), and occurring between − 0.5 and − 0.75 m s−1. However, large inter-participant variability was identified (0.84–1.62 × isometric force), with some participants being unable to produce eccentric forces greater than isometric. Sub-group analyses could not identify differences between individuals who could/could not produce eccentric forces above isometric, although those who could not tended to be taller. Conclusions: These finding suggest that variability exists between participants in the ability to generate maximum eccentric forces during squatting, and the magnitude of eccentric increase above isometric cannot be predicted solely based on a concentric assessment. Therefore, an assessment of eccentric capabilities may be required prior to prescribing eccentric-specific resistance training. [ABSTRACT FROM AUTHOR]

Rationale: Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/−) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/− on innate and MA-modulated reward sensitivity are not known. Objectives: We examined innate reward sensitivity and facilitation by MA in H1+/− mice via intracranial self-stimulation (ICSS). Methods: We used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5–4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. Results: H1+/− mice displayed reduced normalized maximum response rates in response to MA. H1+/− females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. Conclusions: H1+/− mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/− females (lower normalized M50 values). [ABSTRACT FROM AUTHOR]

During coastal storms, forecasters and researchers use numerical models to predict the magnitude and extent of coastal flooding. These models must represent the large regions that may be affected by a storm, and thus, they can be computationally costly and may not use the highest geospatial resolution. However, predicted flood extents can be downscaled (by increasing resolution) as a post-processing step. Existing downscaling methods use either a static extrapolation of the flooding as a flat surface, or rely on subsequent simulations with nested, full-physics models at higher resolution. This research explores a middle way, in which the downscaling includes simplified physics to improve accuracy. Using results from a state-of-the-art model, we downscale its flood predictions with three methods: (1) static, in which the water surface elevations are extrapolated horizontally until they intersect the ground surface; (2) slopes, in which the gradient of the water surface is used; and (3) head loss, which accounts for energy losses due to land cover characteristics. The downscaling methods are then evaluated for forecasts and hindcasts of Hurricane Florence (2018), which caused widespread flooding in North Carolina. The static and slopes methods tend to over-estimate the flood extents. However, the head loss method generates a downscaled flooding extent that is a close match to the predictions from a higher-resolution, full-physics model. These results are encouraging for the use of these downscaling methods to support decision-making during coastal storms. [ABSTRACT FROM AUTHOR]

Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic "pathological" wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams' E medium or in unsupplemented medium under "pathological" conditions (i.e. hypoxia [5% O2], oxidative damage [10 mM H2O2], absence of insulin, excess glucose). Under these "pathological" conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (p < 0.001), associated with reduced keratinocyte proliferation (p < 0.001), cytokeratin 6 expression (p < 0.001) and increased apoptosis (p < 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under "pathological" wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (p < 0.001) and promoted both epidermal keratinocyte proliferation (p < 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under "pathological" conditions (p < 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters. [ABSTRACT FROM AUTHOR]

Background: Though anatoxin-a (antx-a) is a globally important cyanobacterial neurotoxin in inland waters, information on sublethal toxicological responses of aquatic organisms is limited. We examined influences of (±) antx-a (11–3490 µg/L) on photolocomotor behavioral responses and gene transcription associated with neurotoxicity, oxidative stress and hepatotoxicity, in two of the most common alternative vertebrate and fish models, Danio rerio (zebrafish) and Pimephales promelas (fathead minnow). We selected environmentally relevant treatment levels from probabilistic exposure distributions, employed standardized experimental designs, and analytically verified treatment levels using isotope-dilution liquid chromatography tandem mass spectrometry. Caffeine was examined as a positive control. Results: Caffeine influences on fish behavior responses were similar to previous studies. Following exposure to (±) antx-a, no significant photolocomotor effects were observed during light and dark transitions for either species. Though zebrafish behavioral responses profiles were not significantly affected by (±) antx-a at the environmentally relevant treatment levels examined, fathead minnow stimulatory behavior was significantly reduced in the 145–1960 µg/L treatment levels. In addition, no significant changes in transcription of target genes were observed in zebrafish; however, elavl3 and sod1 were upregulated and gst and cyp3a126 were significantly downregulated in fathead minnows. Conclusion: We observed differential influences of (±) antx-a on swimming behavior and gene transcription in two of the most common larval fish models employed for prospective and retrospective assessment of environmental contaminants and water quality conditions. Sublethal responses of fathead minnows were consistently more sensitive than zebrafish to this neurotoxin at the environmentally relevant concentrations examined. Future studies are needed to understand such interspecies differences, the enantioselective toxicity of this compound, molecular initiation events within adverse outcome pathways, and subsequent individual and population risks for this emerging water quality threat. [ABSTRACT FROM AUTHOR]

Naturally occurring protein switches have been repurposed for the development of biosensors and reporters for cellular and clinical applications1. However, the number of such switches is limited, and reengineering them is challenging. Here we show that a general class of protein-based biosensors can be created by inverting the flow of information through de novo designed protein switches in which the binding of a peptide key triggers biological outputs of interest2. The designed sensors are modular molecular devices with a closed dark state and an open luminescent state; analyte binding drives the switch from the closed to the open state. Because the sensor is based on the thermodynamic coupling of analyte binding to sensor activation, only one target binding domain is required, which simplifies sensor design and allows direct readout in solution. We create biosensors that can sensitively detect the anti-apoptosis protein BCL-2, the IgG1 Fc domain, the HER2 receptor, and Botulinum neurotoxin B, as well as biosensors for cardiac troponin I and an anti-hepatitis B virus antibody with the high sensitivity required to detect these molecules clinically. Given the need for diagnostic tools to track the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)3, we used the approach to design sensors for the SARS-CoV-2 spike protein and antibodies against the membrane and nucleocapsid proteins. The former, which incorporates a de novo designed spike receptor binding domain (RBD) binder4, has a limit of detection of 15 pM and a luminescence signal 50-fold higher than the background level. The modularity and sensitivity of the platform should enable the rapid construction of sensors for a wide range of analytes, and highlights the power of de novo protein design to create multi-state protein systems with new and useful functions.A modular de novo designed biosensor platform consisting of a cage and key molecule is developed, and used to create sensors for seven distinct proteins including the spike protein from SARS-CoV-2 and anti-SARS antibodies. [ABSTRACT FROM AUTHOR]

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Background: Insufflation pressures of or in excess of 25 mm Hg CO2 are routinely used during posterior retroperitoneoscopic adrenalectomy (PRA) in most centres. A critical analysis of the surgical literature provides limited evidence to support this strategy. Objective: To determine whether high pressure (≥ 25 mm Hg) compared with lower pressure (< 25 mm Hg) retroperitoneoscopy reduces operating time and complications. Methods: A multi-centre retrospective cohort study was performed using data collected over a period of almost one decade (1st November 2008 until 1st February 2018) from surgical centres in Germany. A total of 1032 patients with benign adrenal tumours were identified. We compared patients undergoing PRA with insufflation pressures of < 25 mm Hg (G20 group) versus ≥ 25 mm Hg (G25 group). A propensity score matching analysis was performed using BMI, tumour size and surgeon's experience as independent variables. The main outcomes were (1) the incidence of perioperative complications and (2) the length of operating time. Results: The baseline patient characteristics were similar in both groups, with the exception of tumour size, BMI and surgeon's experience in PRA. After propensity score matching, perioperative outcomes, especially perioperative complications (3.7% vs. 5.5% in G20 and G25, respectively; p = 0.335) and operation duration (47 min vs. 45 min in G20 and G25, respectively; p = 0.673), did not significantly differ between the groups. Conclusion: Neither patient safety nor operative success was compromised when PRA was performed with insufflation pressures below 25 mm Hg. Prospective studies are required to determine whether an optimal insufflation pressure exists that maximizes patient safety and minimizes the risks of post-surgical complications. Nevertheless, our results call for a careful re-evaluation of the routine use of high insufflation pressures during PRA. In the absence of prospective data, commencing PRA with lower insufflation pressures, with the option of increasing insufflation pressures to counter intraoperative bleeding or exposition difficulties, may represent a reasonable strategy. [ABSTRACT FROM AUTHOR]

Lentiviral vectors (LV) have emerged as a robust technology for therapeutic gene delivery into human cells as advanced medicinal products. As these products are increasingly commercialized, there are concomitant demands for their characterization to ensure safety, efficacy and consistency. Standards are essential for accurately measuring parameters for such product characterization. A critical parameter is the vector copy number (VCN) which measures the genetic dose of a transgene present in gene-modified cells. Here we describe a set of clonal Jurkat cell lines with defined copy numbers of a reference lentiviral vector integrated into their genomes. Genomic DNA was characterized for copy number, genomic integrity and integration coordinates and showed uniform performance across independent quantitative PCR assays. Stability studies during continuous long-term culture demonstrated sustained renewability of the reference standard source material. DNA from the Jurkat VCN standards would be useful for control of quantitative PCR assays for VCN determination in LV gene-modified cellular products and clinical samples. [ABSTRACT FROM AUTHOR]

Empirical historical research typically falls into one of three categories: the study of major historical events; the use of "history as data" to test general theories; and the study of the legacies of historical processes. We argue that because of data sparsity and dynamically unfolding processes, the study of major historical events is less well suited to design-based inference than other types of historical research. Drawing examples from our own work, we propose a set of research procedures for designing causally oriented work, and argue that the construction of a "timeline of relevant counterfactual nodes" can facilitate the organization of a research project investigating complex historical processes. The researcher can focus on relevant counterfactual moments as potential episodes of change using either statistical or qualitative techniques as appropriate, moving forward through the timeline and updating their beliefs about a hypothesized cause's importance across the process. [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts. [ABSTRACT FROM AUTHOR]

Background: Insufficient sleep is associated with arterial stiffness and elevated cardiovascular disease risk. Central hemodynamics are influenced by arterial stiffness, yet independently predict cardiovascular risk. Relationships between sleep characteristics and central hemodynamic parameters are largely unexplored. We aimed to characterize the relationship between self-reported sleep quality and central hemodynamics in healthy individuals. To explore the secondary hypothesis that impairments in glucose metabolism may underlie relationships between sleep and central hemodynamic variables, we also explored associations between self-reported sleep quality and fasting blood glucose values. Methods: Thirty-one healthy study subjects (20 to 69 years, 17 men) were free from metabolic or cardiovascular disease and did not take sleep medication. Self-reported sleep quality was obtained using the Pittsburgh Sleep Quality Index (PSQI) with normal sleepers defined by PSQI scores 0–5 and poor sleepers by PSQI score > 5. Relationships were assessed between PSQI, central hemodynamic profiles (systolic and diastolic blood pressures, pulse and augmentation pressures, augmentation index) estimated from oscillometric pulse wave analysis, and blood glucose values. Results: Central pulse pressure was significantly elevated in poor (PSQI score > 5) compared with that in normal (PSQI scores 0–5) sleepers (P < 0.05). Linear regression models, adjusted for age, gender, and body mass index, demonstrated PSQI score to be an independent predictor (P < 0.05) of both central pulse (β = 0.469) and augmentation (β = 0.364) pressures. Global PSQI scores were not related to fasting blood glucose values (r = 0.045; P > 0.05). Conclusions: Significant relationships between central pulse and augmentation pressures and self-reported sleep quality highlight the importance of considering sleep when examining lifestyle contributors to central hemodynamics. [ABSTRACT FROM AUTHOR]

The presence of complex, core–shell Al3(Zr, Sc) dispersoids in Al-Cu alloys has recently been found to significantly refine θ′ precipitates resulting in increased mechanical properties. The purpose of this work was to take advantage of these effects to develop alloys with enhanced resistance to high-temperature thermal exposure compared to industrial baseline products. A series of Sc-bearing Al-Cu alloys were designed, manufactured using tailored homogenization practices and tested. It was found that a novel Al-Cu-Mn-Zr-Sc alloy exhibited higher tensile strength than AA2219-T8511 after a thermal exposure of 280 °C—24 h. The presence of Sc-containing primary intermetallics was also observed in V-bearing compositions. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to determine the impact of Healthy Families Healthy Futures (HFHF) enhanced with Steps to Success (STS). HFHF is a structured home visiting program for teen parents in Houston that focuses on improving parenting skills and preventing child abuse. HFHF enhanced with STS includes content and activities aimed to reduce repeat pregnancies within 24 months after the first child's birth. Methods: The study team recruited 248 young mothers for the study, primarily through local health clinics and schools, and then randomly assigned them to either a treatment group that was eligible to participate in HFHF enhanced with STS or to a control group. The control group was not offered any other program through the study. Outcomes were measured by a survey administered 12 months after program intake, in five domains aligned with the program's logic model: (1) exposure to information related to program content, (2) contraception knowledge, (3) contraception use, (4) enhanced family functioning, and (5) child health and development. To estimate program impacts, we used ordinary least squares regression, controlling for demographics and baseline measures of the outcome variables, if available. We use both frequentist approaches (calculations of statistical significance) and Bayesian posterior probabilities to interpret the findings. Results: HFHF enhanced with STS significantly (p <.05) impacted exposure to information on parenting and birth control, with effects of 20.8 and 15.4 percentage points, respectively. Using Bayesian posterior probabilities, there is an 85% chance that the program had a favorable effect on these outcomes. We also calculate a probability of 77% that the program had a favorable impact on long-acting reversible contraceptive (LARC) use, but a probability of 89% that the program reduced knowledge of birth control pills; these two results were not statistically significant (p =.17 and.10, respectively). Conclusions for Practice: These findings are primarily favorable and consistent with the program content and goals. Smaller than anticipated sample sizes due to recruitment challenges increased the chances for random error to affect the ability to detect statistically significant differences on many of our other outcomes; Bayesian posterior probabilities can therefore aid in interpreting the impact estimates. More research of this promising model is warranted. [ABSTRACT FROM AUTHOR]

Purpose: The implantation of flow diverters requires administration of dual anti-platelet therapy, posing the potential for complications. The p48MW HPC (phenox, Bochüm, Germany) hydrophilic-coated flow diverting stent is designed to be anti-thrombotic, thus opening the potential for single anti-platelet therapy. We deploy a novel intravascular high-resolution imaging technique, high-frequency optical coherence tomography (HF-OCT), to study in an animal model the acute thrombus formation on coated p48MW devices versus uncoated control devices. Methods: Three pigs were implanted with 4 flow diverters each, two test hydrophilic-coated devices, and two control uncoated devices (p48MW). Each pig was treated with a different anti-platelet regime: no anti-platelet therapy, aspirin only, aspirin and clopidogrel. Twenty minutes after the flow diverter was implanted, an HF-OCT data set was acquired. Acute clot formed on the flow diverter at each covered side branch was measured from the HF-OCT slices. Factors considered to be important were the device type (pHPC versus bare metal), aspirin, clopidogrel, and vessel location. A linear model was constructed from the significant factors. Results: Both coating (p < 0.001) and aspirin (p = 0.003) were significantly related to reduction in clot burden, leading to an approximate 100-fold and 50-fold reduction in clot, respectively. Conclusions: This study shows the power of HF-OCT not only in the detection of clot but also the quantification of clot burden. In an animal model, the pHPC-coated p48MW significantly reduced acute thrombus formation over jailed side branches as compared to the bare metal p48MW that was nearly eliminated when combined with aspirin administration. [ABSTRACT FROM AUTHOR]

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated. High resolution intravascular imaging in the brain is limited by the high tortuosity of the vasculature. Here the authors present a fiber optic imaging technology using high-frequency optical coherence tomography (HF-OCT) to provide volumetric high resolution images in the highly tortuous cerebral vasculature. [ABSTRACT FROM AUTHOR]

The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies. The SARS-CoV-2 3CL main protease (3CL Mpro) is a chymotrypsin-like protease that facilitates the production of non-structural proteins, which are essential for viral replication and is therefore of great interest as a drug target. Here, the authors present the 2.30 Å room temperature crystal structure of ligand-free 3CL Mpro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures. [ABSTRACT FROM AUTHOR]

Discordant elevations of cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) ribonucleic acid (RNA) in chronically treated patients known as 'CSF escape' may present as acute encephalitis. Infectious encephalitis caused by herpes simplex virus (HSV) and other neurotropic viruses have been identified as potential triggers of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Autoantibody-mediated encephalitis has been infrequently reported in HIV infected patients and may mimic HIV encephalitis. We report two adults infected with HIV presenting with encephalopathy and seizures. Case 1 had a monophasic encephalopathy with detection of NMDAR antibodies in the context of HIV CSF escape. There was a clinical response to immunotherapy and anti-retroviral therapy adjustment. Case 2 initially presented in non-convulsive status epilepticus associated with HIV CSF escape. He responded to treatment with anti-epileptic drugs and anti-retroviral therapy alteration, but had two further neurological relapses. NMDAR antibodies were detected during the relapses and a clinical response was observed following treatment with immunotherapy. Clinicians should consider autoimmune encephalitis in HIV infected patients presenting with encephalopathy and seizures, particularly in cases with concomitant HIV CSF escape. [ABSTRACT FROM AUTHOR]

Acute inflammation is a key feature of innate immunity that initiates clearance and repair in infected or damaged tissues. Alternatively, chronic inflammation is implicated in numerous disease processes. The contribution of neuroinflammation to the pathogenesis of neurological conditions, including infection, traumatic brain injury, and neurodegenerative diseases, has become increasingly evident. Potential drivers of such neuroinflammation include toll-like receptors (TLRs). TLRs confer a wide array of functions on different cell types in the central nervous system (CNS). Importantly, how TLR activation affects astrocyte functioning is unclear. In the present study, we examined the role of TLR2/4 signaling on various astrocyte functions (i.e., proliferation, pro-inflammatory mediator production, regulatory mechanisms, etc) by stimulating astrocytes with potent exogenous TLR2/4 agonist, bacterial lipopolysaccharide (LPS). Newborn astrocytes were derived from WT, Tnfα−/−, Il1α−/−/Il1β−/−, and Tlr2−/−/Tlr4−/− mice as well as Sprague Dawley rats for all in vitro studies. LPS activated mRNA expression of different pro-inflammatory cytokines and chemokines in time- and concentration-dependent manners, and upregulated the proliferation of astrocytes based on increased 3H-thymidine update. Following LPS-mediated TLR2/4 activation, TNF-α and IL-1β self-regulated and modulated the expression of pro-inflammatory cytokines and chemokines. Polyclonal antibodies against TNF-α suppressed TLR2/4-mediated upregulation of astrocyte proliferation, supporting an autocrine/paracrine role of TNF-α on astrocyte proliferation. Astrocytes perform classical innate immune functions, which contradict the current paradigm that microglia are the main immune effector cells of the CNS. TNF-α plays a pivotal role in the LPS-upregulated astrocyte activation and proliferation, supporting their critical roles in in CNS pathogenesis. [ABSTRACT FROM AUTHOR]

Seasonal mismatches between electricity supply and demand is increasing due to expanded use of wind, solar and hydropower resources, which in turn raises the interest on low-cost seasonal energy storage options. Seasonal pumped hydropower storage (SPHS) can provide long-term energy storage at a relatively low-cost and co-benefits in the form of freshwater storage capacity. We present the first estimate of the global assessment of SPHS potential, using a novel plant-siting methodology based on high-resolution topographical and hydrological data. Here we show that SPHS costs vary from 0.007 to 0.2 US$ m−1 of water stored, 1.8 to 50 US$ MWh−1 of energy stored and 370 to 600 US$ kW−1 of installed power generation. This potential is unevenly distributed with mountainous regions demonstrating significantly more potential. The estimated world energy storage capacity below a cost of 50 US$ MWh−1 is 17.3 PWh, approximately 79% of the world electricity consumption in 2017. The potential of seasonal pumped hydropower storage (SPHS) plant to fulfil future energy storage requirements is vast in mountainous regions. Here the authors show that SPHS costs vary from 0.007 to 0.2 US$ m−3 of water stored, 1.8 to 50 US$ MWh−1 of energy stored and 0.37 to 0.6 US$ GW−1 of installed power generation capacity. [ABSTRACT FROM AUTHOR]

Background: Some malignancies are known to be associated with increased risk of herpes zoster, but little is known about how associations between cancer and subsequent zoster risk vary by cancer site, by time since cancer diagnosis, and by age.Methods: An age-, sex-, calendar time-, and practice-matched case-control study, nested in the broadly UK representative Clinical Practice Research Datalink (CPRD) primary care database, was analysed using conditional logistic regression to estimate the association between 21 of the most common specific malignancies and subsequent zoster risk. We adjusted for comorbid conditions and other potential confounders, and investigated effect modification by age and time since malignancy diagnosis.Results: A total of 192 081 adult zoster patients and 732 035 controls were included. Malignancy overall was positively associated with zoster risk (adjusted OR 1.29, 95% CI 1.27-1.32), and the association was especially strong for haematological malignancies (OR 2.46, 2.33-2.60). Among specific malignancies, there was evidence that oral, oesophageal, stomach, colorectal, lung, breast, ovarian, prostate, kidney, bladder, and CNS cancers, as well as lymphoma, myeloma, and leukaemia were associated with increased zoster odds (P⩽0.05 in each case), but the magnitude of associations varied widely. The association was typically strongest within 2 years of malignancy diagnosis and decreased with older age for both haematological and solid malignancies.Conclusions: Several cancers were associated with an increased risk of zoster, particularly within the first 2 years after diagnosis and among younger individuals. Knowledge that patients with a recent diagnosis of cancer are at high risk of zoster may encourage initiation of antiviral therapy earlier in the course of zoster when the benefits are greater. Evaluation of whether patients diagnosed with cancer would benefit from early zoster vaccination is warranted. [ABSTRACT FROM AUTHOR]

Blended learning, a combination of face-to-face and computer-assisted pedagogy, is gaining acceptance at universities as an alternative learning experience. Modern technology has given faculty new ways to incorporate active learning and increase student engagement in their courses. Although the broad history of technology-enhanced coursework has demonstrated that student learning is usually very comparable to what occurs in traditional coursework, recent studies focusing specifically on blended learning in totally redesigned classes report positive results. Were those positive results due to the online blending or to the redesign of the class? To answer this question and other limitations and challenges in past studies, the authors present their unique research that measures learning in a blended undergraduate management information systems course where identical classes were compared, one being all face-to-face and one being one-third online. By varying only course modality, this research answers the question of whether blended learning is a superior learning environment in an undergraduate MIS class, a second-level MIS class covering ERP, business processes, databases, advanced spreadsheets, and data analytics. Collecting both quantitative and qualitative data, the authors use a critical realism lens to create a mechanism for learning. Quantitative data, analyzed by multiple regression models and qualitative data, analyzed by content analysis lead to the outcome that learning is comparable to traditional coursework, grade-wise, but students prefer face-to-face class time. It also reveals that self-regulatory skills are evident, confirming that blended learning can aid in the construction of learning. [ABSTRACT FROM AUTHOR]