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Abstract The rapid growth in consumer-facing mobile and sensor technologies has created tremendous opportunities for patient-driven personalized health management. The diagnosis and management of cardiac arrhythmias are particularly well suited to benefit from these easily accessible consumer health technologies. In particular, smartphone-based and wrist-worn wearable electrocardiogram (ECG) and photoplethysmography (PPG) technology can facilitate relatively inexpensive, long-term rhythm monitoring. Here we review the practical utility of the currently available and emerging mobile health technologies relevant to cardiac arrhythmia care. We discuss the applications of these tools, which vary with respect to diagnostic performance, target populations, and indications. We also highlight that requirements for successful integration into clinical practice require adaptations to regulatory approval, data management, electronic medical record integration, quality oversight, and efforts to minimize the additional burden to health care professionals.

Parenting and children's temperament are important influences on language development. However, temperament may reflect prior parenting, and parenting effects may reflect genes common to parents and children. In 561 U.S. adoptees (57% male) and their birth and rearing parents (70% and 92% White, 13% and 4% African American, and 7% and 2% Latinx, respectively), this study demonstrated how genetic propensity for temperament affects language development, and how this relates to parenting. Genetic propensity for negative emotionality inversely predicted language at 27 months ([Beta] = -0.15) and evoked greater maternal warmth ([Beta] = 0.12), whereas propensity for surgency positively predicted language at 4.5 years ([Beta] = 0.20), especially when warmth was low. Parental warmth ([Beta] = 0.15) and sensitivity ([Beta] = 0.19) further contributed to language development, controlling for common gene effects.

PreambleRobotic magnetic navigation (RMN)-guided catheter ablation (CA) technology has been used for the treatment of cardiac arrhythmias for almost 20 years. Various studies reported that RMN allows for high catheter stability, improved lesion formation and a superior safety profile. So far, no guidelines or recommendations on RMN-guided CA have been published.PurposeThe aim of this consensus paper was to summarize knowledge and provide recommendations on management of arrhythmias using RMN-guided CA as treatment of atrial fibrillation (AF) and ventricular arrhythmias (VA).MethodologyAn expert writing group, performed a detailed review of available literature, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Recommendations on RMN-guided CA are presented in a guideline format with three levels of recommendations to serve as a reference for best practices in RMN procedures. Each recommendation is accompanied by supportive text and references. The various sections cover the practical spectrum from system and patient set-up, EP laboratory staffing, combination of RMN with fluoroscopy and mapping systems, use of automation features and ablation settings and targets, for different cardiac arrhythmias.ConclusionThis manuscript, presenting the combined experience of expert robotic users and knowledge from the available literature, offers a unique resource for providers interested in the use of RMN in the treatment of cardiac arrhythmias.

Background Shock‐reduction implantable cardioverter‐defibrillator programming (SRP) was associated with fewer therapies and improved survival in randomized controlled trials, but real‐world studies investigating SRP and associated outcomes are limited. Methods and Results The BIOTRONIK CERTITUDE registry was linked with the Medicare database. We included all patients with an implantable cardioverter‐defibrillator implanted between August 22, 2012 and September 30, 2021 in the United States. SRP was defined as programming to either a therapy rate cutoff ≥188 beats per minute or number of intervals to detection ≥30/40 for treatment. Among 6781 patients (mean 74±9 years; 27% women), 3393 (50%) had SRP. Older age, secondary prevention indication, and device implantation in the southern or western United States were associated with lower use of SRP. The cumulative incidence rate of implantable cardioverter‐defibrillator shocks was lower in the SRP group (5.1% shocks/patient year) compared with the non‐SRP group (7.2% shocks/patient year) (adjusted hazard ratio [HR], 0.83 [95% CI, 0.73–0.96]; P=0.005). Over a median follow‐up of 2.9 years, 739 deaths occurred in the SRP group and 822 deaths occurred in the non‐SRP group (adjusted HR, 0.97 [95% CI, 0.88–1.07]; P=0.569). SRP was associated with a lower all‐cause mortality among patients without ischemic heart disease compared with patients with ischemic heart disease (adjusted HR, 0.64 [95% CI, 0.48–0.87] versus adjusted HR, 1.02 [95% CI, 0.92–1.14]; Pinteraction=0.004). Conclusions Adoption of SRP is low in real‐world clinical practice. Age, clinical variables, and geographic factors are associated with use of SRP. In this study, SRP‐associated decrease in mortality was limited to patients without ischemic heart disease.

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM). Methods SGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years). Results Patients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition. Conclusions These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

Abstract Background The number of migrants and asylum seekers at the Mexico-US border has increased to historic levels. Our objective was to determine the medical diagnoses and treatments of migrating people seeking care in humanitarian clinics in Matamoros, Mexico. Methods We conducted a cross-sectional study of patient encounters by migrating people through a humanitarian clinic in Matamoros, Mexico, from November 22, 2019, to March 18, 2021. The clinics were operated by Global Response Medicine in concert with local non-governmental organizations. Clinical encounters were each coded to the appropriate ICD-10/CPT code and categorized according to organ system. We categorized medications using the WHO List of Essential Medicines and used multivariable logistic regression to determine associations between demographic variables and condition frequency. Results We found a total of 8,156 clinical encounters, which included 9,744 diagnoses encompassing 132 conditions (median age 26.8 years, female sex 58.2%). People originated from 24 countries, with the majority from Central America (n = 5598, 68.6%). The most common conditions were respiratory (n = 1466, 15.0%), musculoskeletal (n = 1081, 11.1%), and skin diseases (n = 473, 4.8%). Children were at higher risk for respiratory disease (aOR = 1.84, 95% CI: 1.61–2.10), while older adults had greater risk for joint disorders (aOR = 3.35, 95% CI: 1.73–6.02). Women had decreased risk for injury (aOR = 0.50, 95% CI: 0.40–0.63) and higher risk for genitourinary diseases (aOR = 4.99, 95% CI: 3.72–6.85) compared with men. Among 10,405 medications administered, analgesics were the most common (n = 3190, 30.7%) followed by anti-infectives (n = 2175, 21.1%). Conclusions In this large study of a migrating population at the Mexico-US border, we found a variety of clinical conditions, with respiratory, musculoskeletal, and skin illnesses the most common in this study period which encompassed a period of restrictive immigration policy and the first year of the COVID-19 pandemic.

Background: Primary hyperoxaluria (PH) is a rare autosomal recessive disorder, mainly due to the increase in endogenous oxalate production, causing a series of clinical features such as kidney stones, nephrocalcinosis, progressive impairment of renal function, and systemic oxalosis. There are three common genetic causes of glycolate metabolism anomalies. Among them, PH type 1 is the most prevalent and severe type, and early end-stage renal failure often occurs. Summary: This review summarizes primary hyperoxaluria through pathophysiology, genotype, clinical manifestation, diagnosis, and treatment options. And explore the characteristics of Chinese PH patients. Key Messages: Diagnosis of this rare disease is based on clinical symptoms, urinary or blood oxalate concentrations, liver biopsy, and genetic testing. Currently, the main treatment is massive hydration, citrate inhibition of crystallization, dialysis, liver and kidney transplantation, and pyridoxine. Recently, RNA interference drugs have also been used. In addition, technologies such as gene editing and autologous liver cell transplantation are also being developed. C.815_816insGA and c.33_34insC mutation in the AGXT gene could be a common variant in Chinese PH1 population. Mutations at the end of exon 6 account for approximately 50% of all Chinese HOGA1 mutations. Currently, the treatment of PH in China still relies mainly on symptomatic and high-throughput dialysis, with poor prognosis (especially for PH1 patients).

Abstract Background Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro. Methods Previously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs. Results The voltage-dependent Ca2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control. Conclusions By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.

Abstract Background Current practices for engaging patients in patient-oriented research (POR) result in a narrow pool of patient perspectives being reflected in POR. This project aims to address gaps in methodological knowledge to foster diversity in POR, through the co-design and evaluation of a series of educational modules for health researchers in British Columbia, Canada. Methods Modules were co-created by a team of academic researchers and patient partners from hardly-reached communities. The modules are presented using the Tapestry Tool, an interactive, online educational platform. Our evaluation framework focused on engagement, content quality, and predicted behavior change. The User Engagement Scale short form (UES-SF) measured participants’ level of engagement with the modules. Survey evaluation items assessed the content within the modules and participants' perceptions of how the modules will impact their behavior. Evaluation items modeled on the theory of planned behavior, administered before and after viewing the modules, assessed the impact of the modules on participants’ perceptions of diversity in POR. Results Seventy-four health researchers evaluated the modules. Researchers’ engagement and ratings of module content were high. Subjective behavioral control over fostering diversity in POR increased significantly after viewing the modules. Conclusions Our results suggest the modules may be an engaging way to provide health researchers with tools and knowledge to increase diversity in health research. Future studies are needed to investigate best practices for engaging with communities not represented in this pilot project, such as children and youth, Indigenous Peoples, and Black communities. While educational interventions represent one route to increasing diversity in POR, individual efforts must occur in tandem with high-level changes that address systemic barriers to engagement.

Background Venoarterial extracorporeal membrane oxygenation (VA‐ECMO) is increasingly used for patients with cardiogenic shock. Although Impella or intra‐aortic balloon pump (IABP) is frequently used for left ventricular unloading (LVU) during VA‐ECMO treatment, there are limited data on comparative outcomes. We compared outcomes of Impella and IABP for LVU during VA‐ECMO. Methods and Results Using the Nationwide Readmissions Database between 2016 and 2020, we analyzed outcomes in 3 groups of patients with cardiogenic shock requiring VA‐ECMO based on LVU strategies: extracorporeal membrane oxygenation (ECMO) only, ECMO with IABP, and ECMO with Impella. Of 15 980 patients on VA‐ECMO, IABP and Impella were used in 19.4% and 16.4%, respectively. The proportion of patients receiving Impella significantly increased from 2016 to 2020 (6.5% versus 25.8%; P‐trend

IntroductionImplantable cardiac monitors (ICMs) provide long-term arrhythmia monitoring, but high rates of false detections increase the review burden. The new “SmartECG” algorithm filters false detections. Using large real-world data sets, we aimed to quantify the reduction in workload and any loss in sensitivity from this new algorithm.MethodsPatients with a BioMonitor IIIm and any device indication were included from three clinical projects. All subcutaneous ECGs (sECGs) transmitted via remote monitoring were classified by the algorithm as “true” or “false.” We quantified the relative reduction in workload assuming “false” sECGs were ignored. The remote monitoring workload from five hospitals with established remote monitoring routines was evaluated. Loss in sensitivity was estimated by testing a sample of 2000 sECGs against a clinical board of three physicians.ResultsOf our population of 368 patients, 42% had an indication for syncope or pre-syncope and 31% for cryptogenic stroke. Within 418.5 patient-years of follow-up, 143,096 remote monitoring transmissions contained 61,517 sECGs. SmartECG filtered 42.8% of all sECGs as “false,” reducing the number per patient-year from 147 to 84. In five hospitals, nine trained reviewers inspected on average 105 sECGs per working hour. This results in an annual working time per patient of 83 min without SmartECG, and 48 min with SmartECG. The loss of sensitivity is estimated as 2.6%. In the majority of cases where true arrhythmias were rejected, SmartECG classified the same type of arrhythmia as “true” before or within 3 days of the falsely rejected sECG.ConclusionSmartECG increases efficiency in long-term arrhythmia monitoring using ICMs. The reduction of workload by SmartECG is meaningful and the risk of missing a relevant arrhythmia due to incorrect filtering by the algorithm is limited.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Abstract Background Early language difficulties are associated with poor school readiness and can impact lifelong attainment. The quality of the early home language environment is linked to language outcomes. However, few home-based language interventions have sufficient evidence of effectiveness in improving preschool children’s language abilities. This study reports the first stage in the evaluation of a theory-based programme, Talking Together (developed and delivered by BHT Early Education and Training) given over 6 weeks to families in the home setting. We aimed to test the feasibility and acceptability of delivering Talking Together in the Better Start Bradford community prior to a definitive trial, using a two-armed randomised controlled feasibility study. Methods Families from a single site within the Better Start Bradford reach area were randomly allocated (1:1) to the Talking Together intervention or a wait list control group. Child language and parent-level outcome measures were administered before randomisation (baseline), pre-intervention (pre-test), 2 months post-intervention start (post-test), and 6 months post-intervention start (follow-up). Routine monitoring data from families and practitioners were also collected for eligibility, consent, protocol adherence, and attrition rates. Descriptive statistics on the feasibility and reliability of potential outcome measures were analysed alongside qualitative feedback on trial design acceptability. Pre-defined progression-to-trial criteria using a traffic light system were assessed using routine monitoring data. Results Two-hundred and twenty-two families were assessed for eligibility; of these, 164 were eligible. A total of 102 families consented and were randomised (intervention: 52, waitlist control: 50); 68% of families completed outcome measures at 6-month follow-up. Recruitment (eligibility and consent) reached ‘green’ progression criteria; however, adherence reached ‘amber’ and attrition reached ‘red’ criteria. Child- and parent-level data were successfully measured, and the Oxford-CDI was identified as a suitable primary outcome measure for a definitive trial. Qualitative data not only indicated that the procedures were largely acceptable to practitioners and families but also identified areas for improvement in adherence and attrition rates. Conclusions Referral rates indicate that Talking Together is a much-needed service and was positively received by the community. A full trial is feasible with adaptations to improve adherence and reduce attrition. Trial registration ISRCTN registry ISRCTN13251954. Retrospectively registered 21 February 2019

Abstract Background Postoperative pain control can be challenging in patients undergoing hepatectomy. A previous retrospective study on hepatobiliary/ pancreatic surgeries showed better postoperative pain control in patients who received propofol TIVA. The aim of this study was to determine the analgesic effect of propofol TIVA for hepatectomy. This clinical study has been registered at ClinicalTrials.gov (NCT03597997). Methods A prospective randomized controlled trial was performed to compare the analgesic effect of propofol TIVA versus inhalational anaesthesia. Patients aged between 18 and 80 years old with an American Society of Anesthesiologist (ASA) physical status of I-III scheduled for elective hepatectomy were recruited. Ninety patients were randomly allocated to receive either propofol TIVA (TIVA group) or inhalational anaesthesia with sevoflurane (SEVO group). Perioperative anaesthetic/analgesic management was the same for both groups. Numerical rating scale (NRS) pain scores, postoperative morphine consumption, quality of recovery, patient satisfaction and adverse effects were evaluated during the acute postoperative period and at 3 and 6 months after surgery. Results No significant differences were found for acute postoperative pain scores (both at rest and during coughing) and postoperative morphine consumption between TIVA and SEVO groups. Patients given TIVA had lower pain scores with coughing at 3 months after surgery (p = 0.014, and FDR

In this study, a tropical cyclone or typhoon rainfall forecast model based on Random Forest is developed to forecast the daily rainfall at 133 weather stations in China. The input factors to the model training process include rainfall observations during 1960–2018, typhoon information (position and intensity), station information (position and altitude), and properties of the western Pacific subtropical high. Model evaluation shows that besides the distance between a station and cyclone, the subtropical high properties are ranked very high in the model’s feature importance, especially the subtropical ridgeline, and intensity. These aspects of the subtropical high influence the location and timing of typhoon landfall. The forecast model has a correlation coefficient of about 0.73, an Index of Agreement of nearly 0.8, and a mean bias of 1.28 mm based on the training dataset. Biases are consistently low, with both positive and negative signs, for target stations in the outer rainband (up to 1000 km, beyond which the model does not forecast) of typhoons. The range of biases is much larger for target stations in the inner-core (0–200 km) region. In this region, the model mostly overestimates (underestimates) the small (large) rain rates. Cases study of Typhoon Doksuri and Talim in 2023, as independent cases, shows the high performance of the model in forecasting the peak rain rates and timing of their occurrence of the two impactful typhoons.

Background: MRI magnetization-prepared rapid acquisition (MPRAGE) is an easily available imaging modality for dementia diagnosis. Previous studies suggested that volumetric analysis plays a crucial role in various stages of dementia classification. In this study, volumetry, radiomics and demographics were integrated as inputs to develop an artificial intelligence model for various stages, including Alzheimer’s disease (AD), mild cognitive decline (MCI) and cognitive normal (CN) dementia classifications. Method: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset was separated into training and testing groups, and the Open Access Series of Imaging Studies (OASIS) dataset was used as the second testing group. The MRI MPRAGE image was reoriented via statistical parametric mapping (SPM12). Freesurfer was employed for brain segmentation, and 45 regional brain volumes were retrieved. The 3D Slicer software was employed for 107 radiomics feature extractions from within the whole brain. Data on patient demographics were collected from the datasets. The feed-forward neural network (FFNN) and the other most common artificial intelligence algorithms, including support vector machine (SVM), ensemble classifier (EC) and decision tree (DT), were used to build the models using various features. Results: The integration of brain regional volumes, radiomics and patient demographics attained the highest overall accuracy at 76.57% and 73.14% in ADNI and OASIS testing, respectively. The subclass accuracies in MCI, AD and CN were 78.29%, 89.71% and 85.14%, respectively, in ADNI testing, as well as 74.86%, 88% and 83.43% in OASIS testing. Balanced sensitivity and specificity were obtained for all subclass classifications in MCI, AD and CN. Conclusion: The FFNN yielded good overall accuracy for MCI, AD and CN categorization, with balanced subclass accuracy, sensitivity and specificity. The proposed FFNN model is simple, and it may support the triage of patients for further confirmation of the diagnosis.

Background Preschool language skills and language delay predict academic and socioemotional outcomes. Children from deprived environments are at a higher risk of language delay, and both minority ethnic and bilingual children can experience a gap in language skills at school entry. However, research that examines late talking (preschool language delay) in an ethnically diverse, bilingual, deprived environment at age 2 is scarce.Methods Data from Born in Bradford’s Better Start birth cohort were used to identify rates of late talking (≤10th percentile on the Oxford-Communicative Development Inventory: Short) in 2-year-old children within an ethnically diverse, predominantly bilingual, deprived UK region (N=712). The relations between known demographic, maternal, distal and proximal child risk factors, and language skills and language delay were tested using hierarchical linear and logistic regression.Results A total of 24.86% of children were classified as late talkers. Maternal demographic factors (ethnicity, born in UK, education, financial security, employment, household size, age) predicted 3.12% of the variance in children’s expressive vocabulary. Adding maternal language factors (maternal native language, home languages) and perinatal factors (birth weight, gestation) to the model predicted 3.76% of the variance. Adding distal child factors (child sex, child age) predicted 11.06%, and adding proximal child factors (receptive vocabulary, hearing concerns) predicted 49.51%. Significant risk factors for late talking were male sex (OR 2.07, 95% CI 1.38 to 3.09), receptive vocabulary delay (OR 8.40, 95% CI 4.99 to 14.11) and parent-reported hearing concerns (OR 7.85, 95% CI 1.90 to 32.47). Protective factors were increased household size (OR 0.85, 95% CI 0.77 to 0.95) and age (OR 0.82, 95% CI 0.70 to 0.96).Conclusions Almost one in four children living in an ethnically diverse and deprived UK area have early language delay. Demographic factors explained little variance in early vocabulary, whereas proximal child factors held more predictive value. The results indicate further research on early language delay is warranted for vulnerable groups.

Abstract Background Facilitated implementation of nurse-initiated protocols to manage fever, hyperglycaemia (sugar) and swallowing difficulties (FeSS Protocols) in 19 Australian stroke units resulted in reduced death and dependency for stroke patients. However, a significant gap remains in translating this evidence-based care bundle protocol into standard practice in Australia and New Zealand. Facilitation is a key component for increasing implementation. However, its contribution to evidence translation initiatives requires further investigation. We aim to evaluate two levels of intensity of external remote facilitation as part of a multifaceted intervention to improve FeSS Protocol uptake and quality of care for patients with stroke in Australian and New Zealand acute care hospitals. Methods A three-arm cluster randomised controlled trial with a process evaluation and economic evaluation. Australian and New Zealand hospitals with a stroke unit or service will be recruited and randomised in blocks of five to one of the three study arms—high- or low-intensity external remote facilitation or a no facilitation control group—in a 2:2:1 ratio. The multicomponent implementation strategy will incorporate implementation science frameworks (Theoretical Domains Framework, Capability, Opportunity, Motivation – Behaviour Model and the Consolidated Framework for Implementation Research) and include an online education package, audit and feedback reports, local clinical champions, barrier and enabler assessments, action plans, reminders and external remote facilitation. The primary outcome is implementation effectiveness using a composite measure comprising six monitoring and treatment elements of the FeSS Protocols. Secondary outcome measures are as follows: composite outcome of adherence to each of the combined monitoring and treatment elements for (i) fever (n=5); (ii) hyperglycaemia (n=6); and (iii) swallowing protocols (n=7); adherence to the individual elements that make up each of these protocols; comparison for composite outcomes between (i) metropolitan and rural/remote hospitals; and (ii) stroke units and stroke services. A process evaluation will examine contextual factors influencing intervention uptake. An economic evaluation will describe cost differences relative to each intervention and study outcomes. Discussion We will generate new evidence on the most effective facilitation intensity to support implementation of nurse-initiated stroke protocols nationwide, reducing geographical barriers for those in rural and remote areas. Trial registration ACTRN12622000028707. Registered 14 January, 2022.

Abstract Background/Objective To compare functional hearing and tinnitus outcomes in treated large (~ 3 cm) vestibular schwannoma (VS) and posterior fossa meningioma cohorts, and construct willingness‐to‐accept profiles for an experimental brain implant to treat unilateral hearing loss. Methods A two‐way MANOVA model with two independent variables (tumor type; time from treatment) and three dependent variables (hearing effort of tumor ear; abbreviated Speech, Spatial, and Qualities of Hearing scale (SSQ12); Tinnitus Functional Index (TFI)) was used to analyze data from VS (N = 32) and meningioma (N = 50) patients who were treated at a tertiary care center between 2010 and 2020. A query to probe acceptance of experimental treatment for hearing loss relative to expected benefit was used to construct willingness‐to‐accept profiles. Results Tumor type was statistically significant on the combined dependent variables analysis (F[3, 76] = 19.172, p 2 years) (p ≤ .017). At the 60% speech understanding level, 77% of respondents would accept an experimental brain implant. Conclusion Hearing outcome is better for posterior fossa meningioma compared to VS. Most patients with hearing loss in the tumor ear would consider a brain implant if the benefit level would be comparable to a cochlear implant. Level of Evidence 2

Artificial intelligence (AI) and machine learning (ML) have significantly impacted the field of cardiovascular medicine, especially cardiac electrophysiology (EP), on multiple fronts. The goal of this review is to familiarize readers with the field of AI and ML and their emerging role in EP. The current review is divided into 3 sections. In the first section, we discuss the definitions and basics of AI, ML, and big data. In the second section, we discuss their application to EP in the context of detection, prediction, and management of arrhythmias. Finally, we discuss the regulatory issues, challenges, and future directions of AI in EP.

The Split wildfire in July 2017, which was one of the most severe wildfires in the history of this Croatian World Heritage Site, is the focus in this study. The Split fire is a good example of a wildfire–urban interface, with unexpected fire behavior including rapid downslope spread to the coastal populated area. This study clarifies the meteorological conditions behind the fire event, those that have limited the effectiveness of firefighting operations, and the rapid escalation and expansion of the fire zones within 30 h. The Split fire propagation was first reconstructed using radio logs, interviews with firefighters and pilots involved in the intervention, eyewitness statements, digital photographs from fire detection cameras, media, and the monthly firefighting journal. Four phases of fire development have been identified. Then, weather observations and numerical simulations using an enhanced-resolution operational model are utilized to analyze the dynamics in each phase of the fire runs. The synoptic background of the event includes large surface pressure gradient between the Azores anticyclone accompanied by a cold front and a cyclone over the southeastern Balkan Peninsula. At the upper level, there was a deep shortwave trough extending from the Baltic Sea to the Adriatic Sea, which developed into a cut-off low. Such synoptic conditions have resulted in the maximum fire weather index in 2017. Combined with topography, they also locally provoke the formation of the strong northeasterly bura wind along the Adriatic coast, which has been accompanied by a low-level jet (LLJ). The bura (downslope wind), with mid- to low-level gravity-wave breaking and turbulence mixing (as in the hydraulic jump theory), also facilitated the subsidence of dry air from the upper troposphere and rapid drying at the surface. This study demonstrates that numerical guidance that indicates the spatial and temporal occurrence of a LLJ is highly capable of explaining the Split fire evolution from the ignition potential to its extinguishment stage. Thus, in addition to the conventional fire weather indices, such products are able to improve fire weather behavior forecasting and in general more effective decision-making in fire management.

Objective: The proportion of ST-segment elevation myocardial infarction (STEMI) patients without standard modifiable risk factors (SMuRFs: hypertension, diabetes, hypercholesterolemia and smoking) has increased over time. The absence of SMuRFs is known to be associated with worse outcomes, but its association with age and sex is uncertain. We sought to evaluate the association between age and sex with the outcomes of post-STEMI patients without SMuRFs among patients without preexisting coronary artery disease. Methods: Patients who underwent primary PCI for STEMI were identified from the Nationwide Readmission Database of the United States. Clinical characteristics, in-hospital, and 30-day outcomes in patients with or without SMuRFs were compared in men versus women and stratified into five age groups. Results: Between January 2010 and November 2014, of 474,234 patients who underwent primary PCI for STEMI, 52,242 (11.0%) patients did not have SMuRFs. Patients without SMuRFs had higher in-hospital mortality rates than those with SMuRFs. Among those without SMuRFs, the in-hospital mortality rate was significantly higher in women than men (10.6% vs 7.3%, p

Abstract Background As health care markets in the United States have become increasingly consolidated, the role of market concentration on physician treatment behavior remains unclear. In cardiology, specifically, there has been evolving treatment of acute myocardial infarction complicated by cardiogenic shock (AMI-CS) with increasing use of mechanical circulatory support (MCS). However, there remains wide variation in it use. The role of market concentration in the utilization of MCS in AMI-CS is unknown. We examined the use of MCS in AMI-CS and its effect on outcomes between competitive and concentrated markets. Methods and results We used the National Inpatient Sample to query patients admitted with AMI-CS between 2003 and 2009. The primary study outcome was the use of mechanical circulatory support. The primary study exposure was market concentration, measured using the Herfindahl-Hirschman Index, which was used to classify markets as unconcentrated (competitive), moderately concentrated, and highly concentrated. Baseline characteristics, procedures, and outcomes were compared for patients in differently concentrated markets. Multivariable logistic regression was used to examine the association between HHI and use of MCS. Results There were 32,406 hospitalizations for patients admitted with AMI-CS. Patients in unconcentrated markets were more likely to receive MCS than in highly concentrated markets (unconcentrated 46.8% [5087/10,873], moderately concentrated 44.9% [2933/6526], and high concentrated 44.5% [6676/15,007], p

Abstract Background Ctns−/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as interleukin (IL)‐1 trigger inflammatory cascades and may be an important cause for cachexia. We employed genetic and pharmacological approaches to investigate the effects of IL‐1 blockade in Ctns−/− mice. Methods We generated Ctns−/− Il1β−/− mice, and we treated Ctns−/− and wild‐type control mice with IL‐1 receptor antagonist, anakinra (2.5 mg/kg/day, IP) or saline as vehicle for 6 weeks. In each of these mouse lines, we characterized the cachexia phenotype consisting of anorexia, loss of weight, fat mass and lean mass, elevation of metabolic rate, and reduced in vivo muscle function (rotarod activity and grip strength). We quantitated energy homeostasis by measuring the protein content of uncoupling proteins (UCPs) and adenosine triphosphate in adipose tissue and skeletal muscle. We measured skeletal muscle fiber area and intramuscular fatty infiltration. We also studied expression of molecules regulating adipose tissue browning and muscle mass metabolism. Finally, we evaluated the impact of anakinra on the muscle transcriptome in Ctns−/− mice. Results Skeletal muscle expression of IL‐1β was significantly elevated in Ctns−/− mice relative to wild‐type control mice. Cachexia was completely normalized in Ctns−/− Il1β−/− mice relative to Ctns−/− mice. We showed that anakinra attenuated the cachexia phenotype in Ctns−/− mice. Anakinra normalized UCPs and adenosine triphosphate content of adipose tissue and muscle in Ctns−/− mice. Anakinra attenuated aberrant expression of beige adipose cell biomarkers (UCP‐1, CD137, Tmem26, and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in inguinal white adipose tissue in Ctns−/− mice. Moreover, anakinra normalized gastrocnemius weight and fiber size and attenuated muscle fat infiltration in Ctns−/− mice. This was accompanied by correction of the increased muscle wasting signalling pathways (increased protein content of ERK1/2, JNK, p38 MAPK, and nuclear factor‐κB p65 and mRNA expression of Atrogin‐1 and Myostatin) and the decreased myogenesis process (decreased mRNA expression of MyoD and Myogenin) in the gastrocnemius muscle of Ctns−/− mice. Previously, we identified the top 20 differentially expressed skeletal muscle genes in Ctns−/− mice by RNAseq. Aberrant expression of these 20 genes have been implicated in muscle wasting, increased energy expenditure, and lipolysis. We showed that anakinra attenuated 12 of those top 20 differentially expressed muscle genes in Ctns−/− mice. Conclusions Anakinra may provide a targeted novel therapy for patients with infantile nephropathic cystinosis.

Abstract Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β −/− /CKD, Il6 −/− /CKD and Tnfα −/− /CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β −/− /CKD mice but were only partially rescued in Il6 −/− /CKD and Tnfα −/− /CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg/kg/day, IP) or saline for 6 weeks and compared with WT/Sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra decreased serum and muscle expression of IL-6, TNF-α and IL-1β in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.

Background There are limited data on the sex‐based differences in the outcome of readmission after cardiac arrest. Methods and Results Using the Nationwide Readmissions Database, we analyzed patients hospitalized with cardiac arrest between 2010 and 2015. Based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes, we identified comorbidities, therapeutic interventions, and outcomes. Multivariable logistic regression was performed to assess the independent association between sex and outcomes. Of 835 894 patients, 44.4% (n=371 455) were women, of whom 80.7% presented with pulseless electrical activity (PEA)/asystole. Women primarily presented with PEA/asystole (80.7% versus 72.4%) and had a greater comorbidity burden than men, as assessed using the Elixhauser Comorbidity Score. Thirty‐day readmission rates were higher in women than men in both PEA/asystole (20.8% versus 19.6%) and ventricular tachycardia/ventricular fibrillation arrests (19.4% versus 17.1%). Among ventricular tachycardia/ventricular fibrillation arrest survivors, women were more likely than men to be readmitted because of noncardiac causes, predominantly infectious, respiratory, and gastrointestinal illnesses. Among PEA/asystole survivors, women were at higher risk for all‐cause (adjusted odds ratio [aOR], 1.07; [95% CI, 1.03–1.11]), cardiac‐cause (aOR, 1.15; [95% CI, 1.06–1.25]), and noncardiac‐cause (aOR, 1.13; [95% CI, 1.04–1.22]) readmission. During the index hospitalization, women were less likely than men to receive therapeutic procedures, including coronary angiography and targeted therapeutic management. While the crude case fatality rate was higher in women, in both ventricular tachycardia/ventricular fibrillation (51.8% versus 47.4%) and PEA/asystole (69.3% versus 68.5%) arrests, sex was not independently associated with increased crude case fatality after adjusting for differences in baseline characteristics. Conclusions Women are at increased risk of readmission following cardiac arrest, independent of comorbidities and therapeutic interventions.

A group of control (CTL) plus ten sensitivity numerical experiments have been conducted to investigate the sensitivity of planetary boundary layer (PBL) schemes in simulating the asymmetric precipitation distribution of typhoon Lekima (2019) during landfall. The simulated track and intensity are quite sensitive to the choice of the PBL scheme. In CTL that applies the Mellor–Yamada Nakanishi and Niino (MYNN) PBL and the surface layer scheme, the observed eyewall replacement 6 h prior to landfall and the asymmetric precipitation during landfall have been simulated well. However, in the PBL1 experiment that applies the Yonsei University (YSU) PBL scheme and the Revised Mesoscale Model version 5 (MM5) Monin–Obukhov surface layer scheme, no double eyewall is simulated. PBL1 and the other sensitivity experiments also simulate more axisymmetric precipitation distribution. PBL1 simulates intensification just before landfall, sustains intensity longer after landfall, but then dissipates quite rapidly. Such differences from CTL are due to larger enthalpy flux, higher PBL height (which is almost unchanged in CTL), and eddy diffusivity extending more into the free atmosphere in PBL1. These factors lead to outward expansion of the radius of maximum wind, larger radial inflow, larger axisymmetric tangential wind in the boundary layer, and larger updrafts in the eyewall. After landfall, larger momentum flux and larger friction velocity in PBL1 enable the more rapid dissipation. The intensification before landfall in PBL1 makes the axisymmetric component stronger. Asymmetry developed in the outer eyewall, and PBL1 was less successful in simulating the eyewall replacement that affects the degree of rainfall asymmetry. These results indicate that the model PBL schemes largely influence the simulated tropical cyclone (TC) intensity and structure including asymmetric rainfall distribution during landfall.

Abstract Objective To identify differentiation features of chemosensory dysfunction in COVID‐19 infection and their primary drivers. Study Design Cross‐sectional cohort comparison. Methods A national anonymous survey was used to query participants regarding nasal symptoms and chemosensory dysfunction including sensitivity levels, and presence or absence of distortions and phantoms within the 6‐week time window surrounding their COVID‐19 testing and survey completion. Results Three‐hundred and sixty‐four respondents who reported COVID‐19 positive (COVID+; n = 176) or COVID‐19 negative (COVID−; n = 188) test results completed the survey. The COVID+ cohort had higher occurrence rates for: (a) chemosensory sensitivity impairments (67.0% vs 30.3%; P

Understanding the relationship between fire behavior and the driving weather conditions is critical for fire management and long-term fire risk assessment. In this study, we focus on two wildfire events: the Split wildfire in Croatia and the Forcett–Dunalley wildfire in Tasmania, Australia. The antecedent weather in both events included extremely dry conditions and higher-than-average air temperatures in the months prior to the events. The synoptic patterns in both events consisted of a large surface pressure gradient, which generated strong wind, driving the fire’s spread. The Weather Research and Forecasting (WRF) model was utilized to simulate fire weather conditions during the development of the two events. In the innermost domain of WRF, resolution is 500 m with explicit moisture calculation only, and there are 66 vertical levels, with about 20 of them to resolve the boundary layer. The WRF simulations are well verified by station observations, including upper-level wind speeds. The convergence line pattern in the Tasmanian event, which was conducive to intense plume development, has been well simulated. Only a slight discrepancy was identified in the simulation of the coastal change in wind direction in the Croatian event. It is identified that in the Split case, bura wind was highly coupled with an upper-level trough, which induced subsidence of the upper-level dry and cold air to the surface, causing rapid drying of the fuel. During the Forcett–Dunalley fire, the atmosphere was unstable, which enabled deep pyrocumulonimbus development. In general, the development from ignition to the timing of the most extreme fire intensity in both events was largely determined by the evolution of the surface to upper-level meteorological drivers. While these extreme meteorological conditions would impact fire-fighting strategies such as aircraft operations, a model-based estimate of the high-risk areas is critical. Our findings would also benefit an estimate of the climatology of fire events with similar behavior and thus a long-term fire risk assessment.

Redox signaling alterations contribute to chronic kidney disease (CKD)-associated cachexia. This review aims to summarize studies about redox pathophysiology in CKD-associated cachexia and muscle wasting and to discuss potential therapeutic approaches based on antioxidant and anti-inflammatory molecules to restore redox homeostasis. Enzymatic and non-enzymatic systems of antioxidant molecules have been studied in experimental models of kidney diseases and patients with CKD. Oxidative stress is increased by several factors present in CKD, including uremic toxins, inflammation, and metabolic and hormone alterations, leading to muscle wasting. Rehabilitative nutritional and physical exercises have shown beneficial effects for CKD-associated cachexia. Anti-inflammatory molecules have also been tested in experimental models of CKD. The importance of oxidative stress has been shown by experimental studies in which antioxidant therapies ameliorated CKD and its associated complications in the 5/6 nephrectomy model. Treatment of CKD-associated cachexia is a challenge and further studies are necessary to investigate potential therapies involving antioxidant therapy.

Severe thunderstorms lead to multiple hazards including torrential precipitation, flash flood, hail, lightning, and wind gusts. The meso- to micro-scale nature of thunderstorms impose great challenges from understanding individual storm dynamics, storm climatology as well as projecting their future activities. High-resolution regional climate models can resolve the convective environments better than global models. Australia, especially the east and southeast parts of the continent, is a global hot spot for severe thunderstorms. This study evaluates the simulated convective environments from the New South Wales (NSW) and Australian Regional Climate Modelling (NARCliM) project based on the parameters of CAPE, CIN, 0–6-km vertical wind shear and storm severity. The ensemble regional downscaling is compared against the fifth-generation European Centre for Medium-range Weather Forecast Reanalysis (ERA5). The results show that although there are apparent biases (generally positive for CAPE and negative for CIN, and slightly overestimated vertical wind shear) in the downscaled storm parameters, the climatology of measures of storm severity over land, including their spatial patterns and seasonality, agree well with ERA5. These results have strong implication on the application of the climate projection to assess future convective environments in the region.

BACKGROUND Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID).METHODS This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Ab and T cell responses to SARS-CoV-2, including neutralization against SARS-CoV-2 variants, were determined before and after 1 and 2 vaccine doses.RESULTS We prospectively followed 150 subjects, 26 healthy controls, 9 patients with IMID on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti–IL-23, 28 on anti–IL-12/23, 9 on anti–IL-17, and 8 on MTX/AZA. Ab and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in patients with IMID compared with healthy controls. Ab levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF–treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2.CONCLUSIONS Our findings support the need for a third dose of the mRNA vaccine and for continued monitoring of immunity in these patient groups.FUNDING Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (to THW and ACG), CIHR FDN-143250 (to THW), GA2-177716 (to VC, ACG, and THW), and GA1-177703 (to ACG) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to ACG).

Background: The optimal timing of catheter ablation for the treatment of ventricular tachycardia (VT) in patients with ischemic cardiomyopathy remains unclear. Studies examining the impact of early preventive ablation of VT on rates of implantable cardioverter-defibrillator (ICD) therapies and mortality have been limited by small sample size. Objectives: To conduct a meta-analysis of randomized controlled trials (RCTs) comparing initial catheter ablation and ICD implantation (preventive ablation arm) vs ICD implantation alone (deferred ablation arm) in patients with ischemic cardiomyopathy and VT. Methods: The primary endpoint was the incidence of appropriate ICD therapy during follow-up. Secondary endpoints included appropriate ICD shock, VT storm, procedural complications, and mortality. Sensitivity analysis, meta-regression, and evaluation of bias were performed. Results: Four RCTs (n = 505) fulfilled inclusion criteria. During follow-up (mean >22 months for all RCTs), preventive ablation was associated with a significant reduction in ICD therapies (odds ratio [95% confidence interval]: 0.53 [0.36–0.78]). The occurrence of ICD shocks and VT storm were also significantly reduced in the preventive ablation group. Among patients with left ventricular ejection fraction (LVEF) >30%, preventive ablation was associated with marked reduction in ICD therapy when compared to deferred ablation (odds ratio [95% confidence interval]: 0.37 [0.19–0.72]). Overall, there was no difference in mortality between treatment groups. Conclusions: Preventive catheter ablation in patients with ischemic cardiomyopathy decreases ICD therapies, ICD shocks, and VT storm without increasing complications, particularly in patients with LVEF >30%. However, early preventive ablation is not associated with any benefit in mortality.

Surface ozone (O3) is an important air pollutant and greenhouse gas. Land use and land cover is one of the critical factors influencing ozone, in addition to anthropogenic emissions and climate. Land use and land cover change (LULCC) can on the one hand affect ozone “biogeochemically”, i.e., via dry deposition and biogenic emissions of volatile organic compounds (VOCs). LULCC can on the other hand alter regional- to large-scale climate through modifying albedo and evapotranspiration, which can lead to changes in surface temperature, hydrometeorology, and atmospheric circulation that can ultimately impact ozone “biogeophysically”. Such biogeophysical effects of LULCC on ozone are largely understudied. This study investigates the individual and combined biogeophysical and biogeochemical effects of LULCC on ozone and explicitly examines the critical pathway for how LULCC impacts ozone pollution. A global coupled atmosphere–chemistry–land model is driven by projected LULCC from the present day (2000) to the future (2050) under RCP4.5 and RCP8.5 scenarios, focusing on the boreal summer. Results reveal that when considering biogeochemical effects only, surface ozone is predicted to have slight changes by up to 2 ppbv maximum in some areas due to LULCC. It is primarily driven by changes in isoprene emission and dry deposition counteracting each other in shaping ozone. In contrast, when considering the combined effect of LULCC, ozone is more substantially altered by up to 5 ppbv over several regions in North America and Europe under RCP4.5, reflecting the importance of biogeophysical effects on ozone changes. In boreal and temperate mixed forests with intensive reforestation, enhanced net radiation and sensible heat induce a cascade of hydrometeorological feedbacks that generate warmer and drier conditions favorable for higher ozone levels. In contrast, reforestation in subtropical broadleaf forests has minimal impacts on boundary-layer meteorology and ozone air quality. Furthermore, significant ozone changes are also found in regions with only modest LULCC, which can only be explained by “remote” biogeophysical effects. A likely mechanism is that reforestation induces a circulation response, leading to reduced moisture transport and ultimately warmer and drier conditions in the surrounding regions with limited LULCC. We conclude that the biogeophysical effects of LULCC are important pathways through which LULCC influences ozone air quality both locally and in remote regions even without significant LULCC. Overlooking the effects of hydrometeorological changes on ozone air quality may cause underestimation of the impacts of LULCC on ozone pollution.

Abstract Patients with chronic kidney disease (CKD) are often 25(OH)D3 and 1,25(OH)2D3 insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D3 and 1,25(OH)2D3 (75 μg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D3 and 1,25(OH)2D3 in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.

Abstract Background It is unclear whether regional anesthesia with infraclavicular nerve block or general anesthesia provides better postoperative analgesia after distal radial fracture fixation, especially when combined with regular postoperative analgesic medications. The aim of this study was to compare the postoperative analgesic effects of regional versus general anesthesia. Methods In this prospective, observer blinded, randomized controlled trial, 52 patients undergoing distal radial fracture fixation received either general anesthesia (n = 26) or regional anesthesia (infraclavicular nerve block, n = 26). Numerical rating scale pain scores, analgesic consumption, patient satisfaction, adverse effects, upper limb functional scores (Patient-Rated Wrist Evaluation, QuickDASH), health related quality of life (SF12v2), and psychological status were evaluated after surgery. Result Regional anesthesia was associated with significantly lower pain scores both at rest and with movement on arrival to the post-anesthetic care unit; and at 1, 2, 24 and 48 h after surgery (p ≤ 0.001 at rest and with movement). Morphine consumption in the post-anesthetic care unit was significantly lower in the regional anesthesia group (p

Post-explant (ex vivo) evaluation of medical devices is an essential part of quality assurance, quality improvement, and further device development. Central to this is detailed pathological analysis. Here, we provide the first such evaluation of an explanted Tiara transcatheter mitral valve prosthesis. (Level of Difficulty: Advanced.)

Abstract Background Ctns−/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns−/− mice are 25(OH)D3 and 1,25(OH)2D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns−/− mice. Methods Twelve‐month‐old Ctns−/− mice and wild‐type controls were treated with 25(OH)D3 and 1,25(OH)2D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns−/− mice using RNAseq. Results Supplementation of 25(OH)D3 and 1,25(OH)2D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2D3 in Ctns−/− mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns−/− mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP‐1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF‐κB pathway) in inguinal white adipose tissue in Ctns−/− mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns−/− mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL‐1β, IL‐6, and TNF‐α as well as an increased gene expression of Murf‐2, atrogin‐1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns−/− mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns−/− mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2D3 normalized the top 20 differentially expressed genes in Ctns−/− mice. Conclusions We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns−/− mice via multiple cellular and molecular mechanisms.

Objectives: This study evaluates the impact of socioeconomic status (SES) on utilization of mechanical circulatory support (MCS) devices and outcomes in cardiogenic shock (CS). Background: CS is associated with significant mortality. There is increasing use of temporary MCS devices in CS, and its impact on outcomes is currently under investigation. There is a lack of data on the effect of SES on the utilization of MCS devices in CS. Methods: CS hospitalizations were obtained from the State Inpatient Databases in 2016 from 9 states representing various regions in the United States. The study had exempt institutional review board status as the database includes deidentified data. Hospitalizations were separated into SES cohorts based on the median household income of the patient residence zip code. Utilization of MCS devices and revascularization procedures along with clinical outcomes with CS were compared across the quartiles. Results: There were 38,520 hospitalizations identified with CS, 42.6% of which were secondary to acute myocardial infarction. Patients from higher SES areas were significantly older but had lower burden of comorbidities. Utilization of temporary MCS devices was higher for hospitalizations from higher SES regions (frequency from the lowest SES quartile to the highest SES quartile: 21.3%, 21.5%, 23.5, and 24.1%, P

Background: An overview of systematic reviews(SRs) and network meta-analysis(NMA) were conducted to evaluate the comparative effectiveness of peri-discharge complex interventions for reducing 30-day readmissions among chronic obstructive pulmonary disease(COPD) patients. Methods: Five databases were searched for SRs of randomized controlled trials(RCTs). An additional search was conducted for updated RCTs from database inception until Jun 2020. Pooled effect of peri-discharge complex interventions was assessed using random-effect pairwise meta-analyses. Comparative effectiveness across different peri-discharge complex interventions was evaluated using NMA. Results: Nine SRs and 11 eligible RCTs(n = 1,422) assessing eight different peri-discharge complex interventions were included. For reducing 30-day all-cause readmissions, pairwise meta-analysis showed no significant difference between peri-discharge complex interventions and usual care, while NMA indicated no significant differences among different peri-discharge complex interventions as well as usual care. For reducing 30-day COPD-related readmissions, peri-discharge complex interventions were significantly more effective than usual care (pooled RR = 0.45, 95% CI:0.24–0.84). Conclusions: Peri-discharge complex interventions may not differ from usual care in reducing 30-day all-cause readmissions among COPD patients but some are more effective for lowering 30-day COPD-related readmission. Thus, complex intervention comprising core components of patient education, self-management, patient-centred discharge instructions, and telephone follow up may be considered for implementation, but further evaluation is warranted.

The Australian Alps are the highest mountain range in Australia, which are important for biodiversity, energy generation and winter tourism. Significant increases in temperature in the past decades has had a huge impact on biodiversity and ecosystem in this region. In this study, observed temperature is used to assess how temperature changed over the Australian Alps and surrounding areas. We also use outputs from two generations of NARCliM (NSW and Australian Regional Climate Modelling) to investigate spatial and temporal variation of future changes in temperature and its extremes. The results show temperature increases faster for the Australian Alps than the surrounding areas, with clear spatial and temporal variation. The changes in temperature and its extremes are found to be strongly correlated with changes in albedo, which suggests faster warming in cool season might be dominated by decrease in albedo resulting from future changes in natural snowfall and snowpack. The warming induced reduction in future snow cover in the Australian Alps will have a significant impact on this region.

Manifestations of infantile nephropathic cystinosis (INC) often include cachexia and deficiency of circulating vitamin D metabolites. We examined the impact of 25(OH)D3 versus 1,25(OH)2D3 repletion in Ctns null mice, a mouse model of INC. Six weeks of intraperitoneal administration of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) resulted in Ctns−/− mice corrected low circulating 25(OH)D3 or 1,25(OH)2D3 concentrations. While 25(OH)D3 administration in Ctns−/− mice normalized several metabolic parameters characteristic of cachexia as well as muscle function in vivo, 1,25(OH)2D3 did not. Administration of 25(OH)D3 in Ctns−/− mice increased muscle fiber size and decreased fat infiltration of skeletal muscle, which was accompanied by a reduction of abnormal muscle signaling pathways. 1,25(OH)2D3 administration was not as effective. In conclusion, 25(OH)D3 supplementation exerts metabolic advantages over 1,25(OH)2D3 supplementation by amelioration of muscle atrophy and fat browning in Ctns−/− mice.