Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II.

The RAS isoforms (KRAS, HRAS and NRAS) have distinct cancer type-specific profiles. NRAS mutations are the second most prevalent RAS mutations in skin and hematological malignancies. Although RAS proteins were considered undruggable for decades, isoform and mutation-specific investigations have produced successful RAS inhibitors that are either specific to certain mutants, isoforms (pan-KRAS) or target all RAS proteins (pan-RAS). While extensive structural and biochemical investigations have focused mainly on K- and H-RAS mutations, NRAS mutations have received less attention, and the most prevalent NRAS mutations in human cancers, Q61K and Q61R, are rare in K- and H-RAS. This manuscript presents a crystal structure of the NRAS Q61K mutant in the GTP-bound form. Our structure reveals a previously unseen pocket near switch II induced by the binding of a ligand to the active form of the protein. This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.

Contribution of systemic factors on macular vessel density: a sex-specific population-based study.

PURPOSE: To evaluate the influence of systemic factors on macular vessel density in quantitative Optical Coherence Tomography Angiography (OCTA) by sex. STUDY DESIGN: A cross-sectional study. METHODS: A total of 2018 adults were recruited in this study. Participants were excluded (n=964) due to missing data, eye-related problems, or low OCTA scan quality. Macular vessel densities were measured with OCTA using split-spectrum amplitude decorrelation angiography algorithm. Only the data from the right eyes were selected for analysis. Multivariable linear regression analysis was performed to determine the associations between macular vessel density and obesity-related systemic factors in each gender group. RESULTS: The right eyes of 1054 participants (59.6% women) were enrolled. Men had significantly higher obesity parameters and associated risk factors. In multivariable linear regression analysis in men, older age and type 2 diabetes mellitus were independently associated with lower superficial retinal vessel density (ß = -0.37, p = 0.002; ß = -1.22, p = 0.03) and deep retinal vessel density, respectively (ß = -0.66, p < 0.001; ß = -1.76, p = 0.02); positive association was also observed between body mass index (BMI) and superficial retinal vessel density (ß = 0.56, p = 0.02). In women, only higher systolic blood pressure was independently associated with a lower deep retinal vessel density (ß = -0.50, p = 0.003). CONCLUSIONS: This large cross-sectional study shows that older age and type 2 diabetes mellitus are associated with lower superficial and deep retinal capillary vessel density in men. This may help clinicians better understand how systemic factors influence retinal vessel density in different genders and future studies can ascertain more potential sex differences.

Real-World Effectiveness of Upadacitinib for Treatment of Rheumatoid Arthritis in Canadian Patients: Interim Results from the Prospective Observational CLOSE-UP Study.

INTRODUCTION: Upadacitinib (UPA), a selective, reversible, oral Janus kinase (JAK)-1 inhibitor, was approved in 2019 in Canada for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). This phase 4 prospective study aimed to characterise the effectiveness of UPA in the real-world population of patients with RA. METHODS: Adults with RA who initiated treatment with once daily UPA (15 mg) and enrolled in the Canadian Real-Life post-marketing Observational Study assessing the Effectiveness of UPadacitinib for treating rheumatoid arthritis (CLOSE-UP) and who completed a 6-month assessment as of 28 February 2023 were included. The primary endpoint of the CLOSE-UP study is the proportion of patients achieving a Disease Activity Score-28 Joint Count C-reactive protein (DAS28-CRP) < 2.6 at 6 months. Data was collected at routine visits. Data analysed and summarised descriptively for the overall interim population and for subgroups based on prior therapy included remission or low disease activity, patient-reported outcomes (PROs), and adverse events. RESULTS: A total of 392 patients were included in the interim analysis. Overall, 63.5% (191/301) of patients achieved a DAS28-CRP score < 2.6 at month 6, with similar rates observed for all subgroups analysed according to prior therapy including those with prior JAK inhibitor exposure (range 57.4-71.0%), and in patients who received UPA monotherapy (71.6% [48/67]). Early (month 3) and sustained improvements up to 6 months were observed for all PROs. The safety profile was consistent with previous reports. CONCLUSION: Real-world improvements in disease activity and PROs in response to UPA treatment were consistent with clinical trial data across a range of Canadian patients with prior therapy exposure and with UPA monotherapy, with an overall favourable benefit-risk profile. TRIAL REGISTRATION: NCT04574492.

Validity of Home Blood Pressure Devices Sold in Canada.

Background: Measurement of home blood pressure is an important tool for the management of hypertension. However, the validity of home devices is of concern. The Recommended Blood Pressure Devices Program of Hypertension Canada reviews and recommends blood pressure devices using international validation standards. We sought to determine the proportion of Hypertension Canada-recommended devices available for purchase in pharmacies and online. Methods: We visited 16 community pharmacies in the Edmonton area to record the blood pressure devices they sold. We also reviewed the 50 most popular devices from online retailers (Amazon, Walmart, Best Buy, and Canadian Tire). All devices were referenced against the Recommended Blood Pressure Device Program of Hypertension Canada (www.hypertension.ca/bpdevices) to determine if the models were recommended. Results: We reviewed 170 devices. Of those sold in pharmacies, 61 of 68 (89.7%) were Hypertension Canada-recommended devices, whereas online retailers had only 46 of 102 (45.1%) recommended devices; P < 0.001. Conclusions: Most blood pressure devices sold in pharmacies are Hypertension Canada recommended, in contrast to less than one-half from online retailers. The lack of validation of many home blood pressure devices could have important clinical implications, leading to over- or undertreatment of hypertension. Clinicians should advise patients on the importance of home blood pressure device validation and direct them to resources such as Hypertension Canada (https://hypertension.ca/public/recommended-devices) for guidance.

Contexte: La mesure de la pression artérielle au domicile est un outil important dans la prise en charge de l'hypertension. Or, il semble que les appareils utilisés à la maison à cette fin ne soient pas toujours des dispositifs validés. Dans le cadre de son Programme de recommandation d'appareils de mesure de la pression artérielle, Hypertension Canada analyse et recommande des tensiomètres selon des normes de validation internationales. Nous avons donc cherché à déterminer la proportion des tensiomètres recommandés par Hypertension Canada qu'il est possible d'acheter dans les pharmacies et en ligne. Méthodologie: Nous avons rendu visite à 16 pharmacies communautaires dans la région d'Edmonton pour recenser les tensiomètres qui y étaient vendus. Nous avons également analysé les 50 tensiomètres les plus vendus par des détaillants en ligne (Amazon, Walmart, Best Buy et Canadian Tire). Nous avons vérifié si chacun des modèles faisait partie de la liste des appareils recommandés par Hypertension Canada (www.hypertension.ca/bpdevices). Résultats: Nous avons passé en revue 170 appareils. Dans les pharmacies, 61 appareils sur 68 (89,7 %) étaient recommandés par Hypertension Canada, alors qu'en ligne, cette proportion n'était que de 46 sur 102 (45,1 %); p < 0,001. Conclusions: La plupart des tensiomètres vendus dans les pharmacies sont recommandés par Hypertension Canada, contrairement à moins de la moitié de ceux qui sont vendus en ligne. L'absence de validation pour de nombreux tensiomètres pourrait avoir d'importantes conséquences cliniques, menant à un traitement excessif ou insuffisant de l'hypertension. Les cliniciens doivent informer les patients de l'importance d'utiliser un tensiomètre validé à la maison et les orienter vers des ressources comme Hypertension Canada (https://hypertension.ca/public/recommended-devices) pour guider leur choix.

Residual Disease Activity In Canadian Patients With Psoriatic Arthritis (PsA) Treated With Advanced Therapies: Results From A Multi-Registry Analysis (UNISON-PsA).

OBJECTIVE: Although patient outcomes in psoriatic arthritis (PsA) have improved with the advent of advanced therapies, there remains a high unmet need to treat residual disease activity. The objective of the current study was to quantify residual disease activity and burden of disease in Canadian patients with PsA. METHODS: This was a multi-region, observational, retrospective analysis of patient data extracted from the Rhumadata™ and the International Psoriasis and Arthritis Research Team (IPART) registries, analyzing de-identified data from patients who had initiated advanced therapy for the treatment of PsA between January 2010 and December 2019. The primary endpoint was the proportion of patients failing to achieve minimal disease activity (MDA) within 6 months; secondary endpoints included clinical and patient-reported burden of disease. Descriptive statistics included summaries by region, treatment class, and number of prior advanced therapies. RESULTS: 1,596 patients were included. The proportion of patients who failed to achieve MDA within 6 months of an advanced therapy was 64.8% in Ontario, 68.3% in Western Canada, 74.8% in Québec and 75.0% in the Atlantic/East region. Failure to achieve MDA was higher amongst patients receiving an IL-17i compared with a TNFi in all regions except Atlantic/East. Between 73.2 to 78.6% of patients reported pain at 6 months, and continuing functional impairment varied from 24.0% in the West to 83.3% in the Atlantic/East. CONCLUSION: There is substantial burden and unmet need for improved therapies for Canadians living with PsA. There is a wide regional variation in outcomes that requires further assessment.

Investigating the effects of the local environment on bottlebrush conformations using super-resolution microscopy.

The single-chain physics of bottlebrush polymers plays a key role in their macroscopic properties. Although efforts have been made to understand the behavior of single isolated bottlebrushes, studies on their behavior in crowded, application-relevant environments have been insufficient due to limitations in characterization techniques. Here, we use single-molecule localization microscopy (SMLM) to study the conformations of individual bottlebrush polymers by direct imaging. Our previous work focused on bottlebrushes in a matrix of linear polymers, where our observations suggested that their behavior was largely influenced by an entropic incompatibility between the bottlebrush side chains and the linear matrix. Instead, here we focus on systems where this effect is reduced: in solvent-swollen polymer materials and in systems entirely composed of bottlebrushes. We measure chain conformations and rigidity using persistence length (lp) as side chain molecular weight (Msc) is varied. Compared to a system of linear polymers, we observe greater flexibility of the backbone in both systems. For bottlebrushes in bottlebrush matrices, we additionally observed a scaling relationship between lp and Msc that more closely follows theoretical predictions. For the more flexible chains in both systems, we reach the edge of our resolution limit and cannot visualize the entire contour of every chain. We bypass this limitation by discussing the aspect ratios of the features within the super-resolution images.

Pharmacological Treatment of Heart Failure: Recent Advances.

BACKGROUND: Heart failure is a clinical condition with high mortality and morbidity that occurs when the heart is unable to pump enough blood to meet the metabolic demands of the body. The pharmacological management of heart failure has been revolutionized over the past decade with novel treatments. OBJECTIVE: The aim of the review is to highlight the recent pharmacological advances in the management of heart failure. RESULTS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i), iron carboxymaltose, finerenone, omecamtiv mecarbil, and vericiguat have been shown to reduce hospitalization for heart failure. However, only SGLT2i, vericiguat, and omecamtiv mecarbil have been shown to reduce cardiovascular death. Finerenone has been shown to reduce cardiovascular events and renal adverse outcomes in patients with diabetes and kidney disease. Currently, only SGLT2i has been studied in patients beyond the heart failure-reduced ejection fraction population. CONCLUSION: The current quadruple therapy in the treatment of heart failure has demonstrated a reduction in the hospitalization of patients and a decrease in mortality associated with the condition. Individualized heart failure therapy research have shown some benefit in select heart failure patients. Further research on novel therapies will help improve heart failure patient outcomes.

A novel speckle-tracking echocardiography parameter assessing left ventricular afterload.

BACKGROUND: Left ventricular stroke work index (LVSWI) and afterload-related cardiac performance (ACP) consider left ventricular (LV) afterload and could be better prognosticators in septic cardiomyopathy. However, their invasive nature prevents their routine clinical applications. This study aimed to investigate (1) whether a proposed speckle-tracking echocardiography parameter, Pressure-Strain Product (PSP), can non-invasively predict catheter-based LVSWI, ACP and serum lactate in an ovine model of septic cardiomyopathy; and (2) whether PSP can distinguish the sub-phenotypes of acute respiratory distress syndrome (ARDS) with or without sepsis-like conditions. METHODS: Sixteen sheep with ARDS were randomly assigned to either (1) sepsis-like (n = 8) or (2) non-sepsis-like (n = 8) group. Each ARDS and sepsis-like condition was induced by intravenous infusion of oleic acid and lipopolysaccharide, respectively. Pulmonary artery catheter-based LVSWI (the product of stroke work index, mean arterial pressure and .0136), ACP (the percentage of cardiac output measured to cardiac output predicted as normal) and serum lactate were measured simultaneously with transthoracic echocardiography. Two PSP indices were calculated by multiplying the mean arterial blood pressure and either global circumferential strain (PSPcirc) or radial strain (PSPrad). RESULTS: PSPcirc showed a significant correlation with LVSWI (r2 = .66, p < .001) and ACP (r2 = .82, p < .001) in the sepsis-like group. Although PSP could not distinguish subphenotypes, PSPcirc predicted LVSWI (AUC .86) and ACP (AUC .88), and PSPrad predicted serum lactate (AUC .75) better than LV ejection fraction, global circumferential and radial strain. CONCLUSIONS: A novel PSP has the potential to non-invasively predict catheter-based LVSWI and ACP, and was associated with serum lactate in septic cardiomyopathy.

Resting echocardiographic parameters can exclude significant coronary artery disease: A comparison with coronary computed tomography angiography.

INTRODUCTION: Coronary computed tomography angiography (CCTA) is known to have a high negative predictive value (NPV) in identifying coronary artery disease (CAD). This study aimed to examine whether resting echocardiographic parameters could exclude significant CAD on CCTA. METHODS: We recruited 142 patients who had undergone both CCTA and echocardiography within a 3-month window. Based on the CCTA findings, patients were divided into two groups: Group A (non-significant CAD, defined as all coronary segments having <50% stenosis) and Group B (significant CAD). Resting echocardiographic parameters were compared between the two groups to identify predictors of non-significant CAD on CCTA. RESULTS: A total 92 patients (mean age, 68 ± 13 years; males, 62%) were eligible for this study; 50 in Group A and 42 in Group B. Among the various echo parameters, left atrial volume index (LAVI) and left ventricular (LV) global longitudinal strain (GLS) were significantly lower in Group A (23.5 ± 7.6 vs. 33.6 ± 7.4 mL/m2 , p < .001; -20.2 ± 1.8% vs. -16.8 ± 2.0%, p < .001, respectively). Analysis of the receiver operating characteristic curve revealed that the cutoff value to exclude significant CAD on CCTA was 29.0 mL/m2 for LAVI (NPV 80.8%) and -18.1% for GLS (NPV 80.7%). The NPV increased to 95.0% when these parameters were combined (LAVI < 29.0 mL/m2 and GLS < -18.1%). CONCLUSION: The combination of resting LAVI and GLS was clinically useful in excluding significant CAD via CCTA.

Fall risk assessment dataset: older-adult participants undergoing the time up and go test.

This article presents a dataset comprising signal data collected from Inertial Measurement Unit (IMU) sensors during the administration of the Time Up and Go (TUG) test for assessing fall risk in older adults. The dataset is divided into two main sections. The first section contains personal, behavioral, and health-related data from 34 participants. The second section contains signal data from tri-axial acceleration and tri-axial gyroscope sensors embedded in an IMU sensor, which was affixed to the participants' waist area to capture signal data while they walked. The chosen assessment method for fall risk analysis is the TUG test, requiring participants to walk a 3-meter distance back and forth. To prepare the dataset for subsequent analysis, the raw signal data underwent processing to extract only the walking periods during the TUG test. Additionally, a low-pass filter technique was employed to reduce noise interference. This dataset holds the potential for the development of effective models for fall risk detection based on insights garnered from questionnaires administered to specialists who observed the experiments. The dataset also contains anonymized participant information that can be explored to investigate fall risk, along with other health-related conditions or behaviors that could influence the risk of falling. This information is invaluable for devising tailored treatment or rehabilitation plans for individual older adults. The complete dataset is accessible through the Mendeley repository."

Five-year (2015-2019) follow-up study of 6,526 cases of medical repatriation of Filipino seafarers.

BACKGROUND: There is a limited number of studies on the medical repatriation of seafarers. The aim of the study was to follow up on the previous 2010-2014 study using data from 2015-2019 to evaluate the epidemiology of medical repatriation among Filipino seafarers. MATERIALS AND METHODS: Data from medical repatriation records of Filipino seafarers from January 2015 to December 2019 were collected from various claims departments of different manning agencies in Manila, Philippines. RESULTS: Data from a total of 6,526 medical repatriation cases and 464,418 deployments in a 5-year period resulted in a medical repatriation rate calculated at 1.4%. We used the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to determine the most common causes of repatriation. We found that these were musculoskeletal disorders, gastrointestinal problems, and traumatic injuries. The distribution of the specific illnesses per organ system is presented. CONCLUSIONS: Filipinos continue to represent the most numerous group of seafarers in the world. The continued profiling of health issues should lead to better health protocols and controlling medical costs. It should also lead to better prioritisation of health protection and care on board ships. Within the present 10-year database of medical repatriations coinciding with the implementation of Maritime Convention Labour Convention 2006, there is a compelling need to compare the two data sets to have an objective evaluation of the convention's projected goals.

HaloTag display enables quantitative single-particle characterization and functionalization of engineered extracellular vesicles.

Extracellular vesicles (EVs) play key roles in diverse biological processes, transport biomolecules between cells, and have been engineered for therapeutic applications. A useful EV bioengineering strategy is to express engineered proteins on the EV surface to confer targeting, bioactivity, and other properties. Measuring how incorporation varies across a population of EVs is important for characterizing such materials and understanding their function, yet it remains challenging to quantitatively characterize the absolute number of engineered proteins incorporated at single-EV resolution. To address these needs, we developed a HaloTag-based characterization platform in which dyes or other synthetic species can be covalently and stoichiometrically attached to engineered proteins on the EV surface. To evaluate this system, we employed several orthogonal quantification methods, including flow cytometry and fluorescence microscopy, and found that HaloTag-mediated quantification is generally robust across EV analysis methods. We compared HaloTag-labeling to antibody-labeling of EVs using single vesicle flow cytometry, enabling us to quantify the substantial degree to which antibody labeling can underestimate the absolute number of proteins present on an EV. Finally, we demonstrate use of HaloTag to compare between protein designs for EV bioengineering. Overall, the HaloTag system is a useful EV characterization tool which complements and expands existing methods.

Sector-Based Regression Strategies to Reduce Refractive Error-Associated Glaucoma Diagnostic Bias When Using OCT and OCT Angiography.

Purpose: This cross-sectional study aimed to investigate the sectoral variance of optical coherence tomography (OCT) and OCT angiography (OCTA) glaucoma diagnostic parameters across eyes with varying degrees of refractive error. Methods: Healthy participants, including individuals with axial ametropia, enrolled in the Hong Kong FAMILY cohort were imaged using the Avanti/AngioVue OCT/OCTA system. The OCT and OCTA parameters obtained include peripapillary nerve fiber layer thickness (NFLT), peripapillary nerve fiber layer plexus capillary density (NFLP-CD), and macular ganglion cell complex thickness (GCCT). Sectoral measurements of NFLT, NFLP-CD, and GCCT were based on sectors and hemispheres. Results: A total of 1339 eyes from 791 participants were stratified based on spherical equivalent refraction: high myopia (<-6 D), low myopia (-6 D to -1 D), emmetropia (-1 D to 1 D), and hyperopia (>1 D). Multivariable broken stick regression models, accounting for age, sex, and signal strength, showed that all NFLT sectors except temporally, the inferior GCCT hemisphere, and half of the NFLP-CD sectors were more affected by ametropia-related covariates than the corresponding global parameters. As expected, the false-positive rates in those sectors were elevated. Finally, sector-specific axial length (AL) and spherical equivalent (SE) adjustments helped reduce the elevated false-positive rates. Conclusions: The effect of optical magnification is even more prominent among sectors than the global parameters. AL- and SE-based adjustments should be individualized to each sector to mitigate this magnification bias effectively. Translational Relevance: Identifying sectoral differences among diagnostic parameters and adopting these sector-based adjustments into commercial OCT systems will hopefully reduce false-positive rates related to refractive error.

Genetic testing practices among specialist physicians who treat prostate cancer A Canadian, cross-sectional survey.

INTRODUCTION: In patients with prostate cancer (PCa), the identification of an alteration in genes associated with homologous recombination repair (HRR) has implications for prognostication, optimization of therapy, and familial risk mitigation. The aim of this study was to assess the genomic testing landscape of PCa in Canada and to recommend an approach to offering germline and tumor testing for HRR-associated genes. METHODS: The Canadian Genitourinary Research Consortium (GURC) administered a cross-sectional survey to a largely academic, multidisciplinary group of investigators across 22 GURC sites between January and June 2022. RESULTS: Thirty-eight investigators from all 22 sites responded to the survey. Germline genetic testing was initiated by 34%, while 45% required a referral to a genetic specialist. Most investigators (82%) reported that both germline and tumor testing were needed, with 92% currently offering germline and 72% offering tissue testing to patients with advanced PCa. The most cited reasons for not offering testing were an access gap (50%), uncertainties around who to test and which genes to test, (33%) and interpreting results (17%). A majority reported that patients with advanced PCa (74-80%) should be tested, with few investigators testing patients with localized disease except when there is a family history of PCa (45-55%). CONCLUSIONS: Canadian physicians with academic subspecialist backgrounds in genitourinary malignancies recognize the benefits of both germline and somatic testing in PCa; however, there are challenges in accessing testing across practices and specialties. An algorithm to reduce uncertainty for providers when ordering genetic testing for patients with PCa is proposed.

Assessment and diagnosis of right ventricular failure-retrospection and future directions.

The right ventricle (RV) has a critical role in hemodynamics and right ventricular failure (RVF) often leads to poor clinical outcome. Despite the clinical importance of RVF, its definition and recognition currently rely on patients' symptoms and signs, rather than on objective parameters from quantifying RV dimensions and function. A key challenge is the geometrical complexity of the RV, which often makes it difficult to assess RV function accurately. There are several assessment modalities currently utilized in the clinical settings. Each diagnostic investigation has both advantages and limitations according to its characteristics. The purpose of this review is to reflect on the current diagnostic tools, consider the potential technological advancements and propose how to improve the assessment of right ventricular failure. Advanced technique such as automatic evaluation with artificial intelligence and 3-dimensional assessment for the complex RV structure has a potential to improve RV assessment by increasing accuracy and reproducibility of the measurements. Further, noninvasive assessments for RV-pulmonary artery coupling and right and left ventricular interaction are also warranted to overcome the load-related limitations for the accurate evaluation of RV contractile function. Future studies to cross-validate the advanced technologies in various populations are required.

Unsupervised Deep Tensor Network for Hyperspectral-Multispectral Image Fusion.

Fusing low-resolution (LR) hyperspectral images (HSIs) with high-resolution (HR) multispectral images (MSIs) is a significant technology to enhance the resolution of HSIs. Despite the encouraging results from deep learning (DL) in HSI-MSI fusion, there are still some issues. First, the HSI is a multidimensional signal, and the representability of current DL networks for multidimensional features has not been thoroughly investigated. Second, most DL HSI-MSI fusion networks need HR HSI ground truth for training, but it is often unavailable in reality. In this study, we integrate tensor theory with DL and propose an unsupervised deep tensor network (UDTN) for HSI-MSI fusion. We first propose a tensor filtering layer prototype and further build a coupled tensor filtering module. It jointly represents the LR HSI and HR MSI as several features revealing the principal components of spectral and spatial modes and a sharing code tensor describing the interaction among different modes. Specifically, the features on different modes are represented by the learnable filters of tensor filtering layers, the sharing code tensor is learned by a projection module, in which a co-attention is proposed to encode the LR HSI and HR MSI and then project them onto the sharing code tensor. The coupled tensor filtering module and projection module are jointly trained from the LR HSI and HR MSI in an unsupervised and end-to-end way. The latent HR HSI is inferred with the sharing code tensor, the features on spatial modes of HR MSIs, and the spectral mode of LR HSIs. Experiments on simulated and real remote-sensing datasets demonstrate the effectiveness of the proposed method.

Do temperature changes cause eczema flares? An English cohort study.

BACKGROUND: It is unclear if ambient temperature changes affect eczema. It is also unclear if people with worse disease are more susceptible to weather-related flares, or specific types of emollient offer protection. OBJECTIVES: To investigate the effect of short-term temperature variations on eczema symptoms in children. METHODS: Data from a UK cohort of 519 children with eczema were combined with data from the Hadley Centre's Integrated Surface Database. Hot and cold weeks were defined by average regional temperature > 75th or < 25th percentile, January 2018 to February 2020. Eczema flares were defined as ≥ 3-point change in Patient-Oriented Eczema Measure (POEM). Random-effects logistic regression models were used to estimate the odds ratios of flares in hot and cold weeks (reference group: temperate weeks). RESULTS: The baseline mean age was 4.9 years (SD 3.2) and the POEM score was 9.2 (SD 5.5). From the 519 participants, there were 6796 consecutively paired POEMs and 1082 flares. Seasonal variation in POEM scores was observed, suggesting symptoms worsening in winter and improving in summer. Odds ratios of flares were: 1.15 [95% confidence interval (CI) 0.96-1.39, P = 0.14] in cold weeks and 0.85 (95% CI 0.72-1.00, P = 0.05) in hot weeks. The likelihood ratio test showed no evidence of this differing by disease severity (P = 0.53) or emollient type used (P = 0.55). CONCLUSIONS: Our findings are consistent with previous studies demonstrating either improvements in eczema symptoms or reduced flares in hot weather. Worse disease and different emollient types did not increase susceptibility or provide protection against temperature changes. Further work should investigate the role of sunlight, humidity, pollution and other environmental factors.

The Dating Metaverse: Why We Need to Design for Consent in Social VR.

This paper presents a participatory design study about how consent to interaction and observation of other users can be supported in social VR. We use emerging VR dating applications, colloquially called the dating metaverse, as context for study of harm-mitigative design structures in social VR given the evidence of harms that occur through dating apps and general social VR applications individually, and the harms that may occur through their convergence. Through design workshops with potential dating metaverse users in the Midwest United States (n=18) we elucidate nonconsensual experiences that should be prevented and participant-created designs for informing and exchanging consent in VR. We position consent as a valuable lens for which to design preventative solutions to harm in social VR by reframing harm as unwanted experiences that happen because of the absence of mechanics to support users in giving and denying agreement to a virtual experience before it occurs.

Donor heart ischemic time can be extended beyond 9 hours using hypothermic machine perfusion in sheep.

BACKGROUND: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD. METHODS: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP. RESULTS: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups. CONCLUSIONS: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation.