"Symptomatic" melanoma brain metastases: A call for clear definitions and adoption of standardized tools.

With improved systemic treatment and prolonged survival even with metastatic disease, diagnosing, treating, and monitoring brain metastases has become a central topic in the care of patients with melanoma. Patients with brain metastases from melanoma are typically excluded from pivotal clinical trials. When allowed, inclusion and exclusion criteria are rather selective and do not reflect the larger population of melanoma patients with brain metastases who frequently present with neurological symptoms and signs and require steroid medications. Moreover, the lack of consensus on reporting symptomatic brain involvement complicates the interpretation and implications of trial results for the overall population of patients with melanoma and brain metastasis. Here, we review the evidence regarding brain metastasis from melanoma and discuss the challenges of longitudinal neurological clinical assessments, including tools to capture cognition and quality of life. Finally, we propose the adoption of standardized tools to interpret neurological deficits in patients with melanoma and brain metastases and to assess the neurological status in the context of clinical trials.

Deployment and validation of the CLL treatment infection model adjoined to an EHR system.

Research algorithms are seldom externally validated or integrated into clinical practice, leaving unknown challenges in deployment. In such efforts, one needs to address challenges related to data harmonization, the performance of an algorithm in unforeseen missingness, automation and monitoring of predictions, and legal frameworks. We here describe the deployment of a high-dimensional data-driven decision support model into an EHR and derive practical guidelines informed by this deployment that includes the necessary processes, stakeholders and design requirements for a successful deployment. For this, we describe our deployment of the chronic lymphocytic leukemia (CLL) treatment infection model (CLL-TIM) as a stand-alone platform adjoined to an EPIC-based Danish Electronic Health Record (EHR), with the presentation of personalized predictions in a clinical context. CLL-TIM is an 84-variable data-driven prognostic model utilizing 7-year medical patient records and predicts the 2-year risk composite outcome of infection and/or treatment post-CLL diagnosis. As an independent validation cohort for this deployment, we used a retrospective population-based cohort of patients diagnosed with CLL from 2018 onwards (n = 1480). Unexpectedly high levels of missingness for key CLL-TIM variables were exhibited upon deployment. High dimensionality, with the handling of missingness, and predictive confidence were critical design elements that enabled trustworthy predictions and thus serves as a priority for prognostic models seeking deployment in new EHRs. Our setup for deployment, including automation and monitoring into EHR that meets Medical Device Regulations, may be used as step-by-step guidelines for others aiming at designing and deploying research algorithms into clinical practice.

A mild phenotype associated with KCNQ1 p.V205M mediated long QT syndrome in First Nations children of Northern British Columbia: effect of additional variants and considerations for management.

Introduction: Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant KCNQ1 p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in KCNQ1 (p.L353L). The CPT1A p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort. Methods: As part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 children from birth to 18 years, with and without the KCNQ1 (p.V205M and p.L353L) and CPT1A variants, alone and in combination. Linear and logistic regression and student t-tests were applied as appropriate. Results: Only the KCNQ1 p.V205M variant conferred a significant increase in peak QTc 23.8 ms (p < 0.001) above baseline, with females increased by 30.1 ms (p < 0.001) and males by 18.9 ms (p < 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2-7.7]; p = 0.019). Conclusion: While the KCNQ1 p.V205M variant prolongs the peak QTc, especially in females, the CPT1A p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the KCNQ1 p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the CPT1A p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype.

Childhood and adolescence physical activity and multimorbidity later in life: A systematic review.

Background: No systematic summary exists on childhood physical activity and later-life multimorbidity risks. We primarily investigated the association of physical activity in childhood and adolescence and the development of multimorbidity in adulthood. Secondarily, we examined whether physical activity level differ in children and adolescents with and without multimorbidity and whether there is a cross-sectional association between physical activity and multimorbidity. Methods: Following Cochrane Handbook guidelines and adhering to PRISMA recommendations, we included cross-sectional, case-control and longitudinal studies that investigated the association between physical activity in children and adolescents and development of multimorbidity. Results were summarized narratively and we assessed the certainty of the evidence using the GRADE approach. The protocol was registered in PROSPERO, CRD42023407063. Results: Of 9064 studies identified, 11 were included in 13 papers. Longitudinals studies suggested that being physically active in childhood and adolescence was associated with a lower risk of multimorbidity in adulthood. Three out of five studies reported lower physical activity level in children and adolescents with multimorbidity compared to those without, and two did not find a between-group difference. Cross-sectional evidence on the association between multimorbidity and lower physical activity was uncertain. Overall, the evidence certainty for all outcomes was considered low due to the indirectness and inconsistency in findings. Conclusions: Childhood and adolescence physical activity appeared to be linked with a reduced risk of later-life multimorbidity but the certainty of the evidence is low. These results support the promotion of physical activity during childhood and adolescence.

Preventing hypothermia in pediatric neurosurgery in Africa-A randomized controlled non-inferiority trial of insulation versus active warming.

PURPOSE: The objective of this study was to compare the efficacy of a low-cost heat-preserving method in preventing intraoperative hypothermia with that of forced-air warming in a resource-limited setting. METHODS: In this randomized controlled non-inferiority trial, we recruited children younger than 12 years scheduled for cranial neurosurgery in a large East-African hospital. Patients were block-randomized by age to intraoperative warming measures using Hibler's method (intervention) or warm air (comparator). Hibler's group patients were circumferentially wrapped in transparent plastic sheeting (providing a vapor-trap) over a layer of cotton blankets, then laid on an insulating foam mattress. Warm air group patients were treated with forced-air convection via an underlying Snuggle Warm™ Pediatric Full Body mattress. Allocated warming measures were initiated in the operating theatre and discontinued upon anesthesia emergence. Perioperative temperatures were measured using noninvasive forehead probes (SpotOn™). The primary outcome was incidence of hypothermia (core temperature < 36.0° for longer than 5 min). Our null hypothesis was that Hibler's method is inferior in efficacy to the warm air method by a margin exceeding 20%. Among secondary outcomes were duration of hypothermia as proportion of surgical duration, incidence of postoperative shivering and rescue measure requirements. RESULTS: We analyzed data for 77 participants (Hibler's = 38; warm air = 39). There was no significant difference between the Hibler's and warm air arms of the study in the primary outcome of incidence of hypothermia (59.0% vs. 60.5% respectively; OR 1.07; 95% CI 0.43-2.65; p = .890). However, the risk difference (1.55%; 95% CI -0.20 to -0.24) exceeded the 0.2 margin and non-inferiority could not be declared. There was considerable need for rescue measures in both groups (71.1 0% vs. 69.2%; OR 1.09; 95% CI 0.41-2.90; p = .861). There was no statistically significant difference between groups for any prespecified secondary outcome. CONCLUSION: Although perioperative core temperatures were not significantly different, we could not declare an inexpensive heat-preserving method non-inferior to warm air convection in preventing intraoperative hypothermia in children undergoing anesthesia for cranial neurosurgery in a resource-limited setting. The extensive need for rescue measures may have masked important differences. TRIAL REGISTRATION: US National Institutes of Health Clinicaltrials.gov database (ID no. NCT02975817).

Monocyte recruitment in venous pulmonary embolism at time of cancer diagnosis in upper gastrointestinal cancer patients.

Upper gastrointestinal cancer is frequently complicated by venous thromboembolisms (VTE), especially pulmonary embolisms (PE) increase the mortality rate. Monocytes are a part of the innate immune system and up-regulation may indicate an ongoing inflammatory response or infectious disease and has lately been associated with a moderate risk of suffering from VTE. This prospectively study aims to compare the incidence of pulmonary embolism with markers of coagulation and compare it to the absolute monocyte count. A consecutive cohort of 250 patients with biopsy proven upper gastrointestinal cancer (i.e. pancreas, biliary tract, esophagus and gastric cancer) where included at the time of cancer diagnosis and before treatment. All patients underwent bilateral compression ultrasonography for detection of deep vein thrombosis (DVT). Of these 143 had an additionally pulmonary angiografi (CTPA) with the staging computer tomography. 13 of 250 patients (5.2%) had a DVT and 11 of 143 (7.7%) had CTPA proven PE. PE was significantly more common among patients with elevated D-dimer (OR 11.62, 95%CI: 1.13-119, P = 0.039) and elevated absolute monocyte count (OR 7.59, 95%CI: 1.37-41.98, P = 0.020). Only patients with pancreatic cancer had a significantly higher risk of DVT (OR 11.03, 95%CI: 1.25-97.43, P = 0.031). The sensitivity of absolute monocyte count was 63.6 (95%CI: 30.8-89.1) and specificity 80.3 (95%CI: 72.5-86.7), with a negative predictive value of 96.4 (95%CI: 91-99) in PE. An increased absolute monocyte count was detected in patients suffering from PE but not DVT, suggesting a possible interaction with the innate immune system.

The Impact of Chronic Disease on the Corrected QT (QTc) Value in Women in a British Columbia First Nations Population.

BACKGROUND: Indigenous women have higher rates of chronic disease than Indigenous men and non-Indigenous women. Long QT syndrome (LQTS) can be inherited or acquired; the latter may occur with chronic disease. A prolonged corrected QT value (QTc) is an independent risk factor for ventricular arrhythmias and sudden death, but few studies have quantified the impact of chronic disease on the QTc. We assessed the association between chronic disease and QTc prolongation in a population of First Nations women previously ascertained to study a high rate of inherited LQTS due to a unique genetic (founder) variant in their community. METHODS: This substudy focusing on women expands on the original research where patients with clinical features of LQTS and their relatives were assessed for genetic variants discovered to affect the QTc. Medical records were retrospectively reviewed and chronic diseases documented. Using multivariate linear regression, adjusting for the effect of genetic variants, age, and QTc-prolonging medications, we evaluated the association between chronic disease and the QTc. RESULTS: In total, 275 women were included. After adjustments, a prolonged QTc was associated with coronary artery disease (26.5 ms, 95% confidence interval [CI] 9.0-44.1 ms; P = 0.003), conduction system disease (26.8 ms, 95% CI 2.2-51.4 ms; P = 0.033), rheumatoid arthritis (28.9 ms, 95% CI 12.7-45.1 ms; P = 0.001), and type 2 diabetes mellitus (17.9 ms, 95% CI 3.6-32.3 ms; P = 0.015). CONCLUSIONS: This quantification of the association between chronic disease and QTc prolongation in an Indigenous cohort provides insight into the nongenetic determinants of QTc prolongation. Corroboration in other populations will provide evidence for generalisability of these results.

Superconducting transition edge bolometer for high-flux neutron detection.

Needs for neutron detection and monitoring in high neutron flux environments are increasing in several different fields. A completely solid-state, current mode bolometric detector is constructed as a solid substrate transition edge sensor based on a high-T[Formula: see text] superconducting meander. The detector consists of four individual pixels of which three pixels include [Formula: see text] neutron absorption layers. The absorbed energy per neutron absorption reaction is modelled and compared to experimental data. The response of the tested detector is directly correlated to a cold neutron beam with a flux of [Formula: see text] modulated by a slit. The signal is found to be an order of magnitude higher than the thermal background. The dynamics described by the temporal saturation constants is governed by a modulation frequency less than [Formula: see text]. The thermal response is dynamic and never fully saturates for [Formula: see text] exposures. The efficiency for this proof-of-principle design is 1-2%. Possibilities for optimization are identified, that will increase the efficiency to become comparable to existing solid boron-10 detectors. The existing detectors with event-based read-out have limited functionality in high flux environments. The superconducting bolometer described in this work using current-mode readout will pave the way for high flux applications.

The Neurological Pupil index for outcome prognostication in people with acute brain injury (ORANGE): a prospective, observational, multicentre cohort study.

BACKGROUND: Improving the prognostication of acute brain injury is a key element of critical care. Standard assessment includes pupillary light reactivity testing with a hand-held light source, but findings are interpreted subjectively; automated pupillometry might be more precise and reproducible. We aimed to assess the association of the Neurological Pupil index (NPi)-a quantitative measure of pupillary reactivity computed by automated pupillometry-with outcomes of patients with severe non-anoxic acute brain injury. METHODS: ORANGE is a multicentre, prospective, observational cohort study at 13 hospitals in eight countries in Europe and North America. Patients admitted to the intensive care unit after traumatic brain injury, aneurysmal subarachnoid haemorrhage, or intracerebral haemorrhage were eligible for the study. Patients underwent automated infrared pupillometry assessment every 4 h during the first 7 days after admission to compute NPi, with values ranging from 0 to 5 (with abnormal NPi being <3). The co-primary outcomes of the study were neurological outcome (assessed with the extended Glasgow Outcome Scale [GOSE]) and mortality at 6 months. We used logistic regression to model the association between NPi and poor neurological outcome (GOSE ≤4) at 6 months and Cox regression to model the relation of NPi with 6-month mortality. This study is registered with ClinicalTrials.gov, NCT04490005. FINDINGS: Between Nov 1, 2020, and May 3, 2022, 514 patients (224 with traumatic brain injury, 139 with aneurysmal subarachnoid haemorrhage, and 151 with intracerebral haemorrhage) were enrolled. The median age of patients was 61 years (IQR 46-71), and the median Glasgow Coma Scale score on admission was 8 (5-11). 40 071 NPi measurements were taken (median 40 per patient [20-50]). The 6-month outcome was assessed in 497 (97%) patients, of whom 160 (32%) patients died, and 241 (47%) patients had at least one recording of abnormal NPi, which was associated with poor neurological outcome (for each 10% increase in the frequency of abnormal NPi, adjusted odds ratio 1·42 [95% CI 1·27-1·64]; p<0·0001) and in-hospital mortality (adjusted hazard ratio 5·58 [95% CI 3·92-7·95]; p<0·0001). INTERPRETATION: NPi has clinically and statistically significant prognostic value for neurological outcome and mortality after acute brain injury. Simple, automatic, repeat automated pupillometry assessment could improve the continuous monitoring of disease progression and the dynamics of outcome prediction at the bedside. FUNDING: NeurOptics.

Quantitative Mapping of Chemical Defects at Charged Grain Boundaries in a Ferroelectric Oxide.

Polar discontinuities, as well as compositional and structural changes at oxide interfaces can give rise to a large variety of electronic and ionic phenomena. In contrast to earlier work focused on domain walls and epitaxial systems, this work investigates the relation between polar discontinuities and the local chemistry at grain boundaries in polycrystalline ferroelectric ErMnO3 . Using orientation mapping and scanning probe microscopy (SPM) techniques, the polycrystalline material is demonstrated to develop charged grain boundaries with enhanced electronic conductance. By performing atom probe tomography (APT) measurements, an enrichment of erbium and a depletion of oxygen at all grain boundaries are found. The observed compositional changes translate into a charge that exceeds possible polarization-driven effects, demonstrating that structural phenomena rather than electrostatics determine the local chemical composition and related changes in the electronic transport behavior. The study shows that the charged grain boundaries behave distinctly different from charged domain walls, giving additional opportunities for property engineering at polar oxide interfaces.

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC. METHODS: We performed methylation-specific PCR of the SFRP1 genes' promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions. RESULTS: The study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%-61.7%) and 19.8% (95% CI 1.9-37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-months CONCLUSIONS: This indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.

Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported. METHODS: We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses. RESULTS: Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher's exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined. CONCLUSIONS: This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.

European coastal monitoring programmes may fail to identify impacts on benthic macrofauna caused by bottom trawling.

Bottom trawling (hereafter trawling) is the dominant human pressure impacting continental shelves globally. However, due to ongoing data deficiencies for smaller coastal vessels, the effects of trawling on nearshore seabed ecosystems are poorly understood. In Europe, the Water Framework Directive (WFD) provides a framework for the protection and improvement of coastal water bodies. It requires member states to track the status of 'biological quality elements' (including benthic macrofauna) using WFD-specific ecological indicators. While many of these metrics are sensitive to coastal pressures such as nutrient enrichment, little is known about their ability to detect trawling impacts. Here, we analysed a comprehensive data set of 5885 nearshore benthic samples - spatiotemporally matched to high-resolution trawling and environmental data - to examine how these pressures affect coastal benthos. In addition, we investigated the ability of 8 widely-used benthic monitoring metrics to detect impacts on benthic biological quality. We found that abundance (N) and species richness (S) were strongly impacted by bottom trawling. A clear response to trawling was also observed for the WFD-specific Benthic Quality Index (BQI). Relationships between N and S, and trawling were particularly consistent across the study area, indicating sensitivity across varying environmental conditions. In contrast, WFD indices such as AZTIs Marine Biotic Index (AMBI), multivariate AMBI (M-AMBI), and the Danish Quality Index (DKI), were unresponsive to trawling. In fact, some of the most heavily trawled areas examined were classified as being of 'high/good ecological status' by these indices. A likely explanation for this is that the indices are calculated using species sensitivity scores, based on expected species response to eutrophication and chemical pollution. While the BQI also uses species sensitivity scores, these are based on observed responses to disturbance gradients comprising a range of coastal pressures. Given the prominent use of AMBI and DKI throughout Europe, our results highlight the considerable risk that the metrics used to assess Good Ecological Status (GES) under the WFD may fail to identify trawling impacts. As trawling represents a widespread source of coastal disturbance, fishing impacts on benthic macrofauna may be underestimated, or go undetected, in many coastal monitoring programmes around Europe.

Quantitative Mass Spectrometry Imaging of Bleomycin in Skin Using a Mimetic Tissue Model for Calibration.

The aim of Quantitative mass spectrometry imaging (Q-MSI) is to provide distribution analysis and quantitation from one single mass-spectrometry-based experiment, and several quantitation methods have been devised for Q-MSI. Mimetic tissue models based on spiked tissue homogenates are considered one of the most accurate ways to perform Q-MSI, since the analyte is present in a well-defined concentration in a sample matrix highly similar to the one of the unknown sample to be analyzed. The delivery of drugs in skin is among the most frequent types of pharmaceutical MSI studies. Here, a mimetic tissue model is extended for use on the skin, which, due to its high collagen content, is different from most other tissue as the homogenates become extremely viscous. A protocol is presented which overcomes this by the addition of water and the handling of the homogenate at an elevated temperature where the viscosity is lower. Using a mimetic tissue model, a method was developed for the quantitative imaging of bleomycin in skin. To compensate for the signal drift and the inhomogeneities in the skin, an internal standard was included in the method. The method was tested on skin from a pig which had had an electropneumatic injection of bleomycin into the skin. Quantification was made at several regions in a cross section of the skin at the injection site, and the results were compared to the results of a quantitative LC-MS on a neighboring tissue biopsy from the same animal experiment. The overall tissue concentration determined by the LC-MS was within the range of the different regions quantified by the Q-MSI. As the model provides the results of the same order of magnitude as a LC-MS, it can either be used to replace LC-MS in skin studies where MSI and LC-MS are today carried out in combination, or it can add quantitative information to skin studies which are otherwise carried out by MSI alone.

Small area disease mapping of cancer incidence in British Columbia using Bayesian spatial models and the smallareamapp R Package.

Introduction: There is an increasing interest in small area analyses in cancer surveillance; however, technical capacity is limited and accessible analytical approaches remain to be determined. This study demonstrates an accessible approach for small area cancer risk estimation using Bayesian hierarchical models and data visualization through the smallareamapp R package. Materials and methods: Incident lung (N = 26,448), female breast (N = 28,466), cervical (N = 1,478), and colorectal (N = 25,457) cancers diagnosed among British Columbia (BC) residents between 2011 and 2018 were obtained from the BC Cancer Registry. Indirect age-standardization was used to derive age-adjusted expected counts and standardized incidence ratios (SIRs) relative to provincial rates. Moran's I was used to assess the strength and direction of spatial autocorrelation. A modified Besag, York and Mollie model (BYM2) was used for model incidence counts to calculate posterior median relative risks (RR) by Community Health Service Areas (CHSA; N = 218), adjusting for spatial dependencies. Integrated Nested Laplace Approximation (INLA) was used for Bayesian model implementation. Areas with exceedance probabilities (above a threshold RR = 1.1) greater or equal to 80% were considered to have an elevated risk. The posterior median and 95% credible intervals (CrI) for the spatially structured effect were reported. Predictive posterior checks were conducted through predictive integral transformation values and observed versus fitted values. Results: The proportion of variance in the RR explained by a spatial effect ranged from 4.4% (male colorectal) to 19.2% (female breast). Lung cancer showed the greatest number of CHSAs with elevated risk (Nwomen = 50/218, Nmen = 44/218), representing 2357 total excess cases. The largest lung cancer RRs were 1.67 (95% CrI = 1.06-2.50; exceedance probability = 96%; cases = 13) among women and 2.49 (95% CrI = 2.14-2.88; exceedance probability = 100%; cases = 174) among men. Areas with small population sizes and extreme SIRs were generally smoothed towards the null (RR = 1.0). Discussion: We present a ready-to-use approach for small area cancer risk estimation and disease mapping using BYM2 and exceedance probabilities. We developed the smallareamapp R package, which provides a user-friendly interface through an R-Shiny application, for epidemiologists and surveillance experts to examine geographic variation in risk. These methods and tools can be used to estimate risk, generate hypotheses, and examine ecologic associations while adjusting for spatial dependency.

How low can you go? Air pollution affects mortality at very low levels.

The World Health Organization (WHO) recently released new guidelines for outdoor fine particulate air pollution (PM2.5) recommending an annual average concentration of 5 µg/m3. Yet, our understanding of the concentration-response relationship between outdoor PM2.5 and mortality in this range of near-background concentrations remains incomplete. To address this uncertainty, we conducted a population-based cohort study of 7.1 million adults in one of the world's lowest exposure environments. Our findings reveal a supralinear concentration-response relationship between outdoor PM2.5 and mortality at very low (<5 µg/m3) concentrations. Our updated global concentration-response function incorporating this new information suggests an additional 1.5 million deaths globally attributable to outdoor PM2.5 annually compared to previous estimates. The global health benefits of meeting the new WHO guideline for outdoor PM2.5 are greater than previously assumed and indicate a need for continued reductions in outdoor air pollution around the world.

Introduction to the special series, "The future of marine environmental monitoring and assessment".

Traditional marine monitoring can be a resource-intensive process that often covers a network of sampling stations where data are collected manually by divers, or discretely using in situ water samples at different depths at fixed positions followed by laboratory analysis. As such, environmental status is often reported after a delay of months or years. However, things are set to change for the better. Recent advances in technologies, such as remote sensing, machine learning techniques, modeling for non-experts, acoustic monitoring, and intelligent integration of modeling and sensor measurements will revolutionize the future of marine environmental monitoring and monitoring systems. This special series touches upon some of the new technologies and models that may be an integrated part of ecosystem assessment and management in the future. Although technologies are being developed and integrated for marine monitoring around the world, the integration with ecosystem models is still in the early days. Still, this series highlights inspirational examples of the time ahead of us. Integr Environ Assess Manag 2022;18:888-891. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Production of a monolithic fuel cell stack with high power density.

The transportation sector is undergoing a technology shift from internal combustion engines to electric motors powered by secondary Li-based batteries. However, the limited range and long charging times of Li-ion batteries still hinder widespread adoption. This aspect is particularly true in the case of heavy freight and long-range transportation, where solid oxide fuel cells (SOFCs) offer an attractive alternative as they can provide high-efficiency and flexible fuel choices. However, the SOFC technology is mainly used for stationary applications owing to the high operating temperature, low volumetric power density and specific power, and poor robustness towards thermal cycling and mechanical vibrations of conventional ceramic-based cells. Here, we present a metal-based monolithic fuel cell design to overcome these issues. Cost-effective and scalable manufacturing processes are employed for fabrication, and only a single heat treatment is required, as opposed to multiple thermal treatments in conventional SOFC production. The design is optimised through three-dimensional multiphysics modelling, nanoparticle infiltration, and corrosion-mitigating treatments. The monolithic fuel cell stack shows a power density of 5.6 kW/L, thus, demonstrating the potential of SOFC technology for transport applications.

A one-time pneumatic jet-injection of 5-fluorouracil and triamcinolone acetonide for treatment of hypertrophic scars-A blinded randomized controlled trial.

BACKGROUND: Patients with hypertrophic scars (HTS) risk reduced quality of life due to itching, pain, poor cosmesis, and restriction of movement. Despite good clinical efficacy, patients are often reluctant to undergo repeated needle injections due to pain or needle phobia. OBJECTIVES: To evaluate the applicability of needle-free pneumatic jet injection (PJI) and assess changes in hypertrophic scars following a single PJI treatment with 5-fluorouracil (5-FU) and triamcinolone acetonide (TAC). METHODS: Twenty patients completed this blinded, randomized, controlled, split-scar trial. The intervention side of the HTS received a one-time treatment with PJIs containing a mixture of TAC + 5-FU injected at 5 mm intervals (mean 7 PJI per HTS); the control side received no treatment. Assessments were made at baseline and 4 weeks posttreatment. Outcome measures included change in (1) Vancouver Scar Scale (VSS) total score and subscores, (2) scar volume and surface area assessed by three-dimensional imaging, (3) skin microarchitecture measured by optical-coherence tomography (OCT), (4) photo-assessed scar cosmesis (0-100), (5) patient-reported pain and satisfaction (0-10), and (6) depiction of drug biodistribution after PJI. RESULTS: PJI with TAC + 5-FU significantly decreased both HTS height (-1 VSS; p = 0.01) and pliability (-1 VSS; p < 0.01) with a nonstatistically significant reduction of -1 in total VSS score (0 in control; p = 0.09). On 3D imaging, a 33% decrease in scar volume (p = 0.016) and a 37% decrease in surface area (p = 0.008) was observed. OCT indicated trends towards smoother scar surface (Ra 11.1-10.3; p = 0.61), normalized dermal microarchitecture (attenuation coefficient: 1.52-1.68; p = 0.44), and a reduction in blood flow between 9% and 17% (p = 0.50-0.79). Despite advances in VSS subscores and OCT, no improved photo-assessed cosmesis was found (-3.2 treatment vs. -1.4 control; p = 0.265). Patient-reported pain was low (2/10) and 90% of the patients that had previously received needle injections preferred PJI to needle injection. Depositions of TAC + FU were imaged reaching deep into the scar at levels corresponding to the reticular dermis. CONCLUSION: A single PJI injection containing 5-FU and TAC can significantly improve the height and pliability of HTS. PJI is favored by the patients and may serve as a complement to conventional needle injections, especially for patients with needle phobia.