Safety, tolerability, and immunogenicity of an adult pneumococcal conjugate vaccine, V116 (STRIDE-3): a randomised, double-blind, active comparator controlled, international phase 3 trial.

BACKGROUND: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. METHODS: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). FINDINGS: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. INTERPRETATION: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. FUNDING: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

Review: Flow Diversion for the Treatment of Middle Cerebral Artery Aneurysms.

The invention of flow diverting stents (FDS) is a novel milestone in the field of endovascular aneurysm therapy, promoting physiological healing of the vessel segment contrary to prior deconstructive treatment strategies, such as coiling. The effects of FDS are based on changes in flow patterns, segmental wall stabilization, and the growth of a neointima. Although flow diversion is already well established for cerebral aneurysms in proximal segments, peripheral locations remain challenging. Especially the middle cerebral artery (MCA) with its predominance of non-collateralized perforators and functional end arteries that supply the eloquent areas of the brain is of major concern.The literature was reviewed for flow diversion of the MCA and antiplatelet therapy.Resulting from the special anatomical characteristics of the MCA, FDS implantation in this territory is completely different from the proximal vessel segments. Still, flow diversion represents an effective endovascular strategy, especially in otherwise non-accessible or sufficiently treatable lesions. However, the risk of ischemic adverse events might be increased. Special attention to the individual decision regarding device selection, antiplatelet regimen, and exact definition of the proximal and distal landing zone considering the jailed side branches is essential for a good angiographic and clinical outcome. · MCA aneurysms can be sufficiently treated by FDS.. · The anatomic and hemodynamic characteristics of the MCA result in an increased risk of thromboembolism.. · Individual device selection and antiplatelet regimen are essential for treatment success.. · Schüngel M, Wohlgemuth WA, Elolf E et al. Review: Flow Diversion for the Treatment of Middle Cerebral Artery Aneurysms. Fortschr Röntgenstr 2024; DOI 10.1055/a-2343-0046.

Premenopausal bilateral oophorectomy and brain white matter brain integrity in later-life.

INTRODUCTION: Premenopausal bilateral oophorectomy (PBO) is associated with later-life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity. METHODS: Female participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40-45 years; 39 with PBO 46-49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype. RESULTS: Females with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity. DISCUSSION: Females who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later-life. These results are important for females considering PBO for noncancerous conditions. HIGHLIGHTS: Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents. Females with PBO < 40 years had higher MD in many regions versus referents. Adjusting for estrogen replacement therapy use did not attenuate results. Females with PBO 45-49 years also had some white matter changes versus referents.

Longitudinal associations of reproductive factors and exogeneous estrogens with neuroimaging biomarkers of Alzheimer's disease and cerebrovascular disease.

INTRODUCTION: Female-specific reproductive factors and exogeneous estrogen use are associated with cognition in later life. However, the underlying mechanisms are not understood. The present study aimed to investigate the effect of reproductive factors on neuroimaging biomarkers of Alzheimer's disease (AD) and cerebrovascular pathologies. METHODS: We evaluated 389 females (median age of 71.7 years) enrolled in the Mayo Clinic Study of Aging with reproductive history data and longitudinal magnetic resonance imaging (MRI) scans. We used linear mixed effect models to examine the associations between reproductive factors and changes in neuroimaging measures. RESULTS: Ever hormonal contraception (HC) use was longitudinally associated with higher fractional anisotropy across the corpus callosum, lower white matter hyperintensity (WMH) volume, and greater cortical thickness in an AD meta-region of interest (ROI). The initiation of menopausal hormone therapy (MHT) > 5 years post menopause was associated with higher WMH volume. DISCUSSION: HC use and initiation of MHT >5 years post menopause were generally associated with neuroimaging biomarkers of cerebrovascular pathologies. HIGHLIGHTS: Hormonal contraception use was associated with better brain white matter (WM) integrity. Initiation of menopausal hormone therapy >5 years post menopause was associated with worsening brain WM integrity. Hormonal contraception use was associated with greater cortical thickness. Ages at menarche and menopause and number of pregnancies were not associated with imaging measures. There were few associations between reproductive factors or exogenous estrogens and amyloid or tau PET.

Epoxiconazole degradation in water samples: a comparative study of Fenton, photo-Fenton, solar photo-Fenton, and solar photolysis processes.

Epoxiconazole (EPO) is classified as a persistent organic pollutant due to its ability to persist in the environment for prolonged periods. Its degradation is pivotal in mitigating its environmental impact. This investigation focuses on assessing the degradation of EPO using various methodologies, namely Fenton, photo-Fenton, solar photo-Fenton, and solar photolysis, conducted in both Milli-Q water and groundwater. These experiments encompassed evaluations at both the standard pH typically used in photo-Fenton reactions and the natural pH levels inherent to the respective aqueous environments. Additionally, EPO degradation products were analyzed after a 60-min reaction. Notably, in systems utilizing groundwater, the inclusion of additional iron was unnecessary, as the naturally occurring iron content in the groundwater facilitated the intended processes. Specifically, in Milli-Q water, solar photo-Fenton demonstrated an EPO degradation efficiency of 97%. Furthermore, the substitution of Milli-Q water with groundwater in Fenton-like processes did not significantly affect the efficacy of EPO degradation. These findings underscore the potential of solar photo-Fenton as an economically viable and environmentally sustainable strategy for EPO degradation.

Tethered Alkylammonium Dications as Electrochemical Interface Modifiers: Chain Length Effect on CO2 Reduction Selectivity at Industry-Relevant Current Density.

The electrochemical reduction of CO2 (CO2RR) has the potential to be an economically viable method to produce platform chemicals synergistically with renewable energy sources. Copper is one of the most commonly used electrocatalysts for this purpose, as it allows C-C bond formation, yielding a broad product distribution. Controlling selectivity is a stepping stone on the way to its industrial application. The kinetics of the reaction can be modified to favor the rates of certain products quickly and inexpensively by applying additives such as ionic liquids and coelectrolytes that directly affect the electrocatalytic interface. In this work, we propose tethered tetraalkylammonium salts as double-charged cationic modifiers of the electrochemical double layer to control CO2RR product selectivity. A novel setup comprising a gas diffusion electrode (GDE) flow cell coupled with real-time mass spectroscopy was used to study the effect of a library of the selected salts. We emphasize how the length of an alkyl linker effectively controls the selectivity of the reaction toward C1, C2, or C3 products at high relevant current densities (Jtotal = -400 mA cm-2) along with the inhibition of the parasitic hydrogen evolution reaction. Standard long-term experiments were performed for quantitative validation and stability evaluation. These results have broad implications for further tailoring an effective catalytic system for selective CO2 reduction reaction.

Assessment of hydraulic and thermal properties of the Antarctic active layer: Insights from laboratory column experiments and inverse modeling.

To better understand the changes in the hydrologic cycle caused by global warming in Antarctica, it is crucial to improve our understanding of the groundwater flow system, which has received less attention despite its significance. Both hydraulic and thermal properties of the active layer, through which groundwater can flow during thawing seasons, are essential to quantify the groundwater flow system. However, there has been insufficient information on the Antarctic active layer. The goal of this study was to estimate the hydraulic and thermal properties of Antarctic soils through laboratory column experiments and inverse modeling. The column experiments were conducted with sediments collected from two lakes in the Barton Peninsula, Antarctica. A sand column was also operated for comparison. Inverse modeling using HydroGeoSphere (HGS) combined with Parameter ESTimation (PEST) was performed with data collected from the column experiments, including permeameter tests, saturation-drain tests, and freeze-thaw tests. Hydraulic parameters (i.e., Ks, θs, Swr, α, ß, and Ss) and thermal diffusivity (D) of the soils were derived from water retention curves and temperature curves with depth, respectively. The hydraulic properties of the Antarctic soil samples, estimated through inverse modeling, were 1.6 × 10-5-3.4 × 10-4 cm s-1 for Ks, 0.37-0.42 for θs, 6.62 × 10-3-1.05 × 10-2 for Swr, 0.53-0.58 cm-1 for α, 5.75-7.96 for ß, and 5.11 × 10-5-9.02 × 10-5 cm-1 for Ss. The thermal diffusivities for the soils were estimated to be 0.65-4.64 cm2 min-1. The soil hydraulic and thermal properties reflected the physical and ecological characteristics of their lake environments. The results of this study can provide a basis for groundwater-surface water interaction in polar regions, which is governed by variably-saturated flow and freeze-thaw processes.

Initial Hemorrhage Control Procedure for Splenic Injuries May Affect Risk of Venous Thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE) continues to be a major cause of morbidity in trauma. It is unclear whether the type of hemorrhage control procedure (i.e., splenectomy versus angioembolization) is associated with an increased risk of VTE. We hypothesize that hemodynamically stable patients undergoing angioembolization for blunt high-grade splenic injuries have lower rates of VTE compared to those undergoing splenectomy. METHODS: The American College of Surgeons Trauma Quality Program dataset from 2017 to 2019 was queried to identify all patients with American Association for the Surgery of Trauma grade 3-5 blunt splenic injuries. Outcomes including VTE rates were compared between those who were managed with splenectomy versus angioembolization. Propensity score matching (1:1) was performed adjusting for age, sex, initial vital signs, Injury Severity Score, and splenic injury grade. RESULTS: The analysis included 4698 matched patients (splenectomy [n = 2349] and angioembolization [n = 2349]). The median (interquartile range) age was 41 (27-58) years and 69% were male. Patients were well matched between groups. Angioembolization was associated with significantly lower VTE than splenectomy (2.2% versus 3.4%, P = 0.010) despite less use of VTE chemoprophylaxis (70% versus 80%, P < 0.001), as well as a relative delay in initiation of chemoprophylaxis (44 h versus 33 h, P < 0.001). Hospital and intensive care unit length of stay and mortality were also significantly lower in the angioembolization group. CONCLUSIONS: Angioembolization is associated with a significantly lower incidence of VTE than splenectomy. Thus, angioembolization should be considered for initial management of hemodynamically stable patients with high-grade blunt splenic injuries in whom laparotomy is not otherwise indicated.

Long-term weight loss of distal gastric bypass is moderately superior compared to proximal gastric bypass in patients with a BMI of 37-44 Kg/m2.

PURPOSE: The laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the standard procedures in metabolic surgery. Different limb lengths have been proposed in the past to maximize weight loss (WL) and reduce metabolic complications. Distal gastric bypass surgery with a very short common channel (CC) (up to 100 cm) has been often criticized due to frequent side effects such as malnutrition, bone weakening and short-bowel syndrome. We introduced a modified version of a distal LRYGB with a 50-70 cm long biliopancreatic limb (BPL) and an intermediate short CC (120-150 cm). Our primary goal was to compare the long-term WL between distal and proximal LRYGB in two cohorts of patients. Secondary outcomes were weight regain (WR), insufficient weight loss (IWL), postoperative complications and metabolic changes 5 years after surgery. METHODS: In this retrospective study we collected data from 160 patients operated between 2014 and 2015, with a BMI of 37-44 Kg/m2. 101 patients underwent a distal and 59 patients a proximal LRYGB in two bariatric centers. WL was calculated as percent of excess of BMI loss (%EBMIL), loss of body mass index (Delta-BMI), percent of excess weight loss (%EWL) and percent of total weight loss (%TWL). Data were collected 3, 6, 9, 12, 24, 48 and 60 months after surgery. RESULTS: The distal LRYGB resulted in significantly better 5-year-WL compared to the proximal bypass in terms of %EBMIL (median at 5 years: 83% vs. 65%, p = 0.001), %TWL (median at 5 years: 32% vs. 26%, p = 0.017) and %EWL (median at 5 years: 65% vs. 51%, p = 0.029), with equal major complications and metabolic alterations. In addition, WR was significantly lower in patients with distal bypass (18% vs. 35%, p = 0.032). CONCLUSIONS: Distal LYRGB with a 120-150 long CC results in better WL and WL-maintenance compared to proximal LRYGB without major side effects after five years.

Mental Health Support Is an Unmet Need for Long-Term Burn Survivors: A Web-Based Survey.

A National Trauma Research Action Plan identified the involvement of burn survivors as critical informants to determine the direction of research. This study employed a web-based survey to identify care gaps in a sample of burn survivors. We surveyed burn survivors from around the United States through social media and email contact with the Phoenix Society for Burn Survivors. We elicited demographic info, burn history, and unmet needs. Statistical analysis was performed to test our hypothesis that lack of access to mental health support/professionals would be identified as an unmet need in long-term burn survivors. Of 178 survey respondents, most were at least ten years removed from the date of their burn injury (n=94, 53%). Compared to those less than 3 years from their burn injury, individuals greater than 10 years were at least 5 times more likely to note lack of access to mental health support [11-20 years OR 8.7, p< 0.001; >20 years OR5.7, p=0.001]. 60% of Spanish speakers reported lack of support group access was among their greatest unmet needs, compared to 37% of English speakers (p=0.184). This study highlights the need for ongoing access to mental health resources in burn survivors. Our findings emphasize that burn injury is not just an acute ailment, but a complex condition that evolves into a chronic disease. Additional studies should focus on the experiences of Spanish-speaking burn survivors, given small sample size leading to a likely clinically significant but not statistically different lack of access to support groups.

Proteomic profiling for biomarker discovery in heparin-induced thrombocytopenia.

ABSTRACT: New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n = 32; HIT ruled out, n = 38; and positive heparin/platelet factor 4 [H/PF4] antibodies, n = 28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using enzyme-linked immunosorbent assay (ELISA) in above mentioned patients and an additional second data set (n = 49). HIT was defined as a positive heparin-induced platelet activation assay (washed platelet assay). Among 98 patients of the primary data set, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive H/PF4 antibodies, and 3 in patients without HIT. The median optical density of a polyspecific H/PF4 ELISA were 3.0, 0.9, and 0.3. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver operating characteristic curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT.

Risks and benefits of hormone therapy after menopause for cognitive decline and dementia: A conceptual review.

OBJECTIVE: The effects on the brain of hormone therapy after the onset of menopause remain uncertain. The effects may be beneficial, neutral, or harmful. We provide a conceptual review of the evidence. METHODS: We 1) provide a brief history of the evidence, 2) discuss some of the interpretations of the evidence, 3) discuss the importance of age at menopause, type of menopause, and presence of vasomotor symptoms, and 4) provide some clinical recommendations. RESULTS: The evidence and the beliefs about hormone therapy and dementia have changed over the last 30 years or more. Five recent observation studies suggested that hormone therapy is associated with an increased risk of dementia, and the association appears not to change with the timing of initiation of therapy. These harmful associations may be explained by a causal effect of hormone therapy on the brain or by several confounding mechanisms. We suggest that the use of hormone therapy should be customized for different subgroups of women. It may be important to subgroup women based on age at onset of menopause, type of menopause, and presence or absence of vasomotor symptoms. In addition, the effects may vary by type, dose, route, and duration of administration of estrogens and by the concurrent use of progestogens. DISCUSSION: The relation of hormone therapy with the risk of dementia is complex. Hormone therapy may have beneficial, neutral, or harmful effects on the brain. Hormone therapy should be guided by the clinical characteristics of the women being treated.

Identification of differentially expressed genes and splicing events in early-onset colorectal cancer.

Background: The incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, < 50 years old) patients versus later-onset colorectal cancer (LOCRC, > 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC. Methods: We performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients. The EOCRC and LOCRC cohorts were matched for demographic and clinical characteristics. We used The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database for validation. We used a series of computational and bioinformatic tools to identify EOCRC-specific differentially expressed genes, molecular pathways, predicted cell populations, differential gene splicing events, and predicted neoantigens. Results: We identified an eight-gene signature in EOCRC comprised of ALDOB, FBXL16, IL1RN, MSLN, RAC3, SLC38A11, WBSCR27 and WNT11, from which we developed a score predictive of overall CRC patient survival. On the entire set of genes identified in normal tissues and tumors, cell type deconvolution analysis predicted a differential abundance of immune and non-immune populations in EOCRC versus LOCRC. Gene set enrichment analysis identified increased expression of splicing machinery in EOCRC. We further found differences in alternative splicing (AS) events, including one within the long non-coding RNA, HOTAIRM1. Additional analysis of AS found seven events specific to EOCRC that encode potential neoantigens. Conclusion: Our transcriptome analyses identified genetic and molecular features specific to EOCRC which may inform future screening, development of prognostic indicators, and novel drug targets.

Reevaluating the FDA's warning against the use of probiotics in preterm neonates: A societal statement by ESPGHAN and EFCNI.

The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.

Outcome of bleomycin electrosclerotherapy of slow-flow malformations in adults and children.

OBJECTIVES: To evaluate the safety and clinical outcome of bleomycin electrosclerotherapy (BEST) for treating extracranial slow-flow malformations. METHODS: In this retrospective investigation of a multicenter cohort presenting symptomatic slow-flow malformations, patient records were analyzed with respect to procedural details and complications. A treatment-specific, patient-reported questionnaire was additionally evaluated, obtained 3-12 months after the last treatment, to assess the subjective outcomes, including mobility, aesthetic aspects, and pain, as well as the occurrence of postprocedural skin hyperpigmentation. All outcome parameters were compared according to patients' age. RESULTS: Overall, 325 BEST treatments were performed in 233 patients after intralesional and/or intravenous bleomycin injection. The total complication rate was 10.2% (33/325), including 29/352 (8.9%) major complications. Patient-reported mobility decreased in 10/133 (8.8%), was stable in 30/113 (26.5%), improved in 48/113 (42.5%), and was rated symptom-free in 25/113 (22.1%) patients. Aesthetic aspects were rated impaired compared to baseline in 19/113 (16.8%), stable in 21/133 (18.6%), improved in 62/113 (54.9%), and perfect in 11/133 (9.7%) patients. Postprocedural skin hyperpigmentation occurred in 78/113 (69%) patients, remaining unchanged in 24/78 (30.8%), reduced in 51/78 (65.5%), and completely resolved in 3/78 (3.8%) patients. The median VAS pain scale was 4.0 (0-10) preprocedural and 2.0 (0-9) postprocedural. Children/adolescents performed significantly better in all parameters compared to adults (≥ 16 years) (mobility, p = 0.011; aesthetic aspects, p < 0.001; pain, p < 0.001). CONCLUSIONS: BEST is effective for treating slow-flow vascular malformations, with few but potentially significant major complications. Regarding patient-reported outcomes, children seem to benefit better compared to older patients, suggesting that BEST should not be restricted to adults. CLINICAL RELEVANCE STATEMENT: Bleomycin electrosclerotherapy is a safe and effective approach and therapy should not be restricted to adults due to good clinical outcomes in children.

Survival of In-Hospital Cardiopulmonary Arrest in Trauma Patients.

INTRODUCTION: Relative to other hospitalized patients, trauma patients are younger with fewer comorbidities, but the incidence and outcomes of in-hospital cardiopulmonary arrest (IHCA) with cardiopulmonary resuscitation (CPR) in this population is unknown. Therefore, we aimed to investigate factors associated with survival in trauma patients after IHCA to test the hypothesis that compared to other hospitalized patients, trauma patients with IHCA have improved survival. METHODS: Retrospective review of the Trauma Quality Improvement Program database 2017 to 2019 for patients who had IHCA with CPR. Primary outcome was survival to hospital discharge. Secondary outcomes were in-hospital complications, hospital length of stay, intensive care unit length of stay, and ventilator days. Data were compared with univariate and multivariate analyses at P < 0.05. RESULTS: In 22,346,677 admitted trauma patients, 14,056 (0.6%) received CPR. Four thousand three hundred seventy-seven (31.1%) survived to discharge versus 26.4% in a national sample of all hospitalized patients (P < 0.001). In trauma patients, median age was 55 y, the majority were male (72.2%). Mortality was higher for females versus males (70.3% versus 68.3%, P = 0.026). Multivariate regression showed that older age 1.01 (95% confidence interval (CI) 1.01-1.02), Hispanic ethnicity 1.21 (95% CI 1.04-1.40), and penetrating trauma 1.51 (95% CI 1.32-1.72) were risk factors for mortality, while White race was a protective factor 0.36 (95% CI 0.14-0.89). CONCLUSIONS: This is the first study to show that the incidence of IHCA with CPR is approximately six in 1000 trauma admissions and 31% survive to hospital discharge, which is higher than other hospitalized patients. Age, gender, racial, and ethnic disparities also influence survival.

Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations.

BACKGROUND: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification. METHODS AND RESULTS: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19). CONCLUSIONS: This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.