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Background: Physical activity prevents cardiovascular disease, but it may also trigger acute cardiac events like sudden cardiac death in patients with underlying heart disease. The chance of surviving an out-of-hospital cardiac arrest remains low, despite improving medical treatment and rescue chain. Prior studies signaled increased survival in exercise related out-of-hospital cardiac arrest. Objective: The aim of this study was to evaluate the differences between exercise related out-of-hospital cardiac arrest and out-of-hospital cardiac arrest during daily activity in an urban setting. Methods: Retrospective analysis of all out-of-hospital cardiac arrests from 2014 to 2021 treated at a cardiac arrest center of a tertiary hospital. The primary outcome was survival to discharge. Secondary outcomes included differences in pre-hospital care, in-hospital treatment, hypoxic ischemic encephalopathy, and laboratory parameters. Results: 478 OHCA patients were reviewed of which 432 patients (exercise related 36 (8.4%) vs. daily activity 396 (91.6%)) were included in the analysis. Patients suffering an exercise related arrest were younger (57 vs 65 years, p = 0.002) and mostly male (88.9 vs 74.5%, p = 0.054).The exercise related cohort received bystander cardiopulmonary resuscitation (77.8 vs 53.4%, p = 0.005) to a higher extent and had a shorter no-flow time (1.5 vs 2 min, p = 0.049). Exercise related arrest patients more often presented with a shockable rhythm (80.6 vs 64.1%, p = 0.032).At hospital admission exercise related arrest patients had a higher initial pH (7.24 vs 7.19, p = 0.015). In the exercise related group, a cardiac cause was numerically more frequent compared to the daily activity group (80.6 vs 68.7%, p = 0.09). In both groups myocardial infarction (47.2 vs 43.2%) was the most common cause, but a primary arrhythmic event (33.3 vs 25.5%) was more often documented in exercise related arrest patients. Exercise related arrest was mostly related to endurance training (52.8%) followed by ball sports (19.4%) and occurred directly during exercise in 77.8% of cases. Patients suffering exercise related arrest had higher survival till discharge (66.7 vs 47.7%, p = 0.036). Conclusion: Based on this observational data from a highly selected group of out-of-hospital cardiac arrest patients treated at a cardiac arrest center, patients suffering an exercise related out-of-hospital cardiac arrest, differed in substantial characteristics and in the first line response compared to daily activity out-of-hospital cardiac arrest patients. The better survival to discharge of the exercise related out-of-hospital cardiac arrest group might be driven by these beneficial differences. This study underlines the need for public awareness for the importance of a fast first response and a broad distribution of automated external defibrillators in public sport areas since most of the exercise related out-of-hospital cardiac arrest patients presented with a cardiac cause and an initial shockable rhythm.

The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8 + T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1 + T cells. Mice treated with PD1-IL2Ra-IL2 show no systemic toxicities observed with unmasked IL-2 treatment yet achieve robust tumor growth control. Furthermore, PD1-IL2Ra-IL2 can be effectively combined with other T cell-mediated immunotherapies to enhance anti-tumor responses. These findings highlight the therapeutic potential of PD1-IL2Ra-IL2 as a targeted, receptor-masked, and "α-maintained" IL-2 therapy for cancer., Competing Interests: Declaration of interests All authors are employees of Regeneron Pharmaceuticals, Inc. and may hold stock or stock options in the company. J.W., T.Z., E.S., and J.C.L. are inventors on US patent US11725034B2; “IL2 agonists and methods of uses thereof”. J.W., N.B., T.Z., J.C.L., S.D., E.S., and E.U. are inventors on a pending US patent application (US20220402989A1; “IL2-based therapeutics and methods of uses thereof”). D.J.D. and J.W. are inventors on a pending US patent application (US20240148867A1; “Methods of treating cancer with a combination of adoptive cell therapy and a targeted immunocytokine”)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The incidence of thyroid nodules has increased as diagnostic imaging has become more prevalent, but the management in transplant candidates, a high-risk population because of the need for chronic immunosuppression, has not been described. We sought to review our institution's approach to thyroid nodules incidentally found during pretransplant workup., Methods: A multisite retrospective review was performed of pretransplant patients with incidental thyroid nodules diagnosed between 2011 and 2021. Demographics, nodule characteristics, treatment timeline, and oncologic outcomes were collected. Patients diagnosed before and after 2017 were compared to evaluate how adoption of Thyroid Imaging Reporting and Data System and expansion of a dedicated transplant center were correlated with changes in patient management., Results: A total of 10,340 patients underwent abdominal transplant, 236 had incidental thyroid nodules. After 2017, radiology recommendations for biopsy decreased from 39% to 29% (P = 0.174) and fewer biopsies were performed, 45%-33% (P = 0.055). Time between imaging and biopsy was significantly shorter after 2017, from 14 mo to 4 (P = 0.038). Overall time from imaging to transplant was also significantly reduced, from 31 mo to 11 (P < 0.001). Thirty-one (13.1%) patients underwent thyroid surgery before transplant and four (1.7%) patients after., Conclusions: In the recent years, thyroid biopsy rates for thyroid incidentalomas found during pretransplant workup have decreased and more closely match imaging-based guideline recommendations. Patients who required biopsy obtained them sooner and underwent transplant surgery sooner. Guideline-driven thyroid incidentaloma workup for the pretransplant population allows for timely and appropriate cancer care while avoiding unnecessary delays in transplant., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Guidelines on myocardial infarction (MI) recommend antithrombotic and anticoagulatory treatment at time of diagnosis. MI with ST segment elevation (STEMI) is mostly a certain diagnosis. Acute coronary syndrome without ST segment elevation (NSTE-ACS) has diagnostic uncertainty and remains a working diagnosis in the prehospital setting., Objective: Assessment of prehospital loading with aspirin and heparin depending on ACS subtype and pretreatment with oral anticoagulants., Methods: The PRELOAD survey was a nationwide German study. STEMI/NSTE-ACS scenarios were designed and varied in pretreatment: I) no pretreatment, II) new oral anticoagulants (NOAC), III) vitamin K antagonist (VKA). Loading strategy was assessed and included: a) aspirin (ASA), b) unfractionated heparin (UFH), c) ASA + UFH, d) no loading., Results: A total of 708 emergency physicians were included. In NSTE-ACS without pretreatment, 79% chose loading (p < 0.001). ASA + UFH (71.4%) was the preferred option. In corresponding STEMI scenario, 100% chose loading and 98.6% preferred ASA + UFH (p < 0.001). In NSTE-ACS with NOAC pretreatment, 69.8% favored loading (p < 0.001); in VKA pretreatment the corresponding rate was 72.3% (p < 0.001). In each scenario, ASA was the preferred option. In STEMI with NOAC pretreatment, 97.5% chose loading (p < 0.001); analogous rate was 96.8% in STEMI with VKA pretreatment (p < 0.001). ASA was the preferred option again., Conclusions: Prehospital loading was the preferred treatment strategy despite the diagnostic uncertainty in NSTE-ACS and guidelines recommending loading at time of diagnosis. Pretreatment with oral anticoagulants resulted in a strategy shift to loading with only aspirin. In STEMI patients, this indicates potential undertreatment., (© 2023. The Author(s).)

A challenge for human immune system (HIS) mouse models has been the lack of human red blood cells (hRBCs) survival after engraftment of these immune-deficient mice with human CD34+ hematopoietic stem cells (HSCs). This limits the use of HIS models for preclinical testing of targets directed at hRBCs-related diseases. Even though human white blood cells can develop in the peripheral blood of these human HSC-engrafted mice, peripheral hRBCs are quickly phagocytosed by murine macrophages upon egress from the bone marrow (BM). Genetic ablation of murine myeloid cells results in severe pathology in resulting mice, rendering such an approach to increase hRBC survival in HIS mice impractical. Heme oxygenase-1 (HMOX-1) deficient mice have reduced macrophages due to toxic build-up of intracellular heme upon engulfment of red blood cells, but do not have an overall loss of myeloid cells. We took advantage of this observation and generated a HMOX-1-/- on a humanized M-CSF/SIRPa/CD47 Rag2-/- IL-2Rg-/- background. These mice have reduced murine macrophages but comparable level of murine myeloid cells to HMOX-1+/+ control mice in the same background. Injected hRBCs survive longer in HMOX-1-/- mice than in HMOX-1+/+ controls. Additionally, upon human HSC-engraftment, hRBCs can be observed in the peripheral blood of HMOX-1-/- humanized M-CSF/SIRPa/CD47 Rag2-/- IL-2Rg-/- mice and hRBC levels can be increased by treatment with human erythropoietin. Since hRBC are present in the peripheral blood of engrafted HMOX-1-/- mice, these mice have the potential to be used for hematological disease modeling, and to test therapeutic treatments for hRBC diseases in vivo., (Copyright © 2024 American Society of Hematology.)

Background: Left ventricular thrombus (LVT) is associated with high rates of systemic embolism. Vitamin K antagonists (VKAs) are the only approved treatment for LVT. Although evidence suggests direct oral anticoagulant (DOACs) to be at least equally effective in general, the efficacy of individual DOACs remains unclear., Methods: A literature search was performed in EMBASE, MEDLINE and Web of Science looking for randomized controlled trials (RCTs) and non-randomized controlled studies of interventions (NRSI) comparing individual DOACs to VKAs for the treatment of LVT. Individual patient data was reconstructed and incorporated in a Bayesian network meta-analysis (NMA) and a Cox frailty regression model., Results: A total of 2545 patients across 19 studies (4 RCTs, 15 NRSI) were included. 1738 received VKAs, 581 received Rivaroxaban, 226 received Apixaban, 82 received Dabigatran and 2 received Edoxaban. LVT resolution was less likely with VKAs compared to Rivaroxaban in the time-to-event analysis (HR 0.66, 95% CI [0.49; 0.91], p = 0.01). There was no difference for other DOACs compared to VKAs. Rivaroxaban reduced ischemic stroke compared to VKAs (OR 0.18, 95% CrI [0.05; 0.49]), other DOACs did not., Conclusion: In this NMA, Rivaroxaban showed faster LVT resolution and consecutively lower odds of ischemic stroke than VKAs while Apixaban and Dabigatran showed at least equal efficacy. Given the quality and size of the available studies, these differences between individual DOACs should be acknowledged as hypothesis generating only. Future adequately powered randomized controlled trials are needed to assess possible time-varying effects between individual DOACs., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment strategies. Lymphotoxin beta receptor (LTβR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and ICB treatment to augment tumor-associated HEV formation. Here, we demonstrated that LTβR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTβR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTβR agonism on DC activation and maturation and associated DC-mediated T cell activation. Single agent LTβR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner, and the LTβR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTβR agonism and lymphotoxin alpha (LT⍺) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTβR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments.

Background: Physical activity prevents cardiovascular disease, but it may also trigger acute cardiac events like sudden cardiac death in patients with underlying heart disease. The chance of surviving an out-of-hospital cardiac arrest remains low, despite improving medical treatment and rescue chain. Prior studies signaled increased survival in exercise related out-of-hospital cardiac arrest., Objective: The aim of this study was to evaluate the differences between exercise related out-of-hospital cardiac arrest and out-of-hospital cardiac arrest during daily activity in an urban setting., Methods: Retrospective analysis of all out-of-hospital cardiac arrests from 2014 to 2021 treated at a cardiac arrest center of a tertiary hospital. The primary outcome was survival to discharge. Secondary outcomes included differences in pre-hospital care, in-hospital treatment, hypoxic ischemic encephalopathy, and laboratory parameters., Results: 478 OHCA patients were reviewed of which 432 patients (exercise related 36 (8.4%) vs. daily activity 396 (91.6%)) were included in the analysis. Patients suffering an exercise related arrest were younger (57 vs 65 years, p  = 0.002) and mostly male (88.9 vs 74.5%, p  = 0.054).The exercise related cohort received bystander cardiopulmonary resuscitation (77.8 vs 53.4%, p  = 0.005) to a higher extent and had a shorter no-flow time (1.5 vs 2 min, p  = 0.049). Exercise related arrest patients more often presented with a shockable rhythm (80.6 vs 64.1%, p  = 0.032).At hospital admission exercise related arrest patients had a higher initial pH (7.24 vs 7.19, p  = 0.015). In the exercise related group, a cardiac cause was numerically more frequent compared to the daily activity group (80.6 vs 68.7%, p  = 0.09). In both groups myocardial infarction (47.2 vs 43.2%) was the most common cause, but a primary arrhythmic event (33.3 vs 25.5%) was more often documented in exercise related arrest patients. Exercise related arrest was mostly related to endurance training (52.8%) followed by ball sports (19.4%) and occurred directly during exercise in 77.8% of cases. Patients suffering exercise related arrest had higher survival till discharge (66.7 vs 47.7%, p  = 0.036)., Conclusion: Based on this observational data from a highly selected group of out-of-hospital cardiac arrest patients treated at a cardiac arrest center, patients suffering an exercise related out-of-hospital cardiac arrest, differed in substantial characteristics and in the first line response compared to daily activity out-of-hospital cardiac arrest patients. The better survival to discharge of the exercise related out-of-hospital cardiac arrest group might be driven by these beneficial differences. This study underlines the need for public awareness for the importance of a fast first response and a broad distribution of automated external defibrillators in public sport areas since most of the exercise related out-of-hospital cardiac arrest patients presented with a cardiac cause and an initial shockable rhythm., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

History: A 65-year-old male patient with a history of sarcomatoid renal cell carcinoma and prior right nephrectomy developed recurrent disease adjacent to the inferior vena cava. The patient underwent surveillance imaging 7 months after initiation of treatment with maximum-dose pazopanib and less than 1 month after completing a 2-month regimen of palliative stereotactic body radiation therapy to the right nephrectomy bed and site of recurrence. (Stereotactic body radiation therapy was initiated 5 months after pazopanib treatment was initiated.) One month after initiating treatment with pazopanib and 6 months before the surveillance imaging, the patient developed diarrhea and required ongoing treatment with loperamide to control symptoms. He denied any fatigue, mouth sores, or extremity pain, but described some abdominal pain and discomfort associated with the diarrhea. He was not experiencing any fevers, and vital signs were normal. White blood cell count was normal at 5100/μL (5.1 ×10 9 /L) (normal range, 4200-10 200/μL [4.2-10.2 ×10 9 /L]), with all components of the differential count also being normal. A normal serum albumin level of 3.9 g/dL (39 g/L) (normal range, 3.5-5.0 g/dL [35-50 g/L]) and low serum total protein level of 6.1 g/dL (61 g/L) (normal range, 6.3-7.9 g/dL [63-79 g/L]) were noted. A comprehensive metabolic panel was performed, indicating a serum chloride level of 98 mmol/L (normal, 100-108 mmol/L) and alkaline phosphatase level of 121 U/L (2.02 μkat/L) (normal, 45-115 U/L [0.75-1.92 μkat/L]). The patient underwent surveillance imaging with contrast-enhanced CT of the abdomen and pelvis in the venous phase (Figure).

Background and Objectives: In light of limited intensive care capacities and a lack of accurate prognostic tools to advise caregivers and family members responsibly, this study aims to determine whether automated cerebral CT (CCT) analysis allows prognostication after out-of-hospital cardiac arrest., Methods: In this monocentric, retrospective cohort study, a supervised machine learning classifier based on an elastic net regularized logistic regression model for gray matter alterations on nonenhanced CCT obtained after cardiac arrest was trained using 10-fold cross-validation and tested on a hold-out sample (random split 75%/25%) for outcome prediction. Following the literature, a favorable outcome was defined as a cerebral performance category of 1-2 and a poor outcome of 3-5. The diagnostic accuracy was compared with established and guideline-recommended prognostic measures within the sample, that is, gray matter-white matter ratio (GWR), neuron-specific enolase (NSE), and neurofilament light chain (NfL) in serum., Results: Of 279 adult patients, 132 who underwent CCT within 14 days of cardiac arrest with good imaging quality were identified. Our approach discriminated between favorable and poor outcomes with an area under the curve (AUC) of 0.73 (95% CI 0.59-0.82). Thus, the prognostic power outperformed the GWR (AUC 0.66, 95% CI 0.56-0.76). The biomarkers NfL, measured at days 1 and 2, and NSE, measured at day 2, exceeded the reliability of the imaging markers derived from CT (AUC NfL day 1: 0.87, 95% CI 0.75-0.99; AUC NfL day 2: 0.90, 95% CI 0.79-1.00; AUC NSE day: 2 0.78, 95% CI 0.62-0.94)., Discussion: Our data show that machine learning-assisted gray matter analysis of CCT images offers prognostic information after out-of-hospital cardiac arrest. Thus, CCT gray matter analysis could become a reliable and time-independent addition to the standard workup with serum biomarkers sampled at predefined time points. Prospective studies are warranted to replicate these findings.

Background: Percutaneous coronary intervention (PCI) is standard of care in patients with acute coronary syndrome (ACS) suitable for interventional revascularization. Intracoronary imaging by optical coherence tomography (OCT) expanded treatment approaches adding diagnostic information and contributing to stent optimization., Objectives: This meta-analysis aimed to assess the effects of OCT-guided vs. angiography-guided PCI in treatment of ACS., Methods: A structured literature search was performed. All controlled trials evaluating OCT-guided vs. angiography-guided PCI in patients with ACS were eligible. The primary end point was major adverse cardiac events (MACE)., Results: Eight studies enrolling 2612 patients with ACS were eligible. 1263 patients underwent OCT-guided and 1,349 patients angiography-guided PCI. OCT guidance was associated with a 30% lower likelihood of MACE (OR 0.70, 95% CI 0.53-0.93, p = 0.01, I 2  = 1%). OCT-guided PCI was also associated with significantly decreased cardiac mortality (OR 0.49, 95% CI 0.25-0.96, p = 0.04, I 2  = 0%). There was no detectable difference in all-cause mortality (OR 1.08, 95% CI 0.51-2.31, p = 0.83, I 2  = 0). Patients in OCT-guided group less frequently required target lesion revascularization (OR 0.26, 95% CI 0.07-0.95, p = 0.04, I 2  = 0%). Analysis of myocardial infarction did not result in significant treatment differences. In subgroup or sensitivity analysis the observed advantages of OCT-guided PCI were not replicable., Conclusion: The evidence suggests that PCI guidance with OCT in ACS decreases MACE, cardiac death and target lesion revascularization compared to angiography. On individual study level, in subgroup or sensitivity analyses these advantages were not thoroughly replicable., (© 2023. The Author(s).)

Reproductive autonomy encompasses one's ability to make decisions around contraceptive use, pregnancy, and childbirth. An individual's geographic location affects access to a wide range of information and care related to reproductive choice. Individuals in rural areas face additional barriers to reproductive health and decision-making than those in urban areas. This phenomenological qualitative study examined the experiences with and perceptions of reproductive decision-making among women in rural Appalachian communities in the United States. Four themes emerged from the data: autonomy tied to choice, role of religion and church on autonomy and decision-making, navigating limited access to care, and shame. Women should be supported in making reproductive health decisions, and efforts are needed to increase autonomy within reproductive health care and decisions. Sexual health programming within school and other community settings should address shame that often occurs around reproductive health topics, particularly among religious communities., Competing Interests: The authors report there are no competing interests to declare., (© 2024 Taylor & Francis Group, LLC.)

Perforated peptic ulcers, though relatively rare, represent critical surgical emergencies with potentially life-threatening consequences. Their significance lies not only in their acute presentation but also in the diagnostic challenges they pose, particularly in patients with complex medical histories. Here we present a case of a 71-year-old female with a complex medical history, including insulin-dependent type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, dementia, diverticulitis, and chronic back pain, who initially were unresponsive and cyanotic. Despite challenges in diagnosis due to her medical complexity and opioid use, she was ultimately diagnosed with a perforated duodenal ulcer. Tragically, despite immediate surgical intervention, she succumbed to her illness, highlighting the complexities involved in managing perforated peptic ulcers, especially in patients with multiple chronic medical conditions. Peptic ulcer disease (PUD) can often remain asymptomatic, leading to delayed diagnosis and potentially life-threatening complications like perforation. Mortality rates associated with perforated peptic ulcers vary widely, ranging from 1.3% to 20%, with risk factors including nonsteroidal anti-inflammatory drug (NSAID) use, Helicobacter pylori infection, smoking, and corticosteroid use. Diagnosis necessitates a high index of suspicion, thorough clinical examination, and imaging modalities such as computed tomography (CT) scans with oral contrast. Treatment strategies range from nonoperative management with intravenous (IV) histamine H2-receptor blockers or proton pump inhibitors (PPIs) to surgical intervention, depending on the patient's hemodynamic stability. However, the case presented underscores the challenges in timely diagnosis and intervention, particularly in patients with complex medical histories, where symptoms may be masked or attributed to other comorbidities. Recent studies indicate a demographic shift toward older age and a higher prevalence among females, emphasizing the importance of increased awareness and vigilance among healthcare providers. Early recognition of symptoms, prompt investigation, and interdisciplinary collaboration are crucial in optimizing outcomes for patients presenting with perforated peptic ulcers, especially in the context of their underlying medical conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Van Ligten et al.)

Background/Objectives: Chronic total occlusion (CTO) is a prevalent finding in patients with coronary artery disease and is associated with increased mortality. Prior reports on the efficacy of percutaneous coronary intervention (PCI) compared to optimal medical therapy (OMT) were controversial. Following the emergence of recently published new evidence, a meta-analysis is warranted. The current meta-analysis assessed the effects of PCI compared to OMT in the treatment of CTO. Methods: A structured literature search was performed. Randomized controlled trials (RCTs) and non-randomized controlled studies of interventions were eligible. The primary outcome was an accumulated composite of cardiac mortality, myocardial infarction and target vessel/lesion revascularization events. Results: Thirty-two studies reporting on 11260 patients were included. Of these, 5712 (50.7%) were assigned to the PCI and 5548 (49.3%) were allocated to the OMT group. The primary outcome occurred in 14.6% of the PCI and 20.1% of the OMT group (12 trials, OR 0.66, 95% CI 0.50 to 0.88, p = 0.005, I 2 = 67%). Subgrouping demonstrated a consistent reduction in the primary outcome for the PCI group in RCTs (six trials, OR 0.58, 95% CI 0.33 to 0.99, p = 0.05). The primary outcome reduction was irrespective of the study design, and it was replicable in sensitivity and subgroup analyses. Advantages in other outcomes were rather related to statistical pooling effects and dominated by observational data. Conclusions: CTO-PCI was associated with improved patient-oriented primary outcome compared to OMT in a study-level meta-analysis. This composite outcome effect was mainly driven by target vessel treatment, but a significant reduction in mortality and myocardial infarction was observed, irrespectively. These findings have hypothesis-generating implications. Future RCTs with adequate statistical power are eagerly awaited.

Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal hepatic function. Wnt signaling is a master regulator of spatial liver zonation. A perivenous-periportal Wnt activity gradient orchestrates metabolic zonation by activating gene expression in perivenous hepatocytes, while suppressing gene expression in their periportal counterparts. However, the understanding as to the liver gene zonation and zonation regulators in diseases is limited. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fat accumulation, inflammation, and fibrosis. Here, we investigated the perturbation of liver gene zonation in a mouse NASH model by combining spatial transcriptomics, bulk RNAseq and in situ hybridization. Wnt-target genes represented a major subset of genes showing altered spatial expression in the NASH liver. The altered Wnt-target gene expression levels and zonation spatial patterns were in line with the up regulation of Wnt regulators and the augmentation of Wnt signaling. Particularly, we found that the Wnt activator Rspo3 expression was restricted to the perivenous zone in control liver but expanded to the periportal zone in NASH liver. AAV8-mediated RSPO3 overexpression in controls resulted in zonation changes, and further amplified the disturbed zonation of Wnt-target genes in NASH, similarly Rspo3 knockdown in Rspo3 +/- mice resulted in zonation changes of Wnt-target genes in both chow and HFD mouse. Interestingly, there were no impacts on steatosis, inflammation, or fibrosis NASH pathology from RSPO3 overexpression nor Rspo3 knockdown. In summary, our study demonstrated the alteration of Wnt signaling in a mouse NASH model, leading to perturbed liver zonation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are or were employees and shareholders of Regeneron Pharmaceuticals. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aims to evaluate the association between social determinants, environmental exposure metrics, and the risk of asthma emergency department (ED) visits in the New York State (NYS) Medicaid population using small-area analysis. Traffic densities for each census tract in NYS were calculated using the length of road segments within each tract and total area of the tract to produce a measure of average number of vehicles per square meter per day. Data on social determinants of health including internal and external environments and other demographic factors were obtained from various sources. Poisson regression analyses were conducted to identify significant factors associated with asthma ED visits in Medicaid claim and encounter data for years 2005-2015. High traffic density in NYS excluding New York City (NYC) correlated with increased risk of asthma ED visits (RR 1.69; 95% CI: 1.42, 2.00), mitigated by adjusting for environmental and social determinants (RR 1.00; 95% CI: 0.85, 1.19). Similar trends were observed in NYC only (RR 1.19; 95% CI: 1.00, 1.41), with the adjusted risk remaining elevated (RR 1.14; 95% CI: 0.98, 1.33) albeit not statistically significant. Living in census tracts with high concentrated disadvantage index, high proportions of minorities, and less green space predicted higher asthma ED visits. We mapped predicted rates and model residuals to identify areas of high risk. Our results support previous findings that environmental and social risk factors in poor and urban areas contribute to asthma exacerbations in the NYS Medicaid population, even if they may not necessarily contribute to its development., Competing Interests: The authors have declared no conflicts of interest., (© 2024 The Authors.)

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies., Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF., Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis., Exposure: Skin biopsy for detection of phosphorylated α-synuclein., Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy., Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected., Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Background: Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab., Methods: Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing., Results: Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here., Conclusions: This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance., Competing Interests: Competing interests: JB-V, NF, RPD, KJC, DS, SJ, LB, NTG, SG, CA, DMF, AC, GT, SRA, and VJ are employees of, and hold stock in, Regeneron Pharmaceuticals, Inc. MST: research funding from Regeneron Pharmaceuticals, Inc.; consulting fees from Gilead, Janssen, Kite, Novartis, Regeneron Pharmaceuticals Inc., and Roche; and support for attending meetings or travel from Amgen and Janssen. RB: employee of Ipsen; and his spouse holds stock options in and is an employee of Sanofi-Pasteur. JD: patient fees to the institution from MorphoSys. RHA: advisory board membership from ADC Therapeutics, Bristol Myers Squibb, Epizyme, Genentech, Gilead, Incyte, Karyopharm, Portola, and Seattle Genetics; and institutional research funding from Cyteir, Forty Seven, Genentech, Gilead, Janssen, Regeneron Pharmaceuticals Inc., and Roche., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists., Competing Interests: PL received speaker honoraria and consulting fees from Astra Zeneca, Bayer, Pfizer, Edwards Lifesciences, and research honoraria from Edwards Lifesciences outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Binzenhöfer, Gade, Roden, Saleh, Lanz, Sierra, Seifert, Scherer, Schrage, Haertel, Spieth, Mangner, Adler, Hoyer, Graf, Billig, Salem, Rangel, Speidl, Hagl, Hausleiter, Massberg, Preusch, Meder, Leistner, Luedike, Rassaf, Zimmer, Westermann, Zeymer, Schäfer, Thiele and Lüsebrink.)

Objectives: This study aims to evaluate the demographic differences between those with adductor spasmodic dysphonia with vocal tremor (AdSD(+)VT) and those without vocal tremor (AdSD(-)VT) and to analyze their response to treatment with botulinum neurotoxin (BoNT-A)., Study Design: Retrospective cohort study., Methods: A database review of all spasmodic dysphonia patients treated with BoNT from 1989 to 2018 at the Mayo Clinic in Arizona was performed. Only patients who had received ≥4 injections of BoNT-A for AdSD were included. Patients were divided into two cohorts: those with coexistent vocal tremor (AdSD(+)VT) and those without vocal tremor (AdSD(-)VT)., Results: The final analysis included 398 patients, with 210 AdSD(+)VT patients (53%) and 188 AdSD(-)VT patients (47%). The length of follow-up and median number of treatments were similar between cohorts. AdSD(+)VT patients were more likely to be female (P < 0.001), and older at onset (P < 0.001) and first injection (P < 0.001). The mean maximal benefit was significantly lower for the AdSD(+)VT cohort (P < 0.01), however the mean length of benefit was similar (P = 0.70)., Conclusions: Demographic differences exist between AdSD(+)VT and AdSD(-)VT patients. AdSD(+)VT patients benefit from BoNT-A treatment; however, our analysis suggests that the degree of their maximal benefit is less than in those without VT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Evaluate optic nerve sheath and pial diameters (ONSD, ONPD) via sonography and computed tomography (CT) after out-of-hospital cardiac arrest (CA) and to compare their prognostic significance with other imaging and laboratory biomarkers., Materials and Methods: A prospective observational study enrolling patients after successful resuscitation between December 2017 and August 2021. ONSD and ONPD were measured with sonography. Additionally, ONSD, and also grey-to-white ratio at basal ganglia (GWR BG ) and cerebrum (GWR CBR ), were assessed using CT. Lactate and neuron specific enolase (NSE) blood levels were measured., Results: Sonographically measured ONSD and ONPD yielded no significant difference between survival and non-survival (p values ≥0.4). Meanwhile, CT assessed ONSD, GWR BG , GWR CBR , and NSE levels significantly differed regarding both, survival (p values ≤0.005) and neurological outcome groups (p values ≤0.04). For survival prognosis, GWR BG , GWR CBR , and NSE levels appeared as excellent predictors; in predicting a good neurological outcome, NSE had the highest accuracy., Conclusions: CT diagnostics, in particular GWR BG and GWR CBR , as well as NSE as laboratory biomarker, appear as excellent outcome predictors. Meanwhile, our data lead us to recommend caution in utilizing sonography assessed ONSD and ONPD for prognostic decision-making post-CA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Examining crack propagation at the interface of bimaterial components under various conditions is essential for improving the reliability of semiconductor designs. However, the fracture behavior of bimaterial interfaces has been relatively underexplored in the literature, particularly in terms of numerical predictions. Numerical simulations offer vital insights into the evolution of interfacial damage and stress distribution in wafers, showcasing their dependence on material properties. The lack of knowledge about specific interfaces poses a significant obstacle to the development of new products and necessitates active remediation for further progress. The objective of this paper is twofold: firstly, to experimentally investigate the behavior of bimaterial interfaces commonly found in semiconductors under quasi-static loading conditions, and secondly, to determine their respective interfacial cohesive properties using an inverse cohesive zone modeling approach. For this purpose, double cantilever beam specimens were manufactured that allow Mode I static fracture analysis of the interfaces. A compliance-based method was used to obtain the crack size during the tests and the Mode I energy release rate (GIc). Experimental results were utilized to simulate the behavior of different interfaces under specific test conditions in Abaqus. The simulation aimed to extract the interfacial cohesive contact properties of the studied bimaterial interfaces. These properties enable designers to predict the strength of the interfaces, particularly under Mode I loading conditions. To this extent, the cohesive zone modeling (CZM) assisted in defining the behavior of the damage propagation through the bimaterial interfaces. As a result, for the silicon-epoxy molding compound (EMC) interface, the results for maximum strength and GIc are, respectively, 26 MPa and 0.05 N/mm. The second interface tested consisted of polyimide and silicon oxide between the silicon and EMC layers, and the results obtained are 21.5 MPa for the maximum tensile strength and 0.02 N/mm for GIc. This study's findings aid in predicting and mitigating failure modes in the studied chip packaging. The insights offer directions for future research, focusing on enhancing material properties and exploring the impact of manufacturing parameters and temperature conditions on delamination in multilayer semiconductors.

Background: The process of gamete formation and early embryonic development involves rapid DNA replication, chromosome segregation and cell division. These processes may be affected by mutations in the BRCA1/2 genes. The aim of this study was to evaluate BRCA mutation inheritance and its effect on early embryonic development according to the parental origin of the mutation. The study question was approached by analyzing in vitro fertilization cycles (IVF) that included pre-implantation testing (PGT-M) for a BRCA gene mutation., Methods: This retrospective cohort study compared cycles of pre-implantation genetic testing for mutations (PGT-M) between male and female patients diagnosed with BRCA 1/2 mutations (cases), to a control group of two other mutations with dominant inheritance (myotonic dystrophy (MD) and polycystic kidney disease (PKD)). Results were compared according to mutation type and through a generalized linear model analysis., Results: The cohort included 88 PGT-M cycles (47 BRCA and 41 non-BRCA) among 50 patients. Maternal and paternal ages at oocyte retrieval were comparable between groups. When tested per cycle, FSH dose, maximum estradiol level, oocytes retrieved, number of zygotes, and number of embryos available for biopsy and affected embryos, were not significantly different among mutation types. All together 444 embryos were biopsied: the rate of affected embryos was comparable between groups. Among BRCA patients, the proportion of affected embryos was similar between maternal and paternal mutation origin (p = 0.24). In a generalized linear model analysis, the relative oocyte yield in maternal BRCA patients was significantly lower (0.7, as related to the non BRCA group)(p < 0.001). Zygote formation and blastulation were not affected by the BRCA gene among paternal cases (P = 0.176 and P = 0.293 respectively), nor by paternal versus maternal BRCA carriage (P = 0.904 and P = 0.149, respectively)., Conclusions: BRCA PGT-M cycles performed similarly compared to non-BRCA cycles. Inheritance rate and cycle parameters were not affected by the parental origin of the mutation., (© 2024. The Author(s).)

Background: Out-of-hospital cardiac arrest (OHCA) remains a frequent medical emergency with low survival rates even after a return of spontaneous circulation (ROSC). Growing evidence supports formation of dedicated teams in scenarios like cardiogenic shock to improve prognosis. Thus, the European Resuscitation Council (ERC) recommended introduction of Cardiac Arrest Centers (CAC) in their 2015 guidelines. Here, we aimed to elucidate the effects of newly introduced CACs in Germany regarding survival rate and neurological outcome., Methods: A multicenter retrospective observational cohort study was performed at three university hospitals and outcomes after OHCA were compared before and after CAC accreditation. Primary outcomes were survival until discharge and favorable neurological status (CPC 1 or 2) at discharge., Results: In total 784 patients (368 before and 416 after CAC accreditation) were analyzed. Rates of immediate percutaneous coronary intervention (40 vs. 52%, p = 0.01) and implementation of extracorporeal CPR (8 vs. 13%, p < 0.05) increased after CAC accreditation. Likelihood of favorable neurological status at discharge was higher after CAC accreditation (71 vs. 87%, p < 0.01), whereas overall survival remained similar (35 vs. 35%, p > 0.99)., Conclusion: CAC accreditation is linked to higher rates of favorable neurological outcome and unchanged overall survival., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘R.W. is employed at Abiomed Inc., Danvers, USA as medical officer. All other authors: none. B.W.B. is member of the editorial board of Resuscitation’., (Copyright © 2023. Published by Elsevier B.V.)