Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes.

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

The different impact of drug-resistant Leishmania on the transcription programs activated in neutrophils.

Drug resistance threatens the effective control of infections, including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial control, but their role in drug-resistant infections is poorly understood. Here, we evaluated human neutrophil response to clinical parasite strains having distinct natural drug susceptibility. We found that Leishmania antimony drug resistance significantly altered the expression of neutrophil genes, some of them transcribed by specific neutrophil subsets. Infection with drug-resistant parasites increased the expression of detoxification pathways and reduced the production of cytokines. Among these, the chemokine CCL3 was predominantly impacted, which resulted in an impaired ability of neutrophils to attract myeloid cells. Moreover, decreased myeloid recruitment when CCL3 levels are reduced was confirmed by blocking CCL3 in a mouse model. Collectively, these findings reveal that the interplay between naturally drug-resistant parasites and neutrophils modulates the infected skin immune microenvironment, revealing a key role of neutrophils in drug resistance.

Structural Neuroimaging of Hippocampus and Amygdala Subregions in Posttraumatic Stress Disorder: A Scoping Review.

Numerous studies have explored the relationship between posttraumatic stress disorder (PTSD) and the hippocampus and the amygdala because both regions are implicated in the disorder's pathogenesis and pathophysiology. Nevertheless, those key limbic regions consist of functionally and cytoarchitecturally distinct substructures that may play different roles in the etiology of PTSD. Spurred by the availability of automatic segmentation software, structural neuroimaging studies of human hippocampal and amygdala subregions have proliferated in recent years. Here, we present a preregistered scoping review of the existing structural neuroimaging studies of the hippocampus and amygdala subregions in adults diagnosed with PTSD. A total of 3513 studies assessing subregion volumes were identified, 1689 of which were screened, and 21 studies were eligible for this review (total N = 2876 individuals). Most studies examined hippocampal subregions and reported decreased CA1, CA3, dentate gyrus, and subiculum volumes in PTSD. Fewer studies investigated amygdala subregions and reported altered lateral, basal, and central nuclei volumes in PTSD. This review further highlights the conceptual and methodological limitations of the current literature and identifies future directions to increase understanding of the distinct roles of hippocampal and amygdalar subregions in posttraumatic psychopathology.

Subcutaneous mastectomy in female-to-male transsexuals is associated with higher risk of postoperative bleeding complications.

Introduction: Chest contouring or subcutaneous mastectomy (SCM) in female-to-male (FtM) transgender individuals is the primary surgery in the gender reassignment process. Many authors report high rates of postoperative bleeding in these patients and discuss a possible influence of preoperative hormone therapy. However, there is a lack of data on the analysis between different surgical techniques and postoperative bleeding risk. Materials and Methods: In this retrospective study, we included 22 FtM transgender individuals who underwent bilateral SCM using 4 different techniques (44 breasts) between June 2014 and September 2023. Postoperative complications regarding surgical techniques and patient demographics were collected and analyzed. Results: SCM with free nipple grafting was the most commonly used technique (n = 12, 54.5%). The mean operative time was 163.4 ± 49.2 minutes. There were no significant differences in operative time between the surgical techniques (p ≥ 0.20 in all cases). The rate of acute postoperative bleeding was 20.5% (n = 9). Acute postoperative bleeding occurred most frequently in patients who received a semi-circular incision for SCM. There was no significant difference in the rate of acute postoperative bleeding between the different surgical techniques. BMI, breast weight, and duration of surgery were not associated with the rate of acute complications (p > 0.17 in all cases). Conclusions: Less invasive SCM techniques in FtM transgender individuals are associated with higher postoperative bleeding risk.

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer.

OBJECTIVES: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for âˆ¼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. MATERIALS AND METHODS: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. RESULTS: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. CONCLUSION: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

Analysis of vascular disruption in zebrafish embryos as an endpoint to predict developmental toxicity.

Inhibition of angiogenesis is an important mode of action for the teratogenic effect of chemicals and drugs. There is a gap in the availability of simple, experimental screening models for the detection of angiogenesis inhibition. The zebrafish embryo represents an alternative test system which offers the complexity of developmental differentiation of an entire organism while allowing for small-scale and high-throughput screening. Here we present a novel automated imaging-based method to detect the inhibition of angiogenesis in early life stage zebrafish. Video subtraction was used to identify the location and number of functional intersegmental vessels according to the detection of moving blood cells. By exposing embryos to multiple tyrosine kinase inhibitors including SU4312, SU5416, Sorafenib, or PTK787, we confirmed that this method can detect concentration-dependent inhibition of angiogenesis. Parallel assessment of arterial and venal aorta ruled out a potential bias by impaired heart or blood cell development. In contrast, the histone deacetylase inhibitor valproic acid did not affect ISV formation supporting the specificity of the angiogenic effects. The new test method showed higher sensitivity, i.e. lower effect concentrations, relative to a fluorescent reporter gene strain (Tg(KDR:EGFP)) exposed to the same tyrosine kinase inhibitors indicating that functional effects due to altered tubulogenesis or blood transport can be detected before structural changes of the endothelium are visible by fluorescence imaging. Comparison of exposure windows indicated higher specificity for angiogenesis when exposure started at later embryonic stages (24 h post-fertilization). One of the test compounds was showing particularly high specificity for angiogenesis effects (SU4312) and was, therefore, suggested as a model compound for the identification of molecular markers of angiogenic disruption. Our findings establish video imaging in wild-type strains as viable, non-invasive, high-throughput method for the detection of chemical-induced angiogenic disruption in zebrafish embryos.

Construct validity of the German version of the Emotion Reactivity Scale.

BACKGROUND: Emotional reactivity is an important construct to consider when studying mental disorders. This study was conducted to translate and assess the factor structure, construct validity and internal consistency of a German version of the Emotion Reactivity Scale (ERS), which is an originally English questionnaire assessing three components of emotional reactivity: sensitivity, intensity and persistence of emotions. METHODS: The German ERS and a range of questionnaires used to assess convergent and discriminant validity were completed by 334 German speaking Swiss participants. RESULTS: Confirmatory factor analysis showed strong support for a bi-factor model, with evaluation indices pointing to a unidimensional construct rather than to domain specific factors. The questionnaire showed good reliability and the factor structure was similar across gender. The ERS showed convergent validity with general psychopathology, behavioral inhibition, negative affect, orienting sensitivity, depressive symptoms and symptoms of disordered eating, and discriminant validity with behavioral activation and alcohol consumption. CONCLUSIONS: Findings support the construct validity of the German ERS and suggest that it assesses a unidimensional construct with high internal consistency. Accounting for the unidimensional nature of the scale and aiming for efficient assessment tools, future research could, based on these findings, develop and evaluate the psychometric properties of a short version of the ERS.

Sex, myelin, and clinical characteristics of Parkinson's disease.

Objective: To determine if there are sex differences in myelin in Parkinson's disease, and whether these explain some of the previously-described sex differences in clinical presentation. Methods: Thirty-three subjects (23 males, 10 females) with Parkinson's disease underwent myelin water fraction (MWF) imaging, an MRI scanning technique of in vivo myelin content. MWF of 20 white matter regions of interest (ROIs) were assessed. Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). Principal component analysis, logistic and multiple linear regressions, and t-tests were used to determine which white matter ROIs differed between sexes, the clinical features associated with these myelin changes, and if overall MWF and MWF laterality differed between males and females. Results: Consistent with prior reports, tremor and bradykinesia were more likely seen in females, whereas rigidity and axial symptoms were more likely seen in males in our cohort. MWF of the thalamic radiation, cingulum, cingulum hippocampus, inferior fronto-occipital fasciculi, inferior longitudinal fasciculi, and uncinate were significant in predicting sex. Overall MWF and asymmetry of MWF was greater in males. MWF differences between sexes were associated with tremor symptomatology and asymmetry of motor performance. Conclusion: Sex differences in myelin are associated with tremor and asymmetry of motor presentation. While preliminary, our results suggest that further investigation of the role of biological sex in myelin pathology and clinical presentation in Parkinson's disease is warranted.

Predictors of lower exercise capacity in patients with cancer.

Maintaining cancer patients' exercise capacity and therefore patients' ability to live a self-determined life is of huge importance, but little is known about major determinants. We sought to identify determinants of exercise capacity in patients with a broad spectrum of cancer types, who were already receiving cancer treatment or about to commence such therapy. Exercise capacity was assessed in 253 consecutive patients mostly suffering from advanced cancer using the 6-min walk test (6-MWT). All patients underwent echocardiography, physical examination, resting electrocardiogram, hand grip strength (HGS) measurement, and laboratory assessments. Patients were divided into two groups according to the median distance in the 6-MWT (459 m). Patients with lower exercise capacity were older, had significantly lower HGS and haemoglobin and higher values of high sensitive (hs) Troponin T and NT-proBNP (all p < 0.05). Whilst the co-morbidity burden was significantly higher in this group, no differences were detected for sex, body mass index, tumor type, or cachexia (all p > 0.2). Using multivariable logistic regression, we found that the presence of anaemia (odds ratio (OR) 6.172, 95% confidence interval (CI) 1.401-27.201, p = 0.016) as well as an increase in hs Troponin T (OR 3.077, 95% CI 1.202-5.301, p = 0.019) remained independent predictors of impaired exercise capacity. Increasing HGS was associated with a reduced risk of a lower exercise capacity (OR 0.896, 95% CI 0.813-0.987, p = 0.026). Screening patients for elevated hs troponin levels as well as reduced HGS may help to identify patients at risk of lower exercise capacity during cancer treatment.

Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.

Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.

Interferon ß-1a ring prophylaxis to reduce household transmission of SARS-CoV-2: a cluster randomised clinical trial.

Background: Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission. Methods: A cluster randomised open label clinical trial was undertaken to determine the effects of pegylated IFNß-1a administration on SARS-CoV-2 household transmission between December 3rd, 2020 and June 29th, 2021. Index cases were identified from databases of confirmed SARS-CoV-2 individuals in Santiago, Chile. Households were cluster randomised (stratified by household size and age of index cases) to receive 3 doses of 125 µg subcutaneous pegylated IFNß-1a (172 households, 607 participants), or standard care (169 households, 565 participants). The statistical team was blinded to treatment assignment until the analysis plan was finalised. Analyses were undertaken to determine effects of treatment on viral shedding and viral transmission. Safety analyses included incidence and severity of adverse events in all treatment eligible participants in the standard care arm, or in the treatment arm with at least one dose administered. Clinicaltrials.gov identifier: NCT04552379. Findings: 5154 index cases were assessed for eligibility, 1372 index cases invited to participate, and 341 index cases and their household contacts (n = 831) enrolled. 1172 participants in 341 households underwent randomisation, with 607 assigned to receive IFNß-1a and 565 to standard care. Based on intention to treat (ITT) and per protocol (PP) analyses for the primary endpoints, IFNß-1a treatment did not affect duration of viral shedding in index cases (absolute risk reduction = -0.2%, 95% CI = -8.46% to 8.06%) and transmission of SARS-CoV-2 to household contacts (absolute risk reduction = 3.87%, 95% CI = -3.6% to 11.3%). Treatment with IFNß-1a resulted in significantly more treatment-related adverse events, but no increase in overall adverse events or serious adverse events. Interpretation: Based upon the primary analyses, IFNß-1a treatment did not affect duration of viral shedding or the probability of SARS-CoV-2 transmission to uninfected contacts within a household. Funding: Biogen PTY Ltd. Supply of interferon as 'Plegridy (peginterferon beta-1a).' The study was substantially funded by BHP Holdings Pty Ltd.

Changes in mental health among U.S. military veterans during the COVID-19 pandemic: A network analysis.

Increases of symptoms of posttraumatic stress disorder (PTSD), anxiety and depression have been observed among individuals exposed to potentially traumatic events in the first months of the COVID-19 pandemic. Similarly, associations among different aspects of mental health, such as symptoms of PTSD and suicidal ideation, have also been documented. However, studies including an assessment prior to the onset and during the height of the pandemic are lacking. We investigated changes in symptoms of PTSD, depression, anxiety, suicidal ideation, and posttraumatic growth in a population-based sample of 1232 U.S. military veterans who experienced a potentially traumatic event during the first year of the pandemic. Symptoms were assessed prior to (fall/winter 2019) and one year into the pandemic (fall/winter 2020). We compared changes in symptom interrelations using network analysis, and assessed their associations with pandemic-related PTSD and posttraumatic growth symptoms. A subtle increase in psychopathological symptoms and a decrease in posttraumatic growth was observed one year into the pandemic. The peripandemic network was more densely connected, and pandemic-related PTSD symptoms were positively associated with age, anxiety, worst-event PTSD symptoms, and pandemic-related posttraumatic growth. Our findings highlight the resilience of veterans exposed to a potentially traumatic event during the first year of a pandemic. Similarly, the networks did not fundamentally change from prepandemic to one year into the pandemic. Despite this relative stability on a group level, individual reactions to potentially traumatic events could have varied substantially. Clinicians should individualize their assessments but be aware of the general resilience of most veterans.

Social participation during the COVID-19 pandemic in persons with a high risk for a severe course of COVID-19 - results of a longitudinal, multi-center observational study in Germany.

Objective: The COVID-19 pandemic has affected how people go about their daily lives, often in various and substantial ways. This study aims to prospectively evaluate the changes in social participation during the COVID-19 pandemic in persons with a high risk for a severe COVID-19 course in Germany. Methods: A paper-pencil-based survey was conducted starting at March 2021. Participants filled out questionnaires at four time points based on their COVID-19 vaccination status: before COVID-19 vaccination, one month, six months and twelve months after COVID-19 vaccination. Social participation measures included the Pandemic Social Participation Questionnaire (PSP-Q) and the Index for measuring participation restrictions (IMET). Repeated measures ANOVA and paired t-test were used to test for changes between time-points. Repeated measures correlation was used to assess the relationship between social participation and local COVID-19 incidences. Results: Data from 245 participants was analyzed before and one month after COVID-19 vaccination. In addition, data from 156 participants was analyzed at time points one, six and twelve months after COVID-19. PSP-Q and IMET scores changed significantly after participants received a COVID-19 vaccination. Between one month and twelve months after vaccination, social participation improved significantly measured by PSP-Q. Social participation was negatively correlated with regional COVID-19 incidences before and after COVID-19 vaccination. Social participation was positively correlated with COVID-19 incidences between one month and twelve months after COVID-19 vaccination. Conclusions: Social participation improved in persons with a high risk for a severe COVID-19 course during the pandemic. The local COVID-19 incidence showed a negative association with social participation only until the fall of 2021 when it was used as the sole metric to regulate COVID-19 protective measures. Although our data describes the trends in social participation, further studies are needed to identify the influencing factors for the observed increase in social participation.

Correlates of avoidance coping in trauma-exposed U.S. military veterans: Results from the National Health and Resilience in Veterans Study.

Avoidant coping strategies, which involve cognitions and behaviors aimed to avoid dealing with stressful experiences, are associated with adverse long-term mental and physical health outcomes. In response to traumatic events, these strategies can be maladaptive as they may interfere with the adaptive integration of traumatic events into consolidated memories. Using data from a nationally representative sample of more than 3000 trauma-exposed U.S. military veterans (mean time since trauma 30.9 years, SD = 19.9), we employed a network analytic approach to examine pairwise associations between key sociodemographic, personality, and psychosocial risk factors in relation to the endorsement of avoidant coping strategies. Results revealed that negative affect symptoms of posttraumatic stress disorder (PTSD) and adverse childhood experiences were positively associated with engagement in avoidance coping, and that greater emotional stability and conscientiousness were negatively associated with this measure. Secondary network analysis of individual negative affect symptoms of PTSD suggested that blaming oneself and/or others for the traumatic event, emotional neglect, and sexual abuse were most strongly linked to avoidance coping. Collectively, these results suggest that strong feelings of blame related to trauma, emotional neglect, and sexual abuse are associated with greater likelihood of engaging in avoidance coping, while emotional stability and conscientiousness are associated with a lower likelihood of engaging in such strategies.

BCG-Induced Immune Training: Interplay between Trained Immunity and Emergency Granulopoiesis.

Bacille Calmette-Guérin (BCG) is the most commonly administered vaccine in human history. The medical application of BCG extends far beyond the fight against tuberculosis. Despite its stellar medical record over 100 years, insight into how BCG provides this vast range of benefits is largely limited, both for its pathogen-specific (tuberculosis) as well as pathogen-agnostic (other infections, autoimmunity, allergies, and cancer) effects. Trained immunity and emergency granulopoiesis have been identified as mediating BCG's pathogen-agnostic effects, for which some of the molecular mechanisms have been delineated. Upon review of the existing evidence, we postulate that emergency granulopoiesis and trained immunity are a continuum of the same effect cascade. In this context, we highlight that BCG's pathogen-agnostic benefits could be optimized by taking advantage of the age of the recipient and route of BCG administration.

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia.

Mutations of the FLT3 gene are among the most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, the specific sites of FLT3-ITD insertion within FLT3 show marked heterogeneity regarding both biological and clinical features. In contrast to the common assumption that ITD insertion sites (IS) are restricted to the juxtamembrane domain (JMD) of FLT3, 30% of FLT3-ITD mutations insert at the non-JMD level, thereby integrating into various segments of the tyrosine kinase subdomain 1 (TKD1). ITDs inserted within TKD1 have been shown to be associated with inferior complete remission rates as well as shorter relapse-free and overall survival. Furthermore, resistance to chemotherapy and tyrosine kinase inhibition (TKI) is linked to non-JMD IS. Although FLT3-ITD mutations in general are already recognized as a negative prognostic marker in currently used risk stratification guidelines, the even worse prognostic impact of non-JMD-inserting FLT3-ITD has not yet been particularly considered. Recently, the molecular and biological assessment of TKI resistance highlighted the pivotal role of activated WEE1 kinase in non-JMD-inserting ITDs. Overcoming therapy resistance in non-JMD FLT3-ITD-mutated AML may lead to more effective genotype- and patient-specific treatment approaches.

Defining the pediatric response to SARS-CoV-2 variants.

The global population has been severely affected by the coronavirus disease 2019 (COVID-19) pandemic, however, with older age identified as a risk factor, children have been underprioritized. This article discusses the factors contributing to the less severe response observed in children following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including, differing viral entry receptor expression and immune responses. It also discusses how emerging and future variants could present a higher risk to children, including those with underlying comorbidities, in developing severe disease. Furthermore, this perspective discusses the differential inflammatory markers between critical and non-critical cases, as well as discussing the types of variants that may be more pathogenic to children. Importantly, this article highlights where more research is urgently required, in order to protect the most vulnerable of our children.

Management of Aortoesophageal Fistula in a Palliative Patient with Non-Small-Cell Lung Cancer: A Case Report.

INTRODUCTION: Aortoesophageal fistulas are a rare but life-threatening complication in patients with thoracic malignancies. CASE PRESENTATION: We describe a case of a 55-year-old female patient with metastatic non-small-cell lung cancer. Due to esophageal tumor compression, a fully covered self-expanding metal stent (fcSEMS) had been deployed in the esophagus several months before. The patient was subsequently admitted to the emergency department with massive hematemesis. Endoscopy suggested a fistula between the aorta and the esophagus proximal of the fcSEMS, which was confirmed by computed tomography and led to hemodynamical relevant upper gastrointestinal bleeding. A thoracic endovascular aortic repair was performed to stop the hemorrhage. After the successful intervention, the patient needed long-term antibiotic treatment, and the fcSEMS remained in place. Afterward, the patient continued palliative tumor therapy using pembrolizumab for further 5 months. The patient died 8 months after the initial admission to the emergency department. CONCLUSION: This is to the best of our knowledge the first case of a technically successful interventional therapy of an aortoesophageal fistula which did not only achieve hemostasis but also enabled the patient to continue tumor therapy to regain quality of life.