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Oftedal et al. generate mice lacking the chaperonin subunit CCT8 in T cells. They find that loss of CCT8 leads to reduced formation of nuclear actin filaments, changes in proteostasis, defective Th2 cell polarization and T cell metabolism and a failed antigenic response to intestinal helminths.

Introduction: Neonatal sepsis is one of the most common causes of neonatal morbidity and mortality in developing countries. Objective: This study aimed to determine the prevalence and factors associated with neonatal sepsis among hospitalized new-borns at Ruvuma, southern Tanzania. Methods: A facility-based retrospective study was conducted at Songea Regional Referral hospital in Ruvuma, during August-October, 2018. A standardized questionnaire was used to collect demographic, obstetric and clinical information from medical case files of patients. Neonatal sepsis was diagnosed clinically. Data were analysed using SPSS version 24.0. Chi square test was used to assess relationship between outcome and exposure variables. Multivariate logistic regression was used to measure association after controlling for confounders, and P-values of

Jana Langbrandtner,1,* Angelika Hüppe,1,* Petra Jessen,2 Jürgen Büning,3 Susanna Nikolaus,4 Heiner Raspe,5 Bernd Bokemeyer6 1Institute of Social Medicine and Epidemiology, University of Luebeck, Ratzeburger Allee, Luebeck, 2Gastroenterology Practice Altenholz-Kiel, Erdbeerfeld, Altenholz, 3Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee, Luebeck, 4Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstraße, Kiel, 5Center for Population Medicine and Health Services Research, University of Luebeck, Ratzeburger Allee, Luebeck, 6Gastroenterology Practice Minden, Uferstraße, Minden, Germany *These authors contributed equally to this work Background/aims: Patients with inflammatory bowel disease (IBD) need comprehensive, interdisciplinary and cross-sectoral health care. In Germany, evidence-based care pathways have been developed to improve the quality of care of IBD patients. We aimed to evaluate the effects of the implementation of some of these recommendations on patient-related outcomes.Methods: In a region of North Germany, outpatients with IBD were recruited by gastroenterologists (intervention group). Three activities based on the recommendations of the IBD pathways were implemented, namely, 1) patient participation in a questionnaire-based assessment of 22 somatic and psychosocial problems combined with individualized care recommendations (patient activation procedure); 2) patient invitation to participate in a 2-day patient education program and 3) invitation to their gastroenterologists to participate in periodic interdisciplinary case conferences. For the control group, IBD patients receiving standard care at gastroenterology practices outside the specified region were recruited by their doctors. At baseline, 6- and 12-month follow-up, study patients were invited to complete questionnaires. Generic health-related quality of life, social participation and self-management skills were the main outcomes.Results: At baseline, 349 patients were included in the study (intervention group: 189; control group: 160); 142 patients from the former and 140 from the latter group returned completed questionnaires at the 12-month follow-up. Over time, improvement in health-related quality of life and social participation was similar in both groups. Participants of the intervention group demonstrated improved self-management skills and more often followed steroid-free medication regimens.Conclusion: In a real-world clinical context, patient activation procedure combined with patient education and case conferences was less effective than expected. The observed beneficial effects, however, encourage the evaluation of more intensive and addressee-centered activities. Keywords: Crohn’s disease, ulcerative colitis, IBD care pathways, quality of care, implementation, evaluation, health services research

Since its first splash 30 years ago, the use of the zebrafish model has been extended from a tool for genetic dissection of early vertebrate development to the functional interrogation of organogenesis and disease processes such as infection and cancer. In particular, there is recent and growing attention in the scientific community directed at the immune systems of zebrafish. This development is based on the ability to image cell movements and organogenesis in an entire vertebrate organism, complemented by increasing recognition that zebrafish and vertebrate immunity have many aspects in common. Here, we review zebrafish immunity with a particular focus on recent studies that exploit the unique genetic and in vivo imaging advantages available for this organism. These unique advantages are driving forward our study of vertebrate immunity in general, with important consequences for the understanding of mammalian immune function and its role in disease pathogenesis.

We consider a semilinear Neumann problem with a parametric reaction which has a concave term and a perturbation which at ±∞ can be resonant with respect to any positive eigenvalue. Using variational methods based on the critical point theory and Morse theory, we show that there exists a critical parameter value λ ∗ > 0 such that if λ ∈(0, λ ∗ ), then the problem has at least three nontrivial smooth solutions.

We consider a nonlinear elliptic Neumann problem driven by the p-Laplacian with a reaction that involves the combined effects of a “concave” and of a “convex” terms. The convex term (p-superlinear term) need not satisfy the Ambrosetti-Rabinowitz condition. Employing variational methods based on the critical point theory together with truncation techniques, we prove a bifurcation type theorem for the equation.

Here we describe a method for the isolation of PCR-ready genomic DNA from various zebrafish tissues that is based on a previously published murine protocol. The DNA solutions are of sufficient quality to allow PCR detection of transgenes from all commonly used zebrafish tissues. In sperm, transgene amplification was successful even when diluted 1000-fold, allowing easy identification of transgenic founders. Given its speed and low cost, we anticipate that the adoption of this method will streamline DNA isolation for zebrafish research.

In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.

DiGeorge syndrome (DGS) is the most common microdeletion syndrome, and is characterized by congenital cardiac, craniofacial and immune system abnormalities. The cardiac defects in DGS patients include conotruncal and ventricular septal defects. Although the etiology of DGS is critically regulated by TBX1 gene, the molecular pathways underpinning TBX1's role in heart development are not fully understood. In this study, we characterized heart defects and downstream signaling in the zebrafish tbx1(-/-) mutant, which has craniofacial and immune defects similar to DGS patients. We show that tbx1(-/-) mutants have defective heart looping, morphology and function. Defective heart looping is accompanied by failure of cardiomyocytes to differentiate normally and failure to change shape from isotropic to anisotropic morphology in the outer curvatures of the heart. This is the first demonstration of tbx1's role in regulating heart looping, cardiomyocyte shape and differentiation, and may explain how Tbx1 regulates conotruncal development in humans. Next we elucidated tbx1's molecular signaling pathway guided by the cardiac phenotype of tbx1(-/-) mutants. We show for the first time that wnt11r (wnt11 related), a member of the non-canonical Wnt pathway, and its downstream effector gene alcama (activated leukocyte cell adhesion molecule a) regulate heart looping and differentiation similarly to tbx1. Expression of both wnt11r and alcama are downregulated in tbx1(-/-) mutants. In addition, both wnt11r (-/-) mutants and alcama morphants have heart looping and differentiation defects similar to tbx1(-/-) mutants. Strikingly, heart looping and differentiation in tbx1(-/-) mutants can be partially rescued by ectopic expression of wnt11r or alcama, supporting a model whereby heart looping and differentiation are regulated by tbx1 in a linear pathway through wnt11r and alcama. This is the first study linking tbx1 and non-canonical Wnt signaling and extends our understanding of DGS and heart development.

Genomic instability plays a crucial role in oncogenesis. Somatically acquired mutations can disable some genes and inappropriately activate others. In addition, chromosomal rearrangements can amplify, delete, or even fuse genes, altering their functions and contributing to malignant phenotypes. Using array comparative genomic hybridization (aCGH), a technique to detect numeric variations between different DNA samples, we examined genomes from zebrafish (Danio rerio) T-cell leukemias of three cancer-prone lines. In all malignancies tested, we identified recurring amplifications of a zebrafish endogenous retrovirus. This retrovirus, ZFERV, was first identified due to high expression of proviral transcripts in thymic tissue from larval and adult fish. We confirmed ZFERV amplifications by quantitative PCR analyses of DNA from wild-type fish tissue and normal and malignant D. rerio T cells. We also quantified ZFERV RNA expression and found that normal and neoplastic T cells both produce retrovirally encoded transcripts, but most cancers show dramatically increased transcription. In aggregate, these data imply that ZFERV amplification and transcription may be related to T-cell leukemogenesis. Based on these data and ZFERV’s phylogenetic relation to viruses of the murine-leukemia-related virus class of gammaretroviridae, we posit that ZFERV may be oncogenic via an insertional mutagenesis mechanism.

Hematopoiesis is precisely orchestrated by lineage-specific DNA-binding proteins that regulate transcription in concert with coactivators and corepressors. Mutations in the zebrafish moonshine (mon) gene specifically disrupt both embryonic and adult hematopoiesis, resulting in severe red blood cell aplasia. We report that mon encodes the zebrafish ortholog of mammalian transcriptional intermediary factor 1gamma (TIF1gamma) (or TRIM33), a member of the TIF1 family of coactivators and corepressors. During development, hematopoietic progenitor cells in mon mutants fail to express normal levels of hematopoietic transcription factors, including gata1, and undergo apoptosis. Three different mon mutant alleles each encode premature stop codons, and enforced expression of wild-type tif1gamma mRNA rescues embryonic hematopoiesis in homozygous mon mutants. Surprisingly, a high level of zygotic tif1gamma mRNA expression delineates ventral mesoderm during hematopoietic stem cell and progenitor formation prior to gata1 expression. Transplantation studies reveal that tif1gamma functions in a cell-autonomous manner during the differentiation of erythroid precursors. Studies in murine erythroid cell lines demonstrate that Tif1gamma protein is localized within novel nuclear foci, and expression decreases during erythroid cell maturation. Our results establish a major role for this transcriptional intermediary factor in the differentiation of hematopoietic cells in vertebrates.

Abstract Databases that link molecular data to clinical outcomes can inform precision cancer research into novel prognostic and predictive biomarkers. However, outside of clinical trials, cancer outcomes are typically recorded only in text form within electronic health records (EHRs). Artificial intelligence (AI) models have been trained to extract outcomes from individual EHRs. However, patient privacy restrictions have historically precluded dissemination of these models beyond the centers at which they were trained. In this study, the vulnerability of text classification models trained directly on protected health information to membership inference attacks is confirmed. A teacher-student distillation approach is applied to develop shareable models for annotating outcomes from imaging reports and medical oncologist notes. ‘Teacher’ models trained on EHR data from Dana-Farber Cancer Institute (DFCI) are used to label imaging reports and discharge summaries from the Medical Information Mart for Intensive Care (MIMIC)-IV dataset. ‘Student’ models are trained to use these MIMIC documents to predict the labels assigned by teacher models and sent to Memorial Sloan Kettering (MSK) for evaluation. The student models exhibit high discrimination across outcomes in both the DFCI and MSK test sets. Leveraging private labeling of public datasets to distill publishable clinical AI models from academic centers could facilitate deployment of machine learning to accelerate precision oncology research.

Abstract Background Invasive blood pressure measurement is the in-hospital gold standard to guide hemodynamic management and consecutively cerebral perfusion pressure in patients with traumatic brain injury (TBI). Its prehospital use is controversial since it may delay further care. The primary aim of this study was to test the hypothesis that patients with severe traumatic brain injury who receive prehospital arterial cannulation, compared to those with in-hospital cannulation, do not have a prolonged time between on-scene arrival and first computed tomography (CT) of the head by more than ten minutes. Methods This retrospective study included patients 18 years and older with isolated severe TBI and prehospital induction of emergency anaesthesia who received treatment in the resuscitation room of the University Hospital of Graz between January 1st, 2015, and December 31st, 2022. A Wilcoxon rank-sum test was used to test for non-inferiority (margin = ten minutes) of the time interval between on-scene arrival and first head CT. Results We included data of 181 patients in the final analysis. Prehospital arterial line insertion was performed in 87 patients (48%). Median (25–75th percentile) durations between on-scene arrival and first head CT were 73 (61–92) min for prehospital arterial cannulation and 75 (60–93) min for arterial cannulation in the resuscitation room. Prehospital arterial line insertion was significantly non-inferior within a margin of ten minutes with a median difference of 1 min (95% CI − 6 to 7, p = 0.003). Conclusion Time-interval between on-scene arrival and first head CT in patients with isolated severe traumatic brain injury who received prehospital arterial cannulation was not prolonged compared to those with in-hospital cannulation. This supports early out-of-hospital arterial cannulation performed by experienced providers.

Abstract Background Little is known about healthcare providers’ (HCPs) contraceptive views for adolescents in Haiti, who experience high rates of unintended pregnancy. We sought to describe HCPs’ perspectives on barriers and facilitators to contraceptive care delivery in rural Haiti. Methods We conducted a cross-sectional survey and qualitative interviews with HCPs in two rural communities in Haiti from 08/2021–03/2022. We assessed demographics, clinical practice behaviors and explored contraception perspectives according to Theory of Planned Behavior constructs: attitudes, subjective norms, and perceived behavioral control (e.g., people’s perceptions of their ability to perform a given behavior, barriers and facilitators of a behavior).15–17 We used descriptive statistics to report proportions and responses to Likert scale and multiple-choice questions. Guided by content analysis, we analyzed interview transcripts through thematic inductive coding and team debriefing. Results Among 58 respondents, 90% (n = 52) were female and 53% (n = 31) were nurses. Most reported always (n = 16, 28%) or very often (n = 21, 36%) obtaining a sexual history for adolescents. A majority agreed/strongly agreed that clinicians should discuss pregnancy prevention (n = 45, 78%), high-risk sexual behaviors (n = 40, 69%), and should prescribe contraception (n = 41, 71%) to adolescents. The most frequently cited provider-level barriers (i.e., significant or somewhat of a barrier) included insufficient contraception knowledge (n = 44, 77%) and time (n = 37, 64%). HCPs were concerned about barriers at the patient-level (e.g. adolescents’ fear of parental notification [n = 37, 64%], adolescents will give inaccurate information about sexual behaviors [n = 25, 43%]) and system-level (e.g. resistance to providing care from administration [n = 33, 57%]). In interviews (n = 17), HCPs generally supported contraception care for adolescents. Many HCPs echoed our quantitative findings on concerns about privacy and confidentiality. HCPs reported concerns about lack of contraception education leading to misconceptions, and community and parental judgement. HCPs expressed interest in further contraception training and resources and noted the importance of providing youth-friendly contraceptive care. Conclusions While HCPs support contraceptive care, we identified actionable barriers to improve care for adolescents in rural Haiti. Future efforts should include increasing HCP knowledge and training, community and parent coalition building to increase contraception support and offering youth-friendly contraceptive care to offset risk for related adverse health outcomes in adolescents in rural Haiti.

PURPOSEGallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations.METHODSPatients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets.RESULTSA total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024).CONCLUSIONThe prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2–targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.