The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens.

The strength with which complexes of self peptide and major histocompatibility complex (MHC) proteins are recognized by the T cell antigen receptor (TCR) dictates the homeostasis of naive CD8(+) T cells, but its effect on reactivity to foreign antigens is controversial. As expression of the negative regulator CD5 correlates with self-recognition, we studied CD5(lo) and CD5(hi) naive CD8(+) T cells. Gene-expression characteristics suggested CD5(hi) cells were better poised for reactivity and differentiation than were CD5(lo) cells, and we found that the CD5(hi) pool also exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during the recognition of foreign antigen. However, the recognition of complexes of foreign peptide and MHC was similar for both subsets. Thus, CD8(+) T cells with higher self-reactivity dominate the immune response to foreign antigens, with implications for T cell repertoire diversity and autoimmunity.

Glucagon-like peptide-1 receptor agonists modestly reduced blood pressure among patients with and without diabetes mellitus: A meta-analysis and meta-regression.

AIM: The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. METHODS: A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. RESULTS: Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. CONCLUSION: Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.

From admissions to licensure: education data associations from a multi-centre undergraduate medical education collaboration.

This paper reports the findings of a Canada based multi-institutional study designed to investigate the relationships between admissions criteria, in-program assessments, and performance on licensing exams. The study's objective is to provide valuable insights for improving educational practices across different institutions. Data were gathered from six medical schools: McMaster University, the Northern Ontario School of Medicine University, Queen's University, University of Ottawa, University of Toronto, and Western University. The dataset includes graduates who undertook the Medical Council of Canada Qualifying Examination Part 1 (MCCQE1) between 2015 and 2017. The data were categorized into five distinct sections: demographic information as well as four matrices: admissions, course performance, objective structured clinical examination (OSCE), and clerkship performance. Common and unique variables were identified through an extensive consensus-building process. Hierarchical linear regression and a manual stepwise variable selection approach were used for analysis. Analyses were performed on data set encompassing graduates of all six medical schools as well as on individual data sets from each school. For the combined data set the final model estimated 32% of the variance in performance on licensing exams, highlighting variables such as Age at Admission, Sex, Biomedical Knowledge, the first post-clerkship OSCE, and a clerkship theta score. Individual school analysis explained 41-60% of the variance in MCCQE1 outcomes, with comparable variables to the analysis from of the combined data set identified as significant independent variables. Therefore, strongly emphasising the need for variety of high-quality assessment on the educational continuum. This study underscores the importance of sharing data to enable educational insights. This study also had its challenges when it came to the access and aggregation of data. As such we advocate for the establishment of a common framework for multi-institutional educational research, facilitating studies and evaluations across diverse institutions. This study demonstrates the scientific potential of collaborative data analysis in enhancing educational outcomes. It offers a deeper understanding of the factors influencing performance on licensure exams and emphasizes the need for addressing data gaps to advance multi-institutional research for educational improvements.

Universal Kardar-Parisi-Zhang Dynamics in Integrable Quantum Systems.

Although the Bethe ansatz solution of the spin-1/2 Heisenberg model dates back nearly a century, the anomalous nature of its high-temperature transport dynamics has only recently been uncovered. Indeed, numerical and experimental observations have demonstrated that spin transport in this paradigmatic model falls into the Kardar-Parisi-Zhang (KPZ) universality class. This has inspired the significantly stronger conjecture that KPZ dynamics, in fact, occur in all integrable spin chains with non-Abelian symmetry. Here, we provide extensive numerical evidence affirming this conjecture. Moreover, we observe that KPZ transport is even more generic, arising in both supersymmetric and periodically driven models. Motivated by recent advances in the realization of SU(N)-symmetric spin models in alkaline-earth-based optical lattice experiments, we propose and analyze a protocol to directly investigate the KPZ scaling function in such systems.

Disentangling Pauli Blocking of Atomic Decay from Cooperative Radiation and Atomic Motion in a 2D Fermi Gas.

The observation of Pauli blocking of atomic spontaneous decay via direct measurements of the atomic population requires the use of long-lived atomic gases where quantum statistics, atom recoil, and cooperative radiative processes are all relevant. We develop a theoretical framework capable of simultaneously accounting for all these effects in the many-body quantum degenerate regime. We apply it to atoms in a single 2D pancake or arrays of pancakes featuring an effective Λ level structure (one excited and two degenerate ground states). We identify a parameter window in which a factor of 2 extension in the atomic lifetime clearly attributable to Pauli blocking should be experimentally observable in deeply degenerate gases with ∼10^{3} atoms. We experimentally observe a suppressed excited-state decay rate, fully consistent with the theory prediction of an enhanced excited-state lifetime, on the ^{1}S_{0}-^{3}P_{1} transition in ^{87}Sr atoms.

Evaluation of an Employment Intervention for Veterans Transitioning From the Military: A Randomized Controlled Trial.

ABSTRACT: Military personnel face numerous challenges transitioning from military jobs to meaningful civilian employment. The Independence Project compared an innovative employment program (National Career Coach Program) with standard employment services (Local Community Resources) in a randomized controlled trial. Study participants were transitioning veterans with self-reported service-connected disabilities seeking permanent employment. The primary outcomes were paid employment and disability ratings over 1 year. Secondary outcomes included health and well-being. At 1-year follow-up, National Career Coach Program participants were significantly more likely to work, had significantly greater earnings, and reported significantly greater improvements in physical and mental health compared with participants assigned to Local Community Resources. Both groups increased in disability ratings over 12 months, with no difference between groups. Multifaceted supports delivered by the National Career Coach Program increased employment, earnings, mental health, and physical health over 1 year. These significant differences appeared even though control group participants achieved considerable employment success.

The effect of height on estimates of the change in BMI-based prevalence of childhood obesity.

BACKGROUND/OBJECTIVES: Body mass index (BMI, body mass/height2) is biased toward height in children. Here we investigate how change in population height affected change in BMI-based estimates of the prevalence of overweight and obesity in Australian children. SUBJECTS/METHODS: Height, weight, and percent body fat (%BF) were measured at ages 8, 10, and 12 years (1855 sets of measures). Age-specific relationships between BMI and height were derived, adjusting for %BF, to estimate the degree of height bias inherent in BMI. Then, from cross-sectional measurements recorded in 1985 (N = 2388) and 1995 (N = 2148) in 8, 10, and 12 year olds, changes in overweight/obesity prevalences were calculated before and after accounting for the BMI-height bias. RESULTS: Estimates of the effect of height on BMI following adjustment for %BF were similar across age groups and all were significant at p < 0.001. Referring to 12 year olds, at the same %BF for a 1% increase in height there was 0.77% (95% CI 0.55, 0.99) increase in BMI in boys, and 0.74% (0.28, 1.02) increase in girls. Between 1985 and 1995, mean height of 12-year-old boys and girls increased 3.9 and 3.2 cm, respectively. In 1985 unadjusted prevalences of combined overweight/obesity in boys and girls were 13.5% and 13.0%, respectively, and in 1995 were 24% and 24.5%. The latter values were reduced to 21.6% and 22.6% after adjusting for increased height. CONCLUSIONS: Previously reported increases in childhood overweight/obesity in Australia between 1985 and 1995 were likely to be moderately overestimated as a result of increased population height; suggesting that population height be taken into account in any pediatric investigation of changes in overweight/obesity prevalence over time.

Immune Pharmacodynamic Responses of the Novel Cancer Immunotherapeutic Imprime PGG in Healthy Volunteers.

Imprime PGG (Imprime) is an i.v. administered, yeast ß-1,3/1,6 glucan in clinical development with checkpoint inhibitors. Imprime-mediated innate immune activation requires immune complex formation with naturally occurring IgG anti-ß glucan Abs (ABA). We administered Imprime to healthy human volunteers to assess the necessity of ABA for Imprime-mediated immunopharmacodynamic (IPD) changes. Imprime (4 mg/kg) was administered i.v. in single and multiple infusions. Subsets of subjects were premedicated with antihistamine and corticosteroid. Peripheral blood was measured before, during and after Imprime administration for IPD changes (e.g., ABA, circulating immune complexes, complement activation, complete blood counts, cytokine/chemokine, and gene expression changes). IPD changes were analyzed based on pretreatment serum ABA levels: low-ABA (<20 µg/ml), mid-ABA (≥20-50 µg/ml), and high-ABA (≥50 µg/ml). At the end of infusion, free serum ABA levels decreased, circulating immune complex levels increased, and complement activation was observed. At ∼1-4 h after end of infusion, increased expression of cytokines/chemokines, a 1.5-4-fold increase in neutrophil and monocyte counts and a broad activation of innate immune genes were observed. Low-ABA subjects typically showed minimal IPD changes except when ABA levels rose above 20 µg/ml after repeated Imprime dosing. Mild-to-moderate infusion-related reactions occurred in subjects with ABA ≥20 µg/ml. Premedications alleviated some of the infusion-related reactions, but also inhibited cytokine responses. In conclusion, ABA levels, being critical for Imprime-mediated immune activation may provide a plausible, mechanism-based biomarker to identify patients most likely to respond to Imprime-based anticancer immunotherapy.

Anatomic accuracy of airway training manikins compared with humans.

Airway simulators, or training manikins, are frequently used in research studies for device development and training purposes. This study was designed to determine the anatomic accuracy of the most frequently used low-fidelity airway training manikins. Computerised tomography scans and ruler measurements were taken of the SynDaver® , Laerdal® and AirSim® manikins. These measurements were compared with human computerised tomography (CT) scans (n = 33) from patients at the University of Michigan Medical Center or previously published values. Manikin measurements were scored as a percentile among the distribution of the same measurements in the human population and 10 out of 27 manikin measurements (nine measurements each in three manikins) were outside of two standard deviations from the mean in the participants. All three manikins were visually identifiable as outliers when plotting the first two dimensions from multidimensional scaling. In particular, the airway space between the epiglottis and posterior pharyngeal wall, through which airway devices must pass, was too large in all three manikins. SynDaver, Laerdal and AirSim manikins do not have anatomically correct static dimensions in relation to humans and these inaccuracies may lead to imprecise airway device development, negatively affect training and cause over-confidence in users.

[Recommendations for Performing Bronchoscopy in Times of the COVID-19 Pandemic - Update 12/2020]. / Empfehlungen zur Durchführung einer Bronchoskopie in Zeiten der COVID-19-Pandemie: Update 12/2020.

The SARS-CoV-19 pandemic continues to be globally related with significant morbidity and mortality, making protective measures to prevent transmission of the virus still necessary. Healthcare employees are exposed to a higher risk of infection and this is particularly true when performing aerosol-generating procedures such as bronchoscopy.Since the publication of recommendations for performing a bronchoscopy in the times of COVID-19 more than six months ago, the risk situation has not changed significantly, but due to the considerable gain in knowledge in the meantime, an update of the recommendations was necessary.The updated recommendations include the reduction of aerosol formation, the personal protection of the people involved in the procedure, as well as measures to better organize the processes in the endoscopy suite in order to perform bronchoscopic procedures securely even in times of COVID-19.

[Recommendations for Performing Bronchoscopy in Times of the COVID-19 Pandemic]. / Empfehlungen zur Durchführung einer Bronchoskopie in Zeiten der COVID-19-Pandemie.

COVID-19, caused by coronavirus SARS-CoV-2 is a new and ongoing infectious disease affecting healthcare systems worldwide. Healthcare worker are at high risk for COIVD-19 and many have been infected or even died in countries severely affected by COVID-19 like China or Italy. Bronchoscopy causes cough and aerosol production and has to be considered a significant risk for the staff to get infected. Particular recommendations should guide to prevent spreading COVID-19 and to protect healthcare worker when performing a bronchoscopy.

Engineering Quantum States of Matter for Atomic Clocks in Shallow Optical Lattices.

We investigate the effects of stimulated scattering of optical lattice photons on atomic coherence times in a state-of-the art ^{87}Sr optical lattice clock. Such scattering processes are found to limit the achievable coherence times to less than 12 s (corresponding to a quality factor of 1×10^{16}), significantly shorter than the predicted 145(40) s lifetime of ^{87}Sr's excited clock state. We suggest that shallow, state-independent optical lattices with increased lattice constants can give rise to sufficiently small lattice photon scattering and motional dephasing rates as to enable coherence times on the order of the clock transition's natural lifetime. Not only should this scheme be compatible with the relatively high atomic density associated with Fermi-degenerate gases in three-dimensional optical lattices, but we anticipate that certain properties of various quantum states of matter-such as the localization of atoms in a Mott insulator-can be used to suppress dephasing due to tunneling.

A Systematic Review of Advocacy Curricula in Graduate Medical Education.

BACKGROUND: Professionalism standards encourage physicians to participate in public advocacy on behalf of societal health and well-being. While the number of publications of advocacy curricula for GME-level trainees has increased, there has been no formal effort to catalog them. OBJECTIVE: To systematically review the existing literature on curricula for teaching advocacy to GME-level trainees and synthesize the results to provide a resource for programs interested in developing advocacy curricula. METHODS: A systematic literature review was conducted to identify articles published in English that describe advocacy curricula for graduate medical education trainees in the USA and Canada current to September 2017. Two reviewers independently screened titles, abstracts, and full texts to identify articles meeting our inclusion and exclusion criteria, with disagreements resolved by a third reviewer. We abstracted information and themes on curriculum development, implementation, and sustainability. Learning objectives, educational content, teaching methods, and evaluations for each curriculum were also extracted. RESULTS: After reviewing 884 articles, we identified 38 articles meeting our inclusion and exclusion criteria. Curricula were offered across a variety of specialties, with 84% offered in primary care specialties. There was considerable heterogeneity in the educational content of included advocacy curriculum, ranging from community partnership to legislative advocacy. Common facilitators of curriculum implementation included the American Council for Graduate Medical Education requirements, institutional support, and preexisting faculty experience. Common barriers were competing curricular demands, time constraints, and turnover in volunteer faculty and community partners. Formal evaluation revealed that advocacy curricula were acceptable to trainees and improved knowledge, attitudes, and reported self-efficacy around advocacy. DISCUSSION: Our systematic review of the medical education literature identified several advocacy curricula for graduate medical education trainees. These curricula provide templates for integrating advocacy education into GME-level training programs across specialties, but more work needs to be done to define standards and expectations around GME training for this professional activity.

Peripartum interventions resulting in reduced perinatal mortality rates, and birth asphyxia rates, over 18 years in a tertiary centre in South India: a retrospective study.

OBJECTIVE: To study the changes in the rates of perinatal mortality, birth asphyxia, and caesarean sections in relation to interventions implemented over the past 18 years, in a tertiary centre in South India. DESIGN: Retrospective study. SETTING: Labour and maternity unit of a tertiary centre in South India. POPULATION OR SAMPLE: Women who gave birth between 2000 and 2018. METHODS: Information from perinatal audits, chart reviews, and data retrieved from the electronic database were used. Interventions implemented during this time period were audits and training, obstetric re-organisation, and minor changes in staffing and infrastructure. MAIN OUTCOME MEASURES: Main outcome measures were perinatal mortality rate, birth asphyxia rate, and caesarean section rate. RESULTS: Perinatal mortality rate decreased from 44 per 1000 births in 2000 to 16.4 per 1000 births in 2018 (P < 0.001). The rates of babies born with birth asphyxia requiring admission to the neonatal unit decreased from 24 per 1000 births in 2001 to 0.7 per 1000 births in 2018 (P < 0.00001). The overall caesarean section rate was maintained close to 30%. CONCLUSION: In a large tertiary hospital in South India, with 14 000 deliveries per year, a policy of rigorous audits of stillbirths and birth asphyxia, electronic fetal monitoring, and the introduction of standardised criteria for trial of scar, reduced the perinatal mortality and the rate of babies born with birth asphyxia over the past 18 years, without an increase in the caesarean section rate. TWEETABLE ABSTRACT: Rigorous perinatal audits with training in fetal cardiotocography, decreased birth asphyxia, without a major increase in caesarean rates.

Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization.

Previously, we demonstrated that nitric oxide (NO) synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor sepiapterin (SP) inhibits tumor progression. Endothelial dysfunction characterizes the poorly functional vasculature of solid tumors, and since NO is critical for regulation of endothelial function we asked whether SP, by recoupling NOS, improves tumor vasculature structure and function-enhancing chemotherapeutic delivery and response to radiotherapy. MMTV-neu mice with spontaneous breast tumors were treated with SP by oral gavage and evaluated by multispectral optoacoustic tomographic analysis of tumor HbO2 and by tissue staining for markers of hypoxia, blood perfusion, and markers of endothelial and smooth muscle proteins. Recoupling tumor NOS activity results in vascular normalization observed as reduced tumor hypoxia, improved tumor percentage of HbO2 and perfusion, as well as increased pericyte coverage of tumor blood vessels. The normalized vasculature and improved tumor oxygenation led to a greater than 2-fold increase in radiation-induced apoptosis compared with radiation or SP alone. High-performance liquid chromatography analysis of tumor doxorubicin levels showed a greater than 50% increase in doxorubicin uptake and a synergistic effect on tumor cell apoptosis. This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy.

Imaging Optical Frequencies with 100 µHz Precision and 1.1 µm Resolution.

We implement imaging spectroscopy of the optical clock transition of lattice-trapped degenerate fermionic Sr in the Mott-insulating regime, combining micron spatial resolution with submillihertz spectral precision. We use these tools to demonstrate atomic coherence for up to 15 s on the clock transition and reach a record frequency precision of 2.5×10^{-19}. We perform the most rapid evaluation of trapping light shifts and record a 150 mHz linewidth, the narrowest Rabi line shape observed on a coherent optical transition. The important emerging capability of combining high-resolution imaging and spectroscopy will improve the clock precision, and provide a path towards measuring many-body interactions and testing fundamental physics.

HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy-treated HIV/HCV-co-infected subjects.

The impact of hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono-infected when compared to HIV/HCV co-infected on antiretroviral therapy (ART) remains poorly understood. A total of 78 African American subjects HCV viraemic/naïve to HCV treatment (33 HCV genotype 1 mono-infected, 45 ART-treated HIV/HCV genotype 1 co-infected) were studied. Clinical and liver enzyme measurements were performed. Whole blood was analysed for immune subset changes by flow cytometry. Peripheral blood mononuclear cells (PBMC) were used for same-day constitutive and in vitro Interferon (IFN)-α-induced signal transducer and activator of transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition-mediated IFN-γ production. Statistical analysis was performed using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T-cell activation/exhaustion, and constitutive STAT-1 phosphorylation compared to HCV. In contrast, CD4+ FoxP3+ CD25+ frequency, IFN-αR expression on NK cells, as well as constitutive and IFN-α-induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load and CD4+ T-cell count had an opposite effect between the two groups on NK cell activity and T-cell activation, respectively. HCV viral load in ART-treated HIV/HCV co-infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono-infection. The more pronounced immune modulation noted in ART-treated HIV-co-infected/untreated HCV viraemic subjects may impact HCV disease progression and/or response to immunotherapy.

Diffusion MRI in early cancer therapeutic response assessment.

Imaging biomarkers for the predictive assessment of treatment response in patients with cancer earlier than standard tumor volumetric metrics would provide new opportunities to individualize therapy. Diffusion-weighted MRI (DW-MRI), highly sensitive to microenvironmental alterations at the cellular level, has been evaluated extensively as a technique for the generation of quantitative and early imaging biomarkers of therapeutic response and clinical outcome. First demonstrated in a rodent tumor model, subsequent studies have shown that DW-MRI can be applied to many different solid tumors for the detection of changes in cellularity as measured indirectly by an increase in the apparent diffusion coefficient (ADC) of water molecules within the lesion. The introduction of quantitative DW-MRI into the treatment management of patients with cancer may aid physicians to individualize therapy, thereby minimizing unnecessary systemic toxicity associated with ineffective therapies, saving valuable time, reducing patient care costs and ultimately improving clinical outcome. This review covers the theoretical basis behind the application of DW-MRI to monitor therapeutic response in cancer, the analytical techniques used and the results obtained from various clinical studies that have demonstrated the efficacy of DW-MRI for the prediction of cancer treatment response. Copyright © 2016 John Wiley & Sons, Ltd.

An SOS inhibitor that binds to free RecA protein: the PsiB protein.

The process of bacterial conjugation involves the transfer of a conjugative plasmid as a single strand. The potentially deleterious SOS response, which is normally triggered by the appearance of single-stranded DNA, is suppressed in the recipient cell by a conjugative plasmid system centered on the product of the psiB gene. The F plasmid PsiB protein inhibits all activities of the RecA protein, including DNA binding, DNA strand exchange, and LexA protein cleavage. The proteins known to negatively regulate recombinases, such as RecA or Rad51, generally work at the level of dismantling the nucleoprotein filament. However, PsiB binds to RecA protein that is free in solution. The RecA-PsiB complex impedes formation of RecA nucleoprotein filaments on DNA.

Parametric Response Mapping of Bronchiolitis Obliterans Syndrome Progression After Lung Transplantation.

Bronchiolitis obliterans syndrome (BOS) remains a major complication after lung transplantation. Air trapping and mosaic attenuation are typical radiological features of BOS; however, quantitative evaluation remains troublesome. We evaluated parametric response mapping (PRM, voxel-to-voxel comparison of inspiratory and expiratory computed tomography [CT] scans) in lung transplant recipients diagnosed with BOS (n = 20) and time-matched stable lung transplant recipients (n = 20). Serial PRM measurements were performed prediagnosis, at time of BOS diagnosis, and postdiagnosis (Tpre , T0 , and Tpost , respectively), or at a postoperatively matched time in stable patients. PRM results were correlated with pulmonary function and confirmed by microCT analysis of end-stage explanted lung tissue. Using PRM, we observed an increase in functional small airway disease (fSAD), from Tpre to T0 (p = 0.006) and a concurrent decrease in healthy parenchyma (p = 0.02) in the BOS group. This change in PRM continued to Tpost , which was significantly different compared to the stable patients (p = 0.0002). At BOS diagnosis, the increase in fSAD was strongly associated with a decrease in forced expiratory volume in 1 s (p = 0.011). Micro-CT confirmed the presence of airway obliteration in a sample of a BOS patient identified with 67% fSAD by PRM. We demonstrated the use of PRM as an adequate output to monitor BOS progression in lung transplant recipients.