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Background Point of care ultrasound (POCUS) education has grown significantly over the past two decades. Like most curricular items, POCUS education is siloed within individual graduate medical education (GME) programs. The purpose of this study was to evaluate the effectiveness of a shared GME POCUS curriculum between five GME programs at a single institution. Methods Post-graduate-year-1 (PGY-1) residents from emergency medicine (EM), family medicine (FM), internal medicine (IM), combined internal medicine-pediatrics (IM-Peds) and combined emergency medicine-pediatrics (EM-Peds) residency programs were enrolled in a core POCUS curriculum. The curriculum included eleven asynchronous online learning modules and ten hands-on training sessions proctored by sonographers and faculty physicians with POCUS expertise. Data was gathered about the curriculum’s effectiveness including participation, pre- and post-curricular surveys, pre- and post-knowledge assessments, and an objective skills assessment. Results Of the 85 residents enrolled, 61 (72%) participated in the curriculum. Engagement varied between programs, with attendance at hands-on sessions varying the most (EM 100%, EM-Peds 100%, FM 40%, IM 22%, Med-Peds 11%). Pre- and post-knowledge assessment scores improved for all components of the curriculum. Participants felt significantly more confident with image acquisition, anatomy recognition, interpreting images and incorporating POCUS findings into clinical practice ( p  < 0.001) after completing the curriculum. Conclusion In this shared GME POCUS curriculum, we found significant improvement in POCUS knowledge, attitudes, and psychomotor skills. This shared approach may be a viable way for other institutions to provide POCUS education broadly to their GME programs.

Superior mesenteric artery syndrome (SMAS), also known as Wilkie’s syndrome, is an exceedingly rare condition concerning intestinal obstruction. SMAS occurs when the space between the superior mesenteric artery (SMA) and the abdominal aorta narrows, resulting in compression of the duodenum. Functionally, the SMA supplies the distal duodenum, two-thirds of the transverse colon, and the pancreas. The location of the SMA is at about the level of the first lumbar vertebra branching off the anterior portion of the abdominal aorta. Generally, SMAS is due to rapid, excessive weight loss, resulting in the loss of the duodenal fat pad. The loss of the fat pad consequently changes the angle between the abdominal aorta and the SMA, or aortomesenteric angle, causing intestinal obstruction. Typical symptoms of acute cases of SMAS include postprandial abdominal pain, nausea, and vomiting; however, chronic cases may present with vague gastrointestinal symptoms and further weight loss. Herein, we discuss the case of a woman with chronic abdominal pain and previous substantial weight loss in whom we note features consistent with SMAS. Several factors can contribute to the syndrome, but, most commonly, it is observed after sudden, significant weight loss accompanied by nonspecific symptoms such as postprandial epigastric pain, emesis, and anorexia. Given that there is continued debate whether the syndrome even exists, SMAS is usually a diagnosis of exclusion, if diagnosed at all. First-line treatment involves conservative management, but if symptoms become too severe, several proven surgical methods are available. SMAS is a rare condition and is difficult to diagnose, but it should be suspected if clinical manifestations are present. This case illustrates the need for primary care physicians to receive additional training on the recognition of rare diseases to broaden their differentials. Training of this sort is especially crucial for rural family medicine residency programs focused on producing full-spectrum physicians.

Introduction Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non‐steroidal anti‐inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short‐term treatment of transgenic AD mice with the pro‐inflammatory cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM‐CSF/sargramostim to safely ameliorate AD symptoms/pathology. Methods A randomized, double‐blind, placebo‐controlled trial was conducted in mild‐to‐moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow‐up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. Results Sargramostim treatment expectedly changed innate immune system markers, with no drug‐related serious adverse events or amyloid‐related imaging abnormalities. At end of treatment (EOT), the Mini‐Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH‐L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo. Discussion The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long‐term safety and efficacy of GM‐CSF/sargramostim in AD is warranted.

BACKGROUNDSepsis encompasses considerable biological and clinical heterogeneity. Previously, 2 phenotypes (\"hyperinflammatory\" and \"hypoinflammatory\") have been consistently identified within sepsis via latent class analysis. These phenotypes differ in their biological features, clinical outcomes, and therapeutic responses to interventions. Prior studies of sepsis heterogeneity have focused primarily on the host response. Here, we investigate the potential influence of the causative pathogen on sepsis heterogeneity and pathobiology.METHODSWe performed a retrospective observational analysis of 8,280 critically ill patients with sepsis to identify associations between pathogen characteristics and the hyperinflammatory and hypoinflammatory patient phenotypes. We also performed controlled murine and swine modeling of sepsis and lung injury and a secondary analysis of 449 patients enrolled in the EUPHRATES randomized controlled trial.RESULTSPathogen characteristics (pathogen identity, burden, virulence, and anatomic site of infection) were strongly and independently associated with the previously reported phenotypes. In a cohort of critically ill patients with sepsis, infection with gram-negative pathogens, primarily Enterobacterales spp. (e.g., Escherichia coli, Klebsiella pneumoniae), was strongly associated with the hyperinflammatory phenotype. The hyperinflammatory phenotype was also independently associated with increased pathogen burden, virulence, and initial anatomic site of infection. In controlled murine and swine modeling, both the identity and burden of the pathogen provoked key biological features of the hyperinflammatory phenotype. Among patients with sepsis, the prognostic value of lactate clearance varied substantially by phenotype. In a secondary analysis of a randomized trial of polymyxin B hemoadsorption (which removes circulating endotoxin), hypoinflammatory patients experienced worse survival.CONCLUSIONSOur results demonstrate the central importance of pathogen features in the clinical and biological heterogeneity of sepsis. Future studies of sepsis pathobiology and heterogeneity should expand their scope beyond the host response, as understanding pathogen-host interactions will be crucial in the development of precision therapeutic strategies to improve patient outcomes.TRIAL REGISTRATIONEUPHRATES trial NCT01046669.FUNDING5P30AG024824, IK2CX002766, R01HL144599, K24HL159247, R01HL158626, R01HL173531, R35GM142992, R35GM145330, R35GM136312, K23HL166880, R35HL140026.

We identified 2 fatal cases of persons infected with hantavirus in Arizona, USA, 2020; 1 person was co-infected with SARS-CoV-2. Delayed identification of the cause of death led to a public health investigation that lasted ≈9 months after their deaths, which complicated the identification of a vector or exposure.

PIP 3 -dependent Rac exchanger 1 (P-Rex1) is abundantly expressed in neutrophils and plays central roles in chemotaxis and cancer metastasis by serving as a guanine-nucleotide exchange factor (GEF) for Rac. The enzyme is synergistically activated by PIP 3 and heterotrimeric Gβγ subunits, but mechanistic details remain poorly understood. While investigating the regulation of P-Rex1 by PIP 3 , we discovered that Ins(1,3,4,5)P 4 (IP 4 ) inhibits P-Rex1 activity and induces large decreases in backbone dynamics in diverse regions of the protein. Cryo-electron microscopy analysis of the P-Rex1·IP 4 complex revealed a conformation wherein the pleckstrin homology (PH) domain occludes the active site of the Dbl homology (DH) domain. This configuration is stabilized by interactions between the first DEP domain (DEP1) and the DH domain and between the PH domain and a 4-helix bundle (4HB) subdomain that extends from the C-terminal domain of P-Rex1. Disruption of the DH–DEP1 interface in a DH/PH-DEP1 fragment enhanced activity and led to a more extended conformation in solution, whereas mutations that constrain the occluded conformation led to decreased GEF activity. Variants of full-length P-Rex1 in which the DH–DEP1 and PH–4HB interfaces were disturbed exhibited enhanced activity during chemokine-induced cell migration, confirming that the observed structure represents the autoinhibited state in living cells. Interactions with PIP 3 -containing liposomes led to disruption of these interfaces and increased dynamics protein-wide. Our results further suggest that inositol phosphates such as IP 4 help to inhibit basal P-Rex1 activity in neutrophils, similar to their inhibitory effects on phosphatidylinositol-3-kinase.

We report on the evolution of tropospheric nitrogen dioxide (NO 2 ) over Spain, focusing on the densely populated cities of Barcelona, Bilbao, Madrid, Sevilla and Valencia, during 17 years, from 1996 to 2012. This data series combines observations from in-situ air quality monitoring networks and the satellite-based instruments GOME and SCIAMACHY. The results in these five cities show a smooth decrease in the NO 2 concentrations of ~2% per year in the period 1996–2008, due to the implementation of emissions control environmental legislation and a more abrupt descend of ~7% per year from 2008 to 2012 as a consequence of the economic recession. In the whole Spanish territory the NO 2 levels have decreased by ~22% from 1996 to 2012. Statistical analysis of several economic indicators is used to investigate the different factors driving the NO 2 concentration trends over Spain during the last two decades.

PIP 3 -dependent Rac exchanger 1 (P-Rex1) is abundantly expressed in neutrophils and plays central roles in chemotaxis and cancer metastasis by serving as a guanine-nucleotide exchange factor (GEF) for Rac. The enzyme is synergistically activated by PIP 3 and heterotrimeric Gβγ subunits, but mechanistic details remain poorly understood. While investigating the regulation of P-Rex1 by PIP 3 , we discovered that Ins(1,3,4,5)P 4 (IP 4 ) inhibits P-Rex1 activity and induces large decreases in backbone dynamics in diverse regions of the protein. Cryo-electron microscopy analysis of the P-Rex1·IP 4 complex revealed a conformation wherein the pleckstrin homology (PH) domain occludes the active site of the Dbl homology (DH) domain. This configuration is stabilized by interactions between the first DEP domain (DEP1) and the DH domain and between the PH domain and a 4-helix bundle (4HB) subdomain that extends from the C-terminal domain of P-Rex1. Disruption of the DH–DEP1 interface in a DH/PH-DEP1 fragment enhanced activity and led to a more extended conformation in solution, whereas mutations that constrain the occluded conformation led to decreased GEF activity. Variants of full-length P-Rex1 in which the DH–DEP1 and PH–4HB interfaces were disturbed exhibited enhanced activity during chemokine-induced cell migration, confirming that the observed structure represents the autoinhibited state in living cells. Interactions with PIP 3 -containing liposomes led to disruption of these interfaces and increased dynamics protein-wide. Our results further suggest that inositol phosphates such as IP 4 help to inhibit basal P-Rex1 activity in neutrophils, similar to their inhibitory effects on phosphatidylinositol-3-kinase.