Let-7 restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis.

Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that the let-7 miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation to safeguard the lung from spontaneous alveolar destruction and fibrosis. Using mice and organoid models with genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells, we demonstrate prevents AT1 differentiation and results in aberrant accumulation of AT2 transitional cells in progressive pulmonary fibrosis. Integration of enhanced AGO2 UV-crosslinking and immunoprecipitation sequencing (AGO2-eCLIP) with RNA-sequencing from AT2 cells uncovered the induction of direct targets of let-7 in an oncogene feed-forward regulatory network including BACH1/EZH2 which drives an aberrant fibrotic cascade. Additional analyses by CUT&RUN-sequencing revealed loss of let-7afd hampers AT1 differentiation by eliciting aberrant histone EZH2 methylation which prevents the exit of AT2 transitional cells into terminal AT1s. This study identifies let-7 as a key gatekeeper of post-transcriptional and epigenetic chromatin signals to prevent AT2-driven pulmonary fibrosis.

Assessing ChatGPT 4.0's test performance and clinical diagnostic accuracy on USMLE STEP 2 CK and clinical case reports.

While there is data assessing the test performance of artificial intelligence (AI) chatbots, including the Generative Pre-trained Transformer 4.0 (GPT 4) chatbot (ChatGPT 4.0), there is scarce data on its diagnostic accuracy of clinical cases. We assessed the large language model (LLM), ChatGPT 4.0, on its ability to answer questions from the United States Medical Licensing Exam (USMLE) Step 2, as well as its ability to generate a differential diagnosis based on corresponding clinical vignettes from published case reports. A total of 109 Step 2 Clinical Knowledge (CK) practice questions were inputted into both ChatGPT 3.5 and ChatGPT 4.0, asking ChatGPT to pick the correct answer. Compared to its previous version, ChatGPT 3.5, we found improved accuracy of ChatGPT 4.0 when answering these questions, from 47.7 to 87.2% (p = 0.035) respectively. Utilizing the topics tested on Step 2 CK questions, we additionally found 63 corresponding published case report vignettes and asked ChatGPT 4.0 to come up with its top three differential diagnosis. ChatGPT 4.0 accurately created a shortlist of differential diagnoses in 74.6% of the 63 case reports (74.6%). We analyzed ChatGPT 4.0's confidence in its diagnosis by asking it to rank its top three differentials from most to least likely. Out of the 47 correct diagnoses, 33 were the first (70.2%) on the differential diagnosis list, 11 were second (23.4%), and three were third (6.4%). Our study shows the continued iterative improvement in ChatGPT's ability to answer standardized USMLE questions accurately and provides insights into ChatGPT's clinical diagnostic accuracy.

Differing Approaches to Pain Management for Intrauterine Device Insertion and Maintenance: A Scoping Review.

Intrauterine devices (IUDs) are considered a reliable contraceptive option for women, but they can come with side effects. There is a disconnect in standard guidelines for IUD insertion within and without the U.S. The objective of this review was to address a gap in the literature regarding official procedures for pain management during IUD implantation. This scoping review was initiated using keywords to extract relevant articles from multiple databases: U.S. National Library of Medicine National Institutes of Health (PubMed), MEDLINE (Ovid), and Excerpta Medica dataBASE (EMBASE, Ovid). Initially, 457 articles were identified and after a rigorous screening and selection process, 37 articles were chosen to be further assessed to ascertain if they met the study's inclusion criteria. Those 37 articles were further evaluated fully to check for relevancy. From that process, 19 articles were chosen for the review, and all passed quality assessment evaluations using the JB Appraisal Tools. To best address the research question, the data from the 19 articles were divided into three categories: 1) circumstantial factors, 2) non-pharmacological methods, and 3) pharmacological methods. Circumstantially, women with previous vaginal deliveries experienced the lowest pain during the procedure, and nulligravid (never pregnant) women experienced the most pain. Lower pain scores were reported by lactating women compared to non-lactating. Black women experienced the most anticipated pain compared to other races. Regarding non-pharmacological methods, different insertion techniques, tools, and the use of a cold compress were found to not affect the level of pain during IUD insertion. Lastly, it was shown that pharmacological methods such as lidocaine gel, lidocaine paracervical block, and lidocaine combined with either diclofenac or prilocaine decreased pain scores at different time stamps of the procedure. Also, oral ketorolac and a vaginal combination of misoprostol and dinoprostone helped reduce pain. Findings from this scoping review revealed a lack of uniformity across practices when performing IUD insertions, possibly due to differences in procedures across circumstantial factors, non-pharmacological methods, and pharmacological methods. More research is needed to investigate the intricacies of pain with IUD insertion. Moving forward, especially following a potential increase in the use of IUDs after the reversal of Roe v. Wade, establishing this gap may lead to a more refined standardized protocol to mitigate pain with IUD insertions.

Investigating the Accuracy of Wheelchair Push Counts Measured by Fitness Watches: A Systematic Review.

Wheelchair users face an elevated risk of metabolic syndromes due to their sedentary lifestyles. One of the methods to prevent and treat various metabolic syndromes is regular physical activity, which varies among individuals based on their abilities. Monitoring physical activity among them can be performed by using wearable physical activity monitors (WPAMs), which utilize accelerometers and algorithms to track wheelchair push counts. However, the accuracy of push count detection varies among the devices due to technological limitations. The objective of this literature review was to evaluate the accuracy of WPAMs, specifically smartwatches, in measuring physical activity in the wheelchair population. This systematic literature review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in November 2022 for relevant articles. The initial search yielded 447 articles, seven of which were selected based on the inclusion criteria, which were as follows: participant ability to maneuver a wheelchair, arm- or wrist-worn WPAMs, and articles published after 2017. Among the devices studied, the Apple Watch was determined to be the most accurate calibration system for wheelchair users, with the lowest mean absolute percentage error (MAPE). Each succeeding generation of the Apple Watch (first to fourth) studied was more accurate than the previous. The review demonstrates that research on wheelchair fitness tracking remains scarce and further studies are required to address this issue.

Over but not gone: lingering epigenetic effects of COVID-19.

'Long COVID' affects nearly one in five adults who have had coronavirus disease 2019 (COVID-19), yet the mechanisms underlying this disorder remain poorly understood. In a new study, Cheong et al. show that the epigenetic and transcriptional state of myeloid immune cells and their progenitors are durably altered in patients following severe COVID-19.

Hematopoietic stem and progenitor cells confer cross-protective trained immunity in mouse models.

Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called "trained immunity." However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to Mycobacterium avium infection. scRNA-seq analysis revealed that HSPCs activate interferon gamma-response genes heterogeneously upon primary challenge, while rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was sufficient to induce similar training. Mice transplanted with influenza-trained HSPCs displayed enhanced immunity against M. avium challenge and vice versa, demonstrating cross protection against antigenically distinct pathogens. Together, these results indicate that heterogeneous responses to infection by HSPCs can lead to long-term production of bone marrow derived macrophages with enhanced function and confer cross-protection against alternative pathogens.

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and long COVID patients.

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as long COVID. The underlying pathophysiology of long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of SARS-CoV-2 infection and certain other post-COVID sequelae, their potential role in long COVID is important to investigate. Here, we apply a well-established, unbiased, proteome-wide autoantibody detection technology (T7 phage-display assay with immunoprecipitation and next-generation sequencing, PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected that separated individuals with prior SARS-CoV-2 infection from those never exposed to SARS-CoV-2, we did not detect patterns of autoreactivity that separated individuals with long COVID from individuals fully recovered from COVID-19. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and long COVID was apparent by this assay.

BATF2 promotes HSC myeloid differentiation by amplifying IFN response mediators during chronic infection.

Basic leucine zipper ATF-like transcription factor 2 (BATF2), an interferon-activated immune response regulator, is a key factor responsible for myeloid differentiation and depletion of HSC during chronic infection. To delineate the mechanism of BATF2 function in HSCs, we assessed Batf2 KO mice during chronic infection and found that they produced less pro-inflammatory cytokines, less immune cell recruitment to the spleen, and impaired myeloid differentiation with better preservation of HSC capacity compared to WT. Co-IP analysis revealed that BATF2 forms a complex with JUN to amplify pro-inflammatory signaling pathways including CCL5 during infection. Blockade of CCL5 receptors phenocopied Batf2 KO differentiation defects, whereas treatment with recombinant CCL5 was sufficient to rescue IFNγ-induced myeloid differentiation and recruit more immune cells to the spleen in Batf2 KO mice. By revealing the mechanism of BATF2-induced myeloid differentiation of HSCs, these studies elucidate potential therapeutic strategies to boost immunity while preserving HSC function during chronic infection.

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients.

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as Long COVID. The underlying pathophysiology of Long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of COVID infection and certain other post-COVID sequelae, their potential role in Long COVID is important to investigate. Here we apply a well-established, unbiased, proteome-wide autoantibody detection technology (PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with Long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected which separates individuals with prior COVID infection from those never exposed to COVID, we did not detect patterns of autoreactivity that separate individuals with Long COVID relative to individuals fully recovered from SARS-CoV-2 infection. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and Long COVID was apparent by this assay.

Let the Kid Speak: Dynamics of Triadic Medical Interactions Involving Pediatric Patients.

Communication in healthcare represents the complex interplay between multiple individual and contextual factors unfolding over the course of the medical encounter. Despite significant improvements in patient-centered care delivery, studies of health communication typically focus exclusively on clinical interactions between adult patients and their clinicians. Much less is known about non-dyadic interactions, such as pediatric triads involving a child patient and accompanying parent. Understanding the dynamics of triadic pediatric healthcare communication is the first step toward evaluating and ultimately optimizing these healthcare interactions. Thus, we undertook a mixed-method analysis of 28 audio-recorded triadic medical interactions between healthcare providers, pediatric asthma and allergy patients, and their parents to explore the prevalence of various features of these interactions. Our findings point to mechanisms through which healthcare providers and parents may facilitate or hinder children's involvement in their own asthma and allergy care, including interruptions, unclarified technical medical language, the flow of information exchange, and the formation of dyadic conversational partnerships (coalitions) between providers and parents. Our analyses further reveal that children's participation during their medical visits was minimal (13% of the interaction). Providers in our sample elicited input directly from pediatric patients more often than from parents, though the difference was small. Taken together, these findings provide a foundation on which to develop training and communication interventions to ensure that children have a voice in their medical care.

Differences in United States college student physical activity and exercise self-efficacy based on gender and race/ethnicity.

OBJECTIVE: Disparities in physical activity (PA) and PA antecedents, such as exercise self-efficacy, based on the intersection of gender and race/ethnicity among college students are poorly understood. This study aimed to examine differences in PA and exercise self-efficacy based on the intersection of gender and race/ethnicity. METHODS: An online survey collected data on demographics (age, gender, race/ethnicity), PA, and exercise self-efficacy from students (n = 5341) enrolled in general health and wellness at a large Northeastern U.S. University. Differences in PA and exercise self-efficacy based on gender and race/ethnicity were examined using two-way ANOVAs. RESULTS: Analyses revealed significant differences in overall PA and exercise self-efficacy based on gender and race/ethnicity. A significant interaction between gender and race/ethnicity was found in relation to PA, but not exercise self-efficacy. CONCLUSION: Findings demonstrate the need for universities to tailor PA promotion efforts, and to consider how gender and race/ethnicity may intersect to influence PA participation.

Clonal hematopoiesis: Mutation-specific adaptation to environmental change.

Clonal hematopoiesis of indeterminate potential (CHIP) describes a widespread expansion of genetically variant hematopoietic cells that increases exponentially with age and is associated with increased risks of cancers, cardiovascular disease, and other maladies. Here, we discuss how environmental contexts associated with CHIP, such as old age, infections, chemotherapy, or cigarette smoking, alter tissue microenvironments to facilitate the selection and expansion of specific CHIP mutant clones. Further, we consider major remaining gaps in knowledge, including intrinsic effects, clone size thresholds, and factors affecting clonal competition, that will determine future application of this field in transplant and preventive medicine.

Pediatric tinnitus: The role of neuroimaging.

Tinnitus is defined as the perception of sound without an external source and can be categorized as either pulsatile or nonpulsatile (ie, continuous). A variety of etiologies have been reported to cause pediatric tinnitus, many with long-lasting implications due to hearing and concentration impairments. Therefore, imaging can be an essential part of the accurate and timely diagnosis of treatable etiologies. We describe neuroimaging findings in different etiologies of pediatric tinnitus. Etiologies of pulsatile tinnitus are frequently vascular in nature and include vascular loops, congenital vascular anomalies or variants, high riding jugular bulbs with or without a jugular bulb diverticulum, idiopathic intracranial hypertension, aneurysms, internal auditory canal hemangiomas, and petrous apex cephaloceles. Etiologies of continuous tinnitus frequently affect the middle/inner ear structures and include vestibular schwannomas, cholesteatomas, trauma, Chiari malformations, and labyrinthitis ossificans. CT and MR are often complementary modalities: CT is better suited to evaluate the integrity of the temporal osseous structures and MR is better suited to evaluate the vestibulocochlear nerve and to assess for the presence of any masses or malformations. Prompt diagnosis of the etiology of tinnitus in pediatric patients is important to avoid any potential long-term developmental impairments. In the approach to pediatric tinnitus, categorizing the symptoms as either pulsatile versus nonpulsatile and then being aware of the possible causes and imaging findings of either can assist both the clinician and the radiologist in making an expeditious diagnosis.

Pediatric spinal cord diffuse midline glioma, H3 K27-altered with intracranial and spinal leptomeningeal spread: A case report.

Primary spinal cord high-grade gliomas, including those histologically identified as glioblastoma (GBM), are a rare entity in the pediatric population but should be considered in the differential diagnosis of intramedullary lesions. Pediatric spinal cord high-grade gliomas have an aggressive course with poor prognosis. The aim of this case report is to present a 15-year-old female adolescent with histopathologically confirmed spinal cord GBM with H3F3A K27 M mutation consistent with a diffuse midline glioma (DMG), H3 K27-altered, CNS WHO grade 4 with leptomeningeal seeding on initial presentation. As imaging features of H3 K27-altered DMGs are non-specific and may mimic more frequently encountered neoplastic diseases as well as demyelinating disorders, severe neurological deficits at presentation with short duration, rapid progression, and early leptomeningeal seeding should however raise the suspicion for a pediatric-type diffuse high-grade glioma like DMG, H3 K27-altered.

Sex trafficking screening and intervention in the emergency department: A scoping review.

INTRODUCTION: Human sex trafficking is a global public health crisis. Emergency departments (EDs) are important access points for trafficked persons who seek medical care. However, because of victims' hesitancy to disclose their situation and health care practitioners' lack of training and institutional protocols, many trafficked persons go unrecognized. METHODS: We performed a scoping review of current literature. PubMed, SCOPUS, and reference lists were searched to identify articles for inclusion. We aimed to identify gaps in knowledge and shortcomings to assist this vulnerable population. Two reviewers independently screened literature search results and abstracted data from included studies. Descriptive analysis was conducted. RESULTS: We selected and analyzed 23 studies that focused on adult human sex trafficking identification, screening, interventions, or education in the ED. Eight (35%) of the publications used a survey model to quantitatively assess outcomes. Many of the other publications were descriptive or qualitative in nature, with some using a structured interview approach. We have observed that no validated or consistent screening tool exists for the identification of possible adult trafficked patients in the ED. However, we found that educational interventions and screening tools can improve health care practitioners' confidence, victim identification, and knowledge of "next steps" for victims. CONCLUSIONS: We found that most ED clinicians and staff have little or no formal training in sex trafficking victim identification, support, institutional protocols, or available local resources. Our review demonstrates a paucity of formal training programs, validated adult screening tools, and standardized institutional protocols to aid in the care of trafficked patients in the ED.

Differences in Glucose Readings Between Right Arm and Left Arm Using a Continuous Glucose Monitor.

OBJECTIVE: Continuous glucose monitoring (CGM) devices are used for evaluating real-time glucose levels to optimize diabetes management. There is limited information, however, on whether readings differ when a device is placed on the right versus the left arm. This study evaluated the mean difference in glucose levels between the right and left arm and the effect of unilateral arm exercise on this difference. The effect of an intermittent fasting diet on body fat percentage was also evaluated. RESEARCH DESIGN AND METHODS: In a prospective trial, 46 adult volunteers self-selected into the intermittent fasting (IF; N = 23) or free-living (FL; N = 23) diet group and were randomized into a unilateral arm exercise group. Volunteers had CGM sensors placed simultaneously on both arms for 12-14 days. RESULTS: The mean glucose level in the right arm was significantly higher than the left arm by 3.7 mg/dL (P < .001), and this result was unaffected by diet or arm exercise. Glucose levels were in euglycemic range for 75.2% of the time in the right arm and 67.5% in the left arm (P < .001). The change from baseline in body fat percentage between the IF and FL diet groups was not significant. CONCLUSIONS: Measured glucose level and time in euglycemic range differ per placement of the CGM device, and the implications of this difference should be considered in clinical practice and research.

Learning to Interpret Pediatric Vocal Fold Mobility: A Laryngeal Ultrasound Training Module.

OBJECTIVES/HYPOTHESIS: Vocal fold movement impairment (VFMI) in infants and children is most commonly evaluated by flexible nasolaryngoscopy (FNL). FNL in this population can be challenging due to movement, floppy supraglottic structures, or secretions. Laryngeal ultrasound (LUS) may be an alternative, less invasive means of evaluating VFMI that also decreases aerosolization during the COVID-19 pandemic. The primary objective was to examine LUS interpretation proficiency for VFMI via an educational module. A secondary outcome was to determine whether quantitative measurements increase interpretation accuracy. STUDY DESIGN: Prospective cohort trial. METHODS: Medical students, residents, fellows, faculty, and staff were recruited to complete the module, composed of a 13-minute teaching video followed by 20 cases. Participants determined both qualitatively (subjective assessment) and then quantitatively (through protractor measurements of the vocal fold to arytenoid angle) whether there was normal versus impaired vocal fold mobility. RESULTS: Thirty participants completed the LUS training module, and about one-third were otolaryngology residents. On average, each participant correctly identified 18 cases. The mean rank percent correct for quantitative measurements was significantly higher than that of qualitative interpretations (P < .0001). Measurements significantly caused participants to change their answer correctly compared to incorrectly (P < .0001). As the module progressed, there was no significant trend of more correct interpretations (P = .30). The sensitivity was higher for quantitative interpretations (89.0% vs. 87.3%) but specificity remained unchanged (92.6%). CONCLUSION: Quantitative measurements may increase LUS interpretation accuracy. There was not a specific number of cases interpreted to achieve learning proficiency. LUS is an easily learned method to evaluate for VFMI across all training levels. LEVEL OF EVIDENCE: 3 (local cohort study nonrandomized) Laryngoscope, 131:2545-2549, 2021.

A wearable patch for continuous analysis of thermoregulatory sweat at rest.

The body naturally and continuously secretes sweat for thermoregulation during sedentary and routine activities at rates that can reflect underlying health conditions, including nerve damage, autonomic and metabolic disorders, and chronic stress. However, low secretion rates and evaporation pose challenges for collecting resting thermoregulatory sweat for non-invasive analysis of body physiology. Here we present wearable patches for continuous sweat monitoring at rest, using microfluidics to combat evaporation and enable selective monitoring of secretion rate. We integrate hydrophilic fillers for rapid sweat uptake into the sensing channel, reducing required sweat accumulation time towards real-time measurement. Along with sweat rate sensors, we integrate electrochemical sensors for pH, Cl-, and levodopa monitoring. We demonstrate patch functionality for dynamic sweat analysis related to routine activities, stress events, hypoglycemia-induced sweating, and Parkinson's disease. By enabling sweat analysis compatible with sedentary, routine, and daily activities, these patches enable continuous, autonomous monitoring of body physiology at rest.

Double Vision and Gait Ataxia in an Immunocompetent 9-Year-Old Girl With Intracranial Phaeohyphomycosis.

ABSTRACT: A 9-year-old girl presented with morning headaches associated with vomiting, gait ataxia, and facial and ocular motor nerve palsies. Her initial imaging was concerning for demyelinating disease. After extensive infectious and rheumatologic workup returned negative, she was treated twice with intravenous immunoglobulin and intravenous steroids with near-complete resolution each time. She returned, however, with worsening neurologic deficits and imaging revealing focal ischemic infarction in the brainstem as well as new-onset hydrocephalus. A multispecialty workup was initiated without conclusive diagnosis. A novel, noninvasive test for plasma cell-free DNA established a diagnosis of Cladophialophora bantiana that was confirmed and validated by a brain biopsy taken during a clinical decompensation. Treatment was initiated with systemic voriconazole and intraventricular amphotericin B.