Faculty Bibliography

STATEMENT OF THE CLINICAL PROBLEM ADDRESSED BY THE CASE/UNASSIGNED:We report an atypical clinical presentation of a rapidly progressive neurologic emergency that required prompt investigation and treatment of impending respiratory failure. We discuss the differential diagnosis, evaluation, emergency management, and treatment options of patients with atypical variants of this disorder. BRIEF DESCRIPTION OF CASE PRESENTATION/UNASSIGNED:A 56-year-old woman with a history of hypothyroidism, anxiety, and depression presented to the emergency department 3 weeks after an upper respiratory and ear infection with cough, pain with sinus palpation, tingling in her fingers bilaterally and right foot, hives, and an episode of blurry vision on awakening. She was discharged home with antibiotics. That evening, she developed rapidly progressing hoarseness and dysphagia and returned to the emergency department. An initial examination and laryngoscopy revealed complete left vocal cord paralysis, consistent with a left cranial nerve X palsy, which prompted a neurologic evaluation. Her examination progressively worsened over the next day requiring mechanical ventilation and ICU admission. SUMMARY OF THE KEY TEACHING POINT IN THE CASE/UNASSIGNED:New-onset bulbar cranial neuropathies should raise concern for neurologic disorders that can be rapidly progressive and result in respiratory failure. Urgent diagnosis and treatment are warranted.

BACKGROUND:Given the cardiovascular, renal, and survival benefits of GLP-1 receptor agonists for diabetes, these agents could be effective among kidney transplant recipients. However, kidney transplant recipients are distinct from GLP-1 receptor agonist trial participants, with longer diabetes duration and severity, greater end-organ damage, increased cardiovascular risk, and multimorbidity. We examined GLP-1 receptor agonist real-world effectiveness and safety in kidney transplant recipients with diabetes. METHODS:This USA-based retrospective cohort study included kidney transplant recipients with type 2 diabetes at transplantation and Medicare as their primary insurance from a national registry linked with Medicare claims. Post-transplantation GLP-1 receptor agonist use was identified through Medicare claims. Death-censored graft loss was estimated using the Fine-Gray sub-distribution hazard model and extended Cox models were used for mortality and safety endpoints. Models incorporated inverse probability of treatment weights. To further test whether bias could affect the main results, a cohort was created in which each GLP-1 receptor agonist user was matched with a kidney transplant recipient who had not started a GLP-1 receptor agonist, was alive with a functioning graft, and had accrued the same amount of post-transplant survival time. FINDINGS/RESULTS:Between Jan 1, 2013 and Dec 31, 2020, we identified 44 536 first time kidney transplant recipients with Medicare as primary payer in the 6 months before and at transplantation. 24 192 patients were excluded as they did not have type 2 diabetes. 2328 patients were ineligible (1916 had missing values and 412 used GLP-1 receptor agonists before transplantation). The primary cohort thus consisted of 18 016 kidney transplant recipients with diabetes. Of these patients, 1969 (10·9%) had at least one GLP-1 receptor agonist prescription filled post-transplant. Compared with patients who had not received a GLP-1 receptor agonist, GLP-1 receptor agonist users were younger (median age at transplant 57 years [IQR 49-64] vs 60 years [51-66], p<0·0001) and more likely to be female (786 [39·9%] vs 5645 [35·2%], p<0·0001). Among GLP-1 receptor agonist users, 552 [28·0%] were non-Hispanic White, 703 [35·7%] were non-Hispanic Black, and 568 [28·8%] were Hispanic. The 5-year unadjusted cumulative incidence of death-censored graft loss from a cohort matched on survival time before GLP-1 receptor agonist initiation was 6·0% for GLP-1 receptor agonist users and 10·7% for non-users (Gray's test p=0·004). The 5-year unadjusted cumulative incidence for mortality from a cohort matched on survival time before GLP-1 receptor agonist initiation was 17·0% for GLP-1 receptor agonist users and 25·8% for non-users (log-rank p=0·0006). The 5-year unadjusted cumulative incidence for mortality was 13·5% for GLP-1 receptor agonist users and 19·9% for non-users (log-rank p<0·0001). GLP-1 receptor agonist use was associated with a 49% lower incidence of death-censored graft loss (adjusted subhazard ratio [aSHR] 0·51, 95% CI 0·36-0·71; p=0·0001) and 31% lower mortality (adjusted hazard ratio [aHR] 0·69, 95% CI 0·55-0·86; p=0·001). Inferences were robust when matched on survival time (death-censored graft loss aSHR 0·53, 95% CI 0·37-0·75; p=0·0005; mortality aHR 0·70, 95% CI 0·55-0·88; p=0·003). Safety endpoints were rare and not associated with GLP-1 receptor agonists, with the exception of diabetic retinopathy (aHR 1·49, 1·11-2·00; p=0·008). INTERPRETATION/CONCLUSIONS:GLP-1 receptor agonists were associated with better graft and patient survival. Clinical trials are needed to confirm these findings. FUNDING/BACKGROUND:National Institutes of Health.

Solid organ transplantation (SOT) offers people with end-stage organ disease an increased quality of life, which includes the return of fertility and the potential for pregnancy. Although the number of pregnancies has increased, definitive recommendations have been lacking. To address reproductive health in SOT recipients, the American Society of Transplantation Women's Health Community of Practice held a virtual Controversies Conference with subject matter experts gathered to discuss topics of contraception, immunosuppression, and pregnancy in SOT recipients and pregnancy post-living donation. This publication is a synthesis of expert guidance and available data regarding pregnancy management and outcomes after all types of SOTs.

The prevalence of vitamin D deficiency among intensive care unit (ICU) patients is potentially associated with an increased risk of mechanical ventilation, sepsis, prolonged hospital stays, and mortality. Although ICU patient care has significantly improved in recent years, the role of vitamin D supplementation remains under investigation. A literature review was conducted using PubMed, Web of Science, Embase, and Cochrane databases, focusing on randomized controlled trials published in the past five years on vitamin D supplementation in adult ICU patients. Patients' baseline vitamin D levels, administration routes, doses, biomarker changes, mechanical ventilation duration, length of hospital stay, and mortality were analyzed. Although vitamin D supplementation appears safe and may reduce ICU stay duration and mechanical ventilation time and improve SOFA scores, its impact on overall mortality remains uncertain. Routine supplementation for all ICU patients is not currently recommended; clinical decisions should consider individual baseline vitamin D levels, patient characteristics, severity of illness, doses, and administration methods.

AIMS/OBJECTIVE:Activation of the transcriptional factor Krüppel-like factor 5 (KLF5) is detrimental to chronic heart failure. We explored the involvement of KLF5 in myocardial ischemia/reperfusion injury. METHODS AND RESULTS/RESULTS:Yorkshire pigs underwent 75΄ of ischemia, followed by 3h or 24h of reperfusion. C57BL/6J mice underwent 30΄ of ischemia, followed by 10', 2h, 12h, 24h, or 4 weeks of reperfusion. Hearts and isolated cardiomyocytes were analyzed for gene expression. We assessed cardiac function, infarct size (IS), oxidative stress, and fibrosis in mice subjected to pharmacologic or genetic KLF5 inhibition, as well as pharmacologic inhibition of NADPH oxidases or Glucose Transporter (GLUT)1 and GLUT4. Bulk RNA sequencing, untargeted 1H-NMR metabolomics and LC-MS lipidomics were performed. Isolated primary murine cardiomyocytes were infected with recombinant adenovirus expressing KLF5. During reperfusion, cardiοmyocyte KLF5 expression was increased in porcine and murine hearts. Pharmacologic or cardiomyocyte-specific genetic inhibition of KLF5 reduced IS and improved cardiac function in mice. Importantly, acute KLF5 inhibition during early reperfusion suppressed fibrosis and preserved systolic cardiac function 4 weeks post-ischemia/reperfusion. This improvement was associated with lower NOX4 expression, less oxidative stress, and suppressed inflammation and cell apoptosis. Pharmacologic inhibition of NOX4 conferred the same benefit. Metabolomic analysis indicated that KLF5 inhibition lowered glucose-derived metabolites (UDP-Glucose and Lactate) at early reperfusion. Accordingly, cardiac GLUT1 and GLUT4 levels were increased with ischemia/reperfusion, which was reverted by KLF5 inhibition. Pharmacologic inhibition of both GLUT1/4 reduced IS. Finally, myocardial KLF5 overexpression increased GLUT1 mRNA levels and mouse mortality. CONCLUSIONS:Ischemia/reperfusion increases cardiomyocyte KLF5 expression in pigs and mice. This constitutes a central element of myocardial injury pathophysiology and is associated with stimulation of GLUT1 and GLUT4 expression, activation of NOX4, oxidative stress, inflammation and apoptosis. Acute KLF5 inhibition during reperfusion constitutes a novel therapeutic approach against myocardial ischemia/reperfusion injury.

PURPOSE/OBJECTIVE:CAR T-cell therapy is an emerging anti-cancer therapeutic using modified T cells to attack a patient's cancer. The purpose of this study was to assess chest CT findings in patients undergoing CAR T-cell therapy to determine the most common CT manifestations. METHODS:We performed a retrospective test-retest study analyzing cases of patients who received CAR T-cell therapy who underwent chest CT prior to therapy and after therapy; a total of 349 patients were identified. CAR T-cell therapy was first administered in the mid 2010's, however we assessed for pre-treatment scans prior to this date. We reviewed patient's charts to collect demographic and clinical data. Two cardiothoracic radiologists reviewed chest CT scans prior to and post CAR T-cell therapy to determine new radiologic features post therapy. We analyzed which findings correlated with specific radiologic features on chest CT using student's t-tests or Chi squared tests. RESULTS:Pleural effusion was the most common CT manifestation resulting from CAR T-cell therapy, found in 26.3 % of patients. Patients with CT manifestations were more likely to present with dyspnea and cough (p = 0.000031 and p = 0.02, respectively). DISCUSSION/CONCLUSIONS:New symptoms in patients treated with CAR T-cell therapy may be an important harbinger of radiologic abnormalities. Clinicians should have a high index of suspicion for pleural effusions in patients presenting with symptoms who have undergone CAR T-cell therapy.

IMPORTANCE/UNASSIGNED:The weak link between subjective symptom-based diagnostics for posttraumatic psychopathology and objective neurobiological indices hinders the development of effective personalized treatments. OBJECTIVE/UNASSIGNED:To identify early neural networks associated with posttraumatic stress disorder (PTSD) development among recent trauma survivors. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This prognostic study used data from the Neurobehavioral Moderators of Posttraumatic Disease Trajectories (NMPTDT) large-scale longitudinal neuroimaging dataset of recent trauma survivors. The NMPTDT study was conducted from January 20, 2015, to March 11, 2020, and included adult civilians who were admitted to a general hospital emergency department in Israel and screened for early PTSD symptoms indicative of chronic PTSD risk. Enrolled participants completed comprehensive clinical assessments and functional magnetic resonance imaging (fMRI) scans at 1, 6, and 14 months post trauma. Data were analyzed from September 2023 to March 2024. EXPOSURE/UNASSIGNED:Traumatic events included motor vehicle incidents, physical assaults, robberies, hostilities, electric shocks, fires, drownings, work accidents, terror attacks, or large-scale disasters. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Connectome-based predictive modeling (CPM), a whole-brain machine learning approach, was applied to resting-state and task-based fMRI data collected at 1 month post trauma. The primary outcome measure was PTSD symptom severity across the 3 time points, assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes included Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) PTSD symptom clusters (intrusion, avoidance, negative alterations in mood and cognition, hyperarousal). RESULTS/UNASSIGNED:A total of 162 recent trauma survivors (mean [SD] age, 33.9 [11.5] years; 80 women [49.4%] and 82 men [50.6%]) were included at 1 month post trauma. Follow-up assessments were completed by 136 survivors (84.0%) at 6 months and by 133 survivors (82.1%) at 14 months post trauma. Among the 162 recent trauma survivors, CPM significantly predicted PTSD severity at 1 month (ρ = 0.18, P < .001) and 14 months (ρ = 0.24, P < .001) post trauma, but not at 6 months post trauma (ρ = 0.03, P = .39). The most predictive edges at 1 month included connections within and between the anterior default mode, motor sensory, and salience networks. These networks, with the additional contribution of the central executive and visual networks, were predictive of symptoms at 14 months. CPM predicted avoidance and negative alterations in mood and cognition at 1 month, but it predicted intrusion and hyperarousal symptoms at 14 months. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this prognostic study of recent trauma survivors, individual differences in large-scale neural networks shortly after trauma were associated with variability in PTSD symptom trajectories over the first year following trauma exposure. These findings suggest that CPM may identify potential targets for interventions.

This article highlights the gender data gaps in clinical trial inclusion and funding, with a particular focus on gynecologic oncology. Female patients have historically been excluded from clinical trials across all medical domains. Despite recent improvements, female patients remain underrepresented in key diseases, including several cancer types, despite experiencing increased burden of disease. Lack of representation is particularly stark for patients in racial, ethnic, and gender minoritized populations, including in gynecologic cancer trials. Furthermore, female health conditions receive disproportionately small amounts of funding relative to their disease burden. Despite their high lethality, gynecologic cancers, including ovarian, cervical, and uterine malignancies, rank among the lowest funded cancer sites from the National Cancer Institute. Likewise, there is significant bias against female investigators with regard to funding, publication, and academic advancement, which affects the prioritization of women's health. In combination, gender disparities at multiple steps along the research pathway from investigator and disease funding to trial inclusion to publication and dissemination of research perpetuate a significant data gap in the diagnosis, treatment, and prevention of diseases affecting female patients, including gynecologic cancers. Strategies to improve this gender gap and prioritize women's health funding include increasing female representation in clinical trials with a specific focus on inclusion of patients from historically marginalized backgrounds, considering disease burden-based funding policies, and prioritizing female academic leadership opportunities.

Policies to implement climate-forcing pollution emission reductions have often been stymied by economic and political divisiveness. However, certain uncontested nonregret public health policies that also carry climate-forcing cobenefits with them could provide more achievable policy pathways to accelerate the implementation of climate mitigation. An International Society for Environmental Epidemiology Policy Committee endorsed pre-28th Conference of the Parties climate meeting workshop brought together experts on environment, diet, civic planning, and health to review current understanding of public health policy approaches that provide climate change mitigation cobenefits by also reducing greenhouse gas emissions. Promising public health policy areas identified as also providing climate mitigation cobenefits included: improving air quality through stronger regulation of harmful combustion-related air pollutants, advancing healthier plant-based public food procurement programs, promoting more sustainable transport options, developing healthier infrastructure (e.g., combustion-free buildings), and reducing the use of climate forcing substances in healthcare. It is concluded that cities, states, and nations, when aided by involved health professionals, can advance many practical public health, diet, and civic planning policies to improve health and well-being that will also serve to translate climate mitigation ambitions into action.

BACKGROUND:It is unknown whether there is a general factor that accounts for the propensity for both physical and mental conditions in different age groups and how it is associated with lifestyle and well-being. METHODS:factor, lifestyles, and well-being was further explored. RESULTS:factor scores significantly correlated with lifestyle and well-being, suggesting healthier lifestyles were associated with a reduced likelihood of physical and mental health comorbidities, which in turn improved well-being. CONCLUSIONS:Contrary to the traditional dichotomy between mental and physical conditions, our study showed a general factor underlying the comorbidity across mental and physical diseases, related to lifestyle and well-being. Our results inform the conceptualization of mental and physical illness as well as future research assessing risk and pathways of disease transmission, intervention, and prevention. Our results also provide a strong rationale for a systematic screening for mental disorders in individuals with physical conditions and vice versa, and for integrated services addressing multimorbidity.