Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV (IMPAACT 2017/MOCHA): a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study.

BACKGROUND: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study. METHODS: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m2 and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had to be willing to continue their pre-study ART during cohort 1. The primary objectives of the study were to confirm doses for oral and injectable cabotegravir and for injectable rilpivirine in adolescents living with HIV. This analysis of participant-reported outcomes included a face scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL) at baseline and week 16 for participants in the USA, South Africa, Botswana, and Thailand. A subset of 11 adolescents and 11 parents or caregivers in the USA underwent in-depth interviews after receipt of one or two injections. This trial is registered at ClinicalTrials.gov, NCT03497676. FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections. INTERPRETATION: High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV. FUNDING: National Institutes of Health and ViiV Healthcare.

Development and evaluation of a novel knowledge assessment tool for pediatric emergency medicine clerkships.

Objectives: This study seeks to determine validity evidence for a newly developed multiple-choice examination (MCE) tool to assess retention and application of medical knowledge of students enrolled in a pediatric emergency medicine (PEM) clerkship. Methods: A team of PEM physicians created a 110-item MCE covering the range of clinical topics in PEM relevant for medical students. The researchers determined examination content using the report of Clerkship Directors in Emergency Medicine and PEM Interest Group of the Society for Academic Emergency Medicine (SAEM). The authors administered the MCE to fourth-year medical students at the end of their PEM rotation from May 2020 to April 2023 at four institutions and then analyzed the examination using four of Messick's five sources of validity evidence: content, response process, internal structure, and relation to other variables. Results: A total of 158 students took the test. In academic year (AY)20-21, 47 students took the test and scored, on average, 81%. After revision of poor and indeterminate questions, the 111 medical students who took the revised version of the test in AY21-AY23 scored on average 77.3% with a standard deviation of 5.7% with a normal distribution in scores. The revised questions were rated as excellent (10.0%), good (26.4%), fair (34.5%), poor (24.5%), or indeterminate (4.5%) based on test item discrimination. There was a positive correlation between MCE scores and students' clinical evaluations but no correlation between MCE scores and scores that students received on their clinical notes or patient presentations during case conference. Conclusions: This novel PEM clerkship examination is a reliable test of medical knowledge. Future directions involve evaluating consequences of the MCE and offering the test to medical students in a dedicated PEM rotation at the national level.

Smallpox lesion characterization in placebo-treated and tecovirimat-treated macaques using traditional and novel methods.

Smallpox was the most rampant infectious disease killer of the 20th century, yet much remains unknown about the pathogenesis of the variola virus. Using archived tissue from a study conducted at the Centers for Disease Control and Prevention we characterized pathology in 18 cynomolgus macaques intravenously infected with the Harper strain of variola virus. Six macaques were placebo-treated controls, six were tecovirimat-treated beginning at 2 days post-infection, and six were tecovirimat-treated beginning at 4 days post-infection. All macaques were treated daily until day 17. Archived tissues were interrogated using immunohistochemistry, in situ hybridization, immunofluorescence, and electron microscopy. Gross lesions in three placebo-treated animals that succumbed to infection primarily consisted of cutaneous vesicles, pustules, or crusts with lymphadenopathy. The only gross lesions noted at the conclusion of the study in the three surviving placebo-treated and the Day 4 treated animals consisted of resolving cutaneous pox lesions. No gross lesions attributable to poxviral infection were present in the Day 2 treated macaques. Histologic lesions in three placebo-treated macaques that succumbed to infection consisted of proliferative and necrotizing dermatitis with intracytoplasmic inclusion bodies and lymphoid depletion. The only notable histologic lesion in the Day 4 treated macaques was resolving dermatitis; no notable lesions were seen in the Day 2 treated macaques. Variola virus was detected in all three placebo-treated animals that succumbed to infection prior to the study's conclusion by all utilized methods (IHC, ISH, IFA, EM). None of the three placebo-treated animals that survived to the end of the study nor the animals in the two tecovirimat treatment groups showed evidence of variola virus by these methods. Our findings further characterize variola lesions in the macaque model and describe new molecular methods for variola detection.

Hyperammonemia in the Pediatric Emergency Department.

ABSTRACT: Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions.

INTRODUCTION: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically similar to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical. METHODS: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the USA. We assessed clinical, pathological, immunophenotypical, and molecular features to identify differentiating criteria. RESULTS: Forty cases were identified: 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p < 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p < 0.001). Dyserythropoiesis was unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the myeloid blasts. DISCUSSION: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time, several significant clinical, morphological, and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail.

Using Follow-Up Telephone Calls to Identify Obstacles to Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting.

BACKGROUND: Despite advances in antiemetic regimens, uncontrolled chemotherapy-induced nausea and vomiting (CINV) remains a problem for patients receiving oncology treatment, leading to decreased quality of life and worse treatment outcomes. OBJECTIVES: The purpose of this pilot project was to use follow-up telephone calls to identify barriers related to successful management and prevention of CINV on a single-center outpatient chemotherapy infusion unit. METHODS: A mixed-methods descriptive design was used for this project. Quantitative data were used to assess barriers to management and prevention of CINV. Secondary multiple regression analysis was used to determine whether barriers could predict CINV. Qualitative data were used to analyze common barriers and themes. FINDINGS: Of the patients called (N = 132), 50% identified a barrier to managing and treating CINV, with the most common barrier being knowledge gaps related to proper use of antiemetics.

Correction: The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways.

[This corrects the article DOI: 10.1158/2767-9764.CRC-21-0022.][This corrects the article DOI: 10.1158/2767-9764.CRC-21-0022.].

Immunodeficiency-Associated Epstein-Barr Virus-Positive B-cell Lymphoproliferative Disorders: A Review and New Paradigm.

Sources of immune deficiency and dysregulation (IDD) are being increasingly recognized and defined, as are IDD-related B-cell lymphoproliferative lesions and lymphomas occurring in these patients. In this review, basic biology of Epstein-Barr virus (EBV) as it relates to classification of EBV-positive B-cell lymphoproliferative disorders (LPDs) is reviewed. Also discussed is the new paradigm of classification of IDD-related LPDs adopted by the fifth edition World Health Organization classification. IDD-related EBV-positive B-cell hyperplasias, LPDs, and lymphomas are discussed with particular attention to unifying and unique features that assist with recognition of these IDD-related lesions and their classification scheme.

Acute Onset of Movement Disorders Accompanying Common Emergency Room Neurologic Disease Processes.

Emergency departments (EDs) of hospitals accredited for trauma and/or comprehensive stroke care treat a large volume of high-acuity patients. In this fast-paced environment, the primary focus is appropriate triage, rapid stabilization, diagnosis, and acute intervention for life-threatening conditions such as cerebral vascular accident (CVA). However, this approach may result in subtle or atypical neurologic signs and symptoms being overlooked. Often, these oversights are innocuous in terms of their influence on overall patient outcomes. They are, in the vernacular, "of academic interest only". These cases provide ED clinicians with a unique opportunity to witness signs and symptoms not classically associated with common neurologic maladies. These unusual manifestations may be fleeting as they often either resolve with intervention or are overshadowed by progressive clinical decline. If such findings are recognized, they can at a minimum provide fascinating insights into neuroanatomic function. At a maximum, early recognition can influence immediate treatments and long-term outcomes. We report three ED patient presentations that shed light on functional neuroanatomical pathways and, in one case, significantly affected a patient's immediate algorithmic care. Two such cases involved acute middle cerebral artery distribution ischemic strokes, which typically present with focal contralateral sensorimotor and potential language deficits. Such events less commonly initially present with involuntary motor movements (dyskinesias). Failure to recognize these less common ictal signs may delay appropriate ED intervention or yield etiologic misdiagnoses. A third case involved a loss of consciousness ictal event secondary to a frontotemporal lobe tumor. This case presented with aphasic stroke-like symptoms along with new acute orofacial dyskinesias. Imaging before and after medical, surgical, and endovascular intervention provided important clinico-anatomic lessons. Furthermore, proposed neurophysiologic mechanisms and review of pertinent literature are provided.

A National Survey of Job Satisfaction and Workload Among Emergency Medicine (EM) Residency Faculty.

INTRODUCTION:  Faculty workload, and its relation to job satisfaction, has not been well studied in Emergency Medicine (EM).  Methods: A cross-sectional survey was conducted among EM physician faculty at 49 residency programs across the United States. We collected information on clinical and non-clinical (education, administration, and research) workload, demographics, and EM department characteristics, as well as job satisfaction measured using the Global Job Satisfaction (GJS) scale. Comparisons were made using Wilcox signed rank tests. Multivariable associations with job satisfaction were assessed in a regression model. RESULTS:  Of 1,791 surveys sent, 265 were completed. The quantity of contracted clinical and non-clinical hours was lower than the actual clinical (difference (95% confidence interval (CI)): 2.7 (1.5-4.1)) and non-clinical hours (6.0 (3.8-8.8)) worked. Respondents preferred a distribution of 50% clinical work. However, the actual percentage was 62% (difference (95% CI): 14.4% (10.8%-17.6%)). Identifying as core faculty and required logging of non-clinical hours were associated with improved job satisfaction while increased percentage of time spent in the clinical and administrative domains were associated with significant declines. CONCLUSIONS:  The estimated actual work performed by EM physician faculty is greater than contracted and misaligned with their preferred type of work, the latter of which is associated with decreased job satisfaction. Improved job satisfaction and faculty retention might be achieved by increasing the percentage of time devoted to education and research, by increasing the core faculty contingent and by implementing tracking of non-clinical efforts.

Integrated Genomic DNA/RNA Profiling vs Fluorescence in Situ Hybridization in the Detection of MYC and BCL2 (and BCL6) Rearrangements in Large B-Cell Lymphomas: Updates Amid the New WHO Classification of Lymphoid Neoplasms.

OBJECTIVES: Large B-cell lymphomas (LBCLs) are a heterogeneous group of lymphoid neoplasms whose molecular and cytogenetic profile has predictive and prognostic implications. The concept of double-hit lymphomas (DHLs) was recently updated in the fifth edition of the World Health Organization classification, with the exclusion of MYC and BCL6 rearranged tumors from the group. Now, DHLs are referred to as diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Fluorescence in situ hybridization (FISH) is the current gold standard for detecting rearrangements in LBCLs, but comprehensive genomic profiling (CGP) has recently been suggested to be at least as accurate as FISH in classifying these neoplasms and providing additional genetic information. METHODS: We analyzed a cohort of 131 patients in whom FISH and CGP studies were performed as part of our normal clinical workflow and compared the effectiveness of FISH and CGP in detecting these clinically relevant rearrangements. RESULTS: Our findings are in agreement with our previously published study, which analyzed a cohort of 69 patients, supporting our hypothesis that the best approach to maximize detection of DHLs while limiting waste seems to be a combination of CGP and MYC break-apart FISH testing, the latter to capture the presence of non-IGH::MYC events. CONCLUSIONS: Our study supports the combined use of FISH and GCP rather than either method alone to better detect MYC and BCL2 (and BCL6) gene rearrangements.

Mysterious Pelvic Hematoma in a Patient Who Speaks a Rare Ethiopian Dialect: A Case Report.

INTRODUCTION: In reporting this case of a patient with spontaneous iliac vein rupture, we highlight the importance of maintaining a high clinical suspicion of this vascular emergency in the at-risk patient. CASE REPORT: A 50-year-old female with an uncommon language barrier presented with left lower abdominal pain after falling. Initial imaging showed pelvic hematoma of unclear etiology. Repeat computed tomography showed expanding hematoma, and after hemodynamic decompensation, exploratory laparotomy revealed a ruptured iliac vein. CONCLUSION: Although rare, spontaneous iliac vein rupture has a high mortality rate, even when identified early. This case serves as a reminder to consider this potentially fatal diagnosis in the at-risk group and highlights the need to remain vigilant in patients who present with unexplained shock. Additionally, this case is a reminder of our duty to provide emergency care that transcends language barriers.

Casein Protein Block to Optimize Immunohistochemistry Detection of Surface Immunoglobulin Heavy Chain Expression in Lymphoid Cells.

We describe our recent experience of studying expression of immunoglobulin (Ig) heavy chain (IgG, IgM, and IgA) in lymphoid cells comprising a research set of formalin-fixed, paraffin-embedded human diffuse large B-cell lymphoma samples. We found that using typical clinical automated immunohistochemistry protocols and usual buffers as blocking agents, the extent of undesirable staining was extreme and impaired our ability to interpret heavy chain Ig expression by individual lymphoid cells. We were not able to optimize this with serial dilutions in antibody concentration or time of primary antibody exposure. We therefore developed an added step of casein protein block, which solved the problem. We are not aware of other such reports in clinical or human research tissue sets and believe this solution may be useful when clinical pathologists or researchers encounter similar technical issues.

Atypical follicular hyperplasia with light chain-restricted germinal centers after COVID-19 booster: a diagnostic pitfall.

There has been a surge in COVID-19 vaccine-associated lymphadenopathy (LAD), including after the booster dose of vaccine. This can create diagnostic dilemmas in oncology patients as the relatively sudden LAD can mimic metastasis or cancer recurrence, at a risk of leading to additional but unnecessary anti-neoplastic therapy. Here we report the histopathologic features in a case of persistent LAD occurring in a patient with history of breast invasive ductal carcinoma which followed a COVID-19 vaccine booster. A needle core and then excisional biopsy showed atypical follicular hyperplasia with features that histologically and phenotypically could mimic follicular lymphoma, but the findings were ultimately interpreted to be reactive in nature and related temporally to COVID-19 vaccine. To our knowledge, this is the first case of an atypical lymphoproliferative lesion with features potentially mimicking lymphoma associated with COVID-19 vaccine.

Long-term outcomes of patients with conjunctival extranodal marginal zone lymphoma.

Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%-79.8%) and 89.4% (95% CI 77.4%-95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%-35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1-2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age > 60 years (PFS: HR = 2.93, 95% CI 1.08-7.95; p = .035, OS: HR = 9.07, 95% CI 1.17-70.26; p = .035) and MALT-IPI 1-2 (PFS: HR = 2.67, 95% CI 1.12-6.31; p = .027, OS: HR = 6.64, 95% CI 1.45-30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04-0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12-0.96 p = .041 and SHR = 0.11, 95% CI 0.03-0.36; p < .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure.