Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.

Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.

Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients.

Human herpesvirus-6B (HHV-6B) reactivation and disease are increasingly reported after CAR-T-cell therapy (CARTx). HHV-6 reactivation in the CAR-T-cell product was recently reported, raising questions about product and patient management. Due to overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide two lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks post-infusion, HHV-6B reactivation occurred in eight of 89 participants; three had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval (CI), 2.2-12.5%). HHV-6B detection was low level (median peak, 435 copies/mL; IQR, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in blood and/or cerebrospinal fluid (CSF) within 12 weeks post-infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing with detection in one. Among 34 patients with CSF HHV-6 testing, one patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94%), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

Dermatologic needs of transgender and gender diverse youth: A retrospective cohort study.

Several dermatologic concerns are known to disproportionally affect transgender and gender-diverse (TGD) adults, but little is known about dermatologic conditions in TGD youth. This study assesses the prevalence of acne, androgenic alopecia, scarring from gender-affirming procedures, and eczema in pediatric TGD patients seen at Boston Children's Hospital between April 2021 and April 2022. The results demonstrate that, for TGD youth, the studied dermatologic concerns are common, referral rates to dermatology are low, and acne is significantly associated with testosterone use. Future studies should examine additional dermatologic concerns and barriers to accessing dermatologic care for this historically underserved population.

Women's Health Information-Seeking Experiences and Preferences for Health Communications on FDA-Regulated Products: A Qualitative Study in Urban Area.

A key part of any effort to ensure informed health care decision-making among the public is access to reliable and relevant health-related information. We conducted focus groups with women from three generations across the Baltimore-Washington metropolitan area to explore their information-seeking motivations, perceptions, challenges, and preferences regarding three FDA-regulated products: drugs, vaccines, and medical devices. The youngest generation discussed seeking health information for their children; the other two sought information for their own needs. All participants noted that finding health information appropriate to their reading level was a challenge, as was identifying reliable sources of information. All generations identified in-person and live interactions as their preferred method of communication and health care providers as their preferred source for information. All three generations recognized the usefulness of websites, and the two older generations acknowledged the advantages of brochures. Our findings suggest approaches the FDA could consider to improve communications: (a) supporting in-person and live health information interactions; (b) leveraging the agency's standing with the public to highlight it as a leading source of validated health information; (c) increasing the FDA website's visibility in internet searches and making its navigation easier; and (d) using multi-pronged approaches and media for various audiences.

Inequities in Technology Access and Digital Health Literacy Among Patients With Dermatologic Conditions: Cross-Sectional Analysis of the National Health Interview Survey.

Certain sociodemographic factors are associated with low technology access and digital healthy literacy.

Health Equity and Policy Considerations for Pediatric and Adult Congenital Heart Disease Care among Minoritized Populations in the United States.

Achieving health equity in populations with congenital heart disease (CHD) requires recognizing existing disparities throughout the lifespan that negatively and disproportionately impact specific groups of individuals. These disparities occur at individual, institutional, or system levels and often result in increased morbidity and mortality for marginalized or racially minoritized populations (population subgroups (e.g., ethnic, racial, social, religious) with differential power compared to those deemed to hold the majority power in the population). Creating actionable strategies and solutions to address these health disparities in patients with CHD requires critically examining multilevel factors and health policies that continue to drive health inequities, including varying social determinants of health (SDOH), systemic inequities, and structural racism. In this comprehensive review article, we focus on health equity solutions and health policy considerations for minoritized and marginalized populations with CHD throughout their lifespan in the United States. We review unique challenges that these populations may face and strategies for mitigating disparities in lifelong CHD care. We assess ways to deliver culturally competent CHD care and to help lower-health-literacy populations navigate CHD care. Finally, we review system-level health policies that impact reimbursement and research funding, as well as institutional policies that impact leadership diversity and representation in the workforce.

Retrograde Flow of Fluid Through the Nasolacrimal Duct System Under General Anesthesia: A Case Report.

This case report describes a rare incident of fluid exhibiting retrograde flow from the nasopharynx through the nasolacrimal duct and accumulating within the eye guard while under general anesthesia. The patient was in a steep Trendelenburg position for several hours and received multiple liters of intravenous fluid. The patient did not have a history of sinusitis, sinus surgery, cocaine use, dacryostenosis and dacryocystitis, or nasolacrimal duct irrigation and probing. This case provides insight into the potential ophthalmic implications of surgical and anesthetic management. While the patient fortunately had no complications, this case also underscores the importance of intraoperative vigilance.

Urticaria in infants: A single-institution retrospective study.

Urticaria in infants can cause significant anxiety in parents, especially if a trigger cannot be identified. In a retrospective study of 246 infants seen for urticaria of unknown etiology at Boston Children's Hospital, 88.2% had resolution of urticaria within 6 weeks. The etiology of urticaria was ultimately established in 62.6% (72/115) of acute urticaria and 12.5% (2/16) of chronic urticaria cases with follow-up data. Pediatric healthcare providers can counsel families that while etiology of urticaria is never determined in over 40% of infants, symptoms are most likely to resolve spontaneously.

Descriptive analysis of targeted carbapenemase genes and antibiotic susceptibility profiles among carbapenem-resistant Acinetobacter baumannii tested in the Antimicrobial Resistance Laboratory Network-United States, 2017-2020.

Acinetobacter baumannii is a Gram-negative bacillus that can cause severe and difficult-to-treat healthcare-associated infections. A. baumannii can harbor mobile genetic elements carrying genes that produce carbapenemase enzymes, further limiting therapeutic options for infections. In the United States, the Antimicrobial Resistance Laboratory Network (AR Lab Network) conducts sentinel surveillance of carbapenem-resistant Acinetobacter baumannii (CRAB). Participating clinical laboratories sent CRAB isolates to the AR Lab Network for characterization, including antimicrobial susceptibility testing and molecular detection of class A (Klebsiella pneumoniae carbapenemase), class B (Active-on-Imipenem, New Delhi metallo-ß-lactamase, and Verona integron-encoded metallo-ß-lactamase), and class D (Oxacillinase, blaOXA-23-like, blaOXA-24/40-like, blaOXA-48-like, and blaOXA-58-like) carbapenemase genes. During 2017‒2020, 6,026 CRAB isolates from 45 states were tested for targeted carbapenemase genes; 1% (64 of 5,481) of CRAB tested for targeted class A and class B genes were positive, but 83% (3,351 of 4,041) of CRAB tested for targeted class D genes were positive. The number of CRAB isolates carrying a class A or B gene increased from 2 of 312 (<1%) tested in 2017 to 26 of 1,708 (2%) tested in 2020. Eighty-three percent (2,355 of 2,846) of CRAB with at least one of the targeted carbapenemase genes and 54% (271 of 500) of CRAB without were categorized as extensively drug resistant; 95% (42 of 44) of isolates carrying more than one targeted gene had difficult-to-treat susceptibility profiles. CRAB isolates carrying targeted carbapenemase genes present an emerging public health threat in the United States, and their rapid detection is crucial to improving patient safety.IMPORTANCEThe Centers for Disease Control and Prevention has classified CRAB as an urgent public health threat. In this paper, we used a collection of >6,000 contemporary clinical isolates to evaluate the phenotypic and genotypic properties of CRAB detected in the United States. We describe the frequency of specific carbapenemase genes detected, antimicrobial susceptibility profiles, and the distribution of CRAB isolates categorized as multidrug resistant, extensively drug-resistant, or difficult to treat. We further discuss the proportion of isolates showing susceptibility to Food and Drug Administration-approved agents. Of note, 84% of CRAB tested harbored at least one class A, B, or D carbapenemase genes targeted for detection and 83% of these carbapenemase gene-positive CRAB were categorized as extensively drug resistant. Fifty-four percent of CRAB isolates without any of these carbapenemase genes detected were still extensively drug-resistant, indicating that infections caused by CRAB are highly resistant and pose a significant risk to patient safety regardless of the presence of one of these carbapenemase genes.

Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study.

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.

Applications of Human Pluripotent Stem Cell-Derived Skin Organoids in Dermatology.

Pluripotent stem cells have the potential to become any cell type, and recently, they have been used to create organoids that can recapitulate several pertinent features of human organs. Skin organoids have been developed that possess many of the crucial accessory organs, including hair follicles, sebaceous glands, nerves, fat, and melanocytes. These skin organoids present the opportunity to study skin development and disease as well as perform screens to identify new drug candidates. In the future, skin organoids might augment clinical practice by serving as source material for transplantation to treat wounds or other conditions. Nevertheless, several limitations, such as the lengthy differentiation protocol, which can result in heterogeneous products, must first be addressed before the full potential of skin organoids can be realized. The purpose of this article is to provide a broad overview of skin organoids so that a broader audience can become familiar with this technology, which has important implications for dermatologic research and medicine.

Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL.

High response rates have been reported after CD19-targeted chimeric antigen receptor-modified (CD19 CAR) T-cell therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), yet the factors associated with duration of response in this setting are poorly characterized. We analyzed long-term outcomes in 47 patients with R/R CLL and/or Richter transformation treated on our phase 1/2 clinical trial of CD19 CAR T-cell therapy with an updated median follow-up of 79.6 months. Median progression-free survival (PFS) was 8.9 months, and the 6-year PFS was 17.8%. Maximum standardized uptake value (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.07-1.23; P < .001) and bulky disease (≥5 cm; HR, 2.12; 95% CI, 1.06-4.26; P = .034) before lymphodepletion were associated with shorter PFS. Day +28 complete response by positron emission tomography-computed tomography (HR, 0.13; 95% CI, 0.04-0.40; P < .001), day +28 measurable residual disease (MRD) negativity by multiparameter flow cytometry (HR, 0.08; 95% CI, 0.03-0.22; P < .001), day +28 MRD negativity by next-generation sequencing (HR, 0.21; 95% CI, 0.08-0.51; P < .001), higher peak CD8+ CAR T-cell expansion (HR, 0.49; 95% CI; 0.36-0.68; P < .001), higher peak CD4+ CAR T-cell expansion (HR, 0.47; 95% CI; 0.33-0.69; P < .001), and longer CAR T-cell persistence (HR, 0.56; 95% CI, 0.44-0.72; P < .001) were associated with longer PFS. The 6-year duration of response and overall survival were 26.4% and 31.2%, respectively. CD19 CAR T-cell therapy achieved durable responses with curative potential in a subset of patients with R/R CLL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease.

The majority of patients with chronic graft-versus-host disease (cGVHD) are steroid refractory (SR), creating a need for safe and effective therapies. Subcutaneous low-dose interleukin-2 (LD IL-2), which preferentially expands CD4+ regulatory T cells (Tregs), has been evaluated in 5 clinical trials at our center with partial responses (PR) in ∼50% of adults and 82% of children by week 8. We now report additional real-world experience with LD IL-2 in 15 children and young adults. We conducted a retrospective chart review of patients with SR-cGVHD at our center who received LD IL-2 from August 2016 to July 2022 not on a research trial. The median age at start of LD IL-2 was 10.4 years (range, 1.2-23.2 years) at a median of 234 days from cGVHD diagnosis (range, 11-542 days). Patients had a median of 2.5 (range, 1-3) active organs at LD IL-2 start and received a median of 3 (range, 1-5) prior therapies. The median duration of LD IL-2 therapy was 462 days (range, 8-1489 days). Most patients received 1 × 106 IU/m2 per day. There were no serious adverse effects. The overall response rate in 13 patients who received >4 weeks of therapy was 85% (complete response, n = 5; PR, n = 6) with responses in diverse organs. Most patients significantly weaned corticosteroids. Tregs preferentially expanded with a median peak fold increase of 2.8 in the ratio of Tregs to CD4+ conventional T cells (range, 2.0-19.8) by 8 weeks on therapy. LD IL-2 is a well-tolerated, steroid-sparing agent with a high response rate in children and young adults with SR-cGVHD.

Competitive Sports Participation is Associated with Decreased Risk of Obesity in Children with Bicuspid Aortic Valve.

Individuals with bicuspid aortic valve (BAV) have historically been advised to avoid contact sports and isometric exercise for risk of increasing aortic dilation and valve disease. There is mounting evidence that current sports participation guidelines qualify children for a high rate of sports exclusion, and that this population is at increased risk of obesity. The primary aim of this study was to evaluate relationship between sports participation and aortic dilation in children with bicuspid aortic valve and secondarily the relationship between competitive sports participation and obesity. We performed a review of children between the ages of 8 and 17 years with isolated BAV followed at Oregon Health & Science University. We excluded those with other congenital heart diseases, genetic conditions, prior cardiac intervention, and inability to ambulate independently. Parents completed a phone survey detailing their child's level of daily activity and participation in competitive sports. Demographic information and most recent echo findings were collected from the electronic medical record. We found no difference between the aortic diameters of athletes vs non-athletes. We also found that sports participation and daily activity were both associated with a decreased likelihood of obesity (OR 0.24, 95% CI 0.078-0.73 and OR 0.24, 95% CI 0.081-0.71 respectively). In summary, in our sample population, competitive sports participation was associated with a decreased risk of obesity. Competitive sports participation does not appear to be associated with an increased risk of aortic dilation in our population.

Current understanding of CTLA-4: from mechanism to autoimmune diseases.

Autoimmune diseases (ADs) are characterized by the production of autoreactive lymphocytes, immune responses to self-antigens, and inflammation in related tissues and organs. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is majorly expressed in activated T cells and works as a critical regulator in the inflammatory response. In this review, we first describe the structure, expression, and how the signaling pathways of CTLA-4 participate in reducing effector T-cell activity and enhancing the immunomodulatory ability of regulatory T (Treg) cells to reduce immune response, maintain immune homeostasis, and maintain autoimmune silence. We then focused on the correlation between CTLA-4 and different ADs and how this molecule regulates the immune activity of the diseases and inhibits the onset, progression, and pathology of various ADs. Finally, we summarized the current progress of CTLA-4 as a therapeutic target for various ADs.

Epidemiology of Salmonellosis Among Infants in the United States: 1968-2015.

OBJECTIVES: Describe characteristics of gastroenteritis, bacteremia, and meningitis caused by nontyphoidal Salmonella among US infants. METHODS: We analyze national surveillance data during 1968-2015 and active, sentinel surveillance data during 1996-2015 for culture-confirmed Salmonella infections by syndrome, year, serotype, age, and race. RESULTS: During 1968-2015, 190 627 culture-confirmed Salmonella infections among infants were reported, including 165 236 (86.7%) cases of gastroenteritis, 6767 (3.5%) bacteremia, 371 (0.2%) meningitis, and 18 253 (9.7%) with other or unknown specimen sources. Incidence increased during the late 1970s-1980s, declined during the 1990s-early 2000s, and has gradually increased since the mid-2000s. Infants' median age was 4 months for gastroenteritis and bacteremia and 2 months for meningitis. The most frequently reported serotypes were Typhimurium (35 468; 22%) for gastroenteritis and Heidelberg for bacteremia (1954; 29%) and meningitis (65; 18%). During 1996-2015 in sentinel site surveillance, median annual incidence of gastroenteritis was 120, bacteremia 6.2, and meningitis 0.25 per 100 000 infants. Boys had a higher incidence of each syndrome than girls in both surveillance systems, but most differences were not statistically significant. Overall, hospitalization and fatality rates were 26% and 0.1% for gastroenteritis, 70% and 1.6% for bacteremia, and 96% and 4% for meningitis. During 2004-2015, invasive salmonellosis incidence was higher for Black (incident rate ratio, 2.7; 95% confidence interval, 2.6-2.8) and Asian (incident rate ratio, 1.8; 95% confidence interval, 1.7-1.8) than white infants. CONCLUSIONS: Salmonellosis causes substantial infant morbidity and mortality; serotype heidelberg caused the most invasive infections. Infants with meningitis were younger than those with bacteremia or gastroenteritis. Research into risk factors for infection and invasive illness could inform prevention efforts.

Warts in pediatric oncology patients: A single-institution retrospective study.

BACKGROUND: Pediatric oncology patients undergoing cancer treatment can often have numerous and recalcitrant cutaneous warts due to their underlying immunosuppression. There are little published data on the optimal management of warts in pediatric oncology patients undergoing active cancer treatment compared to patients having completed treatment. Our objective was to analyze the clinical course of warts treated within this patient population at Boston Children's Hospital over a 10-year period. METHODS: This was a single-institution retrospective study of 72 pediatric oncology patients from 1 September 2011 to 1 September 2021 who were treated for warts at Boston Children's Hospital. All patients had a diagnosis of cutaneous warts with at least one follow-up visit and were receiving active treatment for cancer either during or after concurrent treatment of their warts. We examined the modality and effectiveness of wart treatments while both on and offactive treatment of their cancer. RESULTS: The median age was 12 years (range 4-18). Fifty-four percent of patients were documented to have plantar warts. Sixty percent of patients with a documented number of warts had more than five warts at presentation. For cases in which outcomes were specified, treatment resulted in complete resolution of warts in only 24.0% of patients undergoing active cancer treatment compared to 63.3% of patients not on active treatment. Warts persisted or worsened in 56.0% of patients undergoing active cancer treatment compared to only 13.4% of patients not on active treatment. CONCLUSION: These data may help guide clinicians in evaluating and treating warts in pediatric oncology patients.