Risk factors for prolonged infection and secondary infection in pediatric severe sepsis.

PURPOSE: Sepsis causes significant worldwide morbidity and mortality. Inability to clear an infection and secondary infections are known complications in severe sepsis and likely result in worsened outcomes. We sought to characterize risk factors of these complications. METHODS: We performed a secondary analysis of clinical data from 401 subjects enrolled in the PHENOtyping sepsis-induced Multiple organ failure Study. We examined factors associated with prolonged infection, defined as infection that continued to be identified 7 days or more from initial identification, and secondary infection, defined as new infections identified ≥ 3 days from presentation. Multivariable adjustment was performed to examine laboratory markers of immune depression, with immunocompromised and immunocompetent subjects analyzed separately. RESULTS: Illness severity, immunocompromised status, invasive procedures, and site of infection were associated with secondary infection and/or prolonged infection. Persistent lymphopenia, defined as an absolute lymphocyte count (ALC) < 1000 cells/µL twice in the first five days, and persistent neutropenia, defined as absolute neutrophil count (ANC) < 1000 cells/µL twice in the first five days, were associated with secondary and prolonged infections. When adjusted in multivariable analysis, persistent lymphopenia remained associated with secondary infection in both immunocompromised (aOR = 14.19, 95% CI [2.69, 262.22] and immunocompetent subjects (aOR = 2.09, 95% CI [1.03, 4.17]). Persistent neutropenia was independently associated with secondary infection in immunocompromised subjects (aOR = 5.34, 95% CI [1.92, 15.84]). Secondary and prolonged infections were associated with worse outcomes, including death. CONCLUSIONS: Laboratory markers of immune suppression can be used to predict secondary infection. Lymphopenia is an independent risk factor in immunocompromised and immunocompetent patients for secondary infection.

LTßR Agonism Promotes Anti-Tumor Immune Responses via Modulation of the Tumor Microenvironment.

The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment strategies. Lymphotoxin beta receptor (LTßR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and ICB treatment to augment tumor-associated HEV formation. Here, we demonstrated that LTßR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTßR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTßR agonism on DC activation and maturation and associated DC-mediated T cell activation. Single agent LTßR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner, and the LTßR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTßR agonism and lymphotoxin alpha (LT⍺) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTßR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments.

Evidence-Based Practices for Interviewing Graduate Medical Education Applicants: A Systematic Review.

Background Although the selection interview is a standard admission practice for graduate medical education (GME) programs in the United States, there is a dearth of recent reviews on optimizing the trainee interview process, which has low reliability, high cost, and major risk of bias. Objective To investigate the evidence base for different selection interview practices in GME. Methods We searched 4 literature databases from inception through September 2022. Two investigators independently conducted title/abstract screening, full-text review, data extraction, and quality assessment. Disagreements were mediated by discussion. We used backward reference searching of included articles to identify additional studies. We included studies of different interview methods and excluded literature reviews, non-GME related publications, and studies comparing different applicant populations. We examined study characteristics, applicant and interviewer preferences, and interview format. We evaluated study quality using the Medical Education Research Study Quality Instrument (MERSQI). Results Of 2192 studies, 39 (2%) met our inclusion criteria. The evidence base was rated as moderately low quality using MERSQI criteria. Applicants reported preferences for several one-on-one interviews lasting 15 to 20 minutes, interviews by current trainees, and interviews including social events with only trainees. Applicants had mixed perceptions of virtual versus in-person interviews and reported that virtual interviews saved costs. The multiple mini interview (MMI) required more applicant and interviewer time than individual interviews but demonstrated construct and predictive validity and was preferred by applicants and interviewers. Conclusions Based on moderately low-quality evidence, using the MMI, training interviewers, and providing applicants with basic program information in advance should be considered for GME selection interviews.

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants.

The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases. Furthermore, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade. Here, we developed a tetravalent FGFR3×FGFR3 bispecific antibody that inhibited FGFR3 point mutants and fusion proteins more effectively than any of the conventional FGFR3 antibodies that we produced. Each arm of the bispecific antibody contacted two distinct epitopes of FGFR3 through a cis mode of binding. The antibody blocked dimerization of the most common FGFR3 oncogenic variant (S249C extracellular domain mutation) and inhibited the function of FGFR3 variants that are resistant to pan-FGFR TKIs. The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade.

Gender Diversity and Research Productivity of Journal Editorial and Professional Society Board Members in Medical Education.

Purpose: To describe gender diversity and research productivity among medical education boards. Methods: We examined gender, training status, and research productivity of board members of Journal Citation Reports-listed medical education journals and affiliated professional societies. We determined gender using gendered pronouns and-if unavailable-software. We evaluated differences using χ2 and t-tests. Results: Overall, half of board members but 44% of editors-in-chief and 20% of society leaders were female. Female-led journals and societies had higher female representation than their non-female-led counterparts; trainee board members were more likely to be female. Conclusions: Gender disparities exist among executives on journal and affiliated professional society boards in medical education.

Ethical and Professional Decision-Making Capabilities of Artificial Intelligence Chatbots: Evaluating ChatGPT's Professional Competencies in Medicine.

Purpose: We examined the performance of artificial intelligence chatbots on the PREview Practice Exam, an online situational judgment test for professionalism and ethics. Methods: We used validated methodologies to calculate scores and descriptive statistics, χ2 tests, and Fisher's exact tests to compare scores by model and competency. Results: GPT-3.5 and GPT-4 scored 6/9 (76th percentile) and 7/9 (92nd percentile), respectively, higher than medical school applicant averages of 5/9 (56th percentile). Both models answered 95 + % of questions correctly. Conclusions: Chatbots outperformed the average applicant on PREview, suggesting their potential for healthcare training and decision-making and highlighting risks of online assessment delivery.

The impact of the medical school admissions interview: a systematic review.

Background: Interviews are considered an important part of the medical school admissions process but have been critiqued based on bias and reliability concerns since the 1950s. To determine the impact of the interview, this systematic review investigated the characteristics and outcomes of medical students admitted with and without interviews. Methods: We searched four literature databases from inception through August 2022; all studies comparing medical students admitted with and without interviews were included. We excluded studies from outside the medical school setting and non-research reports. We reviewed interview type, study design, quality, and outcomes. Results: Eight studies from five institutions across five countries were included. Six reported no demographic differences between students admitted with and without interviews; one found that more men were admitted without than with semi-structured interviews, and both cohorts had similar academic and clinical performance. Structured interviews admitted students who scored higher on clinical exams and social competence and lower on academic exams. Cohorts admitted with and without structured interviews had similar mental health issues by their final year of medical school. Discussion: This review suggests that students admitted with and without unstructured and semi-structured interviews were similar demographically, academically, and clinically. Moreover, structured interviews selected more socially competent students who performed better clinically but worse academically. Further research is needed to determine the impact of the selection interview in medical school admissions.

Contexte: Les entrevues sont considérées comme une composante importante du processus d'admission dans les facultés de médecine, mais elles ont été critiquées depuis les années 1950 sur la base de préoccupations liées à la partialité et à la fiabilité. Afin de déterminer l'impact de l'entrevue, nous avons étudié dans cette revue systématique les caractéristiques et les résultats des étudiants en médecine admis ayant passé ou non une entrevue. Méthodes: Nous avons effectué des recherches dans quatre bases de données bibliographiques depuis leur création jusqu'à août 2022; toutes les études comparant les étudiants en médecine admis avec ou sans entrevue ont été incluses. Nous avons exclu les études réalisées en dehors du cadre des facultés de médecine et les rapports ne relevant pas de la recherche. Nous avons examiné le type d'entrevue, la conception de l'étude, la qualité et les résultats. Résultats: Huit études provenant de cinq établissements dans cinq pays ont été incluses. Six d'entre elles ne font état d'aucune différence démographique entre les étudiants admis avec ou sans entrevue ; l'une d'entre elles a révélé que davantage d'hommes étaient admis sans entrevue qu'avec une entrevue semi-structurée, et que les deux cohortes présentaient des rendements universitaires et cliniques similaires. Les entrevues structurées ont permis d'admettre des étudiants qui ont obtenu de meilleurs résultats aux examens cliniques et compétence sociale et de moins bons résultats aux examens universitaires. Les cohortes admises avec et sans entrevues structurées présentaient des problèmes de santé mentale similaires lors de leur dernière année d'études de médecine. Discussion: Cette étude suggère que les étudiants admis avec et sans entrevues non structurées et semi-structurées étaient similaires d'un point de vue démographique, universitaire et clinique. En outre, les entrevues structurées ont permis de sélectionner des étudiants plus compétents sur le plan social, qui ont obtenu de meilleurs résultats cliniques, mais avec une moins bonne performance sur le plan académique. D'autres recherches sont nécessaires pour déterminer l'impact de l'entrevue de sélection sur les admissions dans les facultés de médecine.

Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis.

Importance: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. Objective: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. Design, Setting, and Participants: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. Main Outcomes and Measures: Death while in the PICU. Results: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). Conclusions and Relevance: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.

Trends in Firearm Injury Prevention Research Funding, Clinical Trials, and Publications in the US, 1985-2022.

This cross-sectional study examines federal funding, registered clinical trials, and publications to quantify trends in firearm injury prevention research in the US from 1985 to 2022.

Lung Re-transplantation after prolonged veno-venous extracorporeal membrane oxygenation (ECMO) in a child with chronic lung allograft dysfunction.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) may be used as a bridge to lung transplantation in selected patients with end-stage respiratory failure. Historically, ECMO use in this setting has been associated with poor outcomes Puri V et.al, J Thorac Cardiovasc Surg, 140:427. More recently, technical advances and the implementation of rehabilitation and ambulation while awaiting transplantation on ECMO have led to improved surgical and post-transplant outcomes Kirkby S et.al, J Thorac Dis, 6:1024. METHODS: We illustrate the case of a 6-year-old child who received prolonged ECMO support as a bridge to lung re-transplantation secondary to Chronic Lung Allograft Dysfunction (CLAD). RESULTS: Early rehabilitation was key in improving the overall pre-transplant conditioning during ECMO. CONCLUSIONS: Despite challenges associated with awake/ambulatory ECMO, the use of this strategy as a bridge to lung transplantation is feasible and has resulted in improved pre-transplant conditioning and post-transplant outcomes.

Prevalence and Risk Factors of Self-reported Vision Impairment among Native Hawaiians and Pacific Islanders in the United States.

Racial disparities in vision impairment have been reported among Black, Hispanic, and White Americans. However, there is a paucity of research on vision impairment among Native Hawaiians and Pacific Islanders (NHPIs). The objective of this study was to determine the prevalence of, and risk factors for, self-reported visual impairment in NHPI adults in the United States (US). Data from the NHPI and 2014 National Health Interview Surveys were analyzed using sample weights and variance estimates. Prevalence was calculated for vision impairment and blindness for the NHPI and overall US populations. Sociodemographic and clinical risk factors of vision impairment were explored using descriptive statistics, χ2 tests, and simple and multiple logistic regression. In total, 2 586 NHPIs and 36 673 individuals in the US were included. The prevalence of vision impairment was 8.8% among NHPIs and 9.1% for the overall US population, and the prevalence of blindness was 0.72% for NHPIs and 0.35% for the overall population. Independent risk factors associated with vision impairment were having a Charlson Comorbidity Index over 1 [OR: 2.89, 95% CI: (1.42-5.88)] and having a family income below $35 000 [OR: 2.03, 95% CI: (1.06-3.89)]. In summary, the rate of blindness is higher among NHPIs than the overall US population, especially for older and unemployed individuals with more comorbidities. Higher comorbidity burden, lower family income, and recent eye care were risk factors for vision impairment. More research is necessary to develop targeted and culturally sensitive interventions to promote NHPI eye health.

Regulatory and Informational Gaps in the Over-the-Counter Eye Care Product Industry-Over the Counter, Under the Radar.

This Viewpoint describes the limitations of regulatory oversight for over-the-counter eye care products and challenges in providing clinical recommendations.

Treatments for Acute Nonarteritic Central Retinal Artery Occlusion: Findings From a Cochrane Systematic Review.

Many interventions for nonarteritic central retinal artery occlusion (CRAO) are associated with serious complications and little effect on visual outcomes. We report on the findings of a Cochrane systematic review that searched seven databases for peer-reviewed articles reporting on treatments for acute nonarteritic CRAO. We assessed six randomized controlled trials, including interventions such as tissue plasminogen activator (t-PA), isovolumic hemodilution, eyeball massage, intraocular pressure reduction, anticoagulation, vasodilation, oxygen inhalation, laser embolysis, transcorneal electrical stimulation, thrombolysis, pentoxifylline, and enhanced external counterpulsation. However, none of the randomized controlled trials demonstrated significant improvement in visual acuity at 1 month compared to observation, and some patients treated with t-PA experienced serious adverse effects including intracranial hemorrhage. Proposed interventions for acute nonarteritic CRAO may not be better than observation, but the evidence is uncertain. Larger, well-designed studies are necessary to determine the most effective management option for acute nonarteritic CRAO. [Ophthalmic Surg Lasers Imaging Retina 2023;54:650-653.].