Citations

Abstract Background In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI. Patients and methods This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy. The primary endpoint was relapse-free survival (RFS) from initiation of 2L adjuvant dab/tram (RFS-2), analyzed via Kaplan-Meier methods. Results Thirty-eight patients were included (median age 50 years, 63% male, 87% stage III, median follow-up 19 months from 2L dab/tram initiation). Median dab/tram duration was 10.1 months (range: 1 day–22.7 months), with half discontinuing due to progression or adverse events. Median (95% CI) RFS-2 was 18.9 (14.9–28.1) months, with 91%, 81%, and 58% remaining relapse-free at 6, 12, and 18 months, respectively. Most patients remained distant metastasis-free at 6, 12, and 18 months (97%, 85%, and 71%, respectively). Two patients were deceased at the last follow-up, with 97% alive at 18 months. Conclusions Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

Patients with chronic liver disease commonly have abnormal lung function; however, the impact of smoking on outcomes in these patients is unknown. We hypothesized current or past smoking would be associated with worse survival in patients with advanced liver disease. The Pulmonary Vascular Complications in Liver Disease Study 2 (PVCLD2) was a prospective cohort of patients with advanced liver disease undergoing evaluation for liver transplantation (LT). Patients were classified by self-report as a “non-smoker,” “past smoker,” or “current smoker.” We used Cox proportional hazards models and Fine-Gray models with LT as a competing risk. Models were adjusted for age, sex, body mass index, race, family income, liver disease etiology, and Model for End-Stage Liver Disease-Sodium score. Of the 410 patients included, most (65%) were male and the mean age at enrollment was 56.5 years. One hundred sixty (39%) patients were nonsmokers, 183 (45%) were past smokers, and 67 (16%) were current smokers. In total, 151 (37%) patients received an LT, and 88 (20%) patients died. When compared to nonsmokers, current smokers had a 2.17-fold increase in risk of death overall (95% CI: 1.12–4.18, p = 0.02). There was a 7% increase in overall risk of death for every 5 pack-years increase (95% CI: 1.01–1.13, p = 0.02). With LT as a competing risk, the subdistributional HR of current smokers versus nonsmokers for death was 2.45 (95% CI: 1.31–4.60, p = 0.005). In this model, past smokers displayed a nonsignificant increase in the risk of death compared to nonsmokers (subdistributional HR: 1.58, 95% CI: 0.91–2.72, p = 0.10). Patients with advanced liver disease undergoing evaluation for LT who smoke have an increased risk of death. Smoking cessation could lead to improved overall survival with or without LT.

Background: A retear after anterior cruciate ligament (ACL) reconstruction remains a common and devastating complication. Knee bone morphology is associated with the risk of ACL injuries, ACL retears, and osteoarthritis, and a combination of tools that derive bone shape from clinical imaging, such as magnetic resonance imaging (MRI) and statistical shape modeling, could identify patients at risk of developing these joint conditions. Purpose: To identify bone shape features before primary ACL reconstruction in patients with an eventual retear compared to those with a known intact ACL graft. Study Design: Case-control study; Level of evidence, 3. Methods: Bone was automatically segmented on 2-dimensional proton density–weighted MRI of the knee in patients at the time of the initial ACL injury using deep convolutional neural networks. Patients with a subsequent retear after reconstruction within 3 years (22 femurs, 19 tibias) were compared with those with an intact ACL graft at 3 years (20 femurs, 22 tibias) using statistical shape modeling to identify preoperative bone shape features predictive of a retear after ACL reconstruction. Results: Statistical shape modeling revealed 2 specific bone shape features (modes) in the femur and 1 mode in the tibia that demonstrated significant differences at the time of the initial injury in patients with subsequent retears. In the femur, a narrower intercondylar notch width, a widened medial condylar width, an increased femoral condylar offset ratio, increased surface area along the lateral femoral condyle relative to the medial condyle, and a more prominent trochlear sulcus at the time of the initial injury were associated with retears after ACL reconstruction. In the tibia, a diminished ACL facet prominence, a squared lateral and medial tibial plateaus, and a broader and flattened tibial spine at the time of the initial injury were associated with retears after ACL reconstruction. Conclusion: Using the automatic bone segmentation pipeline on preoperative MRI, the authors identified bone shape features associated with a retear after ACL reconstruction. The use of this pipeline enables large-scale studies of bone shape on MRI and could predict patients at risk of ACL retears to alter treatment decisions.

ABSTRACT Ureaplasma species can cause systemic infections in immunocompromised hosts, including lung transplant recipients. Here, we investigated the impact of prior exposure to Ureaplasma urealyticum on the risk of U. urealyticum and Ureaplasma parvum infection in mice subjected to an immunosuppression regimen similar to that administered to solid organ transplant recipients. Mice were immunized with three intramuscular injections of U. urealyticum , with control mice injected with adjuvant only. Following immunization, mice received tacrolimus, mycophenolate mofetil, and methylprednisolone, and then were challenged with U. urealyticum or U. parvum intraperitoneally and intratracheally over 6 days. Relative U. urealyticum antibody levels in plasma were assessed over time, and lungs were harvested at sacrifice for bacterial load quantification, assessed using a color-changing unit assay. U. urealyticum antibody levels were higher in immunized compared with control animals ( P < 0.0001), even when animals were immunosuppressed. U. urealyticum and U. parvum lung burden was reduced in immunized compared with control mice (~6 log 10 reduction for U. urealyticum and <1 log 10 reduction for U. parvum ; P = 0.008 and 0.046, respectively). In summary, this study shows that prior exposure to live U. urealyticum provides some protection against infection with U. urealyticum . IMPORTANCE Ureaplasma -induced hyperammonemia syndrome is a rare but potentially deadly complication of solid organ transplantation, especially lung transplantation. The pathophysiology of this relatively recently recognized condition is poorly understood, and it is unclear what factors may influence patient susceptibility. This study investigates the possible protective effects of prior exposure to Ureaplasma urealyticum in a mouse model subjected to an immunosuppression regimen similar to that given to lung transplant recipients. The findings show that prior exposure could provide protection against Ureaplasma lung infection.

Objective: Patients with inflammatory bowel disease (IBD) are commonly treated with immunosuppressive therapies that increase the risk for infections, including hepatitis B (HepB) virus. Adult patients with IBD have suboptimal seroprotection rates after vaccination with a 3-dose recombinant recombinant HepB vaccine. Heplisav-B is an adjuvanted 2-dose HepB series that is more immunogenic in the general adult population. Herein, we evaluated the immunogenicity of Heplisav-B in adult patients with IBD. Patients and Methods: We conducted a prospective observational study of adult patients with IBD who were not seroprotected to HepB virus and received a Heplisav-B series with postimmunization HepB surface antibody (anti-HBs) serologic testing. Postimmunization anti-HBs ≥10 IU/mL was considered seroprotection. The primary outcome was the rate of seroprotection. Secondary outcomes were rates of seroprotection in different age groups, those on immunosuppressive therapy, and previous HepB vaccine nonresponders using a univariate analysis. Results: Eighty-five patients met the inclusion criteria with the majority (72%) achieving seroprotection with a median anti-HBs level of 48.7 IU/mL and 28 patients (33%) having an anti-HBs level >100 IU/mL. Those on immunosuppressive therapy [49 (58%), 18 nonresponders, odds ratio: 0.34, 95% CI: 0.12-0.99] and primary nonresponders to a previous HepB series [22 (26%), 11 nonresponders, odds ratio: 0.26, 95% CI: 0.09-0.73] were less likely to achieve seroprotection. Seven patients who did not respond received a third dose of Heplisav-B, and 2 achieved seroprotection. Conclusions: Heplisav-B achieved higher rates of seroprotection than those seen with 3-dose recombinant HepB vaccines in patients with IBD and may be the preferred option.

The Autosomal Dominant Polycystic Kidney Disease (ADPKD) Centers of Excellence (COE) Program, launched by the Polycystic Kidney Disease Foundation in 2022, aims to bridge the gap in specialized care for individuals with ADPKD. This program seeks to enhance the availability of specialized clinicians and simplify the process for patients seeking expert care. It is founded on three pillars: improving care for all individuals with ADPKD, educating and empowering the community, and advancing polycystic kidney disease research. The program draws inspiration from successful models in other diseases, such as cystic fibrosis and muscular dystrophy, which have demonstrated the effectiveness of standardized care centers in improving patient outcomes. Patient and clinician stakeholder interviews have identified key areas where a national program could make a significant effect, including the need for a core care team with defined referral processes, mentorship and shared care models, patient navigation services, and education around expert consensus and care guidelines. The program introduces two designations to accommodate diverse care settings and enhance patient access to specialists: COE and Partner Clinic. The Partner Clinic designation ensures that patients in smaller community practices have access to specialized care through mentorship and guidance from experts at COE. The program also emphasizes the importance of specialized services, especially in underserved communities experiencing health disparities, to manage the complexities of ADPKD care. Patient focus groups have highlighted the need for care navigation services, centralized sources of knowledge, and access to local care. The program aims to address these needs by providing a structured framework for care coordination, enhancing patient self-advocacy, and improving overall outcomes for individuals with ADPKD. Key Points The Autosomal Dominant Polycystic Kidney Disease Centers of Excellence Program aims to improve specialized care for autosomal dominant polycystic kidney disease patients. It introduces two designations to accommodate diverse care settings and enhance patient access to specialists: Center of Excellence and Partner Clinic. The program draws inspiration from successful models in other diseases, such as cystic fibrosis and muscular dystrophy, which have demonstrated the effectiveness of standardized care centers in improving patient outcomes. Key needs and programmatic goals identified through patient and clinician stakeholder interviews include establishing a core care team with defined referral processes, implementing mentorship and shared care models, providing patient navigation services, and offering education on expert consensus and care guidelines.

Importance Data are limited on the longitudinal implications of socioeconomic status (SES) for neurodevelopmental outcomes among persons with complex congenital heart disease (CHD). Objectives To examine the association of family SES, maternal educational level, and maternal IQ with the neurodevelopment of individuals with dextro-transposition of the great arteries (d-TGA) from age 1 to 16 years and to identify how SES-related disparities change with age. Design, Setting, and Participants This cohort study analyzed data of participants enrolled in the Boston Circulatory Arrest Study, a randomized clinical trial conducted in Boston, Massachusetts, from 1988 to 1992. Participants were infants with d-TGA who underwent arterial switch operation and, after operation, underwent in-person neurodevelopmental status evaluations at ages 1, 4, 8, and 16 years. Analyses were conducted from April 2021 to August 2024. Exposures Mean Hollingshead scores at birth, age 1 year, and age 4 years were used to assign participants to SES tertiles (lowest, middle, or highest). Main Outcomes and Measures Age-appropriate neurodevelopmental outcomes assessed at 4 study time points (ages 1, 4, 8, and 16 years) via in-person administration of a range of well-validated measures. Standardized neurodevelopmental composite scores from each evaluation were derived from principal component analysis and compared across SES tertiles, adjusting for birth and medical characteristics. These scores were used to categorize the sample into latent classes; patient and medical factors for a 3-class model were used to estimate latent class using multinomial regression. Results The sample included 164 patients with d-TGA (123 males [75%]; mean [SD] gestational age at birth, 39.8 [1.2] weeks; 3 with Asian [2%], 6 with Black [4%], 5 with Hispanic [3%], and 146 with White [89%] race and ethnicity) and their mothers (mean [SD] age at birth, 28.5 [5.2] years). Lower SES tertile was associated with worse scores on most individual neurodevelopmental tests and worse neurodevelopmental composite scores at ages 4, 8, and 16 years. For example, mean (SD) neurodevelopmental composite scores at age 4 years were –0.49 [0.83] for lowest, 0.00 [0.81] for middle, and 0.47 [1.10] for highest SES tertile ( F 2 = 15.5; P &amp;lt; .001). When measured at consecutive time points, differences between SES tertiles were of similar magnitude. A latent class analysis produced 2- and 3-class models representing patients with stable (103 [64%] and 85 [53%]), improving (20 [13%]), and declining (57 [36%] and 55 [34%]) neurodevelopmental status. Those experiencing declines in neurodevelopmental status were more likely to have younger maternal age at childbirth (26.6 [5.1] vs 29.6 [4.9] and 29.1 [5.1] years; P = .002), lower maternal IQ (91.0 [14.1] vs 100.1 [11.1] and 96.2 [11.0]; P &amp;lt; .001), and lower SES (35.2 [10.8] vs 40.9 [9.9] and 35.8 [10.1]; P = .003) compared with those with stable or improving status. Conclusions and Relevance This cohort study of individuals with d-TGA found an association between lower family SES and worse neurodevelopmental outcomes in childhood and continuing throughout adolescence as well as greater decline in neurodevelopmental status over time. Effective strategies are needed to improve access to neurodevelopmental monitoring and intervention services for children with CHD from lower socioeconomic backgrounds.

ABSTRACT. Encephalitis is a significant global health problem, especially in children. Knowledge of its economic burden is essential for policymakers in prioritizing the development and implementation of interventions but remains limited. An observational study was prospectively conducted at a major children’s hospital in Ho Chi Minh City, Vietnam from 2020 to 2022. Data on direct medical costs, direct nonmedical costs, and productivity costs were collected alongside demographic information, clinical features, diagnosis, severity, and outcomes of study participants. This was used to undertake a cost of illness analysis from a societal perspective. Data were collected from a total of 164 pediatric patients. The median cost of illness was estimated at US $1,859 (interquartile range [IQR]: US $1,273–$3,128). The direct costs were the main cost driver, accounting for 83.9% of the total cost of illness (US $1,560; IQR: US $975–$2,460). The productivity costs accounted for a median of US $275 (IQR: US $154–$474). The cost of illness was higher in more severe patients, patients with sequelae, patients with morbidities, and ventilated patients. Most direct medical costs were attributed to hospitalization and resulted in out-of-pocket payments from the patient’s family (30.2%; US $316). The results showed that the cost of illness of encephalitis in children is considerable and will be useful for policymakers in prioritizing resources for the development and implementation of intervention strategies to reduce the burden of pediatric encephalitis.