The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families.

Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.

Physician services and costs after disclosure of diagnostic sequencing results in the NYCKidSeq program.

PURPOSE: To better understand the effects of returning diagnostic sequencing results on clinical actions and economic outcomes for pediatric patients with suspected genetic disorders. METHODS: Longitudinal physician claims data after diagnostic sequencing were obtained for patients aged 0 to 21 years with neurologic, cardiac, and immunologic disorders with suspected genetic etiology. We assessed specialist consultation rates prompted by primary diagnostic results, as well as marginal effects on overall 18-month physician services and costs. RESULTS: We included data on 857 patients (median age: 9.6 years) with a median follow-up of 17.3 months after disclosure of diagnostic sequencing results. The likelihood of having ≥1 recommendation for specialist consultation in 155 patients with positive findings was high (72%) vs 23% in 443 patients with uncertain findings and 21% in 259 patients with negative findings (P < .001). Follow-through consultation occurred in 30%. Increases in 18-month physician services and costs following a positive finding diminished after multivariable adjustment. Also, no significant differences between those with uncertain and negative findings were demonstrated. CONCLUSION: Our study did not provide evidence for significant increases in downstream physician services and costs after returning positive or uncertain diagnostic sequencing findings. More large-scale longitudinal studies are needed to confirm these findings.

Measuring health-related quality of life in children with suspected genetic conditions: validation of the PedsQL proxy-report versions.

PURPOSE: Measuring health-related quality of life (HRQoL) of children with suspected genetic conditions is important for understanding the effect of interventions such as genomic sequencing (GS). The Pediatric Quality of Life Inventory (PedsQL) is a widely used generic measure of HRQoL in pediatric patients, but its psychometric properties have not yet been evaluated in children undergoing diagnostic GS. METHODS: In this cross-sectional study, we surveyed caregivers at the time of their child's enrollment into GS research studies as part of the Clinical Sequencing Evidence Generating Research (CSER) consortium. To evaluate structural validity of the PedsQL 4.0 Generic Core Scales and PedsQL Infant Scales parent proxy-report versions, we performed a confirmatory factor analysis of the hypothesized factor structure. To evaluate convergent validity, we examined correlations between caregivers' reports of their child's health, assessed using the EQ VAS, and PedsQL scores by child age. We conducted linear regression analyses to examine whether age moderated the association between caregiver-reported child health and PedsQL scores. We assessed reliability using Cronbach's alpha. RESULTS: We analyzed data for 766 patients across all PedsQL age group versions (1-12 months through 13-18 years). Model fit failed to meet criteria for good fit, even after modification. Neither age group (categorical) nor age (continuous) significantly moderated associations between PedsQL scores and caregiver-reported child health. Cronbach's alphas indicated satisfactory internal consistency for most PedsQL scales. CONCLUSION: The PedsQL Generic Core Scales and Infant Scales may be appropriate to measure HRQoL in pediatric patients with suspected genetic conditions across a wide age range. While we found evidence of acceptable internal consistency and preliminary convergent validity in this sample, there were some potential problems with structural validity and reliability that require further attention.

Physician and informal care use explained by the Pediatric Quality of Life Inventory (PedsQL) in children with suspected genetic disorders.

PURPOSE: To examine associations between Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and PedsQL Infant Scales with formal health care resource utilization (HCRU) and informal caregiver burden. METHODS: We studied a pediatric cohort of 837 patients (median age: 8.4 years) with suspected genetic disorders enrolled January 2019 through July 2021 in the NYCKidSeq program for diagnostic sequencing. Using linked ~ nine-month longitudinal survey and physician claims data collected through May 2022, we modeled the association between baseline PedsQL scores and post-baseline HCRU (median follow-up: 21.1 months) and informal care. We also assessed the longitudinal change in PedsQL scores with physician services using linear mixed-effects models. RESULTS: Lower PedsQL total and physical health scores were independently associated with increases in 18-month physician services, encounters, and weekly informal care. Comparing low vs. median total scores, increases were 10.6 services (95% CI: 1.0-24.6), 3.3 encounters (95% CI: 0.5-6.8), and $668 (95% CI: $350-965), respectively. For the psychosocial domain, higher scores were associated with decreased informal care. Based on adjusted linear mixed-effects modeling, every additional ten physician services was associated with diminished improvement in longitudinal PedsQL total score trajectories by 1.1 point (95% confidence interval: 0.6-1.6) on average. Similar trends were observed in the physical and psychosocial domains. CONCLUSION: PedsQL scores were independently associated with higher utilization of physician services and informal care. Moreover, longitudinal trajectories of PedsQL scores became less favorable with increased physician services. Adding PedsQL survey instruments to conventional measures for improved risk stratification should be evaluated in further research.

The Pediatric Quality of Life Inventory (PedsQL) is widely used to measure health-related quality of life in pediatric patients; however, few studies have examined whether the PedsQL is indicative of longitudinal outcomes of morbidity and health care needs. This study captures associations between PedsQL scores with utilization of physician and informal care in children with suspected genetic disorders. We demonstrate that lower PedsQL total and physical health scores are independently associated with greater utilization of physician services and informal care. Moreover, longitudinal trajectories of PedsQL scores become less favorable with increased physician services. Results can inform future applications of PedsQL instruments.

Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing.

PURPOSE: Neurodevelopmental disorders (NDDs) often result from rare genetic variation, but genomic testing yield for NDDs remains below 50%, suggesting that clinically relevant variants may be missed by standard analyses. Here, we analyze "poison exons" (PEs), which are evolutionarily conserved alternative exons often absent from standard gene annotations. Variants that alter PE inclusion can lead to loss of function and may be highly penetrant contributors to disease. METHODS: We curated published RNA sequencing data from developing mouse cortex to define 1937 conserved PE regions potentially relevant to NDDs, and we analyzed variants found by genome sequencing in multiple NDD cohorts. RESULTS: Across 2999 probands, we found 6 novel clinically relevant variants in PE regions. Five of these variants are in genes that are part of the sodium voltage-gated channel alpha subunit family (SCN1A, SCN2A, and SCN8A), which is associated with epilepsies. One variant is in SNRPB, associated with cerebrocostomandibular syndrome. These variants have moderate to high computational impact assessments, are absent from population variant databases, and in genes with gene-phenotype associations consistent with each probands reported features. CONCLUSION: With a very minimal increase in variant analysis burden (average of 0.77 variants per proband), annotation of PEs can improve diagnostic yield for NDDs and likely other congenital conditions.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

PURPOSE: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. METHODS: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. RESULTS: A total of 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs TGPs in Hispanic/Latino(a) (17.2% vs 9.5%, P < .001) and White/European American (19.8% vs 7.9%, P < .001) but not in Black/African American (11.5% vs 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. CONCLUSION: GS may yield up to twice as many diagnoses in pediatric patients compared with TGP testing but not yet across all population groups.

Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program.

Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0-21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.

Detection of mosaic variants using genome sequencing in a large pediatric cohort.

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.

Financial incentives to improve re-engagement in HIV care: results from a randomized pilot study.

OBJECTIVE: Determine the feasibility, acceptability, and preliminary effectiveness of financial incentives to motivate re-engagement in HIV care in Shinyanga, Tanzania. METHODS: Out-of-care people living with HIV (PLHIV) were identified from medical records in four clinics and home-based care providers (HBCs) from April 13, 2018 to March 3, 2020. Shinyanga Region residents, ≥18 years, who were disengaged from care were randomized 1:1 to a financial incentive (∼$10 USD) or the standard of care (SOC), stratified by site, and followed for 180 days. Primary outcomes were feasibility (located PLHIV who agreed to discuss the study), acceptability (enrollment among eligibles), and re-engagement in care (clinic visit within 90 days). RESULTS: HBCs located 469/1,309 (35.8%) out-of-care PLHIV. Of these, 215 (45.8%) were preliminarily determined to be disengaged from care, 201 (93.5%) agreed to discuss the study, and 157 eligible (100%) enrolled. Within 90 days, 71 (85.5%) PLHIV in the incentive arm re-engaged in care vs. 58 (78.4%) in the SOC (Adjusted Risk Difference [ARD] = 0.08, 95% CI: -0.03, 0.19, p = 0.09). A higher proportion of incentivized PLHIV completed an additional (unincentivized) visit between 90-180 days (79.5% vs. 71.6%, ARD = 0.10, 95% CI: -0.03, 0.24, p = 0.13) and remained in care at 180 days (57.8% vs. 51.4%, ARD = 0.07, 95% CI: -0.09, 0.22, p = 0.40). CONCLUSIONS: Short-term financial incentives are feasible, acceptable, and have the potential to encourage re-engagement in care, warranting further study of this approach.

GUÍA: a digital platform to facilitate result disclosure in genetic counseling.

PURPOSE: Use of genomic sequencing is increasing at a pace that requires technological solutions to effectively meet the needs of a growing patient population. We developed GUÍA, a web-based application, to enhance the delivery of genomic results and related clinical information to patients and families. METHODS: GUÍA development occurred in five overlapping phases: formative research, content development, stakeholder/community member input, user interface design, and web application development. Development was informed by formative qualitative research involving parents (N = 22) whose children underwent genomic testing. Participants enrolled in the NYCKidSeq pilot study (N = 18) completed structured feedback interviews post-result disclosure using GUÍA. Genetic specialists, researchers, patients, and community stakeholders provided their perspectives on GUÍA's design to ensure technical, cultural, and literacy appropriateness. RESULTS: NYCKidSeq participants responded positively to the use of GUÍA to deliver their children's results. All participants (N = 10) with previous experience with genetic testing felt GUÍA improved result disclosure, and 17 (94%) participants said the content was clear. CONCLUSION: GUÍA communicates complex genomic information in an understandable and personalized manner. Initial piloting demonstrated GUÍA's utility for families enrolled in the NYCKidSeq pilot study. Findings from the NYCKidSeq clinical trial will provide insight into GUÍA's effectiveness in communicating results among diverse, multilingual populations.

Health- and Vision-Related Quality of Life in a Randomized Controlled Trial Comparing Methotrexate and Mycophenolate Mofetil for Uveitis.

PURPOSE: To evaluate changes in health-related and vision-related quality of life (VRQoL) among patients with noninfectious uveitis who were treated with antimetabolites. DESIGN: Secondary analysis of a randomized controlled trial. PARTICIPANTS: Patients with noninfectious uveitis from India, the United States, Australia, Saudi Arabia, and Mexico. METHODS: From 2013 through 2017, 216 participants were randomized to receive 25 mg weekly oral methotrexate or 1.5 g twice daily oral mycophenolate mofetil. Median changes in quality of life (QoL) were measured using Wilcoxon signed-rank tests, and differences between treatment groups were measured using linear mixed models, adjusting for baseline QoL score, age, gender, and site. Among Indian patients, VRQoL scores from a general scale (the National Eye Institute Visual Function Questionnaire [NEI-VFQ]) and a culturally specific scale (the Indian Visual Function Questionnaire [IND-VFQ]) were compared using Pearson correlation tests. MAIN OUTCOME MEASURES: Vision-related QoL (NEI-VFQ and IND-VFQ) and health-related QoL (HRQoL; physical component score [PCS] and mental component score [MCS] of the Medical Outcomes Study 36-Item Short Form Survey [SF-36v2]) were measured at baseline, the primary end point (6 months or treatment failure before 6 months), and the secondary end point (12 months or treatment failure between 6 and 12 months). RESULTS: Among 193 participants who reached the primary end point, VRQoL increased from baseline by a median of 12.0 points (interquartile range [IQR], 1.0-26.1, NEI-VFQ scale), physical HRQoL increased by a median of 3.6 points (IQR, -1.4 to 14.9, PCS SF-36v2), and mental HRQoL increased by a median of 3.0 points (IQR, -3.7 to 11.9, MCS SF-36v2). These improvements in NEI-VFQ, SF-36v2 PCS, and SF-36v2 MCS scores all were significant (P < 0.01). The linear mixed models showed that QoL did not differ between treatment groups for each QoL assessment (NEI-VFQ, IND-VFQ, PCS SF-36v2, and MCS SF-36v2; P > 0.05 for all). The NEI-VFQ and IND-VFQ scores for Indian participants were correlated highly at baseline and the primary and secondary end points (correlation coefficients, 0.87, 0.80, and 0.90, respectively). CONCLUSIONS: Among patients treated with methotrexate or mycophenolate mofetil for uveitis, VRQoL and HRQoL improved significantly over the course of 1 year and did not differ by treatment allocation. These findings suggest that antimetabolites could improve overall patient well-being and daily functioning.

Complexities of the Microbiome: Jaundice in Patient With Ulcerative Colitis.

Patients with jaundice and abdominal pain should be assessed immediately for biliary obstruction. The development of cholangitis, or an inflammation of the bile ducts, can lead to infection. A nurse practitioner must complete a thorough health history and physical examination to assist in differentiating potential causes of jaundice.

Ring-Opening Polymerization of Cyclic Phosphonates: Access to Inorganic Polymers with a PV-O Main Chain.

We describe a new class of inorganic polymeric materials featuring a main chain consisting of PV-O bonds and aryl side groups, which was obtained with >70 repeat units by ring-opening polymerization of cyclic phosphonates. This monomer-polymer system was found to be dynamic in solution enabling selective depolymerization under dilute conditions, which can be tuned by varying the substituents. The polymers show high thermal stability to weight loss and can be easily fabricated into self-standing thin films. Structural characterizations of the cyclic 6- and 12-membered ring precursors are also described.

The New York pilot newborn screening program for lysosomal storage diseases: Report of the First 65,000 Infants.

PURPOSE: We conducted a consented pilot newborn screening (NBS) for Pompe, Gaucher, Niemann-Pick A/B, Fabry, and MPS 1 to assess the suitability of these lysosomal storage disorders (LSDs) for public health mandated screening. METHODS: At five participating high-birth rate, ethnically diverse New York City hospitals, recruiters discussed the study with postpartum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long-term outcome. RESULTS: Over 4 years, 65,605 infants participated, representing an overall consent rate of 73%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status. CONCLUSION: Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

Interventions to Improve Linkage to HIV Care in the Era of "Treat All" in Sub-Saharan Africa: a Systematic Review.

PURPOSE OF THE REVIEW: In 2015, antiretroviral therapy (ART) was recommended for all people living with HIV (PLHIV) regardless of CD4 count ("Treat All"). To better understand how to improve linkage to care under these new guidelines, we conducted a systematic review of studies evaluating linkage interventions in Sub-Saharan Africa under Treat All. RECENT FINDINGS: We identified 14 eligible articles and qualitatively analyzed the effectiveness of the interventions. Increases in linkage were reported by supply-side and counseling interventions. Mobile testing and economic incentives did not increase linkage. Given the lag time between adoption and implementation, only two of the studies were conducted in a Treat All setting. None of the interventions specifically focused on re-linking PLHIV who had disengaged from care. Future studies must design interventions that target not only newly diagnosed or treatment naïve PLHIV, but should explicitly focus on PLHIV who have disengaged from care.

Lower Prefrontal and Hippocampal Volume and Diffusion Tensor Imaging Differences Reflect Structural and Functional Abnormalities in Abstinent Individuals with Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is known to have adverse effects on brain structure and function. Multimodal assessments investigating volumetric, diffusion, and cognitive characteristics may facilitate understanding of the consequences of long-term alcohol use on brain circuitry, their structural impairment patterns, and their impact on cognitive function in AUD. METHODS: Voxel- and surface-based volumetric estimations, diffusion tensor imaging (DTI), and neuropsychological tests were performed on 60 individuals: 30 abstinent individuals with AUD (DSM-IV) and 30 healthy controls. Group differences in the volumes of cortical and subcortical regions, fractional anisotropy (FA), axial and radial diffusivities (AD and RD, respectively), and performance on neuropsychological tests were analyzed, and the relationship among significantly different measures was assessed using canonical correlation. RESULTS: AUD participants had significantly smaller volumes in left pars orbitalis, right medial orbitofrontal, right caudal middle frontal, and bilateral hippocampal regions, lower FA in 9 white matter (WM) regions, and higher FA in left thalamus, compared to controls. In AUD, lower FA in 6 of 9 WM regions was due to higher RD and due to lower AD in the left external capsule. AUD participants scored lower on problem-solving ability, visuospatial memory span, and working memory. Positive correlations of prefrontal cortical, left hippocampal volumes, and FA in 4 WM regions with visuospatial memory performance and negative correlation with lower problem-solving ability were observed. Significant positive correlation between age and FA was observed in bilateral putamen. CONCLUSIONS: Findings showed specific structural brain abnormalities to be associated with visuospatial memory and problem-solving ability-related impairments observed in AUD. Higher RD in 6 WM regions suggests demyelination, and lower AD in left external capsule suggests axonal loss in AUD. The positive correlation between FA and age in bilateral putamen may reflect accumulation of iron depositions with increasing age.

Kineothrix alysoides, gen. nov., sp. nov., a saccharolytic butyrate-producer within the family Lachnospiraceae.

An anaerobic, saccharolytic, spore-forming, butyrate-producing bacterium, strain KNHs209T, was isolated from a switchgrass microcosm seeded with forest soil. Cells were highly motile rods, often forming long filamentous chains which were easily observed moving under the microscope. Its closest phylogenetic relative was Eisenbergiella tayi (16S rRNA gene sequence identity 94.2 %), although it was easily distinguishable based on its morphology and physiology. Whole-genome sequencing enabled development of a minimal medium, and also suggested that the organism is capable of fixing nitrogen. Its wide variety of growth substrates was mirrored by a high number of encoded chemotaxis receptors (45, the highest in the family Lachnospiraceae). Strain KNHs209T utilized a wide variety of carbohydrates, but not cellulose or xylan. Fermentation products included formate, acetate and butyrate; sulfur compounds and nitrate were not reduced. Strain KNHs209T grew optimally at 35-40 °C and pH 7. The genomic DNA G+C content was 42.74 mol%; the major membrane fatty acids were C14 : 0 and C16 : 0. Based on phenotypic, genomic, phylogenetic and chemotaxonomic analyses, this organism represents a novel genus and species within the family Lachnospiraceae for which the name Kineothrix alysoides, gen. nov., sp. nov. is proposed. The type strain is KNHs209T (=ATCC TSD-26T=DSM 100556T).

A Retrospective Evaluation of Vemurafenib as Treatment for BRAF-Mutant Melanoma Brain Metastases.

BACKGROUND: RAF inhibitors are an effective therapy for patients with BRAF-mutant melanoma and brain metastasis. Efficacy data are derived from clinical studies enriched with physiologically fit patients; therefore, it is of interest to assess the real-world experience of vemurafenib in this population. Tumor-specific genetic variants that influence sensitivity to RAF kinase inhibitors also require investigation. METHODS: Records of patients with BRAF-mutant melanoma and brain metastases who were treated with vemurafenib were reviewed. Clinical data were extracted to determine extracranial and intracranial objective response rates, progression-free survival (PFS), overall survival (OS), and safety. A bait-capture, next-generation sequencing assay was used to identify mutations in pretreatment tumors that could explain primary resistance to vemurafenib. RESULTS: Among patients with intracranial disease treated with vemurafenib, 27 were included in survival analyses and 22 patients were assessable for response. The extracranial and intracranial objective response rates were 71% and 50%, respectively. Discordant responses were observed between extracranial and intracranial metastatic sites in 4 of 19 evaluable patients. Median PFS was 4.1 months (95% confidence interval [CI]: 2.6-7.9); median intracranial PFS was 4.6 months (95% CI: 2.7-7.9), median OS was 7.5 months (95% CI: 4.3-not reached), with a 30.4% 1-year OS rate. Outcomes were influenced by performance status. Vemurafenib was tolerable, although radiation-induced dermatitis occurred in some patients who received whole-brain radiotherapy. Adequate samples for next-generation sequencing analysis were available for seven patients. Melanomas categorized as "poorly sensitive" (≥20% tumor growth, new lesions, or ≤50% shrinkage for <4 months) harbored co-occurring mutations in genes predicted to activate the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway. CONCLUSION: Vemurafenib is highly active in BRAF-mutant melanoma brain metastases but has limited activity in patients with poor performance status. The safety and efficacy of concurrent radiotherapy and RAF inhibition requires careful clinical evaluation. Combination strategies blocking the MAPK and PI3K-AKT pathway may be warranted in a subset of patients. IMPLICATIONS FOR PRACTICE: Vemurafenib is active for BRAF-mutant intracranial melanoma metastases in an unselected patient population typical of routine oncologic practice. Patients with poor performance status appear to have poor outcomes despite vemurafenib therapy. Preliminary data indicate that co-occurring or secondary alterations in the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway are involved in resistance to RAF inhibition, thus providing a rationale for dual MAPK and PI3K-AKT pathway inhibition in this patient population.

Discordance Between HIV Risk Perception, Sexual Behavior, and Pre-exposure Prophylaxis Adherence Among Young Sexual and Gender Minorities in the United States.

PURPOSE: In the United States, youth experience suboptimal HIV pre-exposure prophylaxis (PrEP) adherence. One common idea posits that this is due to their developing decision-making skills. However, quantitative evidence of this assumption is limited. We therefore examined whether individual decision-making factors, such as HIV risk perception and sexual behavior, predicted PrEP adherence in a national trial of young sexual and gender minorities (YSGMs). METHODS: In 2019-2021, the Adolescent Medicine Trials Network for HIV Interventions 142 study enrolled 225 PrEP users (ages 16-24) throughout the country. Regression models estimated the associations between HIV risk perception (using a modified Perceived HIV Risk Scale), sexual behavior (condomless anal sex in ≤ 3 months), and self-reported oral PrEP adherence (≥4 pills in the past week) at the same time point (baseline) and longitudinally (3 months). RESULTS: Baseline risk perception (risk ratio [RR]: 0.92, 95% confidence interval [CI]: 0.82, 1.04) and condomless anal sex (RR: 1.10, 95% CI: 0.97, 1.25) were not associated with PrEP adherence at the same time point and did not predict 3-month adherence (RR: 0.97, 95% CI: 0.85, 1.11; RR: 1.05, 95% CI: 0.93, 1.19, respectively). Baseline risk perception was not associated with condomless anal sex at either time point (baseline RR: 1.16, 95% CI: 0.94, 1.43; 3-month RR: 1.07, 95% CI: 0.90, 1.28). DISCUSSION: In this national trial of YSGM, HIV risk perception and condomless anal sex did not predict PrEP adherence. Targeting individual-level perceptions and behaviors will likely insufficiently address youth's suboptimal PrEP use. Future research should identify YSGM-specific adherence drivers and train providers to recognize such motivations.