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Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus and eczematous lesions. Abrocitinib, a selective Janus kinase 1 (JAK1) inhibitor, has recently been approved in India for moderate-to-severe AD in adults. This prospective real-world case series evaluated the effectiveness and safety of abrocitinib in patients with moderate-to-severe AD who showed an inadequate response to cyclosporine. Nine patients (five females, four males; mean age 19.44 ± 7.68 years, range 10–34 years) were included. Three were adolescents or children in whom abrocitinib was used off-label. The mean disease duration was 13.33 ± 8.06 years, and eight patients had a positive family history of AD. Prior treatments included cyclosporine, methotrexate, and systemic corticosteroids. Abrocitinib was prescribed at a mean dose of 177.77 ± 44.09 mg daily (seven patients received 200 mg, two received 100 mg). Effectiveness was assessed at baseline and weeks 2, 4, 8, and 12 using the Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (PP-NRS). Significant and progressive reductions were observed in all scores. Mean EASI decreased from 48.22 ± 7.88 at baseline to 6.33 ± 3.35 at week 12 ( P < 0.0001). IGA scores improved from 4 to 1.22 ± 0.44, while PP-NRS declined from 8.44 ± 0.52 to 2 ± 0.86 by week 12, with significance evident early in treatment. Most patients demonstrated good adherence, and dose adjustments were required in some cases. One patient developed mild thrombocytopenia. Abrocitinib demonstrated rapid, significant clinical improvement and was generally well-tolerated, supporting its role as an effective option for moderate-to-severe AD, particularly in patients with inadequate response to cyclosporine.

Importance Young adults (YAs; ages 18-39 years) diagnosed with cancer face unique psychosocial challenges, including high distress and poor health-related quality of life (HRQOL). There are few efficacious interventions tailored to their needs. Objective To evaluate the efficacy of Bright IDEAS-YA, a problem-solving skills training intervention tailored for YAs, in reducing distress and improving HRQOL. Design, Setting, and Participants This randomized clinical trial was conducted at 3 academic medical centers and enrolled participants between February 2021 and March 2024. Eligible participants were aged 18 to 39 years, within 4 months of a first cancer diagnosis, and undergoing systemic therapy. Participants completed surveys at baseline and 3, 6, 12, and 24 months. Intervention Bright IDEAS-YA is a 6-session, one-on-one intervention that teaches a structured approach to problem-solving. Enhanced usual care (EUC) included standard psychosocial care plus a list of adolescent and YA resources. Main Outcomes and Measures Primary outcomes were depression and anxiety (Patient-Reported Outcomes Measurement Information System Short Forms) and HRQOL (Functional Assessment of Cancer Therapy-General) at 6 months. Problem-solving ability (Social Problem-Solving Inventory-Revised Short Form) was examined as a mediator. Analyses used linear mixed effects models and mediation analysis. Results Of the 1128 YAs screened, 344 YAs (median [IQR] age, 31.27 [25.78-36.38] years; 251 female [62.5%]) enrolled, with 171 allocated to intervention and 173 allocated to control. Overall, 296 YAs (86.0%) and 280 YAs (81.4%) completed 3- and 6-month surveys, respectively. At 6 months, the intervention group showed significantly greater improvements than EUC in depression (effect size estimate, −3.23 points; 95% CI, −4.93 to −1.53 points; P &amp;lt; .001), anxiety (effect size estimate,−2.43 points; 95% CI, −4.05 to −0.81 points; P = .003), and HRQOL (effect size estimate, 3.40 points; 95% CI, 0.34 to 6.45 points; P = .03). These changes were clinically meaningful. Mediation analyses showed that improvements in depression and anxiety were partially due to increased problem-solving ability, particularly reductions in negative problem orientation. Sex and education were moderators of treatment effect, with the treatment effect on anxiety being greater for males (effect size estimate, −5.29 points; 95% CI, −7.97 to −2.60 points) and the treatment effect on anxiety (effect size estimate, −6.94 points; 95% CI, −10.50 to −3.43 points) and depression (effect size estimate, −7.47 points; 95% CI, −11.20 to −3.74 points; P &amp;lt; .001) being greater for those with lower education. Conclusions and Relevance In this randomized clinical trial of Bright IDEAS-YA, intervention participants had significantly reduced distress and improved HRQOL relative to control. These findings suggest that Bright IDEAS-YA may be offered as supportive care for YAs with cancer to improve psychosocial outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT04585269

ABSTRACT Background Intravesical Bacillus Calmette–Guerin (BCG) is a live attenuated vaccine for tuberculosis. Intravesical BCG (iBCG) administration is a highly effective immunotherapy for non‐muscle invasive bladder cancer (NMIBC). Although live attenuated vaccines are generally contraindicated in solid organ transplant recipients (SOTR), iBCG has been utilized for NMIBC in SOTR. We describe the clinical manifestations, management, and outcomes of disseminated Mycobacterium bovis ‐BCG infection (Mb‐BCGi) following iBCG therapy in SOTR for NMIBC. Methods All adult patients (> 18 years of age) diagnosed with NMIBC who received iBCG across three tertiary referral and transplant centers between 2000 and 2025 were identified. The study cohort consisted of SOTR who had received iBCG for NMIBC and subsequently developed disseminated Mb‐BCGi. English language literature review was performed to identify additional cases. Results A total of 4207 patients received iBCG during the study period. Thirty (0.71%) were SOTR, of whom two (6.7%) developed disseminated Mb‐BCGi, including bloodstream infection and prostate abscesses. Literature review identified two additional disseminated Mb‐BCGi cases in SOTR with lungs, bloodstream, and native kidney involvement, and one fatality. All cases required extended antimycobacterial therapy. Median times from SOT to Mb‐BCGi and from iBCG to Mb‐BCGi were 104 and 8 months, respectively. Conclusion SOTR appear to be at a higher risk of disseminated Mb‐BCGi following iBCG. Administration of iBCG in SOTR with NMIBC warrants careful risk‐benefit assessment and subsequent close monitoring. image

Abstract Purpose: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer. To guide therapeutic development and treatment strategies, we examined prostate tumors and evaluated expression, molecular features, and overall survival (OS), accounting for tissue site, hormone sensitivity status, and race. Experimental Design: A total of 8,157 prostate cancer samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC), or neuroendocrine prostate cancer (NEPC). Expression quartiles were B7-H3–high (&gt;75th percentile) or B7-H3–low (&lt;25th percentile). The OS was evaluated using Kaplan–Meier and Cox proportional hazards models. Results: B7-H3 expression was broadly maintained but varied by tumor site, hormone sensitivity status, and race. High expression aligned with AR-associated transcription factors (HOXB13 and FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, and TMPRSS2:ERG fusions), and actionable surface antigens (TROP2 and NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, and ASCL1) and NEPC-associated surface antigens (DLL3 and CEACAM5). High B7-H3 expression in primary tumors and HSPCs portended adverse OS [hazard ratio (HR), 1.342 and 1.30; confidence interval (CI), 1.19–1.512 and 1.15–1.46; q &lt; 0.0001] although it was favorable in metastatic tumors (HR, 0.823; CI, 0.719–0.942; q = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with the poorest survival in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49–9.29; q = 0.012). Conclusions: Maintained B7-H3 expression in various prostate cancer settings supports its viability as a target. The associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody–drug conjugates suggest potential dual-targeting strategies. See related article by Sharma et al., p. 3365

Background: Multidisciplinary team (MDT) care facilitates coordinated expertise that leads to improved patient safety and outcomes. Yet, no prior study has quantified reported benefits from plastic surgery–inclusive MDTs across several procedures. We thereby hypothesized that plastic surgery–inclusive MDTs would lead to better surgical outcomes following cranioplasty, spine surgery, abdominoperineal resection, abdominal wall reconstruction, and extremity reconstruction, compared with the primary specialties acting alone. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, we searched PubMed, Embase, Scopus, and Web of Science for comparative studies comparing outcomes of care provided by plastic surgery–inclusive MDT and non–plastic surgery–inclusive MDT. Results: Thirty studies with a total of 9614 patients were included. Plastic surgery–inclusive MDT care was associated with reduced odds of wound complications in abdominoperineal resection (odds ratio [OR] = 0.65; 95% confidence interval [CI], 0.47–0.90) and spine procedures (OR = 0.57; 95% CI, 0.33–0.97). In addition, plastic surgery–inclusive MDT care for extremity reconstruction and abdominal wall reconstruction was associated with lower odds of wound complications ([OR = 0.24; 95% CI, 0.12–0.46] [OR = 0.33; 95% CI, 0.12–0.90]), reoperation ([OR = 0.13; 95% CI, 0.04–0.49] [OR = 0.26; 95% CI, 0.03–2.39]), and shorter length of stay (mean difference, −19.5 and −0.62, respectively). Conclusions: Plastic surgery–inclusive MDT care significantly reduces wound complication and reoperation rates across complex surgical procedures. These findings support the formal integration of plastic surgeons within MDTs to improve patient outcomes and surgical safety.

ABSTRACT Current laboratory testing for Lyme disease (LD) relies on serology. We evaluated the performance of standard two-tiered testing (STTT) and modified two-tiered testing (MTTT) algorithms using samples obtained from well-characterized patients with early LD in the U.S. East Coast and Upper Midwest. Participants with signs and symptoms of early LD (cases) and controls were enrolled by Lyme Disease Biobank. We compared the performance of four FDA-cleared STTT or MTTT algorithms using serum samples from 251 participants (107 cases, 69 with a convalescent draw; 144 endemic controls). At the initial blood draw, algorithm sensitivity ranged from 22% to 36%, with specificity ranging from 98% to 100%. MTTT algorithms showed higher sensitivity compared with STTT algorithms ( P ≤ 0.05). One STTT algorithm was less sensitive than the other ( P = 0.035), and there was no significant difference in sensitivity between MTTT algorithms. There was also discordance between algorithms; only 22 of the 45 samples classified as laboratory confirmed by Lyme Disease Biobank testing were positive using all algorithms evaluated. Likelihood of positive two-tiered serology among cases with a suspected erythema migrans (EM) skin lesion increased with longer lesion duration and/or when presenting with >1 constitutional symptom. Participants with suspected EM without constitutional symptoms were unlikely to test positive by any algorithm evaluated. Testing convalescent samples did not improve LD detection, and seroconversion was rare. While MTTT confirmed more early LD cases than STTT, all two-tiered algorithms evaluated were insensitive in this population. Novel diagnostics that improve laboratory confirmation for early LD are urgently needed. IMPORTANCE This study confirms that two-tiered serologic testing algorithms are insensitive in early Lyme disease, particularly within the first 2 weeks after symptom onset or when erythema migrans is not accompanied by constitutional symptoms. It also demonstrates that seroconversion is rare after antibiotic treatment. These results highlight the need for novel diagnostics for early Lyme disease that do not rely on serologic testing.

ABSTRACT Vancomycin is broadly used to treat gram-positive infections in both inpatient and outpatient settings. Its use is primarily for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), which is a common cause of pneumonia, skin and soft tissue infections, and bloodstream infections. Vancomycin therapy requires close clinical monitoring to maintain therapeutic efficacy and, importantly, patient safety. Vancomycin use is associated with acute kidney injury in up to 20% of cases, a number that can be driven down by pharmacokinetic dosing protocols. However, the best mitigation against adverse outcomes associated with vancomycin is to ensure it is only used when needed and rapidly de-escalated when not. As such, many stewardship programs, who are tasked with the safe and effective use of antimicrobial agents, have focused on optimizing vancomycin use. There is a strong correlation with MRSA colonization and infection, and a negative MRSA nares screen has a good negative predictive value for MRSA pneumonia (although this association is less well documented for other infections). As such, detection of MRSA in nares swabs, by nucleic acid amplification tests (NAATs) or culture, is a logical tool for stewarding vancomycin. However, the application of MRSA screening tests as MRSA diagnostics is complex, as these tests are cleared by the U.S. Food and Drug Administration for the detection of MRSA colonization, and not for therapeutic decision making. In this issue of the Journal of Clinical Microbiology, the issue of MRSA nares tests is debated by a clinical pharmacy team and the laboratory. The authors review the clinical evidence and regulatory background in which an MRSA nares NAAT may be used to inform treatment decisions.

BACKGROUND AND OBJECTIVES: Perioperative protocols facilitate earlier discharge without compromising safety in nonfunctioning pituitary adenomas, but no large multicenter studies in the United States have investigated protocols regarding Cushing disease (CD). We sought to characterize perioperative protocols and how their implementation influences clinical outcomes in patients with CD. METHODS: A retrospective analysis was conducted using data from the Registry of Adenomas of the Pituitary and Related Disorders consortium comprising 13 US academic pituitary centers. Institutions were surveyed regarding perioperative procedures for patients undergoing transsphenoidal tumor resection for CD. The impacts of institutional procedures and approaches to implementation on length of stay (LOS) and unplanned 90-day readmission were evaluated. RESULTS: Thirteen institutions contributed survey responses and clinical data for a total of 832 patients meeting inclusion criteria. Ten (76.9%) institutions reported having a postoperative protocol, 9 (69.2%) used a formal document to outline their protocol, and 3 (23.1%) had protocols implemented into hospital policy. Mean LOS was significantly reduced in centers with an established protocol (3.14 vs 3.42 days, P = .032), and more so with a formal document (3.10 vs 3.48 days, P = .001) or hospital policy (2.72 vs 3.36 days, P < .001). Patients treated after protocol implementation experienced shorter LOS ( P < .001). Other factors associated with reduced LOS were presence of a separate CD pathway, intraoperative checklist specific to pituitary surgery, non-narcotic pain regimen, Foley removal order, dedicated outpatient advanced practice provider follow-up, and target discharge date ≤2 days. Intraoperative checklist ( P = .045), non-narcotic pain regimen ( P = .048), nasal packing ( P = .005), and 1-day target discharge date ( P = .032) were important factors against readmission. Compared with microscopic surgery, endoscopic surgery was associated with shorter LOS but increased readmission odds. CONCLUSION: This is the first multicenter study to illustrate that implementation of perioperative protocols is associated with a reduction in LOS and readmission risk in patients with CD.

Submucosal lesions of the esophagus and stomach are commonly discovered as incidental findings during routine endoscopy. These lesions arise from varying layers of the gastrointestinal wall, primarily from the submucosa or the muscularis propria, and can range from benign to malignant. This review provides an overview of common submucosal lesions including gastrointestinal stromal tumors (GIST), leiomyomas, duplication cysts, varices, glomus tumors, lipomas, granular cell tumors, neuroendocrine tumors, pancreatic rest, and schwannomas. We focus on their clinical presentation, endoscopic characteristics, radiologic features, and histopathologic findings to aid in diagnosis.