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A systematic review was conducted of studies published up to 30 August 2024. Studies comparing conventional visual field (VF) indices, ability to detect central visual field defects (CVFDs), structure–function (S-F) concordance, and test characteristics across the HVF 24-2C SITA-Faster, 24-2 SITA-Standard/Faster, and 10-2 SITA-Standard/Fast tests were included. Eight studies with 1239 subjects (49.1% male; mean age, 54.8–66.9 years) were analyzed. The 24-2C produced similar global VF indices compared to the 10-2 and 24-2 (Standard/Faster) (ICC = 0.95 and 0.80, p < 0.001), detected more VF defects and CVFD clusters, and demonstrated greater S-F concordance than the 24-2 (Standard/Faster). Although the 10-2 (Standard/Fast) detected significantly more CVFDs and had a greater S-F concordance, the agreement between the 24-2C and 10-2 grids was substantial (ĸ = 0.488 to 0.708). The 24-2C was also faster compared to the 24-2 Standard and 10-2 (Standard/Fast), with comparable false positives, higher false negatives, and fewer fixation losses than the 24-2 Standard. In conclusion, the HVF 24-2C is quicker and identifies more CVFDs than the 24-2 grid, demonstrates high agreement with the 10-2 grid, and aids in CVFD screening.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Abstract Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with high efficacy in lymphoid malignancies. It targets the B-cell surface protein CD22, which is expressed in most B-cell acute lymphoblastic leukemia (B-ALL) cases, albeit with variable intensity. However, factors governing CD22 expression and thus leukemia sensitivity to InO remain incompletely understood. Using multiomic characterization of 196 human B-ALL samples, coupled with ex vivo InO sensitivity profiling, we showed that early leukemia differentiation arrest at the pre–pro-B stage is associated with resistance to InO. Screening of 1639 transcription factor genes identified early B-cell factor 1 (EBF1) as a key regulator of CD22 expression (false discovery rate of 7.1 × 10−4). When comparing the assay for transposase-accessible chromatin with sequencing profiling results of the most InO-sensitive and -resistant cases (50% lethal concentration &lt;10th vs &gt;90th percentile, n = 18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P = 8 × 10−174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to an ∼50-fold reduction in cell surface CD22 expression and, consequently, an ∼22-fold increase in InO resistance in ALL cell lines. Interestingly, within BCR::ABL1 ALL, we observed intrasubtype heterogeneity linked to EBF1 transcriptional downregulation (P = 1.1 × 10−15) and/or somatic alteration (P = .004), which led to reduced CD22 expression (P = 8.3 × 10−11) and ex vivo and in vivo resistance to InO. Collectively, these findings point to the direct impact of EBF1 on CD22 expression during B-cell development, which, in turn, contributes to interpatient variability in InO response, even within the same subtype of B-ALL.

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD) whose genetic basis remains elusive, likely due to oligogenic complexity. To identify regulators of cardiomyocyte (CM) proliferation relevant to HLHS, we performed a genome-wide siRNA screen in human iPSC-derived CMs, revealing ribosomal protein (RP) genes as the most prominent effectors of CM proliferation. Whole-genome sequencing of 25 HLHS proband–parent trios similarly showed enrichment of rare RP gene variants, including a damaging RPS15A promoter variant shared in a familial CHD case. Cross-species functional analyses demonstrated that perturbation of RP genes impairs cardiac growth: knockdown of RPS15A, RPS17, RPL26L1, RPL39, or RPS15 reduced CM proliferation, caused cardiac malformations in Drosophila , and produced hypoplastic or dysfunctional hearts in zebrafish. Genetic interactions between RP genes and key cardiac transcription factors (TBX5 and NKX2–7) further support their developmental role. Importantly, p53 suppression or Hippo activation partially rescued RP deficiency phenotypes. Together, these findings implicate RP genes as critical regulators of cardiogenesis and candidate contributors to HLHS.

Abstract Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC- CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS and other CHDs.

Abstract INTRODUCTION While cardiac comorbidities or factors predisposing infection are common in patients with ESRD, one less common cause for pleural effusion in peritoneal dialysis (PD) patients is pleuroperitoneal communication. We present herein a case of a PD patient with large, right-sided pleural effusion one year after starting PD. CASE REPORT An 82-year-old female with ESRD managed on home continuous cycling peritoneal dialysis (CCPD) for 1 year presented to the Emergency Department (ED) with new-onset dyspnea. She recently completed a course of vancomycin for bacterial peritonitis secondary to PD catheter infection. She also reported that her home CCPD machine was not draining the fill amount in recent weeks. She was afebrile and hemodynamically stable on arrival. CT at the ED showed a large, right-sided pleural effusion. She underwent thoracentesis with pending fluid analysis, and experienced subsequent improvement in her dyspnea. She was then hospitalized and wished to continue PD over pursuing intermittent hemodialysis (iHD) while workup was pending, despite clinical suspicion for pleuroperitoneal fistula (PPF). She started inpatient CCPD, and drains following each dwell showed less than expected volumes with no additional output on manual drains. She reported worsening dyspnea the next morning, and bedside POCUS confirmed reaccumulation of her pleural effusion. Fluid analysis revealed a transudative pleural fluid profile, with pleural glucose of 583mg/dL and serum glucose of 80mg/dL. Given her recent peritonitis, suspicion was greatest for PPF. The patient was transitioned from PD to iHD to allow time for the suspected fistula to heal, and subsequent imaging obtained during her hospitalization did not show reaccumulation of her unilateral pleural effusion. DISCUSSION Pleuroperitoneal communication may occur due to congenital or acquired diaphagmatic defects, or insults such as the case in our patient with recent peritonitis. In fact, diaphragmatic blebs from age related degeneration and chronic increased intraabdominal pressure have been reported to cause hydrothorax in patients undergoing PD. Diagnosis of PD-associated pleural effusions is based on clinical suspicion, with pleural studies showing high pleural fluid to serum glucose gradient, and imaging commonly showing unilateral right-sided pleural effusions. Recent peritoneal dialysis with low drainage further supports PD as the etiology. Most cases of PD-associated pleural effusions occur soon after PD initiation, but cases occurring years after initiation have been reported. Management involves halting PD and thoracentesis for symptomatic relief. Patients may need transitioning to iHD indefinitely, or may resume PD after a pause if the cause of communication is reversible.

Abstract Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have different clinical trajectories, some with minimal symptom burden, others experiencing recurrent exacerbations, the most severe of which require hospitalization. Existing diagnostics, including spirometry and symptom assessments, lack the precision to identify high-risk patients who may benefit from timely preventive therapies. Nuclear cell-free DNA (ncfDNA) is a well-established marker of systemic tissue injury, implicated in amplifying inflammation by triggering type 1 interferon release by activating DNA-sensing pathways. Because COPD is accompanied by inflammation and tissue injury systemically, we hypothesized that ncfDNA is associated with increased risk of severe exacerbations requiring hospitalization. Methods: Design: We utilized baseline plasma samples randomly selected from 672 individuals with COPD from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) cohort, which prospectively collected exacerbation numbers and type. The primary endpoint was exacerbation requiring hospitalization. Secondary endpoints included total number of exacerbations (defined as use of oral steroids, antibiotics, or healthcare utilization) and severe exacerbations (defined as requiring emergency room care or hospitalization). Measure: We measured plasma ncfDNA using digital droplet PCR. Analysis: We assessed the association of ncfDNA with exacerbation outcomes using negative binomial regression or Cox regression, adjusting for age, percent post-bronchodilator forced expiratory volume in one second (FEV1), supplemental oxygen use, and smoking status. Results: In total, 57% (n=383) of COPD participants experienced exacerbations, 29% (n=197) at least one severe, and 22% (n=145) requiring hospitalization, the latter at a median of 622 days from enrollment (IQR=287-997). Higher ncfDNA levels at enrollment correlated with measures of COPD severity, including baseline FEV1 (beta = -0.12, 95% CI -0.18 to -0.049, p &lt;0.001). Higher ncfDNA associated with increased risk of COPD exacerbation requiring hospitalization (incidence rate ratio (IRR) 1.40, 95% CI 1.12-1.75, p =0.003) and severe exacerbations (IRR 1.36, 95% CI 1.11-1.67, p=0.002) and a trend towards total exacerbations (IRR 1.11, 95% CI 0.98-1.26, p= 0.09). The primary outcome, risk of time-to-first hospitalization, correlated significantly with higher ncfDNA with hazard ratio (HR) 1.23, 95% CI 1.01-1.49, p=0.037. Conclusion: These results suggest that ncfDNA may serve as a predictor for severe and hospitalization-associated COPD exacerbations. To better understand the relationship between ncfDNA and COPD pathophysiology, follow-up studies should explore longitudinal trends and cfDNA tissue sources, and their link to COPD exacerbations.