Citations

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P >.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Objectives: To report the outcomes of minimally invasive (MIS) nephrectomy following immune checkpoint inhibitor (ICI) therapy. Materials and Methods: This multicenter retrospective cohort study included consecutive patients who underwent nephrectomy following ICI therapy at five high-volume US academic centers between 2015 and 2023. Baseline clinical features and perioperative findings were recorded. After propensity-score matching (PSM), outcomes were compared between MIS and open nephrectomies. The primary outcome was 90-day complications, and secondary outcomes included length of hospital stay (LOS) and 90-day readmission. Results: A total of 158 patients were included, of whom 76 and 82 underwent MIS and open nephrectomies, respectively. The MIS procedures included robotic ( n = 56) and laparoscopic ( n = 20). A total of six (8%) patients converted to open. On multivariable analysis, patients with nonmetastatic vs metastatic renal-cell carcinoma (RCC) (hazard ratio [HR] 3.1, p = 0.01), those with smaller tumor size (HR 1.2 for each cm, p = 0.001), and no clinical evidence of inferior vena cava thrombus (HR 29, p = 0.002) were more likely to undergo the MIS approach compared with open approach. After PSM, including 56 MIS and 36 open nephrectomies, the MIS group compared with the open group had lower estimated blood loss (100 vs 460 mL, p < 0.001) and shorter LOS (2 vs 4 days, p < 0.001). Nevertheless, 90-day complications and readmissions were similar between the two groups. There were no 90-day mortality rates in either group. Conclusion: The MIS approach appears safe and offers more favorable perioperative outcomes compared with open surgery in properly selected patients with advanced RCC who are candidates for nephrectomy following ICI therapy.

RATIONALE: Critically ill adults are at risk for a variety of distressing and consequential symptoms both during and after an ICU stay. Management of these symptoms can directly influence outcomes. OBJECTIVES: The objective was to update and expand the Society of Critical Care Medicine’s 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. PANEL DESIGN: The interprofessional inclusive guidelines task force was composed of 24 individuals including nurses, physicians, pharmacists, physiotherapists, psychologists, and ICU survivors. The task force developed evidence-based recommendations using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Conflict-of-interest policies were strictly followed in all phases of the guidelines, including task force selection and voting. METHODS: The task force focused on five main content areas as they pertain to adult ICU patients: anxiety (new topic), agitation/sedation, delirium, immobility, and sleep disruption. Using the GRADE approach, we conducted a rigorous systematic review for each population, intervention, control, and outcome question to identify the best available evidence, statistically summarized the evidence, assessed the quality of evidence, and then performed the evidence-to-decision framework to formulate recommendations. RESULTS: The task force issued five statements related to the management of anxiety, agitation/sedation, delirium, immobility, and sleep disruption in adults admitted to the ICU. In adult patients admitted to the ICU, the task force issued conditional recommendations to use dexmedetomidine over propofol for sedation, provide enhanced mobilization/rehabilitation over usual mobilization/rehabilitation, and administer melatonin. The task force was unable to issue recommendations on the administration of benzodiazepines to treat anxiety, and the use of antipsychotics to treat delirium. CONCLUSIONS: The guidelines task force provided recommendations for pharmacologic management of agitation/sedation and sleep, and nonpharmacologic management of immobility in critically ill adults. These recommendations are intended for consideration along with the patient’s clinical status.

SUMMARY In 13 Smooth Fox Terriers with a congenital form of myasthenia gravis, clinical signs included intermittent, progressive muscle weakness that became more pronounced with exercise; muscle wasting; megaesophagus; and aspiration pneumonia. Neurologic abnormalities were apparent only during periods of weakness and included inability to retract the fore- and hindlimbs from painful stimuli. A decrement of the compound muscle action potential was evident during repetitive supramaximal nerve stimulation. Intravenous injection of a short-acting cholinesterase inhibitor evoked immediate improvement of clinical and electromyographic signs. Intracellular microelectrode studies of a biopsied external intercostal muscle revealed reduced amplitude of miniature end-plate potentials, as occurs in acquired myasthenia gravis. However, in contrast to acquired myasthenia gravis, antibodies directed against acetylcholine receptors were not demonstrable in serum and were not bound to acetylcholine receptors in muscle. Despite lack of complexing with immunoglobulin, the amount of acetylcholine receptor protein in biopsied external intercostal muscles from 9 affected pups was less than 25% of the amount in 5 unaffected littermates. The latter finding accounted for the reduction in amplitude of miniature end-plate potential and the failure of neuromuscular transmission. Treatment with a long-acting cholinesterase inhibitor in 6 cases resulted in temporary improvement in muscle strength.

Abstract Single-cell RNA sequencing (scRNA-seq) enables high-resolution exploration of cellular diversity and gene regulation, yet analyzing such data remains challenging due to technical and methodological limitations. Existing task-specific deep generative models like Variational Auto-Encoder (VAE) and its variants struggle to incorporate external biological knowledge, while transformer-based foundational large Language Models (LLMs or large LaMs) face limitations in computational cost and applicability to tabular gene expression data. Here, we introduce sciL-aMA (single-cell interpretable Language Model Adapter), a novel representation learning frame-work that bridges these gaps by integrating static gene embeddings from multimodal LLMs with scRNA-seq tabular data through a paired-VAE architecture. Our approach generates context-aware representations for both cells and genes and outperforms state-of-the-art methods in key single-cell downstream tasks, including batch effect correction, cell clustering, and cell-state-specific gene marker and module identification, while maintaining computational efficiency. sciL-aMA offers a computationally efficient, unified framework for comprehensive single-cell data analysis and biologically interpretable gene module discovery. Source code is available at https://github.com/microsoft/sciLaMA

Abstract Background Characterization of transplant transmitted infections associated with drowned organ donors and the recipients is not well delineated, posing challenges for optimal management and prophylaxis strategies. Broader organ sharing may pose additional considerations due to pathogen variation. Methods We reviewed 22 potential donor disease transmission events (PDDTEs) from drowned donors reported to the Organ Procurement and Transplantation Network (OPTN) ad hoc Disease Transmission Advisory Committee (DTAC) from 2017-2022 to estimate the incidence of PDDTEs among all US drowned organ donors and identify the most common pathogens in this setting. We also characterized donor/recipient epidemiology, infection timing and risk factors, and recipient survival. Results From 2017-2022, drowning was the mechanism of death in 777/74,232 (1.0%) of all US organ donors, from whom 2500 organs were transplanted. Among the 22 PDDTEs, there were 70 organ recipients. The median donor age was 17.5 years (range 1-70 years) and lung recipients accounted for 5/70 organ recipients. All PDDTE reports were submitted due to recipient disease, and index cases occurred 2-19 days post-transplant. 7/22 (7/777 drowned donors, 0.9%) PDDTEs were associated with pathogens consistent with plausible waterborne transmission, of which 4 were due to invasive molds (Zygomycetes and Scedosporium) and 3 were due to bacteria (Pseudomonas and Legionella). Of the 21 organ recipients from these 7 donors, 8 had proven or probable infections. 6/8 recipients had severe infection with 3 deaths, all from invasive mold infections. There were no identifiable infection risk factors related to drowning water source, donor immersion time, or geographic region. However, donor/recipient regional discordance occurred in 5/21 recipients, demonstrating the trend in broader organ sharing. Conclusion Though rare, organ recipients are at risk for transplant transmitted infection from drowned donors, particularly invasive mold infections. All infections occurred within the first month after transplant with high associated mortality. Though optimal management and prophylaxis strategies in these scenarios remain uncertain, post-transplant vigilance for early infection is paramount. Disclosures Helen S. Te, MD, CVS Caremark: Advisor/Consultant Lara A. Danziger-Isakov, MD, MPH, Aicuris: clinical research contract, paid to institutio|Ansun BioPharma: clinical research contract, paid to institution|Astellas: Advisor/Consultant|Astellas: clinical research contract, paid to institutio|Merck: clinical research contract, paid to institutio|Pfizer: Grant/Research Support|Takeda: clinical research contract, paid to institutio Anil J. Trindade, MD, CareDx, Inc.: Advisor/Consultant|CareDx, Inc.: Grant/Research Support|TFF Pharmaceuticals: Advisor/Consultant|Veloxis Pharmaceuticals, Inc.: Grant/Research Support

Aims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 42, 361–377.

Chronic lymphocytic leukemia (CLL), one of the most common types of leukemia among adults in the US, is characterized by the accumulation of CD5+CD19+ monoclonal B cells. Current clinical treatment approaches for progressive CLL patients focus on novel agents targeting Bruton Tyrosine Kinase (BTK) and Bcl-2. Although clinical trials combining novel agent have shown significant efficacy with high overall response and, in some cases, achievement of high rates of undetectable measurable residual disease (MRD), CLL remains incurable with a majority of patients eventually experiencing relapse of their disease. Therefore, it remains of high interest to expand therapeutic options. Transcriptional chemical inducers of proximity (TCIPs) are small molecules designed and developed by Dr. Gerald R. Crabtree at Stanford University. TCIPs are a new class of anticancer drugs that recruit endogenous cancer drivers or a downstream transcription factor to the promoters of cell death genes and activate their expression, resulting in apoptosis of cancer cells. Current TCIPs are produced by covalently linking small molecules that bind B-cell lymphoma 6 (BCL6) to those that bind to transcriptional activators, such as Bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinases 9 (CDK9). The Stanford team has demonstrated TCIPs generate remarkable killing in diffuse large B cell lymphoma (DLBCL) cell lines, including chemotherapy-resistant, TP53-mutant lines, with a half maximal effective concentration (EC50) of 1-10nM at 72hours (h) and exhibited cell-specific and tissue-specific effects (Gourisankar et al, 2023). We have initiated TCIPs cytotoxicity assessment in primary leukemic cells from untreated CLL patients. Testing two types of TCIPs with a flow cytometry-based apoptosis assay, we found time and dose-dependent drug-associated killing in primary CLL B cells collected from untreated CLL patients over a 24-72h interval. The IC50 for BRD4-BCL6 TCIP JWZ-7-133 at 72h was 560nM while CDK9-BCL6 TCIP BAK-04-232 at 72h was 10nM. After 24, 48, and 72h exposure of CLL B cells to TCIP JWZ-7-133, the IC50 was 1050, 820 and 560nM, respectively. We also found that TCIP JWZ-7-133 exhibited a similar ability to inhibit leukemic cell viability with an IC50 of 1070nM using a cell viability assay, compared to a flow cytometry-based cell death assay (24h IC50 1050nM). CDK9-BCL6 TCIPs are designed and produced by covalently linking BI-3812 (binding to BCL6) and SNS-032 (binding to CDK9) with a rigid linker. BI-3812 is a potent and efficacious BCL6 inhibitor, inhibiting the BTB domain of BCL6, and SNS-032 is a potent and selective inhibitor of CDK9. When CLL B cells were treated with only BI-3812 or SNS-032 or TCIP BAK-04-232 as single agents for 72h, we found that TCIP BAK-04-232 had superior and significant killing effects compared to the single agents, with an IC50 of 10nM. Specifically this killing activity was more than 10-fold compared to SNS-032 alone (IC50 over 100nM), and more than 1,000-fold compared to BI-3812 alone (IC50 over 10,000nM). There remains an urgent to identify new categories of potent drug, inhibitor, or small molecules to expand potential clinical treatment options for patients with CLL. The results presented here indicate that TCIPs targeting BCL6 and BRD4/CDK9 have a strong capacity to induce high levels of cell death in CLL B cells at nanomolar concentrations, and this remarkable killing effect may be due to its unique gain-of-function drug mechanism. TCIPs provide a completely new drug direction and strategy for the design of anticancer drugs: to rewire cancer drivers to activate apoptosis in cancer cells. This study is the first of a kind demonstration of TCIPs in robustly targeting CLL B cells. Further studies to fully validate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the role of TCIPs as a novel therapeutic approach in CLL.