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Portopulmonary hypertension (POPH), pulmonary arterial hypertension that develops in the setting of portal hypertension, has long been of significant interest to the pulmonary, cardiology, and hepatology communities. Optimal management of POPH has been challenging to define due to a lack of evidence from clinical trials regarding pulmonary arterial hypertension therapies and uncertainty regarding the role of liver transplantation (LT). Initially, the high risk of intraoperative and early post-transplant death in predominantly untreated patients with POPH tempered consideration of LT. More recently, the observation that POPH can improve, and sometimes even resolve, following LT, has led to reconsideration of the role of LT in selected patients. The first International Liver Transplantation Society (ILTS) POPH and hepatopulmonary syndrome practice guideline was a multidisciplinary consensus of expert opinions based on available evidence. Since that publication, hemodynamic definitions, management approaches, and POPH MELD exception criteria have evolved, and there have been new randomized controlled trials in POPH as well as studies regarding long-term outcomes. In order to ensure the guidelines remained current and reflected recent evidence, the original writing committee of the 2016 guidelines, leaders of the ILTS Cardiovascular Special Interest Group, and colleagues active in POPH research were invited to participate in the writing committee. In this document, approved for publication by the ILTS executive council, we provide an update to the prior guidelines with expert recommendations to guide and advance POPH management. Recommendations in these guidelines are based on expert opinion and available evidence and were agreed upon by consensus.

Background Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC. Methods PY159 and PY314 were individually evaluated in patients with PROC. Patients were treated with monotherapy (PY159 3 mg/kg or PY314 10 mg/kg), based on the recommended dose for expansion derived from the phase 1a studies. At the time of first progression, patients could continue study drug and crossover to combination therapy with pembrolizumab (200 mg) every 3 weeks at the discretion of the investigator. Disease assessment by Response Evaluation Criteria in Solid Tumor version 1.1 was performed every 6 weeks. Results 17 patients were enrolled in the PY159 study (median age 67, range 22–77; median prior therapies 6, range 2–18) and 16 patients in PY314 (median age 65.5, range 49–81; median prior therapies 4, range 2–10). 7 patients in PY159 and 8 patients in PY314 crossed over to combination therapy. Safety events included the following: treatment-related adverse events occurred in 15 patients (88.2%) in PY159 and 9 patients (56.3%) in PY314. Infusion-related reactions occurred in 6 patients (35.3%) in PY159 and 3 patients (18.8%) in PY314. Immune-related adverse events occurred in 13 patients (76.5%) in PY159 (arthralgias) and 1 patient (6.3%) in PY314 (diarrhea). Serious adverse events occurred in 6 patients (36.3%) in PY159 (1 related) and 12 patients (75%) in PY314 (all unrelated). The best radiographic response in PY159 was stable disease in 8/16 patients (50%; median 16 weeks, range 9–33), and in PY314, it was stable disease in 8/16 patients (50%; median 12 weeks, range 6–36). Median PFS was 2.76 months and 2.69 months in PY159 and PY314, respectively. There were no responses in the crossover arm. Conclusions Both PY159 and PY314 were well tolerated, with an acceptable safety profile, as both single agents and in combination with pembrolizumab. Both agents warrant further investigation in heavily pretreated PROC.

ABSTRACT Background Addition of left heart catheterization (LHC) to exercise protocols allows for a unique focus on parameters of systolic and diastolic responses to increased activity in patients with left ventricular assist device (LVAD) support. Methods A retrospective review was conducted of all consecutive adult patients who underwent LHC with exercise for any indication from June 2017 to June 2023. For all patients, the relationship between exercise and parameters of LV systolic and diastolic response was assessed. Patients were divided into two cohorts based on the indication for testing: hemodynamic optimization (Optim, n = 5) or weaning consideration (Wean, n = 3). Results Eight patients (88% male, median age 57 years (IQR 44, 65)) were included. LVEF was 45% (IQR 45, 56) in Wean and 25% (IQR 20, 42) in Optim. LV systolic work index (LVSWI) increased more rapidly over levels of exercise in Wean vs. Optim (slope 46.3 vs. −0.625; p = 0.044) and LVSWI rose more quickly at lower levels of LV end diastolic pressure (LVEDP) in Wean vs. Optim (slope 219.5 vs. −2.008; p = 0.0026). Pulse power index was higher in Wean patients at baseline (0.046 (IQR 0.04, 0.07) vs. 0.016 (IQR 0.001, 0.04); p = 0.14) and peak exercise (0.12 (IQR 0.12, 0.12) vs. 0.06 (IQR 0.03, 0.1); p = 0.29). Conclusions Patients with favorable remodeling on LVAD support have significantly improved LV systolic and diastolic responses to exercise and a trend of higher systemic pulsatility. Improving our understanding of LV‐LVAD interactions with activity may aid in future efforts to improve exercise tolerance through speed modulation.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.

AbstractMenopause is associated with vascular dysfunction. During the menopausal transition, endogenous oestradiol concentrations diminish. Oestradiol is vasoprotective because it has direct and indirect effects on the vasculature. The present study aimed to determine the effect of acute exogenous oestradiol on endothelium‐dependent, endothelium independent and β2‐adrenergic receptor‐induced vasodilatation in females. Forearm blood flow (venous occlusion plethysmography) was measured during brachial intraarterial infusions of ACh (endothelium‐dependent agonist), sodium nitroprusside (endothelium independent agonist) and terbutaline (β2‐adrenergic receptor agonist) with and without concurrent infusion of 17β‐oestradiol. Nine young premenopausal (age: 26 ± 4 years) and nine postmenopausal (PM, age: 58 ± 4 years, 8 ± 1 years post‐menopause) females completed the study. Concurrent oestradiol infusion augmented the vasodilatory response to ACh, sodium nitroprusside and terbutaline in young premenopausal (all P < 0.05) but not older postmenopausal (all P > 0.05), females. Local infusion of exogenous 17β‐oestradiol augmented endothelial and smooth muscle microvascular vasodilatation in premenopausal but not postmenopausal, females. imageKey points Menopause is associated with vascular dysfunction. Because oestradiol has vasoprotective effects, the menopause‐associated drop in oestradiol concentrations is hypothesized to contribute to vascular dysfunction during the menopause transition. The present study shows that local infusion of exogenous oestradiol augmented microvascular vasodilatation in premenopausal but not postmenopausal females.

Background. Liver transplantation (LT) is the standard treatment for liver failure secondary to alcohol-associated liver disease, but limited literature and best practices exist for post-LT treatment of alcohol use disorder (AUD). This study explores current AUD management practices and providers’ perceived barriers to effective post-LT AUD management. Methods. A 45-item survey on post-LT AUD treatment practices was distributed to members of the American Society of Transplant Surgeons, the Association of Consult/Liaison Psychiatry Transplant Special Interest Group, and both the American Society of Transplantation’s Liver and Intestine Community of Practice and Psychosocial and Ethics Community of Practice discussion boards, between December 2021 and April 2022. Univariate analysis of categorical variables was performed using the chi-square test. Data were analyzed using center volume tertiles, country region, and provider professional activity. Results. Two hundred thirty-two respondents from 70 LT centers across all 11 United Network for Organ Sharing regions completed the survey. Half of the them were attending physicians and 16.4% were nurse coordinators. Most centers (84%) aimed for alcohol abstinence for all post-LT patients. Perceived barriers to AUD treatment efficacy included ongoing desire to drink (18%), denial about alcohol misuse (14.9%), and lack of posttransplant support (14%). Additionally, 62.1% of centers had no policy for prescribing medication-assisted therapy to treat AUD, and 32.7% of centers reported no center-level changes in AUD care. Providers identified primary needs as hiring additional mental health professionals (30.8%), dedicating specific staff to AUD care (24.7%), and standardizing psychiatric/psychological care in transplant clinics (17.2%). Conclusions. Despite the increasing volume of LT for alcohol-associated liver disease, significant perceived barriers to effective AUD treatment remain.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (&amp;lt;60 years vs ≥60 years) and disease duration (&amp;lt;6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

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 (&amp;lt;60 years or ≥60 years) and disease duration (recent [&amp;lt;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 &amp;gt;.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