Citations

Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.

ImportanceGreater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF).ObjectiveTo explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM).Design, Setting, and ParticipantsThis was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024.InterventionSAVM vs sham control procedure.Main Outcomes and MeasuresThe primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP.ResultsA total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, −0.03 mm Hg; 95% CI, −2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, −6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, −9.2% to 18.8%; P = .48).Conclusions and RelevanceResults show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF.Trial RegistrationClinicalTrials.gov Identifier: NCT04592445

Abstract Shortages of antimicrobial agents rank second among all pharmaceutical classes. These shortages are persistent and increasing. The underlying reasons for shortages include manufacturing and quality issues, market economics, and changes in demand. Antimicrobial shortages compromise patient outcomes and increase treatment costs, contribute to antibiotic resistance, and may lead to increased adverse effects.

Summary Cannabis use is becoming increasingly common, both for recreational and medical purposes. However, there is a paucity of data regarding cannabis use in the context of eosinophilic esophagitis (EoE). We aimed to determine the impact of cannabis use on presentation and treatment response in EoE. To this end, we conducted a retrospective cohort study at a large academic medical center of newly diagnosed EoE patients age ≥ 12 years. Self-reported cannabis use status, baseline characteristics, and treatment response to topical corticosteroids and dietary therapy data were extracted. Bivariate and multivariable analyses were used to compare cannabis users and non-users at time of EoE diagnosis and to assess treatment response. Of 983 EoE patients, 80 reported using cannabis, with the majority reporting daily use and administration by inhalation. Baseline symptoms and peak eosinophil count were similar between cannabis users and non-users; cannabis users were less likely to have baseline endoscopic findings of exudates, edema, and stricture, and lower total Endoscopic Reference Score. On multivariable analysis, younger age, male sex, non-White race, and psychiatric diagnosis were independently associated with history of cannabis use at EoE presentation and stricture was independently associated with cannabis non-use. Post-treatment symptom and histologic responses were similar between cannabis users and non-users though there was a higher odds of post-treatment endoscopic inflammatory features with cannabis use. In conclusion, despite presenting with milder initial endoscopic findings, cannabis users exhibited greater inflammatory findings after treatment, highlighting a potential negative influence of cannabis use on EoE management.

Abstract Traumatic brain injury (TBI) annually impacts 69 million individuals worldwide. Mild TBI constitutes approximately 90% of all TBIs. Chronic pain post-mTBI occurs in 29% to 58% of patients. This study aims to introduce a predictive model for chronic pain development in individuals diagnosed with mild traumatic brain injury (mTBI) immediately postinjury. We included individuals who had sustained mTBI in motor vehicle accident (MVA). All patients had initial assessments within the first 72 hours (representing the subacute period) after the injury and performed follow-ups for 1 year. Machine learning model was applied to the integrated measures of clinical pain, pain-related psychological parameters, mTBI clinical signs, and sociodemographic information. This study included 203 patients experiencing acute head or neck pain attributable to mTBI post-MVA. We categorized these patients into 2 groups: patients who progressed to develop chronic head or neck pain (n = 89, 43.8%) and patients who recovered (low/mild pain) (n = 114, 56.2%). Severity of the subacute neck pain, number of painful body areas, and education years were identified as the most significant factors predicting chronic pain. The optimized predictive model demonstrated high efficacy, with an accuracy of 83%, a sensitivity of 92%, and an area under the receiver operating characteristic curve of 0.8. Our findings indicate feasibility in predicting chronic post-MVA pain within the critical 72-hour window postinjury using simple bedside metrics. This approach offers a promising avenue for the early detection of individuals at increased risk for chronic pain, enabling the implementation of targeted early interventions.

Abstract One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

Key Points PIEZO1 activation reduces cystogenesis: Yoda1 activates PIEZO1, raising calcium and lowering cAMP, reducing cyst growth in autosomal dominant polycystic kidney disease models. Context-dependent role of PIEZO1: PIEZO1 knockout in mice with or without polycystic kidneys does not affect cyst formation, suggesting redundancy in mechanosensitive pathways. Therapeutic potential: Findings support PIEZO1 activation as a part of combination therapy to slow cyst growth in autosomal dominant polycystic kidney disease, needing more in vivo studies. Background The disruption of calcium signaling associated with polycystin deficiency is a key factor in abnormal epithelial growth in autosomal dominant polycystic kidney disease. Calcium homeostasis can be influenced by mechanotransduction. The mechanosensitive cation channel PIEZO1 has been implicated in sensing intrarenal pressure and regulating urinary osmoregulation, but its role in kidney cystogenesis is unclear. Methods We hypothesized that altered mechanotransduction contributes to cystogenesis in autosomal dominant polycystic kidney disease and that activation of mechanosensitive cation channels could be a therapeutic strategy. Results We demonstrate that Yoda1, a PIEZO1 activator, increases intracellular calcium and reduces forskolin-induced cAMP levels in mouse inner medullary collecting duct (mIMCD3) cells. Notably, knockout of polycystin-2 attenuated the efficacy of Yoda1 in reducing cAMP levels in mIMCD3 cells. Yoda1 also reduced forskolin-induced mIMCD3 cyst surface area in vitro and cystic index in mouse metanephros ex vivo in a dose-dependent manner. However, collecting duct–specific PIEZO1 knockout neither induced cystogenesis in wild-type mice nor altered cystogenesis in the Pkd1 RC/RC mouse model. Conclusions These findings support the potential role of PIEZO1 agonists in mitigating cystogenesis by increasing intracellular calcium and reducing cAMP levels, but the unaltered in vivo cystic phenotype after PIEZO1 knockout in the collecting duct suggests possible redundancy in mechanotransductive pathways.