Citations

Background: Obese patients experience more complications after autologous breast reconstruction. This study evaluates how bariatric surgery modulates risk of complications in the setting of microvascular breast reconstruction. Methods: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program databases were queried for patients with body mass index (BMI) greater than or equal to 35 kg/m2 undergoing bariatric surgery from 2017 to 2022. Outcomes included BMI and obesity-related comorbidities before and 1 year after bariatric surgery. Paired Breast Reconstruction Risk Assessment scores were analyzed to evaluate risk modulation before and after bariatric surgery in the setting of microvascular breast reconstruction. Results: A total of 1026 patients were included with an average age of 47 and BMI of 44.7 kg/m2. Comorbidities included hypertension (n = 601 [59%]), type 2 diabetes (n = 291 [28%]), and cardiovascular disease (n = 10 [1%]). One-year outcomes after bariatric surgery included an average BMI of 32.7 kg/m2, with remission of type 2 diabetes in 29% of patients. Paired Breast Reconstruction Risk Assessment analysis for microvascular breast reconstruction before and after bariatric surgery showed reduction in 30-day surgical complications (40.4% versus 24.8%; P < 0.0001), with an absolute risk reduction of 15%, a relative risk reduction of 36%, and a number needed to treat of 7. Each 1-kg/m2 reduction in preoperative BMI was associated with a 3.4% reduction in surgical complications (P < 0.0001). Conclusion: There is potential efficacy for metabolic bridge therapy in reducing complications for obese patients undergoing microvascular breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.

Background: Ibrutinib, a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed in vivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both in vivo and ex vivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.

Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing or constriction of the cerebral arteries that supply blood to the brain. The initial manifestation of RCVS often includes a “thunderclap” headache that is sudden, severe, and often disabling. Stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and antipsychotics with serotonergic activity can alter the cerebral arterial tone, trigger vasoconstriction, and place patients at risk of a cerebrovascular accident. Thus, psychiatric medications are commonly discontinued on admission for RCVS, and psychiatry is often consulted for input on acute medication management and longitudinal treatment options. Currently, there is a dearth of literature on managing psychiatric medications in RCVS, resulting in variable practice patterns that place patients at risk of withdrawal, decompensation, and relapse. In this article, we provide a case example and aim to consolidate the limited data surrounding the management of psychiatric illness with comorbid RCVS in our discussion. There is a clear concern about worsening and even potentially lethal consequences due to serotonin or stimulant-induced vasospasm both during an acute episode and in long-term management of RCVS. We discuss the underlying pathophysiologic mechanisms proposed for serotonergic-, noradrenergic-, and dopaminergic-induced cerebral vasospasm and how this correlates with the clinical management of patients on psychiatric medications. These data will then be organized to create a risks versus benefits outline to equip psychiatrists to make decisions about when to stop and when to restart psychiatric medications in the setting of RCVS.

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.