Citations

Abstract Rationale High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

Background: Intracardiac thrombosis (ICT) during liver transplantation (LT) is a rare but life-threatening complication with limited data regarding its risk factors, management, and outcomes. This study aimed to identify factors associated with ICT development, define predictors of intraoperative outcomes, and propose a novel classification and management algorithm for ICT. Methods: A multicenter, international retrospective case-control study was conducted on liver transplant recipients from seven centers between January 2005 and December 2023. ICT cases were identified through transesophageal echocardiography (TEE) or autopsy and matched 1:1 with controls. Results: Among 11 077 liver transplant recipients screened, 133 patients (1.2%) developed ICT. ICT occurred predominantly after reperfusion (58%). Compared to controls, ICT cases exhibited higher preoperative international normalized ratio ( P = 0.001) and fibrinogen levels ( P = 0.014). Post-reperfusion syndrome ( P < 0.001), disseminated intravascular coagulation ( P < 0.001), and primary graft failure ( P = 0.002) were also more common in the ICT group. Continuous veno-venous hemofiltration during surgery (odds ratio [OR] 8.20, 95% confidence interval [CI]: 2.09–38.1; P = 0.004) was associated with ICT development. ICT was associated with markedly higher rates of cardiac arrest ( P < 0.001) and intraoperative mortality ( P < 0.001), with thrombus location in the left heart chambers representing a significant predictor of mortality (OR 20.7, 95% CI: 6.25–81.3; P < 0.001). ICT grades 2 and 3 were associated with a markedly increased risk of intraoperative cardiac arrest ( P < 0.05). Importantly, delayed use of TEE was strongly associated with intraoperative death (OR 6.27, 95% CI: 1.45–27.1; P = 0.014). The 90-day mortality was 43% in ICT cases compared to 4.5% in controls, while 1-year mortality was 46% versus 10.5%, respectively. Conclusions: ICT during LT is a rare but severe complication associated with intraoperative mortality and poor short-term survival. Coagulation profile and intraoperative management play critical roles in ICT development. The early use of TEE enables timely diagnosis and intervention, improving patient outcomes. We propose a novel ICT classification offering a systematic framework for risk stratification and management to mitigate progression and mortality.

Background and objectives Arteriovenous malformations (AVMs) with perinidal aneurysms and single draining vein are associated with an elevated risk of rupture and increased procedural complexity. The role of preoperative embolization in this high-risk anatomical subset remains unclear. This study aimed to evaluate the safety and efficacy of microsurgery with preoperative embolization, compared with microsurgery alone in patients with such AVMs. Methods We conducted a multicenter retrospective analysis of an AVM registry from the MISTA (Multicenter International Study for Treatment of Brain AVMs) consortium and included AVMs with perinidal aneurysms and a single draining vein. Baseline characteristics, angiographic outcomes, functional outcomes, and complication rates were compared. Propensity score weighting (PSW) using the covariate balancing method was applied to adjust for baseline differences. Results Out of a total of 1919 patients, 65 met the inclusion criteria; 45 patients underwent preoperative embolization followed by microsurgery, and 20 underwent microsurgery alone. After adjustment, complete obliteration rates were similar between groups (OR 0.87, 95% CI 0.04 to 16.33, P=0.92), as were rates of functional independence at discharge and follow-up. Overall complication, symptomatic complication, and mortality rates did not differ significantly between groups. However, permanent complications were significantly lower in patients with preoperative embolization (OR 0.06, 95% CI 0.004 to 0.84, P=0.03). Discussion In patients with AVMs featuring perinidal aneurysms and single draining vein, preoperative embolization followed by microsurgery was associated with fewer permanent complications and no increase in adverse outcomes compared with microsurgery alone. However, given the small number of events, this finding should be interpreted cautiously.

Abstract Background DNA methyltransferase 1 (DNMT1) is essential for DNA methylation and chromatin stability. DNMT1 on chromosome 19p 13.2 mutations in this gene lead to a dominantly inherited neurodegenerative phenotype with a triad of symptoms shared by all patients that includes: 1) Peripherally sensory neuropathy; 2) Sensorineural hearing loss; 3) Early on set dementia. Some patients also have seizure, narcolepsy, cerebellar ataxia, optic nerve atrophy. Importantly, almost phenotype mutations patients are can grow up until adulthood, symptoms begin at middle aged, and death typically occurs around age of 50 years. The initial clinical terms Hereditary Sensory and Autonomic Neuropathy type 1 E (HSAN1E: OMIM-614116). Aims & Objectives In DNMT1 mutations t he mutation in p.Tyr495 changing to cystaine (Y495C), the first discovard and common mutation of hereditary sensory neuropathy 1E, we producted the mutation knock-in mouse model of Y495C, verify the effect on homozygous and heterozygous mutant mice. To invastigate of impact phenotype changing the landscape of gene expression, compair wild -type littermate and tne mutant mouse. Method By using Gene knockin technichs, the process of tardeted insertion of the exogenous gene (Dnmt1 TAT&gt;TGT) at a specific locus (Exon 19) in genomic Dnmt1, generate homozygous and heterozygouse mutant mouse. Experimental Design: To compair with wild-type littermate with mutant mouse model, parformed Rotor rod test as a neurophysiology and Nerve conduction study as a sensory test. Neuropathologically, we also parformed sciatic notch light microscopy epoxy-embedded methyl bluestained nerve. Results DNMT1 mutation knock in mouse model; Homozygous Y495C/Y495C mice were small and immatureness copaired to wt/Y495C heterozygpus one, were lethal 9.5 days during gestation. On the other hand heterozygous wt/Y495C mutant mouse catch up, give birth and grew up normally. At 9 month old Y495C mice, their sciatic notch light microscopy epoxy-embedded methyl bluestained nerve showed the characteristic fiber loss and axional degeneration. At 10-12 months and 16-18 months old, in nerve conduction study and Rotor-Rod testing, wt/Y495C mice decreased SNAP-Amplitude reduced, total running time of Rotor-Rod test dicreased with their ages. Discussion & Conclusions Heterozygous mutation in DNA metyrtransferase 1 (DNMT1) Y495C mice presented normal neural development and lifespan as well as the disease of human being (HSAN1E). Around 30's age, the patient's sensory loss become clearly present periferal sensory neuropathy. The gait disturbance is also gradually advanced with ataxia. Axonal degeneration at 9 month, deteriorating sensorimotor coordination manifested with age by Rotor-Rod test. Dementing status of DNMT1E shows FTD like symptons which advanced prominent around 40's. Reducing total ranning time by Rotre-Rod test may means loss of urge and attetion as a frontal lobe sign. Y495C homozygous mutant mice die during gestation. Homozygous genome methyration reduction cause newral hypogenesis of the fetus. The mutation in p.Tyr495 changing to cystaine (Y495C) are located in the middle part of TS domain which is hot spot mutant site, where a highly-conserved region has been identified essential for the binding of heterochromatin.

Background: Treatment decisions in patients with anterior cruciate ligament (ACL) injuries are influenced by multiple factors, such as the desire to return to sports or symptomatic instability. Identifying the differential treatment effect of ACL reconstruction (ACLR) compared with nonoperative management on a patient-specific level can inform surgical decision-making. Hypothesis: Unsupervised machine learning can identify distinct patient subgroups based on outcome achievement after ACL injury, and ACLR will exert a protective effect on the development of posttraumatic osteoarthritis (PTOA) over nonoperative management. Study Design: Cohort study; Level of evidence, 3. Methods: A longitudinal populational registry identified patients with ACL injuries from 1990 to 2016 with a minimum 7.5-year follow-up. An unsupervised random forest algorithm was utilized to develop and validate patient subgroups. Treatment effects of ACLR on outcomes were analyzed using a machine learning causal inference estimator. Patient subgroup membership was incorporated into a multivariable logistic regression to identify factors predictive of optimal outcomes. Results: A total of 923 patients (785 primary ACLR, 138 nonoperative) were included. The random forest algorithm arrived at an optimal partition of 2 subgroups, with 653 patients in the optimal outcome subgroup (368 male [56.4%]; mean age, 26.0 ± 10.2 years; mean body mass index [BMI], 26.5 ± 4.30) and 270 patients in the suboptimal outcome subgroup (152 male [56.3%]; mean age, 35.0 ± 10.1 years; mean BMI, 30.5 ± 5.54). The latter group demonstrated significantly increased rates of secondary meniscal injury, development of symptomatic PTOA, and progression to total knee arthroplasty (TKA) at the final follow-up (all P < .01). In the optimal outcome subgroup, ACLR had significantly protective treatment effects on the risk of secondary meniscal injury (average treatment effect [ATE], 61%), contralateral ACL injury (ATE, 8%), symptomatic PTOA (ATE, 16%), and progression to TKA (ATE, 6%) (all P < .01). Conversely, in the suboptimal outcome subgroup, ACLR only protected against symptomatic PTOA (ATE, 11%) and progression to TKA (ATE, 8%) (both P < .01). Conclusion: Two clinically meaningful subgroups were identified from retrospectively collected data and found to experience differential treatment responses after ACL injuries. ACLR decreased the rate of development of PTOA and TKA in both subgroups but was not as effective in preventing secondary meniscal injuries or contralateral ACL injuries in patients who were older, heavier, or had concomitant medial meniscus injuries.

BACKGROUND: Patients with functioning pituitary adenomas (FPA) require a multidisciplinary team-based approach to select best medical, surgical, and radiation treatments, including stereotactic radiosurgery (SRS). OBJECTIVE: The aim of this study was to provide evidence-based recommendations on the use of SRS for adult patients with FPA. METHODS: PubMed and Embase were searched from data base inception to June 8, 2021. Full-text articles were then screened using published exclusion/inclusion criteria. Evidence tables were developing based on data extraction from the full-text reviews, and evidence-based recommendations were finalized. RESULTS: Of the total 1842 abstracts pertinent to this topic, 343 full articles met eligibility. Of these, 21 met entry criteria and were included in the evidence tables. The provided Class III evidence supported 2 Level III recommendations: 1. SRS, hypofractionated SRS, fractionated (>5 fractions) radiotherapy, and conventional radiation therapy provide excellent radiographic control with variable hormonal reduction and endocrine remission rates. For SRS and fractionated radiotherapy hormonal reduction may continue for up to 10 years after treatment. 2. Clinicians may continue to administer endocrine suppressive medical treatment before SRS as this may not affect radiographic control. CONCLUSION: This systematic review provides evidence-based recommendations to guide providers caring for adult patients with FPA when making decisions pertinent to radiosurgery. The CNS Guidelines Committee will continue to pursue timely updates to further improve the care of patients with this diagnosis.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Abstract The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P&lt; .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P&lt; .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T–related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Objectives Guidelines advise repeat screening within four months if Papanicolaou (Pap) results are unsatisfactory for evaluation. This utilizes healthcare system resources and may decrease patient satisfaction due to needing a second clinic appointment. We assessed unsatisfactory Pap test (UPT) rates and associations with clinician and patient characteristics to inform future interventions to decrease UPTs. Setting Multisite midwestern United States primary care practice. Methods Retrospective analysis of women aged 21–65 with a Pap between 7/1/2021 and 6/30/2023. Bivariate and multivariable logistic regression analyses were conducted to assess for associations between UPTs and clinician gender, degree, residency status, and experience. Results Of 51,195 Paps completed, 2.3% were unsatisfactory. Female clinicians performed the most Pap tests (83.2%) with slightly less likelihood of UPTs compared with male clinicians ( p = 0.015). There was no significant difference comparing physicians to advanced practice providers in UPTs ( p = 0.18). Residency training level did not affect UPT rates ( p = 0.95). Clinician experience was associated with higher UPT rates in first and fourth quartiles (least and most Paps performed) compared to middle two quartiles ( p = 0.004). UPTs were more likely among women aged > 50 years old ( p < 0.001), married ( p < 0.001), and Asian ( p < 0.001). Conclusions Clinician characteristics played a small role in predicting UPTs but patient age may be the factor most amenable to intervention to lower UPTs. Transitioning to primary human papillomavirus (HPV) screening in peri/post-menopausal women could decrease UPTs given Paps are performed on the clinician-collected cervical specimen only if HPV testing is positive.