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Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Beck, David B; Bodian, Dale L; Shah, Vandan; Mirshahi, Uyenlinh L; Kim, Jung; Ding, Yi; Magaziner, Samuel J; Strande, Natasha T; Cantor, Anna; Haley, Jeremy S; Cook, Adam; Hill, Wesley; Schwartz, Alan L; Grayson, Peter C; Ferrada, Marcela A; Kastner, Daniel L; Carey, David J; Stewart, Douglas R
IMPORTANCE:VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. OBJECTIVE:To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. DESIGN, SETTING, AND PARTICIPANTS:This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. EXPOSURES:Exome sequencing was performed. MAIN OUTCOMES AND MEASURES:Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays. RESULTS:In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669). CONCLUSIONS AND RELEVANCE:This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
PMID: 36692560
ISSN: 1538-3598
CID: 5415112

Blood pressure after endovascular thrombectomy and outcomes in acute ischemic stroke patients: A systematic review and individual patient data meta-analysis [Meeting Abstract]

Katsanos, A; Malhotra, K; Ahmed, N; Seitidis, G; Mistry, E; Mavridis, D; Kim, J -T; Veroniki, A A; Maier, I; Matusevicius, M; Khatri, P; Anadani, M; Goyal, N; Arthur, A; Sarraj, A; Yaghi, S; Shoamanesh, A; Catanese, L; Kantzanou, M; Psaltopoulou, T; Rentzos, A; Psychogios, M -N; Van, Adel B; Spiotta, A; Sandset, E C; De, Havenon A; Alexandrov, A; Petersen, N; Tsivgoulis, G
Background and Aims: In this systematic review and individual patient data meta-analysis we aim to explore the association between blood pressure (BP) levels after endovascular thrombectomy (EVT) and the clinical outcomes of acute ischemic stroke (AIS) patients with large vessel occlusion (LVO).
Method(s): A study was eligible if it enrolled AIS patients older than 18 years, with an LVO treated with either successful or unsuccessful EVT, and provided either individual or mean 24-hour systolic BP values after the end of the EVT procedure. Individual patient data from all studies were analyzed using a generalized linear mixed-effects model.
Result(s): A total of 5874 patients (mean age: 69+/-14 years, 50% women, median NIHSS on admission:16) from 7 published studies were included. Increasing mean systolic BP levels per 10 mm Hg during the first 24 hours after the end of the EVTwere associated with a lower odds of functional improvement (unadjusted common OR=0.82, 95%CI:0.80-0.85; adjusted common OR=0.88, 95%CI:0.84-0.93) and modified Ranking Scale score<=2 (unadjusted OR=0.82, 95%CI:0.79-0.85; adjusted OR=0.87, 95%CI:0.82-0.93), and a higher odds of all-cause mortality (unadjusted OR=1.18, 95%CI:1.13-1.24; adjusted OR=1.15, 95%CI:1.06-1.23) at 3 months. Higher 24-hour mean systolic BP levels were also associated with an increased likelihood of early neurological deterioration (unadjusted OR=1.14, 95%CI:1.07-1.21; adjusted OR=1.14, 95%CI:1.03-1.24) and a higher odds of symptomatic intracranial hemorrhage (unadjusted OR=1.20, 95%CI:1.09-1.29; adjusted OR=1.20, 95% CI:1.03-1.38) after EVT.
Conclusion(s): Increased mean systolic BP levels in the first 24 hours after EVT are independently associated with a higher odds of symptomatic intracranial hemorrhage, early neurological deterioration, threemonth mortality, and worse three-month functional outcomes
ISSN: 2396-9881
CID: 5024672

Implementation of a Preoperative Anemia Clinic Utilizing a Minimal Staffing Model

Mabry, Christian; Perelman, Seth; Kim, Jung T; Blitz, Jeanna D
We present a process map for the implementation of a program to treat preoperative anemia utilizing 1 existing anesthesiologist in the preoperative evaluation clinic. In the first 7 months postimplementation, 342 patients were screened for anemia, 166 were diagnosed, and 107 were treated. The mean increase in hemoglobin in treated patients was ~2 g/dL (range 0-4.9 g/dL). Two patients' surgeries were delayed in favor of treatment and 3 surgical patients, who had received 2 complete iron infusions, received an intraoperative transfusion. The total revenue generated for the institution was enough to subsidize the cost of an additional anesthesiologist.
PMID: 31770131
ISSN: 2575-3126
CID: 4215882

Medical therapy for atherosclerotic cardiovascular disease in patients with myocardial injury after non-cardiac surgery

Chen, Jin F; Smilowitz, Nathaniel R; Kim, Jung T; Cuff, Germaine; Boltunova, Alina; Toffey, Jason; Berger, Jeffrey S; Rosenberg, Andrew; Kendale, Samir
BACKGROUND:Myocardial injury after non-cardiac surgery (MINS) is a common post-operative cardiovascular complication and is associated with short and long-term mortality. The objective of this study was to describe the contemporary management of patients with and without MINS after total joint and spine orthopedic surgery at a large urban health system in the United States. METHODS:Adults admitted for total joint and major spine surgery from January 2013 through December 2015 with ≥1 cardiac troponin (cTn) measurement during their hospitalization were identified. MINS was defined by a peak cTn above the 99th percentile of the upper reference limit. Demographics, medical comorbidities, and admission and discharge medications were reviewed for all patients. RESULTS:A total of 2561 patients underwent 2798 orthopedic surgeries, and 236 cases of MINS were identified. Patients with MINS were older (71.9 ± 10.9 vs. 67.0 ± 10.0, p < 0.001) and more likely to have cardiovascular risk factors, including hypertension, chronic kidney disease, prior stroke, coronary artery disease, prior MI, and a history of heart failure. Among patients with MINS, only 112 (47.5%) were discharged on a combination of aspirin and statin. Patients with MINS were more likely to be prescribed a statin (154 [65.3%] vs. 1463 [57.1%], p = 0.018), beta-blocker (147 [62.3%] vs. 1194 [46.6%], p < 0.001), and oral anticoagulation (65 [27.5%] vs. 436 [17.0%], p < 0.001) than patients without MINS. CONCLUSIONS:The proportion of patients with MINS who were prescribed medical therapy for atherosclerotic cardiovascular disease was low. Additional efforts to determine optimal management of MINS are warranted.
PMID: 30598249
ISSN: 1874-1754
CID: 3563312

In Reply

Blitz, Jeanna D; Kendale, Samir M; Jain, Sudheer K; Cuff, Germaine E; Kim, Jung T; Rosenberg, Andrew D
PMID: 28418972
ISSN: 1528-1175
CID: 2532332

Auricular Acupressure in the Prevention of Postoperative Nausea and Emesis A Randomized Controlled Trial

Feng, Cynthia; Popovic, Jovan; Kline, Richard; Kim, Jung; Matos, Rafael; Lee, Sarah; Bosco, Joseph
INTRODUCTION: Successful antiemesis contributes significantly to quality, safety, and patient satisfaction. Patients undergoing general anesthesia often experience postoperative nausea and vomiting (PONV). Acupressure offers a side effect-free alternative to common first-line antiemetics. Because the patient may perceive needle acupuncture as uncomfortable, acupressure is a desirable alternative for the prevention of PONV. METHODS: This study was a randomized, prospective, double-blinded clinical trial investigating the effect of acupressure in patients with a history of PONV and motion sickness. The three auricular acupressure points chosen were shen men, point zero, and the subcortex point. Rescue treatment for PONV with 4 mg intravenous ondansetron was used if the patient reported persistent nausea. A blinded observer recorded antiemetic rescue data, and postoperative analgesic use was recorded over 24 hours. Nausea, vomiting, and retching were assessed in the post-anesthesia care unit (PACU). RESULTS: Using univariate analysis, we ruled out the null hypothesis of equal means as a function of intervention group (p = 0.001). Pair-wise comparisons revealed a difference between placebo and test groups (p = 0.000) and also sham and test groups (p = 0.033) where age (p = 0.048) and gender (p = 0.003) were significant covariates. DISCUSSION: Our data reveal that auricular acupressure significantly decreases nausea during the PACU stay and within the 24 hours postoperatively. It is not clear whether the intervention decreases nausea as a primary effect or as a secondary result by decreasing narcotic requirements. Also, perception of nausea may be in part subjective. This is evidenced by our results in which subjects who received sham points fared better than the placebo subjects.
PMID: 28583057
ISSN: 2328-5273
CID: 2609442

Polycomb-mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer

Fong, Ka Wing; Zhao, Jonathan C; Kim, Jung; Li, Shangze; Yang, Yeqing Angela; Song, Bing; Rittie, Laure; Hu, Ming; Yang, Ximing J; Perbal, Bernard; Yu, Jindan
The lethal phenotype of castration-resistant prostate cancer (CRPC) is generally caused by augmented signaling from the androgen receptor (AR). Here we report that the AR-repressed gene CCN3/NOV inhibits AR signaling and acts in a negative feedback loop to block AR function. Mechanistically, a cytoplasmic form of CCN3 interacted with the AR N-terminal domain to sequester AR in the cytoplasm of prostate cancer cells, thereby reducing AR transcriptional activity and inhibiting cell growth. However, constitutive repression of CCN3 by the Polycomb tumor suppressor protein EZH2 disrupted this negative feedback loop in both CRPC and enzalutamide-resistant prostate cancer cells. Notably, restoring CCN3 was sufficient to effectively abolish CPRC cell growth in vitro and in vivo. Taken together, our findings establish CCN3 as a pivotal regulator of AR signaling and prostate cancer progression and they establish a functional intersection between Polycomb and AR signaling in CRPC.
PMID: 27815387
ISSN: 1538-7445
CID: 2304252

General anesthesia in a patient with citrullinemia using Precedex as an adjunct to prevent delayed emergence

Patel, Hersh; Kim, Jung; Huncke, Tessa Kate
Citrullinemia type I is a rare autosomal recessive genetic condition that causes reduced activity of the enzyme, argininosuccinate synthase, which is needed for proper urea metabolism. The end result is hyperammonemia which can cause life-threatening neurologic symptoms and global developmental delay. Previous case reports of the anesthetic management of patients with citrullinemia describe delayed recovery possibly related to elevated ammonia levels postoperatively or choice of intraoperative anesthetics which have included narcotics. In this case report, we present the anesthetic management of a 16-year-old adolescent girl with citrullinemia type I undergoing a vagus nerve stimulator revision. We used the alpha-2-adrenergic agonist, dexmedetomidine, as an adjunct to avoid narcotics to prevent delayed emergence. She was admitted for hydration the night before the procedure and had a baseline ammonia level of 33 mumol/L (reference, 9-33 mumol/L). Anesthetic maintenance consisted of 2% sevoflurane, dexmedetomidine 0.5 mug/kg per hour, and intravenous acetaminophen given toward the conclusion of the surgery. The patient awoke immediately at the end of the procedure and was extubated in the operating room. Postprocedure, her ammonia level was less than 9 mumol/L. She appeared to be free of pain, was tolerating gastric tube feeds postprocedure, and was discharged to home on the day of surgery. Effective management of ammonia levels in this patient using preoperative hydration and dexmedetomidine as an adjunct to general anesthesia may have helped to prevent delayed emergence.
PMID: 27555199
ISSN: 1873-4529
CID: 2221162

Preoperative Evaluation Clinic Visit Is Associated with Decreased Risk of In-hospital Postoperative Mortality

Blitz, Jeanna D; Kendale, Samir M; Jain, Sudheer K; Cuff, Germaine E; Kim, Jung T; Rosenberg, Andrew D
BACKGROUND: As specialists in perioperative medicine, anesthesiologists are well equipped to design and oversee the preoperative patient preparation process; however, the impact of an anesthesiologist-led preoperative evaluation clinic (PEC) on clinical outcomes has yet to be fully elucidated. The authors compared the incidence of in-hospital postoperative mortality in patients who had been evaluated in their institution's PEC before elective surgery to the incidence in patients who had elective surgery without being seen in the PEC. METHODS: A retrospective review of an administrative database was performed. There were 46 deaths from 64,418 patients (0.07%): 22 from 35,535 patients (0.06%) seen in PEC and 24 from 28,883 patients (0.08%) not seen in PEC. After propensity score matching, there were 13,964 patients within each matched set; there were 34 deaths (0.1%). There were 11 deaths from 13,964 (0.08%) patients seen in PEC and 23 deaths from 13,964 (0.16%) patients not seen in PEC. A subanalysis to assess the effect of a PEC visit on deaths as a result of failure to rescue (FTR) was also performed. RESULTS: A visit to PEC was associated with a reduction in mortality (odds ratio, 0.48; 95% CI, 0.22 to 0.96, P = 0.04) by comparison of the matched cohorts. The FTR subanalysis suggested that the proportion of deaths attributable to an unanticipated surgical complication was not significantly different between the two groups (P = 0.141). CONCLUSIONS: An in-person assessment at the PEC was associated with a reduction in in-hospital mortality. It was difficult to draw conclusions about whether a difference exists in the proportion of FTR deaths between the two cohorts due to small sample size.
PMID: 27433746
ISSN: 1528-1175
CID: 2184972

An analysis of anesthetic interventions and anesthesia start times [Meeting Abstract]

Jain; Bloom, M J; Kendale, S; Kim, J; Russo, L; Cuff, G; Rosenberg, A D
INTRODUCTION: As the healthcare landscape evolves, hospital administrators are requiring healthcare providers, including anesthesiologists, to be more efficient and cost-effective. Currently, no national benchmark exists for intraoperative anesthesia induction and preparation times. Without an existing standard, healthcare administrators may have unrealistic expectations as to what the average "anesthesia induction time" should be. To help establish a baseline, we have provided the average "anesthesia induction" times for 40,120 out of 52,349 cases performed in our institution based upon the number of anesthetic procedures/interventions performed to prepare a patient for surgery. METHODS: With IRB approval, a retrospective analysis of 52,349 cases was performed from our electronic medical record in a 15-month period. 12,247 anesthetic interventions were excluded for incomplete documentation of data points or for extreme outliers in the data set, considered being five standard deviations away from mean. The average time from "wheels into the operating room" to "ready for surgical preparation and positioning" of 40,102 cases were recorded based upon the number of anesthetic procedures/ interventions performed. RESULTS: CONCLUSIONS: Our results reveal the average intraoperative anesthesia ready time based on the number of anesthetic procedures/ interventions performed in an academic medical center. This data may help administrators and anesthesiology departments create realistic models toward perioperative efficiency. Further analysis of the data is needed to differentiate the average anesthesia ready time of cases based on staffing (attending alone versus with house staff or nurse anesthetist). (Figure Presented)
ISSN: 0003-2999
CID: 1923502