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Novel Role of the EBV-Encoded Deubiquitinating Enzyme (BPLF1) in mTOR-Mediated Cell Growth and Proliferation Pathways
No full textEpstein-Barr Virus (EBV) is an oncogenic gamma-herpesvirus that infects over 95% of the population worldwide. It serves as the etiological agent of infectious mononucleosis and drives several lethal immunoblastic lymphomas in immunocompromised individuals, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. EBV encodes a deubiquitinating (DUB) enzyme, BamHI P fragment left open reading frame-1 (BPLF1) which plays a critical role in EBV-induced infectious virus production, B-cell immortalization, and tumorigenesis. To explore the molecular interactions of BPLF1, we conducted an affinity-based mass spectrometry screen, which showed that BPLF1 directly interacts with the mechanistic target of rapamycin (mTOR). mTOR, a major regulator of cell growth and proliferation, is present in the cell in two complexes: mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Dysregulation of the mTOR pathway is a well-established contributor to carcinogenesis. Notably, a shift from predominant mTORC1 activity to an increased mTORC2 activity has been implicated in the tumorigenic process.
To investigate BPLF1’s deubiquitinating activity on its mTOR complex interacting partners, we overexpressed constructs of a truncated wild-type (WT) BPLF1 and an enzymatically inactive (C61S) BPLF1 mutant in cultured cells. Immunoprecipitations followed by western blot analysis were conducted to assess the ubiquitination status of mTOR. Previous studies have demonstrated that the lysosomal localization of mTORC1, which is crucial for its activation, is dependent on K63-linked ubiquitination of mTOR. To further evaluate BPLF1’s impact on mTOR localization, we utilized lysosomal fractionation to isolate and analyze mTOR’s subcellular distribution. The phosphorylation states of downstream effectors of mTORC1 were also assessed as markers of mTORC1 activation. Additionally, the effects of the mTORC1 inhibitor rapamycin and the mTORC2 inhibitor JR-AB2-011 on infectious virus production were evaluated by flow cytometry using Green Fluorescent Protein (GFP)-tagged virus and quantitative PCR.
We found that BPLF1 exhibits direct DUB activity on mTOR, specifically cleaving both K48- and K63-linked ubiquitin chains. Additionally, WT BPLF1 diminished the lysosomal localization of mTORC1 and reduced the phosphorylation of mTORC1 downstream effectors, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase beta-1 (S6K1). An immunoprecipitation analysis of mTOR revealed a decrease in mTORC1 complex formation in the presence of WT BPLF1 without any apparent effect on the formation of mTORC2. Notably, the inhibition of mTORC1 resulted in an increase in infectious virus production, whereas inhibition of mTORC2 led to a decrease in viral production. These findings highlight the differential roles of mTORC1 and mTORC2 in modulating EBV infectious virus production.
We also observed that BPLF1’s deubiquitinating activity disrupts mTORC1 formation and activation. Specifically, BPLF1 reduces mTORC1’s localization to the lysosome and inhibits its activation, thereby preventing the downstream phosphorylation of effectors essential for regulating cell growth and proliferation. It appears that EBV exploits BPLF1 to disrupt mTORC1 activity, a mechanism that supports the production of infectious virus. Additionally, mTORC2 activity also plays a crucial role in viral production, suggesting that other viral factors may cooperate with BPLF1 to optimize the mTOR pathway in favor of the virus. Given BPLF1’s critical involvement in infectious virus production, its potential contribution to EBV’s oncogenic properties through modulation of the mTOR signaling pathway warrants further study
Transvaginal Ovarian Drilling for Polycystic Ovary Syndrome Prior to in Vitro Fertilization Dramatically Improves Embryo Yield, Implantation, and Ongoing Pregnancy Rates
No full textPurpose: To evaluate the effect of transvaginal ovarian drilling (TVOD) on IVF outcomes in subjects with clomiphene-resistant PCOS and a history of IVF failure. Methods: Between 2008 and 2011, 19 subjects with sonographically PCOS and a history of failure to ovulate to high-dose clomiphene citrate were prospectively followed and underwent TVOD at a university hospital-based IVF program. Results: In 15 subjects who underwent 30 fresh paired IVF cycles TVOD resulted in a significantly higher number of oocytes retrieved (7.2 ± 5.9 vs. 13.2 ± 5.9, p = 0.007), mature oocytes retrieved (4.6 ± 3.4 vs. 9.5 ± 5.2, p = 0.002), embryos (3.8 ± 2.7 vs. 8.5 ± 4.5, p = 0.0002), and blastocysts (0.73 ± 1.33 vs. 2.77 ± 2.7, p = 0.037). Among all IVF cycles, 19 subjects underwent 23 fresh IVF cycles prior to TVOD and 21 fresh cycles within 6 months following TVOD lead to higher implantation (0.10 vs. 0.37, p = 0.001), clinical pregnancy (17.4% vs. 61.9%, p = 0.002), and ongoing pregnancy rates (4.4% vs. 47.6%, p = 0.014). Conclusion: In this prospective cohort study, TVOD appears to markedly improve IVF outcomes in subjects with clomiphene resistant PCOS and a history of IVF failure
Lip and Jaw Tremor in Parkinson’s Disease
No full textBackground: Parkinson’s disease (PD) is characterized clinically by the presence of bradykinesia, rigidity, and tremor. Although upper limb rest tremor is the most common form of tremor in PD, lip/jaw tremor is identified in a proportion of these patients. Methods: We aimed to assess the frequency, features, and correlates of lip/jaw tremor in PD. Results: We studied 229 consecutive patients with PD. There were 39 (17%) patients with lip/jaw tremor, 22 of them (56.4%) were males. Slight lip/jaw tremor was identified in n = 10 (25.6%), mild in n = 15 (38.5%), moderate in n = 13 (33.3%) and severe in n = 1 (2.6%) case. Patients with lip/jaw tremor had a positive association with older age, greater limb rest tremor scores (P = 0.009), and higher total MDS-UPDRS-III scores (P \u3c 0.001) in the multivariate regression analysis. There were 6 patients with isolated lip/jaw tremor (i.e. without limb rest tremor). These patients were all male (P = 0.038), tended to be older (75.7 vs. 67.7 years, P = 0.078) and had greater cognitive impairment (P = 0.034) than the rest of the cohort, but there was no association with other body tremors or total motor score. Conclusions: Lip/jaw tremor was identified in 17% of cases; it was associated with greater motor severity and limb rest tremor, suggesting shared pathophysiology with limb rest tremor. A subgroup with isolated lip/jaw tremor showed reduced cognitive performance, but no association with other body tremors
Early Coronary Angiography in Patients With Out-Of-Hospital Cardiac Arrest Without ST-Segment Elevation: A Systematic Review, Meta-Analysis, and Comparative Analysis of Studies
No full textOut-of-hospital cardiac arrest has a high mortality rate. Unlike ST-elevation myocardial infarction, the results of performing early coronary angiography (CAG) in non-ST-elevation myocardial infarction patients are controversial. This study aimed to compare early and nonearly CAG in this population, in addition to the identification of differences between randomized controlled trials (RCTs) and observational studies conducted in this regard. A systematic search in PubMed, Embase, and Cochrane library was performed to identify the relevant studies. Random-effect meta-analysis was done to calculate the pooled effect size of early versus nonearly CAG outcomes in all studies in addition to each of the RCT and observational subgroups of the studies. The relative risk ratio (RR), along with its 95% confidence interval (CI), was used as a measure of difference. A total of 16 studies including 5234 cases were included in our analyses. Compared with observational cohorts, RCT studies had patients with higher baseline comorbidities (older age, hypertension, diabetes, and coronary artery disease). Random-effect analysis revealed a lower rate of in-hospital mortality in the early-CAG group (RR, 0.79; 95% CI, 0.65-0.97; P = 0.02); however, RCT studies did not find a statistical difference in this outcome (RR, 1.01; 95% CI, 0.83-1.23; P = 0.91). Moreover, mid-term mortality rates were lower in the early-CAG group (RR, 0.87; 95% CI, 0.78-0.98; P = 0.02), mostly due to observational studies. There was no significant difference between the groups in other efficacy and safety outcomes. Although early CAG was associated with lower in-hospital and mid-term mortality in overall analyses, no such difference was confirmed by the results obtained from RCTs. Current evidence from RCTs may not be representative of real-world patients and should be interpreted within its limitation
Outcomes of Grafting Extracellular Matrix With Bone Marrow Aspirate Concentrate in Pediatric and Adolescent Patients With Capitellar Osteochondritis Dissecans
No full textBackground: Humeral capitellar osteochondritis dissecans (OCD) lesions can be challenging to treat. Past studies have demonstrated grafting with extracellular matrix with bone marrow aspirate concentrate (ECM-BMAC) to be a viable technique for treatment of talar dome OCD, although little literature exists regarding application of this technique to the capitellum. This study aimed to report patient-reported outcomes (PROs) and return to sport (RTS) of pediatric patients at ≥1 year postoperatively who underwent ECM-BMAC grafting for capitellar OCD lesions. Methods: A consecutive, single-surgeon series of patients aged \u3c18 years with unstable, contained humeral capitellar OCD who underwent ECM-BMAC grafting and had ≥1-year of clinical follow-up were included. Elbow range of motion (ROM), RTS time, postoperative sport level, and complications were recorded at follow-up visits. PROs, including Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS), Quick Disabilities of the Arm, Shoulder, and Hand questionnaire, Patient-Reported Outcomes Measurement Information System (PROMIS) mobility, PROMIS pain interference, and PROMIS upper extremity, were obtained at baseline and ≥1 year postoperatively. Both PROs and ROM were compared pre- and postoperatively using Wilcoxon signed-rank tests based on normality testing with Shapiro-Wilk tests. Results: Twenty patients were included (mean age 12.8 ± 1.4 years) with an average 22.2 ± 13.0 months’ follow-up. Fifteen patients (75%) were female. The most common primary sports were gymnastics, baseball/softball, and racquet sports. Flexion improved significantly at ≥1 year postoperation, whereas extension remained close to full pre- and postoperatively. PROs improved from pre- to postoperative for all assessed instruments except for the HSS Pedi-FABS, which was statistically no different. Eighteen patients returned to their primary sport at the same competitive level or higher at a mean 5.8 ± 1.2 months. The 2 patients who did not return to their primary sport changed sports because of preferences unrelated to their elbow. There were no complications (eg, infection, stiffness, revision surgery). Conclusions: This study demonstrated that ECM-BMAC grafting is a viable treatment strategy for pediatric patients with unstable, contained capitellar OCD lesions. We observed favorable PROs ≥1 year postoperatively with an ~90% RTS rate at an average of 5.8 months, supporting the results of this technique that has demonstrated success in other anatomic regions and adult populations. These findings suggest ECM-BMAC grafting to be a viable treatment option for contained capitellar OCD lesions. Although these early results are promising, longer-term research studies are paramount in determining the outcomes of patients with capitellar OCD lesions treated with ECM-BMAC grafting
The Risk Analysis Index Predicts 30-Day Periprosthetic Fracture Following Primary Total Hip Arthroplasty
No full textIntroduction: As the number of patients requiring total hip arthroplasty (THA) continues to increase, it is critical to develop tools that predict postoperative periprosthetic fracture (PPF). One way to risk stratify patients undergoing THA is using a frailty score. Recently, the Risk Analysis Index (RAI) has emerged as a potentially more accurate marker of frailty and predictor of postoperative complications following spine surgery. Our study aims to assess the association between frailty, as rated by RAI, and PPF within 30 days following primary THA. Methods: The ACS NSQIP database was queried from the years 2015–2020 analyzing patients who underwent primary THA. The RAI scored patients on a scale from 0 to 81 and grouped them into four categories based on their frailty score: robust, normal, frail, and severely frail. Multivariate analysis was performed, controlling for age, female sex, American Society of Anesthesiologists (ASA) score, and tobacco smoking, with the primary outcome being PPF within 30 days of surgery. Results: A total of 186,756 patients were included in this study– 372 (0.2 %) of which had PPFs within the 30-day postoperative period. Increasing frailty, as measured by RAI, was a significant predictor of PPF following primary THA in normal, frail, and severely frail patients. Female sex and ASA status also showed increased risk of PPF. Furthermore, each additional unit on the RAI scale increased the odds of PPF by 7.5 %. Discussion: Frailty has been identified as a predictor of adverse postoperative outcomes in patients undergoing THA, however, this study is the first to find a significant association between frailty and PPF within 30 days of THA. Incorporating frailty assessment into preoperative discussions may aid surgeons in risk stratification, inform surgical decision-making, and enhance the effectiveness of postoperative monitoring following THA
Global Cardiac Anesthesia Workforce Assessment: A Cross-Sectional Observational Survey Study
No full textObjective: The primary aim of this survey was to assess the demographics, training background, practice setting, and work environment of cardiac anesthesiologists globally. Design: Cross-sectional study of the global cardiac anesthesia workforce. A multilingual web-based survey was conducted between June 1 and December 31, 2023. Setting: The survey was distributed via cardiac anesthesia societies, special interest groups, and social media using a non-probabilistic sample and with snowballing techniques. Participants: Anesthesiologists actively practicing cardiac anesthesia. Interventions: None. Measurements and Main Results: In total, 3,430 participants from 99 countries responded. Results were summarized as descriptive data comparing geographical regions, and noticeable differences for individual countries were assessed. Most of the workforce (85.9%, n = 2,913/3,390) that responded to the survey were between 31 and 60 years of age. Australia/New Zealand/Oceania (51.1%, n = 48/94) and Asia (45.2%, n = 606/1,341) had the largest percentages of respondents working in the above 50 years of age group. Globally, 48.4% (n = 1,347/2,780) of respondents reported having completed an accredited adult cardiac fellowship, and 42.7% (n = 918/2,148) replied to have had only informal training “on the job.” When it comes to transesophageal echocardiography, 44.6% (n = 1,240/2,780) of the global workforce reports not having had any formal training. Large differences in training background were noticed by country and region. Most of the workforce (43.3%, n = 1,149/2,652) indicated working between 41 and 60 hours per week. However, more than one of four (26.8%, n = 711/2,652) cardiac anesthesiologists work between 61 to 80 hours, and one out of ten (10.5%, n = 279/2,652) has a workload of more than 81 hours per week. A majority (68%, n = 1,778/2,609) of cardiac anesthesiologists evaluated their compensation/salary as less than adequate or just adequate but not enough to save for retirement. Regarding work-life balance, there was a significant variation in how practitioners assessed their personal situations. Almost half (46.3%, n = 1,185/2,560) of the workforce consider making changes to reduce their workload, and only 23.1% (n = 592/2,560) evaluated their work-life balance as just right. A validated, non-proprietary single-question item assessing emotional exhaustion as one of the three established criteria for burnout was incorporated into the survey. The overall prevalence of burnout, i.e. emotional exhaustion, among cardiac anesthesiologists was 31.7% (n = 827/2,609). In the regression analysis, an increase in clinical work hours (OR = 1.28; CI [1.16, 1.42]; p \u3c 0.001), the number (OR = 1.05; CI [1.02, 1.08]; p \u3c 0.001) and type (OR =1.09; CI [1.0, 1.19]; p = 0.03) of cardiac call, all increased the odds for burnout. Compared to taking all cardiac call in the hospital, taking no cardiac call at all, significantly decreased the risk for burnout. Similarly, compared to compensation that was perceived as less than adequate, i.e., even needing a second income, higher compensation assessment was associated with an increasingly lower risk for burnout. Other factors mitigating burnout risk include older age groups (OR = 0.78; CI [0.67, 0.90]; p \u3c 0.001), and a more positive outlook on work-life balance (OR = 0.88; CI [0.85, 0.92]; p \u3c 0.001). The geographical region had a small but significant association with burnout (OR 1.12; CI [1.06, 1.18]; p \u3c 0.001). Asia, as the geographical region of practice, had the highest odds for burnout overall (41.3%, n = 342/829) and also the most respondents (15.6%, n = 129/829) in the highest answer option category, i.e., feeling completely burned out. Conclusions: A global survey of the cardiac anesthesia workforce found inconsistency in the training, job satisfaction, and daily practice of cardiac anesthesiologists. The rate of burnout was high, and many respondents would like to make work-related changes to improve work-life balance
Early versus Late Venous Thromboembolism Prophylaxis in Patients With Severe Blunt Solid Organ Injury
No full textBackground: Patients with blunt solid organ injury (BSOI) face heightened thromboembolic risks, prompting scrutiny of early versus late venous thromboembolic (VTE) prophylaxis effects. Methods: Analyzing TQIP data (2017–2019) for adults (≥18 years) with severe BSOI under non-operative management and VTE prophylaxis, we classified patients into early (≤48 h) and late (\u3e48 h) prophylaxis groups. We conducted a propensity score matching (PSM) to balance the population based on demographics, organ injury severity, vital signs and need for blood transfusion. Data were compared post-PSM. Results: Among 23,668 patients, mortality was 3.1 %, with 42.2 % receiving early and 57.8 % late VTE prophylaxis. Early prophylaxis correlated with lower mortality (2.1 % vs. 3.9 %), lower rates of failure of non-operative management (12.4 % vs. 16.6 %), stroke (0.7 % vs. 1.2 %), DVT (2.1 % vs. 4.9 %) and PE (1.4 % vs. 2.3 %) (p \u3c 0.001 for all). Late prophylaxis associated with longer hospitalization and ICU stays (p \u3c 0.001 for both). Post-match data showed that compared to early VTE prophylaxis, patients that received late VTE prophylaxis had higher mortality rates (2.5 % vs. 1.9 %), failure of non-operative management (14.6 % vs. 11.8 %), longer hospital (15.8 (8.7) vs. 12.4 (6.7) days) and ICU (8.9 (4.7) vs. 6.8 (3.4) days) LOS, and higher rates of developing thrombotic complications during hospital stay (p \u3c 0.05, for all). Conclusion: Early VTE prophylaxis not only proves safe for isolated solid organ injury patients but also is associated with lower mortality, mitigating thromboembolic risks and shortening hospital and ICU stays. Level of evidence: Level III retrospective stud