METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.

S-methylation of drugs containing thiol-moieties often alters their activity and results in detoxification. Historically, scientists attributed methylation of exogenous aliphatic and phenolic thiols to a putative S-adenosyl-L-methionine (SAM)-dependent membrane-associated enzyme referred to as thiol methyltransferase (TMT). This putative TMT appeared to have a broad substrate specificity and methylated the thiol metabolite of spironolactone, mertansine, ziprasidone, captopril, and the active metabolites of the thienopyridine prodrugs, clopidogrel, and prasugrel. Despite TMT's role in the S-methylation of clinically relevant drugs, the enzyme(s) responsible for this activity remained unknown. We recently identified methyltransferase-like protein 7B (METTL7B) as an alkyl thiol methyltransferase. METTL7B is an endoplasmic reticulum-associated protein with similar biochemical properties and substrate specificity to the putative TMT. Yet, the historic TMT inhibitor 2,3-dichloro-α-methylbenzylamine (DCMB) did not inhibit METTL7B, indicating that multiple enzymes contribute to TMT activity. Here we report that methyltransferase-like protein 7A (METTL7A), an uncharacterized member of the METTL7 family, is also a SAM-dependent thiol methyltransferase. METTL7A exhibits similar biochemical properties to METTL7B and putative TMT, including inhibition by DCMB (IC50 = 1.17 µM). Applying quantitative proteomics to human liver microsomes and gene modulation experiments in HepG2 and HeLa cells, we determined that TMT activity correlates closely with METTL7A and METTL7B protein levels. Furthermore, purification of a novel His-GST-tagged recombinant protein and subsequent activity experiments prove that METTL7A can selectively methylate exogenous thiol-containing substrates, including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. We conclude that the METTL7 family encodes for two enzymes, METTL7A and METTL7B, which are now renamed thiol methyltransferase 1A (TMT1A) and thiol methyltransferase 1B (TMT1B), respectively, that are responsible for thiol methylation activity in human liver microsomes. SIGNIFICANCE STATEMENT: We identified methyltransferase-like protein 7A (thiol methyltransferase 1A) and methyltransferase-like protein 7B (thiol methyltransferase 1B) as the enzymes responsible for the microsomal alkyl thiol methyltransferase (TMT) activity. These are the first two enzymes directly associated with microsomal TMT activity. S-methylation of commonly prescribed thiol-containing drugs alters their pharmacological activity and/or toxicity, and identifying the enzymes responsible for this activity will improve our understanding of the drug metabolism and pharmacokinetic (DMPK) properties of alkyl- or phenolic thiol-containing therapeutics.

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: outcomes of a dedicated anesthesia and surgery protocol.

BACKGROUND: Patients requiring percutaneous endoscopic gastrostomy (PEG) for amyotrophic lateral sclerosis (ALS) related dysphagia represent a clinical challenge. Diminished pulmonary function and aspiration risks can lead to anesthesia-related complications, and gastric displacement from hemidiaphragm elevation may preclude safe gastric access. This study reports the efficacy and outcomes of a dedicated anesthesia/surgery management protocol for ALS patients undergoing PEG. METHODS: In 2013, a PEG placement protocol for ALS patients was developed emphasizing efficient pre-operative evaluation, rapidly metabolized anesthetic agents, and minimization of opioid use. Outcomes were analyzed retrospectively. Preoperative weight loss, pulmonary function tests, total analgesia, procedural time, and 90-day morbidity and mortality were recorded. RESULTS: From 2013-2019, 67 ALS patients (mean age 65.3 years, 52.2% female) received a PEG under the protocol. Mean percentage weight loss 6 months before PEG was 9.3 ± 5.1% with 38.8% of patients meeting criteria for severe malnutrition. Mean anesthesia time (propofol induction to anesthesia emergence) was 34.5 ± 10.8 min and mean operative time (endoscope insertion to dressing placement) was 16.4 ± 8.2 min. Regional anesthesia with liposomal bupivacaine was performed in 76.1%. All attempts at PEG placement were successful. With a mean follow-up of 6.1 ± 6.8 months, all PEGs were functional and there were no surgical site complications. Thirty-day readmission rate was 7.0% and 90-day mortality was 22.4% (46.7% occurring within 30 days). Mean time from surgery to death was 8.8 ± 7.8 months. CONCLUSIONS: Protocols for optimizing PEG may help overcome challenges present in the ALS patient population. Despite patient comorbidities, protocol implementation and dedicated team members resulted in a high procedural success rate and low complication rate. Further study is warranted to optimize the timing of PEG placement in relation to ALS disease progression and determine the utility of regional anesthesia during PEG placement.

Presence of social media mentions for vascular surgery publications is associated with an increased number of literature citations.

OBJECTIVE: The past two decades have seen a vast expansion of social media in all aspects of our lives. Scholars and journals are steadily increasing their social media presence to reach a wider audience. We compared the social media mentions (SMs) of vascular surgery publications and their effect on the literature citations (LCs) for them. METHODS: A total of 169 articles from three renowned vascular surgery journals (Journal of Vascular Surgery [JVS], Annals of Vascular Surgery, and European Journal of Vascular and Endovascular Surgery) in October 2016 were collected. All three journals are published by the same publisher (Elsevier). SMs were tracked using Altmetric Bookmarklet for Twitter and Facebook mentions. The LCs were evaluated using Scopus and Google Scholar. The number of citations was compared between those with and without any SMs and among the three journals using nonparametric Kruskal-Wallis tests. The proportion of articles with SMs was compared among the three journals using a χ2 test. The relationship between the numbers of SMs and LCs was assessed using the Spearman rank correlation coefficient and reported as 95% confidence intervals. Statistical significance was assigned at P < .05. RESULTS: Of the 169 articles examined, 51 (30.2%) had a presence regarding social media usage. JVS has both Twitter and Facebook presence. The Annals of Vascular Surgery and European Journal of Vascular and Endovascular Surgery only have Twitter accounts. JVS had the highest total number of citations, number of LCs per manuscript, and SMs per manuscript. A significant difference was found in the median, Q1 (median of the lower half of the data), and Q3 (median of the upper half of the data) number of total Google citations between those articles with and without SMs (median, 8.0; Q1, 3.0; Q3, 17.0; vs median, 3.0; Q1, 0.0; Q3, 8.0, respectively; Kruskal-Wallis P < .001). Similarly, a significant difference was found in the median number of total Scopus citations between those articles with and without SMs (median, 5.0; Q1, 2.0; Q3, 13.0 vs median, 2.0; Q1, 0.0; Q3, 6.0, respectively; Kruskal-Wallis P < .001). Articles with a SM showed a 2.7- fold increase in median total citations in Google and a 2.5-fold increase in median total citations in Scopus. The Spearman correlation coefficients to determine the relationship between the absolute number of SMs and LCs revealed a positive, but weak, correlation, largely driven by the majority of articles with no SMs. The difference in the median number of citations among the three journals was not statistically significant, either by Google (P = .22) or Scopus (P = .08), nor was the difference in the proportion of articles with SMs among the journals statistically significant (P = .36). CONCLUSIONS: The presence of SMs for vascular surgery publications, especially clinical science articles, was associated with a significantly increased number of median LCs during the 3 years after publication. The three journals did not differ with respect to the median number of citations or proportion of articles with SMs.

Preoperative leukocytosis among female patients predicts poor postoperative outcomes following endovascular aneurysm repair for intact infrarenal abdominal aortic aneurysms.

OBJECTIVES: Elevated white blood cell count (WBC) can be predictive of adverse outcomes following vascular interventions, but the association has not established using multi-institutional data. We evaluated the predictive value of preoperative WBC after endovascular aneurysm repair (EVAR) for nonruptured abdominal aortic aneurysms (AAAs) in a nationally representative surgical database. METHODS: Patients with nonruptured AAA undergoing EVAR were identified in the vascular-targeted National Surgical Quality Improvement Program (NSQIP) database. Baseline characteristics were compared between patients with WBC <10 K/µL and WBC ≥10 K/µL. Multivariable logistic regression analyses were performed to assess the odds of outcomes. The primary outcome was 30-day mortality. Multiple secondary outcomes including length of stay (LOS) > 1 week, 30-day readmission, lower extremity (LE) ischemia, ischemic colitis, myocardial infarction, and others were assessed based on WBC and patient sex. RESULTS: A total of 10,955 patients were included, with a mean WBC 7.7 ± 2.7 K/µL. Patients with WBC ≥10 K/µL were younger (71.8 ± 9.5 years vs 74.1 ± 8.7 years; P < .001) and were more likely to be diabetic, on steroids, smokers, functionally dependent, and presenting emergently (all P ≤ .009). Aneurysm diameter was larger in patients with WBC ≥10 K/µL (5.9 ± 1.5 cm vs 5.7 ± 1.5 cm; P < .001). Patients with WBC ≥10 K/µL had more mortality (2.4% vs 1.3%), LOS >1 week (13.5% vs 6.7%), 30-day readmissions (9.8% vs 7.3%), LE ischemia (2.3% vs 1.4%), ischemic colitis (1.2% vs 0.5%), and myocardial infarction (2.0% vs 1.1%) (all P ≤ .008). Female patients with WBC ≥10 K/µL, compared with male patients with WBC ≥10 K/µL, had more adverse events, including mortality, LOS >1 week, 30-day readmission, and LE ischemia (all P ≤ .025). With each incremental increase in WBC by 1 K/µL, the adjusted odds ratio of adverse outcomes for all patient was higher (mortality: 1.05; 95% confidence interval [CI], 1.00-1.10; readmission: 1.03; 95% CI, 1.00-1.06; LOS >1 week: 1.08; 95% CI, 1.05-1.10; and ischemic colitis: 1.11; 95% CI, 1.05-1.16; all P < .05). The effect was more pronounced in female patients and was statistically significant. CONCLUSIONS: WBC is a predictor of adverse outcomes in patients undergoing EVAR for nonruptured AAA. After adjusting for associated risk factors, the effect of increasing WBC was more prominent for female patients. Preoperative WBC should be used as a prognostic factor to predict adverse outcomes among patients undergoing EVAR.

Factors Affecting the Interest in a Surgical Career among Medical Students at a Nonurban, Tertiary Care Academic Institution.

BACKGROUND: Present day medical students are inherently different from those in the past by growing up in a uniquely different environment that shapes their personal and professional values which affects their career decisions. Vascular surgery (VS) task force is facing a shortage in the near future. The purpose of this analysis is to gain a better understanding of the medical students' perceptions about surgery in general and VS in particular. Our institution is a large, tertiary care medical center, which is in a nonurban location. Our goal was to identify any barriers in the recruitment of prospective students to VS and to implement directives to address such barriers. METHODS: An online questionnaire was distributed to Penn State Hershey College of Medicine medical students. Our institution has an established 0 + 5 VS residency program and a VS interest group. It was designed to understand potential barriers in the recruitment of medical students choosing VS as a career. Survey consisted of 23 questions, which were carefully designed to collect information about student demographics, interest in medical profession in general, opinions about the field of surgery, and reasons for having an interest or no interest in VS. RESULTS: Five hundred sixty medical students at Penn State Hershey College of Medicine were surveyed, of whom 143 (26%) completed the survey. About 58.7% were females and two-thirds of the respondents were in the age range of 21-25 years. The following factors were significantly associated with pursing surgical career: Medical Student Year III (odds ratio [OR] 0.36, confidence interval [CI] 0.19-0.69), surgical mentorship (OR 6.01, CI 1.30-28), wanting more exposure to VS (OR 6.15, CI 2.07-18.23), and opportunity to complete training within 5 years (OR 1.14, CI 1.03-1.25) (all P < 0.05). Specifically, for VS, following factors were found to be associated with increased likelihood of choosing a VS career: variety of operative cases, ability to operate on multiple anatomic areas of the body, and opportunity to complete training within 5 years (all P < 0.05). Following factors were associated with not choosing a VS career: surgical career not for me, long duration of surgical training, financial aid burden, marital status, and complexity of operations (all P < 0.05). Students cited following concerns for choosing a surgical career: burnout (61%), stress (12.8%), work hours (12.1%), and stressful life style (5.7%). CONCLUSIONS: Potential barriers of students in choosing a surgical career are fundamentally grounded in their overall perception of surgery but are independently associated with their level of education (medical student-III versus others), strong surgical mentorship, the desire to be exposed to VS, and the opportunity to complete subspecialty surgical training within 5 years. For VS, attractive factors were variety of operative cases, ability to operate on multiple anatomic areas of the body, and opportunity to complete training within 5 years. Overall, burnout associated with surgical career is the most common concern for medical students.

Utilizing student-led contact tracing initiative to alleviate COVID-19 disease burden in central Pennsylvania.

PURPOSE: Contact tracing elicits probable contacts from COVID-19 cases. Our student-led contact tracing initiative promoted isolation of both confirmed and probable cases and quarantine of contacts to reduce disease in Central Pennsylvania. METHODS: Close contacts of COVID-19 cases were contacted by tracers, advised to quarantine, and monitored for 14 days for symptoms. Symptomatic contacts were classified as probable cases and advised to isolate. Data was collected from March 24, 2020 to May 26, 2020. Poisson regression and linear regression were utilized to examine the relationships between case and number of contacts and proportion of symptomatic contacts. RESULTS: Study sample comprised of 346 confirmed and 157 probable cases. Our results indicate a significant difference in percent of household contacts who became symptomatic between confirmed and probable cases (22% vs. 3%; adjusted P<.01). Similarly, probable cases had significantly fewer non-household contacts compared to confirmed cases (0.87 vs. 0.55; adjusted P<.01). CONCLUSIONS: Timely notification of exposure to a COVID-19 positive individual by student contact tracers allowed for probable cases to quarantine early in the disease process. Our data suggests that early quarantine and/or isolation may have directly contributed to probable cases having fewer non-household contacts and a smaller proportion of symptomatic household-contacts compared to confirmed cases.

A systematic review of the outcomes of percutaneous treatment modalities for pathologic saphenous and perforating veins.

OBJECTIVE: Minimally invasive techniques have been increasingly used to treat pathologic perforator veins (PVs). The goal of the present study was to summarize the current literature and determine the outcomes of treating PVs with or without the great saphenous vein/small saphenous vein using endovenous laser ablation (EVLA), radiofrequency ablation (RFA), and ultrasound-guided sclerotherapy (USGS). METHODS: A systematic review of the literature on the percutaneous treatment of PVs (35 studies) was conducted in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies reported up to March 2020 were included. The incidence of several end points at different follow-up periods were calculated according to the availability of data within 3 to 12 months after the index procedure. RESULTS: Of the 35 studies, 15 (n = 1677) had reported on EVLA with or without sclerotherapy and/or microphlebectomy, 12 (n = 1477) had investigated the outcomes of RFA ablation with/without sclerotherapy, and 8 (n = 331) had investigated USGS alone. All techniques were safe in terms of periprocedural adverse events, with only a few complications occurring in each group. Immediate procedural success (within 30 days) was 95% in the EVLA group, 91% in the RFS group, and 58% to 70% in the USGS group. At 12 months of follow-up, the occlusion rates were 89%, 77%, and 83% in the EVLA, RFA, and USGS groups, respectively. The 12-month pooled estimate of ulcer healing between the EVLA and RFA groups was similar, although no direct comparisons were performed. CONCLUSIONS: Treatment of PVs with percutaneous techniques, such as EVLA, RFA, and USGS, is safe and associated with high technical success. EVLA and RFA exhibited the most favorable outcomes. Additional research is needed to validate these results, which were based on the limited level of evidence available to better determine the most optimal treatment approach for lower limb pathologic PVs.

Endovascular repair of a cadaveric vascular allograft nonanastomotic pseudoaneurysm.

Patients who have undergone revascularization with a cryopreserved cadaveric arterial allograft (CCAA) require lifelong surveillance because of the risk of allograft failure. The reported long-term complications of these grafts include thrombosis, anastomotic pseudoaneurysm, and graft disruption. We have described a case in which a CCAA developed a nonanastomotic pseudoaneurysm at the site of a previously ligated branch vessel and was repaired using a covered stent graft. This case demonstrates that spontaneous rupture of CCAA branches is a late complication that can occur when using these grafts and that endovascular methods are an option for repair.