Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC.

Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.

PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours.

Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell-mediated anti-tumour immunity and CAR T-cell therapy against solid tumours.

Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity.

Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet-fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.

Medical students' perception of what embodies an effective surgeon educator.

BACKGROUND: Effective surgeon educators likely help medical students develop competency and may inspire pursuit of surgical training. We sought to determine the qualities medical students believe embody effective surgical educators. METHODS: Mixed-methods study of nationally electronically recruited 3rd-year medical students using virtual semi-structured interviews and anonymous quantitative survey to determine the most critical and most frequently encountered qualities of effective surgical educators. Thematic analysis using grounded theory was undertaken. RESULTS: Data saturation occurred after 9 interviews. Themes of effective surgical educators included: engagement (acknowledging student, knowing their name, talking to the student), fostering a positive learning environment (non-threatening, non-shaming questioning), inclusion (giving responsibility/appropriate autonomy), and understanding how to teach a novice (teaching the student how to learn, adapt to learner). On quantitative analysis of Likert based survey, encouraging, promoting a positive learning climate, timely constructive feedback, and questioning were ranked as most critical. CONCLUSION: Students highly value positive learning climate and inclusion. Faculty Development to promote these traits may improve clerkship learning and experience.

Perceptions and behaviors of learner engagement with virtual educational platforms.

BACKGROUND: The COVID-19 pandemic has increased utilization of educational technology for surgical education. Our aim was to determine attitudes and behaviors of surgical education champions towards virtual educational platforms and learner engagement. METHODS: An electronic survey was distributed to all Association of Surgical Education members addressing i) methods of engagement in virtual learning ii) ways to improve engagement and iii) what influences engagement. Stratified analysis was used to evaluate differences in responses by age, gender, level of training and specialty. RESULTS: 154 ASE members completed the survey (13% response rate). 88% respondents accessed virtual learning events at home. Most (87%) had joined a virtual learning event and then participated in another activity. 1 in 5 who did this did so "always" or "often". Female respondents were more likely than males to join audio and then participate in another activity (62.3% v 37.7%, p = 0.04). CONCLUSIONS: Virtual platforms do not automatically translate into increased learner engagement. Careful design of educational strategies is essential to increase and maintain learner engagement when utilizing virtual surgical education.

A possible case of hantavirus infection in a Borneo orangutan and its conservation implication.

BACKGROUND: Natural infection of hantavirus in orangutans has never been reported. METHODS: Enzyme-linked immunosorbent assays (ELISA), Indirect immunofluorescence assay (IFA), and RT-PCR were used to diagnosis a suspected case in a pet orangutan in southern Taiwan. RESULTS: Although the RT-PCR result was negative, the high IgG titer in the beginning and its dramatic drop after treatments suggested a recent Seoul-type hantavirus infection. CONCLUSIONS: Hantavirus transmission and its potential damage to wild orangutans should not be overlooked.

Avian pox infection in a free-living crested serpent eagle (Spilornis cheela) in southern Taiwan.

Avian pox viruses (APVs) have been reported to cause infection in diverse avian species worldwide. Herein we report the first case of APV infection in a free-living bird, a subadult crested serpent eagle (Spilornis cheela), in Taiwan. In addition to the typical wart-like lesions distributed on the cere, eyelid, and face, there were also yellowish nodules below the tongue and on the hard palate. Phylogenetic analysis of the 4b core protein gene showed that the APV is very close to that found in white-tailed sea eagle (Haliaeetus albicilla) in Japan recently. Because both cases are located on the same major flyway for migratory birds, the impact of this virus with regard to the wild and migratory raptor species along the East Asian-Australasian Flyway and West Pacific Flyway requires immediate investigation.

Assessing learner engagement with virtual educational events: Development of the Virtual In-Class Engagement Measure (VIEM).

BACKGROUND: The COVID-19 pandemic has necessitated virtual education, but effects on learner engagement are unknown. We developed a virtual in-class engagement measure (VIEM) to assess learner engagement in online surgical education events. METHODS: Using the STROBE, an observer collected tool to document student engagement, as a template an ASE committee workgroup developed the VIEM. The VIEM had two parts: observer assessment and learner self-assessment of engagement. Trained observers collected engagement data from two institutions using the VIEM. Surgical attendings, fellows and residents were observed during virtual learning events. Educator attitudes towards online teaching were also assessed via survey. RESULTS: 22 events with 839 learners were observed. VIEM distinguished between sessions with low and high engagement. 20% of learners pretended to participate. Half of instructors were comfortable with virtual teaching, but only 1/3 believed was as effective as in-person. 2/3 of teachers believed video learners were more engaged than audio learners. CONCLUSIONS: Virtual platforms do not automatically translate into increased engagement. Standard tools such as VIEM may help with assessment of engagement during virtual education.

"Optimization of Surgical Resident Safety and Education During the COVID-19 Pandemic - Lessons Learned".

The COVID-19 pandemic has engendered rapid and significant changes in patient care. Within the realm of surgical training, the resultant reduction in clinical exposure and case volume jeopardizes the quality of surgical training. Thus, our general surgery residency program proceeded to develop a tailored approach to training that mitigates impact on resident surgical education and optimizes clinical exposure without compromising safety. Residents were engaged directly in planning efforts to craft a response to the pandemic. Following the elimination of elective cases, the in-house resident complement was effectively decreased to reduce unnecessary exposure, with a back-up pool to address unanticipated absences and needs. Personal protective equipment availability and supply, the greatest concern to residents, has remained adequate, while being utilized according to current guidelines. Interested residents were given the opportunity to work in designated COVID ICUs on a volunteer basis. With the decrease in operative volume and clinical duties, we shifted our educational focus to an intensive didactic schedule using a teleconferencing platform and targeted areas of weakness on prior in-service exams. We also highlighted critical COVID-19 literature in a weekly journal club to better understand this novel disease and its effect on surgical practice. The long-term impact of the COVID-19 pandemic on resident education remains to be seen. Success may be achieved with commitment to constant needs assessment in the changing landscape of healthcare with the goal of producing a skilled surgical workforce for public service.

A matched comparison of laparoscopic versus open inguinal hernia repair in patients with liver disease using propensity score matching.

PURPOSE: Patients with liver cirrhosis may require inguinal hernia repair. It is unknown if surgical approach, laparoscopic or open, affects outcomes in this high-risk patient population. This study compares complications, deaths, and length of stay between open and laparoscopic inguinal hernias in patients with liver disease. METHODS: All patients (N = 145,780) who were diagnosed with inguinal hernia (ICD-9-codes: 550.00, 550.02, 550.10, 550.12, 550.90, and 550.92) and had unilateral repair surgery (current procedure codes: 49505, 49507, 49525, and 49650) between 2005 and 2014 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Data collected included patient demographics, comorbid conditions, postsurgical diagnosis, and outcomes. Multivariate logistic regression models were employed to evaluate the associations between various outcomes and surgical approach. RESULTS: The percentage of open inguinal hernia repair (OIHR) decreased from 84.08% in 2005 to 74.66% in 2014. The mean MELD score was 9.09 ± 4.02 among open surgery patient group, which was higher than the mean MELD score (8.03 ± 2.78) among laparoscopic surgery group. After propensity score matching for patient characteristics, open and laparoscopic inguinal hernia groups had similar length of stay with a slightly longer operation time being observed among laparoscopic group. Overall complications rates were similar (OR 0.87, 95% CI 0.-1.15, p = 0.32) as was overall mortality (0.27% among open surgery patients and 0.12% among laparoscopic patients, OR 0.42, 95% CI 0.15-1.21, p = 0.96). CONCLUSION: Laparoscopic inguinal hernia repair demonstrates similar morbidity and mortality when compared to open repairs in patients with liver disease suggesting that both are viable repair options.

Bootstrapped Biocatalysis: Biofilm-Derived Materials as Reversibly Functionalizable Multienzyme Surfaces.

Cell-free biocatalysis systems offer many benefits for chemical manufacturing, but their widespread applicability is hindered by high costs associated with enzyme purification, modification, and immobilization on solid substrates, in addition to the cost of the material substrates themselves. Herein, we report a "bootstrapped" biocatalysis substrate material that is produced directly in bacterial culture and is derived from biofilm matrix proteins, which self-assemble into a nanofibrous mesh. We demonstrate that this material can simultaneously purify and immobilize multiple enzymes site specifically and directly from crude cell lysates by using a panel of genetically programmed, mutually orthogonal conjugation domains. We further demonstrate the utility of the technique in a bienzymatic stereoselective reduction coupled with a cofactor recycling scheme. The domains allow for several cycles of selective removal and replacement of enzymes under mild conditions to regenerate the catalyst system.

MicroRNA-185-5p modulates chemosensitivity of human non-small cell lung cancer to cisplatin via targeting ABCC1.

OBJECTIVE: MicroRNA-185-5p (miR-185-5p) dysregulation is found in various human cancers. Our purpose is to investigate the association of miR-185-5p expression with the sensitivity of non-small cell lung cancer (NSCLC) to cisplatin. MATERIALS AND METHODS: Real-time PCR or Western blot assay was performed to detect the expression of mature miR-185-5p and ATP-binding cassette, subfamily C, member 1 (ABCC1) protein. Cell lines with abnormal expression of miR-185-5p were generated using miR-185-5p inhibitor and mimics. The viabilities of treated cells were analyzed using MTT assay. Cell apoptosis was evaluated by TUNEL assay. Apoptosis-related protein expressions were tested by Western blot. Dual-luciferase assay was applied to assess the target gene of miRNA. RESULTS: The expression level of miR-185-5p in A549 cell line was significantly higher than that in A549/DDP cell line (p < 0.05). Transfection of miR-185-5p mimics increased the sensitivity of A549 cells to cisplatin and the expression of an apoptosis-related factor, and restrained cell proliferation. MiR-185-5p inhibitor promoted cisplatin resistance and cell growth in A549 cells, and declined apoptosis-related factor levels. ABCC1 was verified as the target gene of miR-185-5p. MiR-185-5p exhibited negative correlation with ABCC1 in A549/DDP cells. CONCLUSIONS: The results of the present study demonstrated that inhibition of miR-185-5p was involved in chemo-resistance of NSCLC cells to cisplatin via down-regulating ABCC1.

Laparoendoscopic techniques for occult gastrointestinal bleeding.

Up to 5% of gastrointestinal bleeds occur between the ligament of Treitz and the ileocecal valve. These patients present with occult bleeding and pose diagnostic and therapeutic challenges. Currently, an array of technology exists for diagnostic purposes, including upper and lower endoscopies, capsule endoscopy, nuclear scans, angiography, and intraoperative endoscopy. All of these modalities have advantages and disadvantages. However, the diagnostic gold standard for occult gastrointestinal bleeding does not exist. We present a case of an 18-year-old male with occult gastrointestinal bleeding to illustrate the variety of available modalities. Initially, the patient underwent upper, lower, and push endoscopies. Subsequently, he had a nuclear bleeding scan, video capsule endoscopy, and an angiogram. Ultimately, the patient had a diagnostic laparoscopy with mobilization of the terminal ileum and right colon. The bowel was exteriorized and an intraoperative endoscopy was performed through a small bowel enterotomy. Multiple arteriovenous malformations (AVMs) were ascertained and resected. This case is presented in detail and the technique of intraoperative endscopy is reviewed. The diagnostic literature regarding AVMs is also reviewed.

Timing of recanalization after intravenous thrombolysis and functional outcomes after acute ischemic stroke.

BACKGROUND: Recanalization of occluded intracranial arteries remains the aim of intravenous (IV) tissue plasminogen activator (tPA) therapy in acute ischemic stroke (AIS). OBJECTIVE: To examine the timing and impact of recanalization on functional outcomes in AIS. DESIGN: A longitudinal cohort of consecutive IV tPA­treated patients with AIS from January 2007 through December 2010. Data were collected for demography, risk factors, stroke subtypes, blood pressure, and National Institutes of Health Stroke Scale scores. Early recanalization (ER) was identified by transcranial Doppler monitoring during the first 2 hours of treatment. Recanalization was reevaluated at 24 hours by computed tomographic angiography (CTA). Patients with ER and patent index artery at 24 hours on CTA were labeled as having persistent recanalization (PR). Recanalization at 24 hours on CTA regardless of transcranial Doppler status was labeled as CTR. Favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 3 months. SETTING: University hospital stroke center. PATIENTS: A total of 240 patients with AIS who underwent IV tPA treatment. RESULTS: Of 2238 patients with AIS, 240 (11%) received IV tPA. The median age was 65 years (range, 19-92 years) and 44% of the study group was male. The median National Institutes of Health Stroke Scale score was 17 (range, 3-35) and the median onset-to-treatment time was 149 minutes (range, 46-270 minutes). Of the 240 patients, 122 (50.8%) achieved favorable outcomes at 3 months. Data for ER, PR, and CTR were analyzed for 160 patients. Early recanalization was seen in 82 patients (51.3%); 67 cases (81.7%) had PR and 84 cases (52.5%) had CTR. National Institutes of Health Stroke Scale score at onset (odds ratio per 1-point increase, 0.938; 95% CI, 0.888-0.991), ER (odds ratio, 3.048; 95% CI, 1.537-6.046), PR (odds ratio, 5.449; 95% CI, 2.382-12.464), and CTR (odds ratio, 4.329; 95% CI, 2.131-8.794) were independent predictors of favorable outcomes. CONCLUSIONS: Intravenous tPA­induced arterial recanalization within the first 24 hours in AIS is a strong predictor of favorable outcomes at 3 months.

An ORS-ICP-MS method for monitoring trace levels of cobalt and chromium in whole blood samples from hip arthroplasty patients with metal-on-metal prostheses.

OBJECTIVE: To develop a rapid and reliable method, using an octopole reaction system (ORS) ICP-MS, capable of monitoring trace levels of Co and Cr in whole blood samples from hip arthroplasty patients with metal-on-metal prostheses. DESIGN AND METHOD: Whole blood is diluted 10-fold with an alkaline diluent and analyzed using an Agilent 7500 CE ORS-ICP-MS. RESULTS: Limit of quantification of 0.03 µg/L Co and 0.20 µg/L Cr in patient samples. <6% covariance obtained for quality control materials analyzed over 10 runs. CONCLUSION: This method is capable of monitoring trace levels of Co and Cr in diluted whole blood samples with a vial to vial run time of approximately 2 min. Results are comparable to those obtained using high resolution (HR) ICP-MS with sample digestion.

Usefulness of CT angiography for therapeutic decision making in thrombolyzing intubated patients with suspected basilar artery thrombosis.

BACKGROUND AND AIMS: Acute ischemic stroke (AIS) due to basilar artery thrombosis (BAT) causes high mortality and severe disability. Early neurological assessment and timely thrombolysis might improve outcome. BAT is difficult to diagnose due to wide spectrum of presentation and decreased conscious level. Emergency physicians often intubate BAT patients with airway compromise before arrival of stroke neurologist. We evaluated role of computerized tomography (CT) angiography (CTA) of brain and cervical arteries in early diagnosis of acute BAT in intubated patients and facilitating decision for thrombolysis. METHODS: Consecutive AIS patients presenting between 2007 and 2009 within 6 hours of symptom onset, with sudden deterioration in conscious level and intubation before assessment by neurologist, were included. All patients underwent brain CT and CTA. Outcomes were assessed at 3 months. RESULTS: Thrombolytic therapy, mainly intravenous tissue plasminogen activator (IV-TPA), was administered to 161 (8.4%) of 1,917 AIS patients during the study period. Acute BAT contributed 10.9% of our cohort. CTA was performed in 152 (94.4%) patients and the rest were excluded due to their impaired renal functions. Five patients (3 males, mean age 72 years) presenting with acute obtundation and airway compromise were intubated, sedated, and paralyzed before assessment by neurologist. CTA showed BAT in all. IV-TPA was initiated at 213 ± 59 minutes in 4 patients while 1 received intraarterial thrombolysis at 13 hours. There was no intracranial hemorrhage. Mean length of hospital stay was 11.8 days. Despite severe stroke at presentation, good functional recovery at 3 months (modified Rankin scale [mRS] 1) occurred in 2 patients; mRS 4 in 1, and 2 died. CONCLUSION: In patients with BAT, intubated before assessment by neurologist, CTA might help in confirming the diagnosis and facilitating therapeutic decision making for initiating thrombolysis.

Role of investigating thrombophilic disorders in young stroke.

Our knowledge about various inherited and acquired causes of thrombophilic disorders has increased significantly during the past decade. Technology for various diagnostic tests for these rare disorders has matched the rapid advances in our understanding about the thrombophilic disorders. Inherited thrombophilic disorders predispose young patients for various venous or arterial thrombotic and thromboembolic episodes. Our understanding has also improved about various gene-gene and gene-environment interactions and their impact on the resultant heterogenous clinical manifestations. We describe various thrombophilic disorders, their diagnostic tests, pathogenic potential in isolation or with other concurrent inherited/acquired defects and possible therapeutic and prophylactic strategies. Better understanding, optimal diagnostic and screening protocols are expected to improve the diagnostic yield and help to reduce morbidity, disability, and mortality in relatively younger patients harbouring these inherited and acquired thrombophilic disorders.