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IntroductionRevisional bariatric surgery is being increasingly performed and is associated with higher operative risks. Optimal techniques to minimize complications remain controversial. Here, we report a retrospective review of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) Participant User Files (PUF) database, comparing outcomes between revision RBS and LBS.MethodsThe 2015 and 2016 MBSAQIP PUF database was retrospectively reviewed. Revision cases were identified using the Revision/Conversion Flag. Selected cases were further stratified by surgical approach. Subgroup analysis of sleeve gastrectomy and gastric bypass cases was performed. Case–controlled matching (1:1) was performed of the RBS and LBS cohorts, including gastric bypass and sleeve gastrectomy cohorts separately. Cases and controls were match by demographics, ASA classification, and preoperative comorbidities.Results26,404 revision cases were identified (93.3% LBS, 6.7% RBS). 85.6% were female and 67% white. Mean age and BMI were 48 years and 40.9 kg/m2. 1144 matched RBS and LBS cases were identified. RBS was associated with longer operative duration (p < 0.0001), LOS (p = 0.0002) and a higher rate of ICU admissions (1.3% vs 0.5%, p = 0.05). Aggregate bleeding and leak rates were higher in the RBS cohort. In both gastric bypass and sleeve gastrectomy cohorts, the robotic-assisted surgery remain associated with longer operative duration (p < 0.0001). In gastric bypass, rates of aggregate leak and bleeding were higher with robotic surgery, while transfusion was higher with laparoscopy. For sleeve gastrectomy cases, reoperation, readmission, intervention, sepsis, organ space SSI, and transfusion were higher with robotic surgery.ConclusionIn this matched cohort analysis of revision bariatric surgery, both approaches were overall safe. RBS was associated with longer operative duration and higher rates of some complications. Complications were higher in the robotic sleeve cohort. Robotic is likely less cost-effective with no clear patient safety benefit, particularly for sleeve gastrectomy cases.

Previously we showed that YAP/TAZ promote not only proliferation but also differentiation of immature Schwann cells (SCs), thereby forming and maintaining the myelin sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required for mature SCs to restore peripheral myelination, but not to proliferate, after nerve injury. We find that YAP/TAZ dramatically disappear from SCs of adult mice concurrent with axon degeneration after nerve injury. They reappear in SCs only if axons regenerate. YAP/TAZ ablation does not impair SC proliferation or transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We also show that both YAP and TAZ are redundantly required for optimal remyelination. These findings suggest that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ are essential for functional regeneration of peripheral nerve.

CRISPR-associated protein 9 (Cas9)-mediated genome editing provides a promising cure for HIV-1/AIDS; however, gene delivery efficiency in vivo remains an obstacle to overcome. Here, we demonstrate the feasibility and efficiency of excising the HIV-1 provirus in three different animal models using an all-in-one adeno-associated virus (AAV) vector to deliver multiplex single-guide RNAs (sgRNAs) plus Staphylococcus aureus Cas9 (saCas9). The quadruplex sgRNAs/saCas9 vector outperformed the duplex vector in excising the integrated HIV-1 genome in cultured neural stem/progenitor cells from HIV-1 Tg26 transgenic mice. Intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 excised HIV-1 proviral DNA and significantly reduced viral RNA expression in several organs/tissues of Tg26 mice. In EcoHIV acutely infected mice, intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 reduced systemic EcoHIV infection, as determined by live bioluminescence imaging. Additionally, this quadruplex vector induced efficient proviral excision, as determined by PCR genotyping in the liver, lungs, brain, and spleen. Finally, in humanized bone marrow/liver/thymus (BLT) mice with chronic HIV-1 infection, successful proviral excision was detected by PCR genotyping in the spleen, lungs, heart, colon, and brain after a single intravenous injection of quadruplex sgRNAs/saCas9 AAV-DJ/8. In conclusion, in vivo excision of HIV-1 proviral DNA by sgRNAs/saCas9 in solid tissues/organs can be achieved via AAV delivery, a significant step toward human clinical trials. [Display omitted] Yin et al. use multiplex CRISPR/Cas9 genome editing technology to excise the HIV-1 provirus in a precise manner in three different HIV-1 animal models via in vivo AAV gene delivery. The feasibility of HIV excision in infected cells in vivo paves the way toward human clinical trials to cure HIV-1 infection.

ObjectivePatients eligible for lung cancer screening are at risk for structural lung abnormalities, especially emphysema. Our aim was to assess the association between emphysema as determined by radiologist and quantitative CT (QCT) analysis, and the presence of spirometric abnormalities in an urban largely minority population undergoing lung cancer screening.DesignRetrospective cohort study.SettingCentralised lung cancer screening programme in an urban academic medical centre in Philadelphia, Pennsylvania, USA.Participants2111 individuals who underwent low-dose CT (LDCT) from October 2021 to October 2022 had CT scans interpreted by radiologists for the presence of emphysema, 629 of whom underwent spirometry. 181 patients underwent AI-assisted QCT analysis for emphysema at −950 and −910 HU, all of whom underwent spirometry.Primary and secondary outcome measuresDiagnostic tests for presence of emphysema as defined by radiologist and by AI-assisted QCT analysis for emphysema and the association with spirometric obstruction.ResultsA total of 2111 individuals underwent LDCT from October 2021 to October 2022. 323 (51.4%) individuals with radiology-determined emphysema had airflow obstruction. 108 (17.2%) individuals without emphysema had no airflow obstruction. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of radiology detected emphysema for airflow obstruction are 81.3%, 53.4%, 72.2%, 59.34%, respectively. In the Temple Healthy Chest Initiative (THCI) QCT subcohort of 181 individuals who underwent spirometry and low-attenuation area (%LAA)-910 HU, 91 (50%) individuals had %LAA-910 HU≥6% and airflow obstruction. 33 (18%) individuals with %LAA-910<6% had no airflow obstruction. Sensitivity, specificity, PPV and NPV for the presence of airflow obstruction based on %LAA–910 HU≥6% were 63%, 49%, 73% and 59%, respectively.ConclusionsData from the THCI demonstrates high rates of emphysema as detected by radiologic qualitative interpretation and quantitative analysis. Using a cut-off of ≥6% for LAA at −910 HU, there is a high sensitivity and PPV for associated spirometric obstruction and thus should drive providers to obtain prebronchodilator spirometry to detect chronic obstructive pulmonary disease at an earlier stage.

IntroductionRobotic-assisted bariatric surgery is increasingly performed. There remains controversy about the overall benefit of robotic-assisted (RBS) compared to conventional laparoscopic (LBS) bariatric surgery. In this study, we used a large national risk-stratified bariatric clinical database to compare outcomes between robotic and laparoscopic gastric bypass (RNYGB) and sleeve gastrectomy (SG).MethodsA retrospective analysis of the 2015 and 2016 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) Participant Use Data File (PUF) was performed. Primary robotic and laparoscopic RYNGB and SG were analyzed. Descriptive analysis was performed of the unmatched cohorts, followed by 1:3 case-controlled matching. Cases and controls were matched by patient demographics and pre-operative comorbidities, and peri-operative outcomes compared.Results77,991 Roux-en-Y gastric bypass (RnYGB) (7.5% robotic-assisted) and 189,503 SG (6.8% robotic-assisted) cases were identified. Operative length was significantly higher in both the robotic-assisted RnYGB and SG cohorts (p < 0.0001). Outcomes were similar between the robotic-assisted and laparoscopic RnYGB cohorts, except a lower mortality rate (p = 0.05), transfusion requirement (p = 0.005), aggregate bleeding (p = 0.04), and surgical site infections (SSI) (p = 0.006) in the robotic-assisted cohort. Outcomes were also similar between robotic-assisted and laparoscopic SG, except for a longer length of stay (p < 0.0001) and higher rates of conversion (p < 0.0001), 30-day intervention (p = 0.01), operative drain present (p < 0.0001), sepsis (p = 0.01), and organ space SSI (p = 0.0002) in the robotic cohort. Bleeding was lower in the robotic SG cohort and mortality was similar.ConclusionBoth robotic-assisted and laparoscopic RnYGB and SG are overall very safe. Robotic-assisted gastric bypass is associated with a lower mortality and morbidity; however, a clear benefit for robotic-assisted SG compared to laparoscopic SG was not seen. Given the longer operative and hospital duration, robotic SG is not cost-effective.

We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in nonliver tissues and whether TMAO promotes inflammation via trained immunity (TI). We found that endoplasmic reticulum (ER) stress genes were coupregulated with MitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas; TMAO transdifferentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1. TMAO upregulated 3 mitochondrial genes, downregulated inflammation inhibitor DARS2, and induced mitoROS, and mitoTEMPO inhibited TMAO-induced ICAM-1. β-Glucan priming, followed by TMAO restimulation, upregulated TNF-α by inducing metabolic reprogramming, and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided potentially novel insights regarding TMAO roles in inducing EC activation and innate immune transdifferentiation and inducing metabolic reprogramming and TI for enhanced vascular inflammation, and they have provided new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammation, transplantation, aging, and cancer.

IntroductionObesity is a risk factor for poor patient outcomes after organ transplantation (TXP). While metabolic and bariatric surgery (MBS) is safe and effective in treating severe obesity, the role of MBS in transplant patients continues to evolve.MethodsA retrospective analysis was performed of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) patients in the 2017 Metabolic and Bariatric Surgery Accreditation Quality and Improvement Project (MBSAQIP) database. Propensity and case-control matching, and multivariable logistic regression were performed for 30-day post-operative outcomes.ResultsA total of 336 transplant patients were compared with 157,413 patients without transplant. Propensity and case-control matching reveal no significant differences in mortality (p > 0.2). However, case-control matching revealed longer operative time (104 min versus 76 min, p < 0.001), increased length of stay (2 days versus 1 day, p < 0.05), perioperative transfusions (2% versus 0.22%, p = 0.009), and leak rates (2.2% versus 0.55%, p = 0.02) in the transplant cohort. On multivariable regression analysis, prior transplantation was associated with higher rates of overall (OR 1.6, p = 0.007) and bariatric-related morbidity (OR 1.78, p = 0.004), leak (OR 3.47, p = 0.0027), and surgical site infection (OR 3.32, p = 0.004). Prior transplantation did not predict overall (p = 0.55) nor bariatric-related mortality (p = 0.99).ConclusionMBS in prior solid organ transplantation patients is overall safe, but is associated with increased operative time and length of stay, as well as higher rates of some post-operative morbidity.

To determine the roles of endoplasmic reticulum (ER) stress and trained immunity, we performed transcriptome analyses on the thoracic aorta (TA) and abdominal aorta (AA) from the angiotensin II (Ang II)-HFD-ApoE-KO aneurysm model and made significant findings: 1) Ang II bypassed HFD-induced metabolic reprogramming and induced stronger inflammation in AA than in TA; 2) Ang II and HFD upregulated 890 genes in AA versus TA and induced cytokine signaling; 3) Ang II AA and TA upregulated 73 and 68 cytokines, scRNA-Seq identified markers of macrophages and immune cells, cell death regulators, respectively; transdifferentiation markers of neuron, glial, and squamous epithelial cells were upregulated by Ang II-AA and TA; and pyroptosis signaling with IL-1β and caspase-4 were more upregulated in Ang II-AA than in TA; 4) Six upregulated transcriptomes in patients with AAA, Ang II AA, Ang II TA, additional aneurysm models, PPE-AAA and BAPN-Ang II-AAA, were partially overlapped with 10 lists of new ER stress gene sets including 3 interaction protein lists of ER stress regulators ATF6, PERK, and IRE1, HPA ER localization genes, KEGG signal genes, XBP1 transcription targets, ATF4 (PERK) targets, ATF6 targets, thapsigargin ER stress genes, tunicamycin-ER stress genes, respectively; 5) Ang II-AA and TA upregulated ROS regulators, MitoCarta genes, trained immunity genes, and glycolysis genes; and 6) Gene KO transcriptomes indicated that ATF6 and PERK played more significant roles than IRE1 in promoting AAA and trained immunity whereas antioxidant NRF2 inhibited them. Our unprecedented ER-focused transcriptomic analyses have provided novel insights on the roles of ER as an immune organelle in sensing various DAMPs and initiating ER stress that triggers Ang II-accelerated trained immunity and differs susceptibilities of thoracic and abdominal aortas to diseases.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in aortic diseases. Innate immunity is the main driving force for cardiovascular diseases. To determine the roles of innate immunity in VSMC and aortic pathologies, we performed transcriptome analyses on aortas from ApoE angiotensin II (Ang II)-induced aortic aneurysm (AAA) time course, and ApoE atherosclerosis time course, as well as VSMCs stimulated with danger-associated molecular patterns (DAMPs). We made significant findings: 95% and 45% of the upregulated innate immune pathways (UIIPs, based on data of 1226 innate immune genes) in ApoE Ang II-induced AAA at 7 days were different from that of 14 and 28 days, respectively; and AAA showed twin peaks of UIIPs with a major peak at 7 days and a minor peak at 28 days; all the UIIPs in ApoE atherosclerosis at 6 weeks were different from that of 32 and 78 weeks (two waves); analyses of additional 12 lists of innate immune-related genes with 1325 cytokine and chemokine genes, 2022 plasma membrane protein genes, 373 clusters of differentiation (CD) marker genes, 280 nuclear membrane protein genes, 1425 nucleoli protein genes, 6750 nucleoplasm protein genes, 1496 transcription factors (TFs) including 15 pioneer TFs, 164 histone modification enzymes, 102 oxidative cell death genes, 68 necrotic cell death genes, and 47 efferocytosis genes confirmed two-wave inflammation in atherosclerosis and twin-peak inflammation in AAA; DAMPs-stimulated VSMCs were innate immune cells as judged by the upregulation of innate immune genes and genes from 12 additional lists; DAMPs-stimulated VSMCs increased trans-differentiation potential by upregulating not only some of 82 markers of 7 VSMC-plastic cell types, including fibroblast, osteogenic, myofibroblast, macrophage, adipocyte, foam cell, and mesenchymal cell, but also 18 new cell types (out of 79 human cell types with 8065 cell markers); analysis of gene deficient transcriptomes indicated that the antioxidant transcription factor NRF2 suppresses, however, the other five inflammatory transcription factors and master regulators, including AHR, NF-KB, NOX (ROS enzyme), PERK, and SET7 promote the upregulation of twelve lists of innate immune genes in atherosclerosis, AAA, and DAMP-stimulated VSMCs; and both SET7 and trained tolerance-promoting metabolite itaconate contributed to twin-peak upregulation of cytokines in AAA. Our findings have provided novel insights on the roles of innate immune responses and nuclear stresses in the development of AAA, atherosclerosis, and VSMC immunology and provided novel therapeutic targets for treating those significant cardiovascular and cerebrovascular diseases.

PurposeAccurate estimation of esophageal hiatus surface area (HSA) prior to surgical repair of hiatal hernia is difficult. The ability to do so may assist with following progression of hiatal hernias, choosing the optimal surgical approach and post-surgical evaluation. We developed a method for measurement of HSA using multi-planar reconstruction (MPR) of multi-detector computed tomography (MDCT) scans and sought to validate our method using intra-operative HSA measurements.MethodsPatients with thoracic or abdominal CT scans who were scheduled to undergo hiatal hernia repair were identified. A radiologist performed MPR of each MDCT scan to obtain the measured HSA (mHSA). Estimated HSA (eHSA) was obtained using intra-operative measurements of crura length and distance between crural edges. The association between eHSA and the corresponding mHSA was assessed using Pearson correlation. The intra-class correlation coefficient was calculated to assess both intra-observer and inter-observer agreement for the MDCT–MPR technique.ResultsOf 30 subjects included, 16 (53.3%) were female and the median age was 68.5 years. All patients underwent robotic-assisted laparoscopic hiatal hernia repair. The median HSA was 8.1 cm2 based on intra-operative measurements and 9.9 cm2 based on CT measurements. The correlation coefficient for eHSA and corresponding mHSA was 0.83 (p < 0.001). The intra-class correlation coefficient was 0.97 (p < 0.001) for intra-observer agreement and 0.97 (p < 0.001) for inter-observer agreement.ConclusionWe developed a MDCT–MPR technique that measures HSA in vivo. This technique is reproducible and can be used for pre-operative planning and post-operative follow-up of patients with symptomatic hiatal hernia.