Kinetic networks identify TWIST2 as a key regulatory node in adipogenesis.

Adipocytes contribute to metabolic disorders such as obesity, diabetes, and atherosclerosis. Prior characterizations of the transcriptional network driving adipogenesis have overlooked transiently acting transcription factors (TFs), genes, and regulatory elements that are essential for proper differentiation. Moreover, traditional gene regulatory networks provide neither mechanistic details about individual regulatory element-gene relationships nor temporal information needed to define a regulatory hierarchy that prioritizes key regulatory factors. To address these shortcomings, we integrate kinetic chromatin accessibility (ATAC-seq) and nascent transcription (PRO-seq) data to generate temporally resolved networks that describe TF binding events and resultant effects on target gene expression. Our data indicate which TF families cooperate with and antagonize each other to regulate adipogenesis. Compartment modeling of RNA polymerase density quantifies how individual TFs mechanistically contribute to distinct steps in transcription. The glucocorticoid receptor activates transcription by inducing RNA polymerase pause release, whereas SP and AP-1 factors affect RNA polymerase initiation. We identify Twist2 as a previously unappreciated effector of adipocyte differentiation. We find that TWIST2 acts as a negative regulator of 3T3-L1 and primary preadipocyte differentiation. We confirm that Twist2 knockout mice have compromised lipid storage within subcutaneous and brown adipose tissue. Previous phenotyping of Twist2 knockout mice and Setleis syndrome Twist2 -/- patients noted deficiencies in subcutaneous adipose tissue. This network inference framework is a powerful and general approach for interpreting complex biological phenomena and can be applied to a wide range of cellular processes.

Transcription inhibition suppresses nuclear blebbing and rupture independently of nuclear rigidity.

Chromatin plays an essential role in the nuclear mechanical response and determining nuclear shape, which maintain nuclear compartmentalization and function. However, major genomic functions, such as transcription activity, might also impact cell nuclear shape via blebbing and rupture through their effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with several RNA polymerase II inhibitors in wild-type cells and perturbed cells that presented increased nuclear blebbing. Transcription inhibition suppressed nuclear blebbing for several cell types, nuclear perturbations and transcription inhibitors. Furthermore, transcription inhibition suppressed nuclear bleb formation, bleb stabilization and bleb-based nuclear ruptures. Interestingly, transcription inhibition did not alter the histone H3 lysine 9 (H3K9) modification state, nuclear rigidity, and actin compression and contraction, which typically control nuclear blebbing. Polymer simulations suggested that RNA polymerase II motor activity within chromatin could drive chromatin motions that deform the nuclear periphery. Our data provide evidence that transcription inhibition suppresses nuclear blebbing and rupture, in a manner separate and distinct from chromatin rigidity.

The ability of a 3-gene host signature in blood to distinguish tuberculous meningitis from other brain infections.

BACKGROUND: Tuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections. METHODS: The expression of 3 genes (Dual specificity phosphatase 3- DUSP3, Guanylate-binding protein- GBP5, Krupple-like factor 2- KLF2) was analysed by RNA sequencing of archived whole blood from four cohorts of Vietnamese adults: 281 with TBM; 279 with pulmonary tuberculosis; 50 with other brain infections; and 30 healthy controls. 'TB scores' (combined 3-gene expression) were calculated following published methodology and discriminatory performance compared using area under a receiver operator characteristic curve (AUC). RESULTS: GBP5 was upregulated in TBM compared to other brain infections (p < 0.001), with no difference in DUSP3 and KLF2 expression. The diagnostic performance of GBP5 alone (AUC 0.74 (95% CI 0.67-0.81)) was slightly better than the 3-gene TB score (AUC 0.66, 95% CI 0.58-0.73) in TBM. Both GBP5 expression and TB score were higher in HIV-positive participants (P < 0.001), with good diagnostic performance of GBP5 alone (AUC 0.86, 95% CI 0.80-0.93). CONCLUSION: The 3-gene host signature in whole blood has the ability to discriminate TBM from other brain infections, including in HIV-positive individuals. Validation in large prospective diagnostic study is now required.

Adaptive response of Pseudomonas aeruginosa under serial ciprofloxacin exposure.

Understanding the evolution of antibiotic resistance is important for combating drug-resistant bacteria. In this work, we investigated the adaptive response of Pseudomonas aeruginosa to ciprofloxacin. Ciprofloxacin-susceptible P. aeruginosa ATCC 9027, CIP-E1 (P. aeruginosa ATCC 9027 exposed to ciprofloxacin for 14 days) and CIP-E2 (CIP-E1 cultured in antibiotic-free broth for 10 days) were compared. Phenotypic responses including cell morphology, antibiotic susceptibility, and production of pyoverdine, pyocyanin and rhamnolipid were assessed. Proteomic responses were evaluated using comparative iTRAQ labelling LC-MS/MS to identify differentially expressed proteins (DEPs). Expression of associated genes coding for notable DEPs and their related regulatory genes were checked using quantitative reverse transcriptase PCR. CIP-E1 displayed a heterogeneous morphology, featuring both filamentous cells and cells with reduced length and width. By contrast, although filaments were not present, CIP-E2 still exhibited size reduction. Considering the MIC values, ciprofloxacin-exposed strains developed resistance to fluoroquinolone antibiotics but maintained susceptibility to other antibiotic classes, except for carbapenems. Pyoverdine and pyocyanin production showed insignificant decreases, whereas there was a significant decrease in rhamnolipid production. A total of 1039 proteins were identified, of which approximately 25 % were DEPs. In general, there were more downregulated proteins than upregulated proteins. Noted changes included decreased OprD and PilP, and increased MexEF-OprN, MvaT and Vfr, as well as proteins of ribosome machinery and metabolism clusters. Gene expression analysis confirmed the proteomic data and indicated the downregulation of rpoB and rpoS. In summary, the response to CIP involved approximately a quarter of the proteome, primarily associated with ribosome machinery and metabolic processes. Potential targets for bacterial interference encompassed outer membrane proteins and global regulators, such as MvaT.

Contemporary trends of leadless pacemaker implantation in the United States.

INTRODUCTION: Leadless pacemakers (LPM) have established themselves as the important therapeutic modality in management of selected patients with symptomatic bradycardia. To determine real-world utilization and in-hospital outcomes of LPM implantation since its approval by the Food and Drug Administration in 2016. METHODS: For this retrospective cohort study, data were extracted from the National Inpatient Sample database from the years 2016-2020. The outcomes analyzed in our study included implantation trends of LPM over study years, mortality, major complications (defined as pericardial effusion requiring intervention, any vascular complication, or acute kidney injury), length of stay, and cost of hospitalization. Implantation trends of LPM were assessed using linear regression. Using years 2016-2017 as a reference, adjusted outcomes of mortality, major complications, prolonged length of stay (defined as >6 days), and increased hospitalization cost (defined as median cost >34 098$) were analyzed for subsequent years using a multivariable logistic regression model. RESULTS: There was a gradual increased trend of LPM implantation over our study years (3230 devices in years 2016-2017 to 11 815 devices in year 2020, p for trend <.01). The adjusted mortality improved significantly after LPM implantation in subsequent years compared to the reference years 2016-2017 (aOR for the year 2018: 0.61, 95% CI: 0.51-0.73; aOR for the year 2019: 0.49, 95% CI: 0.41-0.59; and aOR for the year 2020: 0.52, 95% CI: 0.44-0.62). No differences in adjusted rates of major complications were demonstrated over the subsequent years. The adjusted cost of hospitalization was higher for the years 2019 (aOR: 1.33, 95% CI: 1.22-1.46) and 2020 (aOR: 1.69, 95% CI: 1.55-1.84). CONCLUSION: The contemporary US practice has shown significantly increased implantation rates of LPM since its approval with reduced rates of inpatient mortality.

Development of a comorbidity index for patients undergoing abdominal aortic aneurysm repair.

BACKGROUND: Endovascular aneurysm repair (EVAR) and open surgical repair (OSR) are two modalities to treat patients with abdominal aortic aneurysm (AAA). Alternative to individual comorbidity adjustment, a summary comorbidity index is a weighted composite score of all comorbidities that can be used as standard metric to control for comorbidity burden in clinical studies. This study aimed to develop summary comorbidity indices for patients who underwent AAA repair. METHODS: Patients who went under EVAR or OSR were identified in National Inpatient Sample (NIS) between the last quarter of 2015 to 2020. In each group, patients were randomly sampled into experimental (2/3) and validation (1/3) groups. The weights of Elixhauser comorbidities were determined from a multivariable logistic regression and single comorbidity indices were developed for EVAR and OAR groups, respectively. RESULTS: There were 34,668 patients underwent EVAR (2.19% mortality) and 4792 underwent OSR (10.98% mortality). Both comorbidity indices had moderate discriminative power (EVAR c-statistic, 0.641; 95% confidence interval [CI], 0.616-0.665; OSR c-statistic, 0.600; 95% CI, 0.563-0.630) and good calibration (EVAR Brier score, 0.021; OSR Brier score, 0.096). The indices had significantly better discriminative power (DeLong P <.001) than the Elixhauser Comorbidity Index (ECI) (EVAR c-statistic, 0.572; 95% CI, 0.546-0.597; OSR c-statistic, 0.502; 95% CI, 0.472-0.533). For internal validation, both indices had similar performance compared with individual comorbidity adjustment (EVAR DeLong P = .650; OSR DeLong P = .431). These indices demonstrated good external validation, exhibiting comparable performance to their respective validation groups (EVAR DeLong P = .891; OSR DeLong P = .757). CONCLUSIONS: ECI, the comorbidity index formulated for the general population, exhibited suboptimal performance in patients who underwent AAA repair. In response, we developed summary comorbidity indices for both EVAR and OSR for AAA repair, which were internally and externally validated. The EVAR and OSR comorbidity indices outperformed the ECI in discriminating in-hospital mortality rates. They can standardize comorbidity measurement for clinical studies in AAA repair, especially for studies with small samples such as single-institute data sources to facilitate replication and comparison of results across studies.

Comparative assessment of racial disparity in 30-day outcomes for Asian Americans undergoing carotid endarterectomy.

OBJECTIVE: Carotid endarterectomy (CEA) is an effective treatment for carotid stenosis. All previous studies on racial disparity of CEA outcomes omitted Asian Americans. This study aimed to address this gap by investigating racial disparities in 30-day outcomes following CEA among Asian Americans. METHODS: Asian American and Caucasian patients who underwent CEA were identified in the American College of Surgeons National Surgical Quality Improvement Program targeted database from 2011 to 2021. Patients with age less than 18 years old were excluded. Patients with symptomatic and asymptomatic carotid stenosis were examined separately. A 1:5 propensity-score matching was used to address preoperative differences. Thirty perioperative outcomes were assessed. RESULTS: There were 380 Asian Americans (2.27%) and 13,250 Caucasians (79.18%) with symptomatic carotid stenosis who underwent CEA. Also, 289 Asian Americans (1.40%) and 18,257 Caucasians (88.14%) with asymptomatic carotid stenosis had CEA. Asian Americans undergoing CEA presented with higher comorbid burdens and more severe symptomology. Also, asymptomatic Asian Americans were more likely to undergo surgeries for mild stenosis (<50%), which is not in line with practice guidelines. After 1:5 propensity-matching, all symptomatic Asian Americans were matched to 1550 Caucasian patients, and all asymptomatic Asian Americans were matched to 1445 Caucasians; preoperative differences were addressed. Asian Americans exhibited low overall 30-day mortality (symptomatic, 1.61%; asymptomatic, 0.35%) and stroke (symptomatic, 2.26%; asymptomatic, 0.69%). All perioperative outcomes were comparable to Caucasians, with the exception that Asian Americans experienced longer operation times. CONCLUSIONS: Evidence suggested that Asian Americans with asymptomatic stenosis were underrepresented in CEA. After propensity-score matching, Asian Americans demonstrated comparable 30-day outcomes to Caucasians. These suggest that, when afforded equal access to quality health care, CEA serves as an effective treatment for carotid stenosis among Asian Americans. Therefore, efforts may be aimed at addressing health care access, potentially in the screening for asymptomatic carotid stenosis in Asian Americans. This would ensure they have equitable benefits from CEA. Nevertheless, the exact preoperative differences and long-term CEA outcomes in Asian Americans should warrant further examination in future studies.

Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i.

BACKGROUND: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines as the first-line (1 L) treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced/metastatic breast cancer (HR+/HER2- LABC/mBC). Although there are many treatment options, there is no clear standard of care for patients following 1 L CDK4/6i. Understanding the real-world effectiveness of subsequent therapies may help to identify an unmet need in this patient population. This systematic literature review qualitatively synthesized effectiveness and safety outcomes for treatments received in the real-world setting after 1 L CDK4/6i therapy in patients with HR+/ HER2- LABC/mBC. METHODS: MEDLINE®, Embase, and Cochrane were searched using the Ovid® platform for real-world evidence studies published between 2015 and 2022. Grey literature was searched to identify relevant conference abstracts published from 2019 to 2022. The review was conducted in accordance with PRISMA guidelines (PROSPERO registration: CRD42023383914). Data were qualitatively synthesized and weighted average median real-world progression-free survival (rwPFS) was calculated for NCCN/ESMO-recommended post-1 L CDK4/6i treatment regimens. RESULTS: Twenty records (9 full-text articles and 11 conference abstracts) encompassing 18 unique studies met the eligibility criteria and reported outcomes for second-line (2 L) treatments after 1 L CDK4/6i; no studies reported disaggregated outcomes in the third-line setting or beyond. Sixteen studies included NCCN/ESMO guideline-recommended treatments with the majority evaluating endocrine-based therapy; five studies on single-agent ET, six studies on mammalian target of rapamycin inhibitors (mTORi) ± ET, and three studies with a mix of ET and/or mTORi. Chemotherapy outcomes were reported in 11 studies. The most assessed outcome was median rwPFS; the weighted average median rwPFS was calculated as 3.9 months (3.3-6.0 months) for single-agent ET, 3.6 months (2.5-4.9 months) for mTORi ± ET, 3.7 months for a mix of ET and/or mTORi (3.0-4.0 months), and 6.1 months (3.7-9.7 months) for chemotherapy. Very few studies reported other effectiveness outcomes and only two studies reported safety outcomes. Most studies had heterogeneity in patient- and disease-related characteristics. CONCLUSIONS: The real-world effectiveness of current 2 L treatments post-1 L CDK4/6i are suboptimal, highlighting an unmet need for this patient population.

The 5-Factor Modified Frailty Index is a Concise and Effective Predictor of 30-Day Adverse Outcomes in Carotid Endarterectomy.

INTRODUCTION: Frailty is a clinically identifiable condition characterized by heightened vulnerability. The 5-item Modified Frailty Index provides a concise calculation of frailty that has proven effective in predicting adverse perioperative outcomes across a variety of surgical disciplines. However, there is a paucity of research examining the validity of 11-item Modified Frailty Index (mFI-5) in carotid endarterectomy (CEA). This study aimed to investigate the association between mFI-5 and 30-day outcomes of CEA. METHODS: Patients underwent CEA were identified from American College of Surgeons National Surgical Quality Improvement Program targeted database from 2012 to 2021. Patients with age<18 were excluded. Patients were stratified into four cohorts based on their mFI-5 scores: 0, 1, 2, or 3+. Multivariable logistic regression was used to compare 30-day perioperative outcomes adjusting for preoperative variables with P value<0.1. RESULTS: Compared to controls (mFI-5 = 0), patients mFI-5 = 1 had higher risk of stroke (adjusted odds ratio [aOR] = 1.333, P = 0.02), unplanned operation (aOR = 1.38, P < 0.01), and length of stay (LOS) > 7 days (aOR = 0.814, P < 0.01). Patients with mFI-5 = 2 had higher stroke (aOR = 1.719, P < 0.01), major adverse cardiovascular events (MACE) (aOR = 1.315, P = 0.01), sepsis (aOR = 2.243, P = 0.01), discharge not to home (aOR = 1.200, P < 0.01), 30-day readmission (aOR = 1.405, P < 0.01). Compared with controls, patients with mFI-5≥3 had higher mortality (aOR = 1.997 P = 0.02), MACE (aOR = 1.445, P = 0.03), cardiac complications (aOR = 1.901, P < 0.01), pulmonary events (aOR = 2.196, P < 0.01), sepsis (aOR = 3.65, P < 0.01), restenosis (aOR = 2.606, P = 0.02), unplanned operation (aOR = 1.69, P < 0.01), LOS>7 days (aOR = 1.425, P < 0.01), discharge not to home (aOR = 2.127, P < 0.01), and 30-day readmission (aOR = 2.427, P < 0.01). CONCLUSIONS: The mFI-5 is associated with 30-day mortality and complications including stroke, MACE, cardiac complications, pulmonary complications, sepsis, and restenosis. Additionally, elevated mFI-5 scores correlate with an increased likelihood of unplanned operations, extended LOS, discharge to facilities other than home, and 30-day readmissions, all of which could negatively impact long-term prognosis. Therefore, mFI-5 can serve as a concise yet effective metric of frailty in patients undergoing CEA.

Adverse Events from Fluoroscopic versus Portable Placement of Peripherally Inserted Central Catheters and Central Venous Catheters in Pediatric Patients.

PURPOSE: To compare the outcomes of fluoroscopic versus portable placement of peripherally inserted central catheters (PICCs) and central venous catheters (CVCs) in pediatric patients. MATERIALS AND METHODS: This is a single-center, retrospective review of 346 upper-extremity PICC placements (286 fluoroscopic and 60 portable; mean age, 9.83 years [SD ± 5.58]; 49.1% female) and 138 tunneled femoral CVC placements (56 fluoroscopic and 82 portable; mean age, 0.23 years [SD ± 0.36]; 57.0% female). Portable placements used mobile plain-film radiography. All lines were placed by board-certified interventional radiologists. RESULTS: Fluoroscopic PICC placements had a lower procedure time (43.9 vs 57.9 minutes; P < .001), radiation dosage (342 vs 590 mGy·cm2; P < .001), incidence of technical failure (0% vs 3.3%; P = .029), and incidence of catheter malfunction (1.7% vs 12.1%; P < .001) compared with portable PICC placements. Fluoroscopic CVC placements had a lower procedure time (42.6 vs 54.8 minutes; P < .001) and radiation dosage (63.8 vs 405 mGy·cm2; P < .001) compared with portable CVC placements. No technical failures were found in either CVC groups and the difference was nonsignificant for catheter malfunction (0% vs 7.3%; P = .081). Fluoroscopic placements of PICCs and CVCs had a lower incidence rate of central line-associated bloodstream infection compared with portable placements (0.71 vs 2.22 cases per 1,000 line-days; P = .046). Overall, fluoroscopic placements of PICCs and CVCs had fewer adverse events compared with portable placements (3.2% vs 14.8%; P < .001). Portable procedure setting was the only significant factor associated with adverse events (odds ratio, 33.77; 95% CI, 4.56-757.01). CONCLUSIONS: Fluoroscopic placements of PICCs and CVCs are associated with lower procedure time, radiation dose, and risk of adverse events compared with portable placements in pediatric patients.

The 5-Factor Modified Frailty Index is a Succinct yet Effective Predictor of Adverse Outcomes in Patients Undergoing Open Surgery for Abdominal Aortic Aneurysm.

BACKGROUND: Frailty is an age-related, clinically recognizable state marked by increased susceptibility. The 5-item Modified Frailty Index (mFI-5) offers a concise assessment of frailty and has demonstrated its efficacy in various surgical fields. While the mFI-5 has been validated for endovascular aneurysm repair for abdominal aortic aneurysm (AAA), its applicability in open surgical repair (OSR) for AAA remains largely unexplored. This study sought to evaluate the utility of mFI-5 in predicting 30-day outcomes following OSR for AAA. METHODS: Patients underwent OSR for AAA were identified in American College of Surgeons National Surgical Quality Improvement Program-targeted database from 2012 to 2021. Patients were stratified into 3 cohorts: mFI-5 score of 0 (control), 1, and 2+. Multivariable logistic regression was used to compare 30-day perioperative outcomes between frail patients and controls adjusting preoperative variables with P value <0.1. RESULTS: Of the 5,249 patients who underwent OSR for AAA, 1,043 were controls, 2,938 had an mFI-5 score of 1 and 1,268 had an mFI-5 score of 2+. When compared to the control group, patients with an mFI-5 = 1 were more likely to have pulmonary events (adjusted odds ratio (aOR) = 1.452, P < 0.01), bleeding events (aOR = 1.33, P < 0.01), wound complications (aOR = 2.214, P < 0.01), ischemic colitis (aOR = 1.616, P = 0.01), and unplanned reoperation (aOR = 1.292, P = 0.04). Those with an mFI-5 = 2+ demonstrated higher risks of mortality (aOR = 1.709, P < 0.01), major adverse cardiovascular events (aOR = 1.347, P = 0.04), pulmonary events (aOR = 2.045, P < 0.01), renal dysfunction (aOR = 1.568, P < 0.01), sepsis (aOR = 1.587, P = 0.01), bleeding events (aOR = 1.429, P < 0.01), wound complications (aOR = 2.338, P < 0.01), ischemic colitis (aOR = 1.775, P = 0.01), unplanned reoperation (aOR = 1.445, P = 0.01), operation over 4 hours (aOR = 1.34, P < 0.01), length of stay over 7 days (aOR = 1.324, <0.01), discharge not to home (aOR = 1.547, P < 0.01), 30-day readmission (aOR = 1.657, P = 0.01). CONCLUSIONS: The mFI-5 emerges as a succinct yet effective indicator of frailty for patients undergoing OSR for AAA. Especially, an mFI-5 score of 2+ is linked with increased 30-day mortality and complications. As such, mFI-5 can be used as a valuable screening tool for frailty in patients undergoing OSR for AAA.

Locoregional Anesthesia Has Lower Risks of Cardiac Complications Than General Anesthesia After Prolonged Endovascular Repair of Abdominal Aortic Aneurysms.

OBJECTIVES: Although general anesthesia is the primary anesthesia in endovascular aneurysm repair (EVAR), some studies suggest locoregional anesthesia could be a feasible alternative for eligible patients. However, most evidence was from retrospective studies and was subjected to an inherent selection bias that general anesthesia is often chosen for more complex and prolonged cases. To mitigate this selection bias, this study aimed to compare 30-day outcomes of prolonged, nonemergent, intact, infrarenal EVAR in patients undergoing locoregional or general anesthesia. In addition, risk factors associated with prolonged operative time in EVAR were identified. DESIGN: Retrospective large-scale national registry study. SETTING: American College of Surgeons National Surgical Quality Improvement Program targeted database from 2012 to 2022. PARTICIPANTS: A total of 4,075 out of 16,438 patients (24.79%) had prolonged EVAR. Among patients with prolonged EVAR, 324 patients (7.95%) were under locoregional anesthesia. There were 3,751 patients (92.05%) under general anesthesia, and 955 of them were matched to the locoregional anesthesia cohort. INTERVENTIONS: Patients undergoing infrarenal EVAR were included. Exclusion criteria included age <18 years, emergency cases, ruptured abdominal aortic aneurysm, and acute intraoperative conversion to open. Only cases with prolonged operative times (>157 minutes) were selected. A 1:3 propensity-score matching was used to address demographics, baseline characteristics, aneurysm diameter, distant aneurysm extent, and concomitant procedures between patients under locoregional and general anesthesia. Thirty-day postoperative outcomes were assessed. Moreover, factors associated with prolonged EVAR were identified by multivariate logistic regression. MEASUREMENTS AND MAIN RESULTS: Except for general anesthesia contraindications, patients undergoing locoregional or general anesthesia exhibited largely similar preoperative characteristics. After propensity-score matching, patients under locoregional and general anesthesia had a lower risk of myocardial infarction (0.93% v 2.83%, p = 0.04), but comparable 30-day mortality (3.72% v 2.72%, p = 0.35) and other complications. Specific concomitant procedures, aneurysm anatomy, and comorbidities associated with prolonged EVAR were identified. CONCLUSIONS: Locoregional anesthesia can be a safe and effective alternative to general anesthesia, particularly in EVAR cases with anticipated complexity and prolonged operative times, as it offers the potential benefit of reduced cardiac complications. Risk factors associated with prolonged EVAR can aid in preoperative risk stratification and inform the decision-making process regarding anesthesia choice.

Prior abdominal surgery is not associated with 30-day mortality or morbidities after endovascular repair of complex abdominal aortic aneurysm.

BACKGROUND: Prior abdominal surgery (PAS) has the potential to affect outcomes of abdominal aortic aneurysm (AAA) repair. Recently, endovascular aneurysm repair (EVAR) has been expanded among patients with complex AAA, which involves visceral branches in the upper abdominal aortic. However, outcomes of EVAR for complex AAA in patients with PAS have not been examined. This study aimed to investigate the impact of PAS on 30-day outcomes in EVAR for complex AAA. METHODS: Patients who underwent EVAR for complex AAA were identified in ACS-NSQIP targeted database from 2012 to 2022. Complex AAA was defined as juxtarenal, suprarenal, or pararenal proximal extent, Type IV thoracoabdominal aneurysm, or aneurysms treated with Zenith Fenestrated endograft. Patients with age less than 18 years, ruptured AAA with or without hypotension, acute intraoperative conversion to open, and emergency presentation were excluded. Multivariable logistic regression was used to compare 30-day postoperative outcomes of patients with and without PAS. Demographics, baseline characteristics, aneurysm diameter, indication for surgery, proximal and distant aneurysm extent, anesthesia, and concomitant procedures were adjusted. RESULTS: There were 515 (28.34%) and 1302 (71.66%) patients with and without PAS, respectively, who underwent EVAR for complex AAA. Patients with and without PAS had comparable 30-day mortality (3.11% vs 3.00%, aOR = 0.766, 95 CI = 0.407-1.442, p = .41). Organ system complications including cardiac complications, stroke, pulmonary complications, and renal complications were comparable between patients with and without PAS. All other 30-day outcomes were similar between groups. However, patients with PAS had higher 30-day readmission rate (11.65% vs 7.14%, aOR = 1.634, 95 CI = 1.145-2.331, p = .01). CONCLUSION: While PAS has high prevalence among patients undergoing EVAR for complex AAA, it does not impact 30-day mortality and morbidities. Thus, EVAR for complex AAA can be considered safe for patients with PAS in terms of short-term outcomes, despite the long-term prognosis in these patients being needed in further studies.

First report of pepper yellow leaf curl Thailand virus infecting hot chili in central Vietnam and Laos.

Hot chili pepper (Capsicum annuum) cultivation has been on the rise in South East Asia to meet export demands. In Thailand, the top chili exporter in South East Asia, chili production has been severely hampered by pepper yellow leaf curl disease (YLCD) caused by the begomovirus pepper yellow leaf curl Thailand virus (PepYLCThV) (Chiemsombat et al., 2018; Suwor et al., 2021). In the neighbouring countries of Laos and Vietnam, a limited survey of chili fields (200 plants in total) in Savannakhet (Savannakhet University campus, n = 150), Laos and Quang Nam province (Ka Dang commune, Dong Giang district, n = 50), central Vietnam in 2023 led to the finding of eight plants (5 in Laos and 3 in Vietnam) exhibiting YLCD-like symptoms, which included bright yellow color in young leaves and leaf curl and mosaic chlorosis in mature leaves (Fig. S1). Total DNA was extracted from leaves of two symptomatic plants (one from Savannakhet and one from Quang Nam) using a cetyltrimethylammonium bromide-based DNA extraction protocol (Doyle & Doyle, 1987; Nguyen et al., 2023). Next, PCR were performed using newly designed PepYLCThV-specific primers based on PepYLCThV sequences in GenBank (Table 1). PCR products of expected sizes were observed in samples with disease symptoms, but not from DNA extracted from C. annuum (cv. VA.99999) grown at the Institute of Biotechnology in Thua Thien Hue, Vietnam (Fig. S2). The amplicons were Sanger sequenced (Apical Scientific, Selangor, Malaysia) and the complete bipartite genome sequence of two isolates ('Sava01' from Laos and 'QNam01' from Vietnam) were obtained. The sequences of the DNA-A component from isolates 'Sava01' (GenBank PP437580) and 'QNam01' (GenBank PP437581) exhibited the highest sequence identity of 99.2% and 94.7% with the PepYLCThV isolate 'ChiangDaoS1' (GenBank OM677627), respectively (Table 2). Conversely, the sequences of the DNA-B component from the isolates 'Sava01' (GenBank PP437579) and 'QNam01' (GenBank PP437582) exhibited the highest similarity of 91.8% and 90.9% with the PepYLCThV isolate 'KKN601' (GenBank MW715820), respectively (Table 2). These results confirmed the presence of PepYLCThV in hot chili pepper plants exhibiting YLCD-like symptoms in central Vietnam and Laos. Infectious clones of PepYLCThV DNA-A and DNA-B (isolate 'QNam01') were created based on the pLX-AS vector as described by Pasin (2022), and transformed into Agrobacterium tumefaciens EHA105. The resulting bacteria were cultured in LB broth containing rifampicin (25 µg/mL) and kanamycin (50 µg/mL) at 28°C and used for agroinoculation of Nicotiana benthamiana (n = 6) and C. annuum (cv. VA.99999, n = 6) (4-6 leaf plants) as described by Pasin (2022). In all N. benthamiana plants, agroinoculation with both DNA-A and DNA-B infectious clones caused stunted growth, severe leaf curl, with yellow and white patches 21 days post inoculation (Fig. S3). In C. annuum plants, symptom expression, which included leaf curl and stunted leaves with yellow mosaic patterns, was observed in two out of six inoculated plants six weeks postinoculation (Fig. S3). PCR assays confirmed the presence of PepYLCThV DNA in N. benthamiana and C. annuum symptomatic leaves (Fig. S4). To our knowledge, this is the first report of pepper yellow leaf curl Thailand virus in hot chili pepper in Laos and central Vietnam. Appropriate containment and management strategies should be developed and implemented to control the spread of this disease in hot chili pepper crops in both countries.

Risk factors associated with the severity of pericoronitis of mandibular third molar.

PURPOSE: The factors related to pericoronitis severity are unclear, and this study aimed to address this knowledge gap. MATERIALS AND METHODS: In total, 113 patients with pericoronitis were included, and their demographic, clinical, and radiographic characteristics were recorded. The Patient-Clinician Pericoronitis Classification was used to score and categorize the severity of pericoronitis. Statistical analysis was conducted to examine the participants' characteristics, validity of the Patient-Clinician Pericoronitis Classification, and risk factors associated with the severity of pericoronitis. RESULTS: The demographic, clinical, and radiographic characteristics of males and females were similar, except for Winter's classification, pain, and intraoral swelling. The constructive validity of the Patient-Clinician Pericoronitis Classification was confirmed with three latent factors, including infection level, patient discomfort, and social interference. Ordinal logistic multivariate regression analysis revealed that upper respiratory tract infection was the sole risk factor associated with pericoronitis severity in males (odds ratio = 4.838). In females, pericoronitis on the right side (odds ratio = 2.486), distal radiolucency (odds ratio = 5.203), and menstruation (odds ratio = 3.416) were significant risk factors. CONCLUSION: This study demonstrated the constructive validity of the Patient-Clinician Pericoronitis Classification. Among females, pericoronitis in mandibular third molars on the right side with radiolucency in menstruating individuals was more severe. In males, upper respiratory tract infection was the sole risk factor associated with pericoronitis severity. CLINICAL RELEVANCE: Individuals with risk factors should be aware of severe pericoronitis in the coming future.

Essential Oil from Vietnamese Peperomia leptostachya Hook. & Arn. (Piperaceae): Chemical Composition, Antioxidant, Anti-Inflammatory, Cytotoxic Activities, and In Silico Analysis.

This study is the first to investigate the chemical composition and antioxidant, anti-inflammatory, and cytotoxic activities of Peperomia leptostachya leaf oil. A yellow oil was obtained through hydro-distillation, with a yield of 0.1% (w/w). The GC-MS analysis revealed 66 compounds, constituting 99.6% of the oil. Sesquiterpene hydrocarbons predominated (70.4%), followed by monoterpene hydrocarbons (13.2%), oxygenated sesquiterpenes (12.4%), non-terpenic compounds (2.0%), and oxygenated monoterpenes (1.6%). Major constituents included germacrene D (25.1%), (E)-caryophyllene (17.4%), bicyclogermacrene (6.6%), α-pinene (6.2%), and ß-pinene (4.7%). The assessment of antioxidant capacity via 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay yielded a weak effect, with an IC50 value > 100 µg/mL. The inhibition of lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells was quantified using the MTT assay, showing an IC50 value of 15.15 ± 0.68 µg/mL. Furthermore, cytotoxic effects on SK-LU-1 cell line growth were evaluated using the sulforhodamine B assay, resulting in an IC50 value of 37.45 ± 2.43 µg/mL. The anti-inflammatory activity was notable among the analyzed bioactivities of this oil. By employing a computational model, the predominant secondary metabolites in the essential oil were selected as candidates for interaction analysis with cyclooxygenase-2, an enzyme implicated in the inflammatory response. Our findings suggest that P. leptostachya leaf oil could serve as a potential source of natural compounds with prospective therapeutic effects in treating inflammatory conditions.

The Association between Red Blood Cell Distribution Width and Mortality Risk after Hip Fracture: A Meta-Analysis.

Background and Objectives: Hip fractures in the elderly pose a considerable health risk and cause concern. Red blood cell distribution width (RDW) is a valuable marker for identifying patients at high risk of age-related mortality and various disorders and diseases. However, its association with poor patient outcomes following hip fractures has yet to be fully established. Hence, the purpose of this meta-analysis was to investigate and gain a better understanding of the relationship between RDW levels and the risk of mortality after hip fractures. Materials and Methods: PubMed, Embase, Web of Science, and other databases were comprehensively searched until April 2023 to identify relevant studies. The meta-analysis included observational studies finding the association between RDW at admission or preoperation and short-term and long-term mortality rates following hip fractures. The results were presented in terms of odds ratios (ORs) or hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Results: This meta-analysis included 10 studies involving 5834 patients with hip fractures. Patients with preoperative RDW of over 14.5% had higher risks of 1-year (OR: 5.40, 95% CI: 1.89-15.48, p = 0.002) and 3-month (OR: 2.91, 95% CI: 1.42-5.95, p = 0.004) mortality. Higher admission or preoperative RDW was significantly associated with an 11% higher mortality risk after 1 year (HR: 1.11, 95% CI: 1.06-1.17, p < 0.00001). Patients with higher preoperative RDW had a significantly higher risk of 6-month mortality, which was three times that of those with lower preoperative RDW (OR: 3.00, 95% CI: 1.60-5.61, p = 0.0006). Higher preoperative RDW was correlated to a higher 30-day mortality risk (OR: 6.44, 95% CI: 3.32-12.47, p < 0.00001). Conclusions: Greater RDW values at admission or before surgery were associated with a higher risk of short-term and long-term mortality following hip fractures. Because RDW can be easily measured using a routine blood test at a low cost, this parameter is promising as an indicator of mortality in elderly patients with hip fractures.

Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis.

BACKGROUND: The sinoatrial node (SAN) functions as the pacemaker of the heart, initiating rhythmic heartbeats. Despite its importance, the SAN is one of the most poorly understood cardiac entities because of its small size and complex composition and function. The Hippo signaling pathway is a molecular signaling pathway fundamental to heart development and regeneration. Although abnormalities of the Hippo pathway are associated with cardiac arrhythmias in human patients, the role of this pathway in the SAN is unknown. METHODS: We investigated key regulators of the Hippo pathway in SAN pacemaker cells by conditionally inactivating the Hippo signaling kinases Lats1 and Lats2 using the tamoxifen-inducible, cardiac conduction system-specific Cre driver Hcn4CreERT2 with Lats1 and Lats2 conditional knockout alleles. In addition, the Hippo-signaling effectors Yap and Taz were conditionally inactivated in the SAN. To determine the function of Hippo signaling in the SAN and other cardiac conduction system components, we conducted a series of physiological and molecular experiments, including telemetry ECG recording, echocardiography, Masson Trichrome staining, calcium imaging, immunostaining, RNAscope, cleavage under targets and tagmentation sequencing using antibodies against Yap1 or H3K4me3, quantitative real-time polymerase chain reaction, and Western blotting. We also performed comprehensive bioinformatics analyses of various datasets. RESULTS: We found that Lats1/2 inactivation caused severe sinus node dysfunction. Compared with the controls, Lats1/2 conditional knockout mutants exhibited dysregulated calcium handling and increased fibrosis in the SAN, indicating that Lats1/2 function through both cell-autonomous and non-cell-autonomous mechanisms. It is notable that the Lats1/2 conditional knockout phenotype was rescued by genetic deletion of Yap and Taz in the cardiac conduction system. These rescued mice had normal sinus rhythm and reduced fibrosis of the SAN, indicating that Lats1/2 function through Yap and Taz. Cleavage Under Targets and Tagmentation sequencing data showed that Yap potentially regulates genes critical for calcium homeostasis such as Ryr2 and genes encoding paracrine factors important in intercellular communication and fibrosis induction such as Tgfb1 and Tgfb3. Consistent with this, Lats1/2 conditional knockout mutants had decreased Ryr2 expression and increased Tgfb1 and Tgfb3 expression compared with control mice. CONCLUSIONS: We reveal, for the first time to our knowledge, that the canonical Hippo-Yap pathway plays a pivotal role in maintaining SAN homeostasis.

Light-Powered Reversible Guest Release and Uptake from Zn4L4 Capsules.

A strategy for light-powered guest release from a tetrahedral capsule has been developed by incorporating azobenzene units at its vertices. A new Zn4L4 tetrahedral capsule bearing 12 diazo moieties at its metal-ion vertices was prepared from a phenyldiazenyl-functionalized subcomponent and a central trialdehyde panel. Ultraviolet irradiation caused isomerization of the peripheral diazo groups from the thermodynamically preferred trans configuration to the cis form, thereby generating steric clash and resulting in cage disassembly and concomitant guest release. Visible-light irradiation drove cage re-assembly following re-isomerization of the diazo groups to the trans form, resulting in guest re-uptake. A detailed 19F NMR study elucidated how switching led to guest release: each metal vertex tolerated only one cis-azobenzene moiety, with further isomerization leading to cage disassembly.

Plant associated protists-Untapped promising candidates for agrifood tools.

The importance of host-associated microorganisms and their biotic interactions for plant health and performance has been increasingly acknowledged. Protists, main predators and regulators of bacteria and fungi, are abundant and ubiquitous eukaryotes in terrestrial ecosystems. Protists are considered to benefit plant health and performance, but the community structure and functions of plant-associated protists remain surprisingly underexplored. Harnessing plant-associated protists and other microbes can potentially enhance plant health and productivity and sustain healthy food and agriculture systems. In this review, we summarize the knowledge of multifunctionality of protists and their interactions with other microbes in plant hosts, and propose a future framework to study plant-associated protists and utilize protists as agrifood tools for benefiting agricultural production.