Impact of Weight Gain on Cardiovascular Outcomes in Patients With Atrial Fibrillation.

BACKGROUND: The long-term impact of weight gain (WG) on cardiovascular outcomes among patients with atrial fibrillation (AF) is unclear. METHODS AND RESULTS: We studied 62 871 (mean age, 72±12, 43% women) adult patients with AF evaluated at the University of Pittsburgh Medical Center between January 1, 2010, and May 13, 2021. Serial body mass index, risk factors, comorbidities, and subsequent death and hospitalization were ascertained and stratified according to percentage WG (≥0% to <5%, ≥5% to <10%, and ≥10%). Over 4.9±3.19 years of follow-up, 27 114 (43%) patients gained weight (61%, ≥0% to <5%; 23%, ≥5% to <10%; 16%, ≥10%). Patients with progressive WG were incrementally younger (P<0.001) women (40%, 42%, and 47%) with lower median household income (P=0.002) and active smoking (8%, 13% and 13%), and they were less likely to be on a non-vitamin K oral anticoagulant (39%, 37%, and 32%). WG was incrementally associated with a significant increase in risk of hospitalization for AF (≥10% WG; hazard ratio [HR], 1.2 [95% CI, 1.2-1.3]; P<0.0001), heart failure (≥10% WG; HR, 1.44 [95% CI, 1.3-1.6]; P<0.001; ≥5% to <10% WG; HR, 1.17 [95% CI, 1.1-1.2]; P<0.001), myocardial infarction (≥10% WG; HR, 1.2 [95% CI, 1.3-1.6]; P<0.001) and all-cause stroke (4.2%, 4.3%, and 5.6%) despite significantly lower mean CHADS2Vasc score (2.9±1.7, 2.7±1.6, and 2.7±1.7). Patients with more WG were significantly more likely to receive cardiac and electrophysiologic interventions. CONCLUSIONS: Among patients with AF, WG is incrementally associated with increased hospitalization for cardiovascular causes, particularly heart failure, stroke, myocardial infarction, and AF.

Ultrasound enhanced siRNA delivery using cationic liposome-microbubble complexes for the treatment of squamous cell carcinoma.

Rationale: Microbubble (MB) contrast agents combined with ultrasound targeted microbubble cavitation (UTMC) are a promising platform for site-specific therapeutic oligonucleotide delivery. We investigated UTMC-mediated delivery of siRNA directed against epidermal growth factor receptor (EGFR), to squamous cell carcinoma (SCC) via a novel MB-liposome complex (LPX). Methods: LPXs were constructed by conjugation of cationic liposomes to the surface of C4F10 gas-filled lipid MBs using biotin/avidin chemistry, then loaded with siRNA via electrostatic interaction. Luciferase-expressing SCC-VII cells (SCC-VII-Luc) were cultured in Petri dishes. The Petri dishes were filled with media in which LPXs loaded with siRNA against firefly luciferase (Luc siRNA) were suspended. Ultrasound (US) (1 MHz, 100-µs pulse, 10% duty cycle) was delivered to the dishes for 10 sec at varying acoustic pressures and luciferase assay was performed 24 hr later. In vivo siRNA delivery was studied in SCC-VII tumor-bearing mice intravenously infused with a 0.5 mL saline suspension of EGFR siRNA LPX (7×108 LPX, ~30 µg siRNA) for 20 min during concurrent US (1 MHz, 0.5 MPa spatial peak temporal peak negative pressure, five 100-µs pulses every 1 ms; each pulse train repeated every 2 sec to allow reperfusion of LPX into the tumor). Mice were sacrificed 2 days post treatment and tumor EGFR expression was measured (Western blot). Other mice (n=23) received either EGFR siRNA-loaded LPX + UTMC or negative control (NC) siRNA-loaded LPX + UTMC on days 0 and 3, or no treatment ("sham"). Tumor volume was serially measured by high-resolution 3D US imaging. Results: Luc siRNA LPX + UTMC caused significant luciferase knockdown vs. no treatment control, p<0.05) in SCC-VII-Luc cells at acoustic pressures 0.25 MPa to 0.9 MPa, while no significant silencing effect was seen at lower pressure (0.125 MPa). In vivo, EGFR siRNA LPX + UTMC reduced tumor EGFR expression by ~30% and significantly inhibited tumor growth by day 9 (~40% decrease in tumor volume vs. NC siRNA LPX + UTMC, p<0.05). Conclusions: Luc siRNA LPXs + UTMC achieved functional delivery of Luc siRNA to SCC-VII-Luc cells in vitro. EGFR siRNA LPX + UTMC inhibited tumor growth and suppressed EGFR expression in vivo, suggesting that this platform holds promise for non-invasive, image-guided targeted delivery of therapeutic siRNA for cancer treatment.

Effect of an Arsenic Mitigation Program on Arsenic Exposure in American Indian Communities: A Cluster Randomized Controlled Trial of the Community-Led Strong Heart Water Study Program.

BACKGROUND: Chronic arsenic exposure has been associated with an increased risk of cardiovascular disease; diabetes; cancers of the lung, pancreas and prostate; and all-cause mortality in American Indian communities in the Strong Heart Study. OBJECTIVE: The Strong Heart Water Study (SHWS) designed and evaluated a multilevel, community-led arsenic mitigation program to reduce arsenic exposure among private well users in partnership with Northern Great Plains American Indian Nations. METHODS: A cluster randomized controlled trial (cRCT) was conducted to evaluate the effectiveness of the SHWS arsenic mitigation program over a 2-y period on a) urinary arsenic, and b) reported use of arsenic-safe water for drinking and cooking. The cRCT compared the installation of a point-of-use arsenic filter and a mobile Health (mHealth) program (3 phone calls; SHWS mHealth and Filter arm) to a more intensive program, which included this same program plus three home visits (3 phone calls and 3 home visits; SHWS Intensive arm). RESULTS: A 47% reduction in urinary arsenic [geometric mean (GM)=13.2 to 7.0µg/g creatinine] was observed from baseline to the final follow-up when both study arms were combined. By treatment arm, the reduction in urinary arsenic from baseline to the final follow-up visit was 55% in the mHealth and Filter arm (GM=14.6 to 6.55µg/g creatinine) and 30% in the Intensive arm (GM=11.2 to 7.82µg/g creatinine). There was no significant difference in urinary arsenic levels by treatment arm at the final follow-up visit comparing the Intensive vs. mHealth and Filter arms: GM ratio of 1.21 (95% confidence interval: 0.77, 1.90). In both arms combined, exclusive use of arsenic-safe water from baseline to the final follow-up visit significantly increased for water used for cooking (17% to 53%) and drinking (12% to 46%). DISCUSSION: Delivery of the interventions for the community-led SHWS arsenic mitigation program, including the installation of a point-of-use arsenic filter and a mHealth program on the use of arsenic-safe water (calls only, no home visits), resulted in a significant reduction in urinary arsenic and increases in reported use of arsenic-safe water for drinking and cooking during the 2-y study period. These results demonstrate that the installation of an arsenic filter and phone calls from a mHealth program presents a promising approach to reduce water arsenic exposure among private well users. https://doi.org/10.1289/EHP12548.

Outcomes of Aortomitral Continuity Reconstruction During Concomitant Aortic and Mitral Valve Replacement.

OBJECTIVES: To describe outcomes of reconstruction of the aortomitral continuity (AMC) during concomitant aortic and mitral valve replacement (ie, the "Commando" procedure). DESIGN: A retrospective study of consecutive cardiac surgeries from 2010 to 2022. SETTING: At a single institution. PARTICIPANTS: All patients undergoing double aortic and mitral valve replacement. INTERVENTIONS: Patients were dichotomized by the performance (or not) of AMC reconstruction. MEASUREMENTS AND MAIN RESULTS: A total of 331 patients underwent double-valve replacement, of whom 21 patients (6.3%) had a Commando procedure. The Commando group was more likely to have had a previous aortic valve replacement (AVR) or mitral valve replacement (MVR) (66.7% v 27.4%, p < 0.001), redo cardiac surgery (71.4% v 31.3%, p < 0.001), and emergent/salvage surgery (14.3% v 1.61%, p = 0.001), whereas surgery was more often performed for endocarditis in the Commando group (52.4% v 22.9%, p = 0.003). The Commando group had higher operative mortality (28.6% v 10.7%, p = 0.014), more prolonged ventilation (61.9% v 31.9%, p = 0.005), longer cardiopulmonary bypass time (312 ± 118 v 218 ± 85 minutes, p < 0.001), and longer ischemic time (252 ± 90 v 176 ± 66 minutes, p < 0.001). Despite increased short-term morbidity in the Commando group, Kaplan-Meier survival estimation showed no difference in long-term survival between each group (p = 0.386, log-rank). On multivariate Cox analysis, the Commando procedure was not associated with an increased hazard of death, compared to MVR + AVR (hazard ratio 1.29, 95% CI: 0.65-2.59, p = 0.496). CONCLUSIONS: Although short-term postoperative morbidity and mortality were found to be higher for patients undergoing the Commando procedure, AMC reconstruction may be equally durable in the long term.

Reinterventions After Repair of Acute Type A Aortic Dissection: Incidence, Outcomes, and Risk Factors.

BACKGROUND: This study reports the incidence, outcomes, and risk factors for aortic reinterventions after repair of acute type A aortic dissection (ATAAD). METHODS: This was an observational study of aortic operations from 2010 to 2021. All patients with ATAAD undergoing open aortic arch reconstruction were included. Patients were dichotomized by the need for reintervention, which included reinterventions proximal to or distal to the index aortic repair. Propensity matching was used to determine the impact of reintervention on long-term outcomes. The cumulative incidence function for reintervention was estimated, and multivariable Fine-Gray analysis was performed to identify variables associated with reintervention, with death treated as a competing event. RESULTS: We identified 601 patients undergoing surgery for ATAAD. An aortic reintervention was required in 71 (11.8%), comprising a proximal reintervention in 12 patients, a distal reintervention in 56, and both in 3. The cumulative incidence of reintervention was 11.6% (95% CI, 8.9%-14.6%) at 5 years and was 16.0% (95% CI, 12.2%-20.3%) at 10 years, with a median time to reintervention of 4.0 years (interquartile range, 0.9-7.5 years). Multivariable analysis using the Fine-Gray method showed no operative variables were associated with reinterventions. Among the 71 reinterventions, there were 4 (5.6%) operative deaths. After propensity matching, there was no difference in Kaplan-Meier survival estimates across each group (P = .138 by log-rank statistics). CONCLUSIONS: The cumulative incidence of aortic reintervention after ATAAD repair was reasonably low (16% at 10 years), reinterventions were relatively safe (6% operative mortality), and reinterventions did not significantly impact long-term survival.

Lower-extremity malperfusion syndrome in patients undergoing proximal aortic surgery for acute type A aortic dissection.

Objective: Data regarding management of lower-extremity malperfusion in the setting of type A aortic dissection are limited. This study aimed to compare acute type A aortic dissection with lower-extremity malperfusion outcomes in patients undergoing lower-extremity revascularization with no revascularization. Methods: Consecutive patients undergoing acute type A aortic dissection surgery were identified from a prospectively maintained database. Perioperative variables were compared between patients with and without lower-extremity malperfusion. Factors associated with lower-extremity malperfusion, revascularization, and mortality were determined using univariable Cox regression and Firth's penalized likelihood modeling. Results: From January 2007 to December 2021, 601 patients underwent proximal aortic repair for acute type A aortic dissection at a quaternary care center. Of these, 85 of 601 patients (14%) presented with lower-extremity malperfusion and were more often male (P = .02), had concomitant moderate or greater aortic insufficiency (P = .05), had lower ejection fraction (P = .004), had preoperative dialysis dependence (P = .01), and had additional cerebral, visceral, and renal malperfusion syndromes (P < .001). Kaplan-Meier estimated survival fared worse with lower-extremity malperfusion compared with no lower-extremity malperfusion at 1, 5, and 10 years (84% vs 77%, 74% vs 71%, 65% vs 52%, respectively, P = .03). In the lower-extremity malperfusion group, 15 of 85 patients (18%) underwent lower-extremity revascularization without significant differences in postoperative morbidity and mortality compared with patients not undergoing revascularization. Need for peripheral revascularization was associated with peripheral vascular disease (hazard ratio, 3.7 [1.0-14.0], P = .05) and pulse deficit (hazard ratio, 5.6 [1.3-24.0], P = .02) at presentation. Conclusions: Patients presenting with type A aortic dissection and lower-extremity malperfusion have worse overall survival compared with those without lower-extremity malperfusion. However, not all patients with type A aortic dissection and lower-extremity malperfusion require revascularization.

A sonogram radiomics model for differentiating granulomatous lobular mastitis from invasive breast cancer: a multicenter study.

PURPOSE: To construct a nomogram based on sonogram features and radiomics features to differentiate granulomatous lobular mastitis (GLM) from invasive breast cancer (IBC). MATERIALS AND METHODS: A retrospective collection of 213 GLMs and 472 IBCs from three centers was divided into a training set, an internal validation set, and an external validation set. A radiomics model was built based on radiomics features, and the RAD score of the lesion was calculated. The sonogram radiomics model was constructed using ultrasound features and RAD scores. Finally, the diagnostic efficacy of the three sonographers with different levels of experience before and after combining the RAD score was assessed in the external validation set. RESULTS: The RAD score, lesion diameter, orientation, echogenicity, and tubular extension showed significant differences in GLM and IBC (p < 0.05). The sonogram radiomics model based on these factors achieved optimal performance, and its area under the curve (AUC) was 0.907, 0.872, and 0.888 in the training, internal, and external validation sets, respectively. The AUCs before and after combining the RAD scores were 0.714, 0.750, and 0.830 and 0.834, 0.853, and 0.878, respectively, for sonographers with different levels of experience. The diagnostic efficacy was comparable for all sonographers when combined with the RAD score (p > 0.05). CONCLUSION: Radiomics features effectively enhance the ability of sonographers to discriminate between GLM and IBC and reduce interobserver variation. The nomogram combining ultrasound features and radiomics features show promising diagnostic efficacy and can be used to identify GLM and IBC in a noninvasive approach.

Discovery of Core-Fucosylated Glycopeptides as Diagnostic Biomarkers for Early HCC in Patients with NASH Cirrhosis Using LC-HCD-PRM-MS/MS.

Aberrant changes in site-specific core fucosylation (CF) of serum proteins contribute to cancer development and progression, which enables them as potential diagnostic markers of tumors. An optimized data-dependent acquisition (DDA) workflow involving isobaric tags for relative and absolute quantitation-labeling and enrichment of CF peptides by lens culinaris lectin was applied to identify CF of serum proteins in a test set of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis (N = 16) and hepatocellular carcinoma (HCC, N = 17), respectively. A total of 624 CF peptides from 343 proteins, with 683 CF sites, were identified in our DDA-mass spectrometry (MS) analysis. Subsequently, 19 candidate CF peptide markers were evaluated by a target parallel reaction-monitoring-MS workflow in a validation set of 58 patients, including NASH-related cirrhosis (N = 29), early-stage HCC (N = 21), and late-stage HCC (N = 8). Significant changes (p < 0.01) were observed in four CF peptides between cirrhosis and HCC, where peptide LGSFEGLVn160LTFIHLQHNR from LUM in combination with AFP showed the best diagnostic performance in discriminating HCC from cirrhosis, with an area under curve (AUC) of 0.855 compared to AFP only (AUC = 0.717). This peptide in combination with AFP also significantly improved diagnostic performance in distinguishing early HCC from cirrhosis, with an AUC of 0.839 compared to AFP only (AUC = 0.689). Validation of this novel promising biomarker panel in larger cohorts should be performed.

The Long-Term Impact of Diastolic Dysfunction After Routine Cardiac Surgery.

OBJECTIVE: To determine the impact of diastolic dysfunction (DD) on survival after routine cardiac surgery. DESIGN: This was an observational study of consecutive cardiac surgeries from 2010 to 2021. SETTING: At a single institution. PARTICIPANTS: Patients undergoing isolated coronary, isolated valvular, and concomitant coronary and valvular surgery were included. Patients with a transthoracic echocardiogram (TTE) longer than 6 months prior to their index surgery were excluded from the analysis. INTERVENTIONS: Patients were categorized via preoperative TTE as having no DD, grade I DD, grade II DD, or grade III DD. MEASUREMENTS AND MAIN RESULTS: A total of 8,682 patients undergoing a coronary and/or valvular surgery were identified, of whom 4,375 (50.4%) had no DD, 3,034 (34.9%) had grade I DD, 1,066 (12.3%) had grade II DD, and 207 (2.4%) had grade III DD. The median (IQR) time of the TTE prior to the index surgery was 6 (2-29) days. Operative mortality was 5.8% in the grade III DD group v 2.4% for grade II DD, 1.9% for grade I DD, and 2.1% for no DD (p = 0.001). Atrial fibrillation, prolonged mechanical ventilation (>24 hours), acute kidney injury, any packed red blood cell transfusion, reexploration for bleeding, and length of stay were higher in the grade III DD group compared to the rest of the cohort. The median follow-up was 4.0 (IQR: 1.7-6.5) years. Kaplan-Meier survival estimates were lower in the grade III DD group than in the rest of the cohort. CONCLUSIONS: These findings suggested that DD may be associated with poor short-term and long-term outcomes.

GlycoSLASH: Concurrent Glycopeptide Identification from Multiple Related LC-MS/MS Data Sets by Using Spectral Clustering and Library Searching.

Liquid chromatography coupled with tandem mass spectrometry is commonly adopted in large-scale glycoproteomic studies involving hundreds of disease and control samples. The software for glycopeptide identification in such data (e.g., the commercial software Byonic) analyzes the individual data set and does not exploit the redundant spectra of glycopeptides presented in the related data sets. Herein, we present a novel concurrent approach for glycopeptide identification in multiple related glycoproteomic data sets by using spectral clustering and spectral library searching. The evaluation on two large-scale glycoproteomic data sets showed that the concurrent approach can identify 105%-224% more spectra as glycopeptides compared to the glycopeptide identification on individual data sets using Byonic alone. The improvement of glycopeptide identification also enabled the discovery of several potential biomarkers of protein glycosylations in hepatocellular carcinoma patients.

Mass spectrometry based biomarkers for early detection of HCC using a glycoproteomic approach.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform the current serum-based markers are described and discussed. Also, recent developments in isoform analysis of glycans and glycopeptides and in various mass spec fragmentation methods will be described and discussed.

Outcomes of Transcatheter Aortic Valve Replacement in Patients With Concomitant Aortic Regurgitation.

BACKGROUND: This study sought to evaluate outcomes of transcatheter aortic valve replacement (TAVR) in patients with moderate or greater aortic regurgitation (AR). METHODS: This was an observational study using an institutional database of TAVRs from November 2012 to April 2022. The study compared outcomes of TAVR in patients with isolated aortic stenosis (AS) vs patients with AS and concomitant AR (moderate or greater). Those patients with trace or mild AR were excluded. Clinical and echocardiographic outcomes were compared, with end points established by the Valve Academic Research Consortium 3. Kaplan-Meier survival estimation and Cox regression for mortality were performed. Competing-risk cumulative incidence estimates for heart failure readmissions were also compared. RESULTS: Of 3295 patients, 605 (53.4%) had severe AS with no AR and 529 (46.6%) had severe AS with moderate or severe AR. There were no significant differences in in-hospital mortality, length of stay, stroke, myocardial infarction, permanent pacemaker requirement, transfusion requirement, minor or major vascular complications, or 30-day readmissions between the 2 groups (P > .05). There were also no significant differences in annular dissection or rupture, coronary obstruction, or device embolization. Mean gradient and paravalvular leak rates at 30 days and 1 year were similar between the groups. Survival estimates were comparable, and, on multivariable Cox regression, mixed aortic valvular disease was not associated with an increased hazard of death as compared with isolated AS (hazard ratio, 1.01; 95% CI, 0.81-1.25; P = .962). Cumulative incidence estimates for heart failure readmissions were comparable between groups. CONCLUSIONS: TAVR can be safely performed in patients with mixed valvular disease, with outcomes comparable to those in isolated AS.

Hydrophobic-action-driven removal of six organophosphorus pesticides from tea infusion by modified carbonized bacterial cellulose.

The abuse of organophosphorus pesticides (OPPs) in tea planting makes it easy to transfer from tea into its infusion, bringing potential health risks to consumers. Thus, it is essential to adopt reliable techniques to remove OPPs from tea infusion. In this study, three treatment methods were used to modify carbonized bacterial cellulose (CBC) to improve its adsorption performance. Among them, CBC treated by hydrazine hydrate (N-CBC) had the best adsorption effect, whose removal rate for dicrotophos is 13 times that of CBC. The in-depth study of adsorption mechanism proved that hydrophobic interaction dominated the adsorption of OPPs onto N-CBC. The pseudo-second-order kinetic model and Langmuir isotherm model were more suitable to describe the process. Additionally, there were no significant changes in tea infusion quality after N-CBC treatment. This work clarifies that N-CBC benefitted from simple preparation method, excellent adsorption performance and unique adsorption mechanism has potential applications in tea infusion.

Contrast-Enhanced Ultrasound with Deep Learning with Attention Mechanisms for Predicting Microvascular Invasion in Single Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: Prediction of microvascular invasion (MVI) status of hepatocellular carcinoma (HCC) holds clinical significance for decision-making regarding the treatment strategy and evaluation of patient prognosis. We developed a deep learning (DL) model based on contrast-enhanced ultrasound (CEUS) to predict MVI of HCC. MATERIALS AND METHODS: We retrospectively analyzed the data for single primary HCCs that were evaluated with CEUS 1 week before surgical resection from December 2014 to February 2022. The study population was divided into training (n = 198) and test (n = 54) cohorts. In this study, three DL models (Resnet50, Resnet50+BAM, Resnet50+SE) were trained using the training cohort and tested in the test cohort. Tumor characteristics were also evaluated by radiologists, and multivariate regression analysis was performed to determine independent indicators for the development of predictive nomogram models. The performance of the three DL models was compared to that of the MVI prediction model based on radiologist evaluations. RESULTS: The best-performing model, ResNet50+SE model achieved the ROC of 0.856, accuracy of 77.2, specificity of 93.9%, and sensitivity of 52.4% in the test group. The MVI prediction model based on a combination of three independent predictors showed a C-index of 0.729, accuracy of 69.4, specificity of 73.8%, and sensitivity of 62%. CONCLUSION: The DL algorithm can accurately predict MVI of HCC on the basis of CEUS images, to help identify high-risk patients for the assist treatment.

Unspecific reactivity must be excluded in COVID-19 epidemiological analyses or virus tracing based on serologic testing: Analysis of 46,777 post-pandemic samples and 1,114 pre-pandemic samples.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Serologic testing is complementary to nucleic acid screening to identify SARS-CoV-2. This study aimed to evaluate unspecific reactivity in SARS-CoV-2 serologic tests. Materials and methods: Total anti-SARS-CoV-2 antibodies from 46,777 subjects who were screened for SARS-CoV-2 were retrospectively studied to evaluate the incidence and characteristics of the unspecific reactivity. A total of 1,114 pre-pandemic samples were also analysed to compare unspecific reactivity. Results: The incidence of unspecific reactivity in anti-SARS-CoV-2 total antibody testing was 0.361% in 46,777 post-pandemic samples, similar to the incidence of 0.359% (4/1,114) in 1,114 pre-pandemic samples (p = 0.990). Subjects ≥ 19 years old had a 2.753-fold [95% confidence interval (CI), 1.130-6.706] higher probability of unspecific reactivity than subjects < 19 years old (p = 0.026). There was no significant difference between the sexes. The unspecific reactivity was associated with 14 categories within the disease spectrum, with three tops being the skin and subcutaneous tissue diseases (0.93%), respiratory system diseases (0.78%) and neoplasms diseases (0.76%). The percentage of patients with a titer ≥ 13.87 cut-off index (COI) in the unspecific reactivity was 7.69%. Conclusion: Our results suggest a unspecific reactivity incidence rate of 0.361% involving 14 categories on the disease spectrum. Unspecific reactivity needs to be excluded when performing serologic antibody testing in COVID-19 epidemiological analyses or virus tracing.

Sweet taste perception in mice is blunted by PTBP1-regulated skipping of Tas1r2 exon 4.

Taste perception, initiated by activation of taste receptors in taste bud cells, is crucial for regulating nutrient intake. Genetic polymorphisms in taste receptor genes cannot fully explain the wide individual variations of taste sensitivity. Alternative splicing (AS) is a ubiquitous posttranscriptional mode of gene regulation that enriches the functional diversity of proteins. Here, we report the identification of a novel splicing variant of sweet taste receptor gene Tas1r2 (Tas1r2_∆e4) in mouse taste buds and the mechanism by which it diminishes sweet taste responses in vitro and in vivo. Skipping of Tas1r2 exon 4 in Tas1r2_∆e4 led to loss of amino acids in the extracellular Venus flytrap domain, and the truncated isoform reduced the response of sweet taste receptors (STRs) to all sweet compounds tested by generating nonfunctional T1R2/T1R3 STR heterodimers. The splicing factor PTBP1 (polypyrimidine tract-binding protein 1) promoted Tas1r2_∆e4 generation through binding to a polypyrimidine-rich splicing silencer in Tas1r2 exon 4, thus decreasing STR function and sweet taste perception in mice. Taken together, these data reveal the existence of a regulated AS event in Tas1r2 expression and its effect on sweet taste perception, providing a novel mechanism for modulating taste sensitivity at the posttranscriptional level.

The impact of prior cardiac surgery on patients undergoing surgical repair for acute type A aortic dissection.

OBJECTIVE: To determine the impact of reoperative versus first-time sternotomy for emergent open repair of acute Type A aortic dissection (ATAAD). METHODS: This was an observational study of consecutive aortic surgeries from 2007 to 2021. Kaplan-Meier survival estimation and multivariable Cox regression analysis were performed to assess the impact of reoperative versus first-time sternotomy upon survival after ATAAD repair. RESULTS: A total of 601 patients with ATAAD were identified, of which 72 (12%) underwent reoperative sternotomy. The reoperative group had a higher prevalence of baseline comorbidities, including hypertension, diabetes, peripheral vascular disease, atrial fibrillation, and coronary artery disease. Central cannulation of the aorta was achieved at a similar rate across each group (81.9% vs. 81.5%, p = .923), and cardiopulmonary bypass (CPB) time was similar across each group (204 ± 84.8 vs. 203 ± 72.4 min, p = .923). Postoperative outcomes were similar across both groups, including in-hospital mortality, stroke, pulmonary complications, renal failure, and reexploration for excessive bleeding. Five-year survival was 74.5% (70.5, 78.3) for the first-time group and was 71.6% (60.0, 81.9) for the reoperative group. After multivariable Cox regression, reoperative sternotomy was not significantly associated with an increased hazard of death compared to first-time sternotomy (hazards ratio: 0.90, 95% confidence interval: 0.56, 1.43, p = .642). CONCLUSIONS: These findings suggest that re-sternotomy can be safely performed with similar outcomes as first-time sternotomy. Central initiation of CPB after sternal reentry limits CPB time and may therefore represent a protective strategy that enhances outcomes for patients presenting with ATAAD and prior cardiac surgery.

Sex-based outcomes after surgery for acute type A aortic dissection.

BACKGROUND: While prior data have suggested worse outcomes in women after acute type A aortic dissection (ATAAD) repair when compared to men, results have been inconsistent across studies over time. This study sought to evaluate the impact of sex on short- and long-term outcomes after ATAAD repair. METHODS: This was a retrospective study utilizing an institutional database of ATAAD repairs from 2007 to 2021. Patients were stratified according to sex. Kaplan-Meier survival estimation and multivariable Cox regression were performed. Supplementary analysis using propensity score matching was also performed. RESULTS: Of the 601 patients who underwent ATAAD repair, 361 were males (60.1%) and 240 (39.9%) were females. Females were significantly older, more likely to have hypertension, and more likely to have chronic lung disease. Females were also significantly more likely than males to undergo hemiarch replacement, while males were significantly more likely than females to undergo total arch replacement and frozen elephant trunk. Operative mortality was 9.4% among males and 13.8% among females, though this was not a statistically significant difference (p = .098). Postoperative complications were comparable between groups. Kaplan-Meier survival estimates were similar for men and women, and, on multivariable Cox regression, sex was not significantly associated with long-term survival (hazard ratio: 1.00, 95% confidence interval: 0.73, 1.37, p = .986). Outcomes remained comparable after supplementary propensity score matched analysis. CONCLUSION: ATAAD repair can be performed with comparable short-term and long-term outcomes in both men and women.

Sequential Method for Analysis of CTCs and Exosomes from the Same Sample of Patient Blood.

Circulating tumor cells (CTCs) and exosomes, both released from the primary tumor into peripheral blood, are a promising source of cancer biomarkers. They are detectable in the blood and carry a large diversity of biological molecules, which can be used for the diagnosis and monitoring of minimally invasive cancers. However, due to their intrinsic differences in counts, size, and molecular contents, studies have focused on only one type of vesicle. Herein, we have developed an integrated system to sequentially isolate CTCs and exosomes from a single patient blood sample for further profiling and analysis. The CTCs are isolated using a commercial filtration method and then the remaining blood is processed using multiple cycles of ultracentrifugation to isolate the exosomes. The method uses two available technologies where the eluent from CTC isolation is usually discarded and interfaces them, so that the eluent can be interfaced to exosome isolation methods. The CTCs are identified based on fluorescence staining of their surface markers, while the exosomes are analyzed using transmission electron microscopy, nanosight tracking analysis, and mass spec proteomic analysis. This analysis showed CTCs detected by their surface markers for metastatic hepatocellular carcinoma (HCC), while essentially none were detected for cirrhosis. The exosome analysis resulted in the identification of ∼500-1000 exosome proteins per sample confirmed by detection of exosome surface markers CD9, CD63, CD81, and TSG101 in addition to proteins related to cancer progression. Proteins enriched in HCC exosomes were shown to be involved in the immune response, metastasis, and proliferation.

The impact of prolonged mechanical ventilation after acute type A aortic dissection repair.

OBJECTIVE: Patients with type A aortic dissection have increased resource use. The objective of this study was to describe the relationship between prolonged mechanical ventilation and longitudinal survival in patients undergoing type A aortic dissection repair. METHODS: We conducted a retrospective analysis of patients with type A aortic dissection undergoing repair from 2010 to 2018; Kaplan-Meier function and adjusted Cox regression analysis were used to compare in-hospital mortality and longitudinal survival accounting for time on mechanical ventilatory support. RESULTS: A total of 552 patients were included. The study population was divided into 12 hours or less (n = 291), more than 12 to 24 or less hours (n = 101), more than 24 to 48 hours or less (n = 60), and more than 48 hours (n = 100) groups. Patients within the 12 or less hours group were the youngest (60.0 vs 63.5 years vs 63.6 vs 62.8 years; P = .03) and less likely to be female (31.6% vs 43.6% vs 46.7% vs 56.0%; P < .001). On the other hand, the more than 48 hours group presented with malperfusion syndrome at admission more often (24.4% vs 29.7% vs 28.3% vs 53.0%; P < .001) and had longer cardiopulmonary and ischemic times (P < .05). In-hospital mortality was significantly higher in the more than 48 hours group (5.2% vs 6.9% vs 3.3% vs 30.0%; P < .001). Multivariable analysis demonstrated worse longitudinal survival for the 24 to 48 hours group (hazard ratio, 1.94, confidence interval, 1.10-3.43) and more than 48 hours ventilation group (hazard ratio, 2.25, confidence interval, 1.30-3.92). CONCLUSIONS: The need for prolonged mechanical ventilatory support is prevalent and associated with other perioperative complications. More important, after adjusting for other covariates, prolonged mechanical ventilation is an independent factor associated with increased longitudinal mortality.