Systematic review of intermediate and long-term results of thoracic outlet decompression.

Thoracic outlet syndrome (TOS) consists of a group of disorders resulting from compression of the neurovascular bundle exiting through the thoracic outlet. TOS can be classified as follows based on the etiology of the pathophysiology: neurogenic TOS, venous TOS, arterial TOS, and mixed TOS. The constellation of symptoms a patient may experience varies, depending on the structures involved. Due to the wide range of etiologies and presenting symptoms, treatments for TOS also differ. Furthermore, most studies focus on the perioperative and short-term outcomes after surgical decompression for TOS. This systematic review aimed to provide a pooled analysis of studies to better understand the intermediate and long-term outcomes of surgical decompression for TOS. We conducted a systematic literature search in the Ovid MEDLINE, Embase, and Google Scholar databases for studies that analyzed long-term outcomes after surgical decompression for TOS. The inclusion period was from January 2015 to May 2023. The primary outcome was postoperative QuickDASH Outcome Measure scores. A total of 16 studies were included in the final analysis. The differences between postoperative and preoperative QuickDASH Outcome Measure scores were calculated, when possible, and there was a mean overall difference of 33.5 points (95% CI, 25.2-41.8; P = .001) after surgical decompression. There was a higher proportion of excellent outcomes reported for patients undergoing intervention for arterial and mixed TOS etiologies, whereas those with venous and neurogenic etiologies had the lowest proportion of excellent outcomes reported. Patients with neurogenic TOS had the highest proportion of poor outcomes reported. In conclusion, surgical decompression for TOS has favorable long-term outcomes, especially in patients with arterial and mixed etiologies.

KAP1 negatively regulates RNA polymerase II elongation kinetics to activate signal-induced transcription.

Signal-induced transcriptional programs regulate critical biological processes through the precise spatiotemporal activation of Immediate Early Genes (IEGs); however, the mechanisms of transcription induction remain poorly understood. By combining an acute depletion system with high resolution genomics approaches to interrogate synchronized, temporal transcription, we reveal that KAP1/TRIM28 is a first responder that fulfills the temporal and heightened transcriptional demand of IEGs. Unexpectedly, acute KAP1 loss triggers an increase in RNA polymerase II elongation kinetics during early stimulation time points. This elongation defect derails the normal progression through the transcriptional cycle during late stimulation time points, ultimately leading to decreased recruitment of the transcription apparatus for re-initiation thereby dampening IEGs transcriptional output. Collectively, KAP1 plays a counterintuitive role by negatively regulating transcription elongation to support full activation across multiple transcription cycles of genes critical for cell physiology and organismal functions.

Assessment of fitness for open repair in patients with infrarenal abdominal aortic aneurysms.

OBJECTIVE: Endovascular aortic repair (EVAR) was originally designed as a treatment modality for patients with abdominal aortic aneurysms (AAAs) deemed unfit for open repair. However, the definition of "unfit for open repair" is largely subjective and heterogenous. The purpose of this study was to compare patients deemed unfit for open repair who underwent EVAR to a matched cohort who underwent open repair for infrarenal AAAs. METHODS: The Vascular Quality Initiative of the Society for Vascular Surgery was queried for patients who underwent EVAR and open infrarenal AAA repair from 2003 to 2022. Patients that underwent EVAR were included if they were deemed unfit for open repair by the operating surgeon. EVAR patients deemed unfit because of a hostile abdomen were excluded. Patients in both the open and EVAR datasets were excluded if their repair was deemed non-elective or if they had prior aortic surgery. EVAR patients were matched to a cohort of open patients. The primary outcome for this study was 1-year mortality. Secondary outcomes included 30-day mortality, major adverse cardiac events, pulmonary complications, non-home discharge, reinterventions, and 5-year survival. RESULTS: A total of 5310 EVAR patients were identified who were deemed unfit for open repair. Of those, 3028 EVAR patients (57.0%) were able to be matched 1:1 to a cohort of open patients. Open patients had higher rates of major adverse cardiac events (20.2% vs 4.4%; P < .001), pulmonary complications (12.8% vs 1.6%; P < .001), non-home discharges (28.5% vs 7.9%; P < .001), and 30-day mortality (4.5% vs 1.4%; P < .001). There were no differences in early survival, but open repair had better middle and late survival compared with EVAR over the course of 5 years. A total of 74 EVAR patients (2.4%) had reinterventions during the study period. EVAR patients that required interventions had higher 1-year (40.5% vs 7.3%; P < .001) and 5-year mortality (43.2% vs 14.1%; P < .001) compared with those that did not require reinterventions. EVAR patients who had reinterventions had higher 1-year (40.5% vs 6.3%; P < .001) and 5-year (43.2% vs 20.3%; P = .006) mortality compared with their matched open cohort. CONCLUSIONS: Patients undergoing EVAR for AAAs who are deemed unfit for open repair have better perioperative morbidity and mortality compared with open repair. However, patients who had an open repair had better middle and late survival over the course of 5 years. The categorization of unfitness for open surgery may be inaccurate and re-evaluation of this terminology/concept should be undertaken.

Factors associated with failure to operate and its impact on survival in early-stage pancreatic cancer.

INTRODUCTION: Curative intent for localized pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) requires surgery, but despite improved perioperative outcomes, surgery remains underutilized. This study analyzed the Texas Cancer Registry (TCR) to identify resectable PDAC patients who underwent curative-intent surgery in Texas between 2004 and 2018. We then evaluated demographic and clinical factors associated with failure to operate and survival (OS). METHODS: We identified patients with localized PDAC or regional lymph node spread between 2004 and 2018 in the TCR. Resection rates were determined and multivariable regression and cox proportional hazards were used to identify factors associated with failure to OS. RESULTS: Of 4274 patients, 22% underwent resection, 57% were not offered surgery, 6% had comorbidities precluding surgery, and 3% refused. Resection rates decreased from 31% in 2004 to 22% in 2018. Increasing age was associated with failure to operate (odds ratio [OR] 2.55; 95% confidence interval [CI] 1.80-3.61; p < 0.0001) while treatment at a Commission on Cancer (CoC) center correlated with reduced failure to operate (OR 0.63; 95% CI 0.50-0.78; p < 0.0001). Resection correlated with survival (HR 0.34; 95% CI 0.31-0.38; p < 0.0001) as did treatment at a National Cancer Institute (NCI)-designated center (hazard ratio 0.79; 95% CI 0.70-0.89; p < 0.0001). CONCLUSIONS: Surgery is underutilized for the treatment of resectable PDAC in Texas with decreasing utilization, annually. Evaluation at CoC was associated with improved resection rates and NCI was associated with increased survival. Expanding access to multidisciplinary care including trained hepato-pancreatico-biliary surgeons may improve outcomes for PDAC patients.

Selection criterion for endovascular aortic repair in those with chronic kidney disease.

OBJECTIVE: Endovascular aortic repair (EVAR) is the preferred method of repair for abdominal aortic aneurysms (AAAs). However, patients with advanced chronic kidney disease (CKD) are a high-risk group, and it is unknown which patients with CKD benefit from EVAR vs continued surveillance. The purpose of this study was to identify which patients with advanced CKD may benefit from EVAR. METHODS: The Vascular Quality Initiative Database was utilized to identify elective EVARs for AAAs. Patients were excluded if they underwent urgent or emergent repairs. CKD stages were categorized based on preoperative estimated glomular filtration rate (eGFR) and dialysis status. Predicted 1-year mortality of untreated AAAs was calculated by modifying a validated comorbidity score that predicts 1-year mortality (Gagne Index) without repair. The primary outcome was actual 1-year mortality, which was compared with the predicted 1-year mortality without repair. RESULTS: A total of 34,926 patient met study criteria. There were differences in Gagne Indices among the varying classes of CKD. Patients with CKD 4 and CKD 5 had the highest 1-year mortality rates, followed by CKD 3b, which was significantly higher than those with CKD 1 and CKD 2. Patients with CKD 4 had no differences between actual 1-year mortality with EVAR and predicted 1-year survival without EVAR across all AAA sizes. Those with CKD 5 had worse actual 1-year survival with EVAR than predicted 1-year survival without EVAR for AAAs <5.5 cm. Patients with CKD 5 only experienced an actual mortality benefit with EVAR compared with predicted 1-year mortality without EVAR for AAAs ≥7.0 cm. CONCLUSIONS: The current data suggest that patients with CKD 3b, 4, and 5 represent a high-risk group who may not benefit from elective EVAR utilizing traditional size criteria. Patients with CKD 4 and 5 with AAAs <5.5 cm do not benefit from elective EVAR. In patients with CKD 5, elective EVAR may need to be reserved for AAAs ≥7.0 cm unless there are other concerning anatomic characteristics.

Survival after multiple episodes of cardiac arrest.

BACKGROUND: Cardiopulmonary resuscitation (CPR) is widely used in response to cardiac arrest. However, little is known regarding outcomes for those who undergo multiple episodes of cardiac arrest while in the hospital. OBJECTIVES: The purpose of this study was to evaluate the association of multiple cardiac events with in-hospital mortality for patients admitted to our tertiary care hospital who underwent multiple code events. METHODS: We performed a retrospective cohort study on all patients who underwent cardiac arrest from 2012 to 2016. Primary outcome was survival to discharge. Secondary outcomes included post-cardiac-arrest neurologic events (PCANE), non-home discharge, and one-year mortality. RESULTS: There were 622 patients with an overall mortality rate of 78.0%. Patients undergoing CPR for cardiac arrest once during their admission had lower in-hospital mortality rates compared to those that had multiple (68.9% versus 91.3%, p<.01). Subset analysis of those who had multiple episodes of CPR revealed that more than one event within a 24-hour period led to significantly higher in-hospital mortality rates (94.7% versus 74.4%, p<.01). Other variables associated with in-hospital mortality included body mass index, female sex, malignancy, and increased down time per code. Patients that had a non-home discharge were more likely to have sustained a PCANE than those that were discharged home (31.4% versus 3.9%, p<.01). A non-home discharge was associated with higher one-year mortality rates compared to a home discharge (78.4% versus 54.3%, p=.01). CONCLUSION: Multiple codes within a 24-hour period and the average time per code were associated with in-hospital mortality in cardiac arrest patients.

BNT162b2-induced neutralizing and non-neutralizing antibody functions against SARS-CoV-2 diminish with age.

Each severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant renews concerns about decreased vaccine neutralization weakening efficacy. However, while prevention of infection varies, protection from disease remains and implicates immunity beyond neutralization in vaccine efficacy. Polyclonal antibodies function through Fab domains that neutralize virus and Fc domains that induce non-neutralizing responses via engagement of Fc receptors on immune cells. To understand how vaccines promote protection, we leverage sera from 51 SARS-CoV-2 uninfected individuals after two doses of the BNT162b2 mRNA vaccine. We show that neutralizing activities against clinical isolates of wild-type and five SARS-CoV-2 variants, including Omicron BA.2, link to FcγRIIIa/CD16 non-neutralizing effector functions. This is associated with post-translational afucosylation and sialylation of vaccine-specific antibodies. Further, polyfunctional neutralizing and non-neutralizing breadth, magnitude, and coordination diminish with age. Thus, studying Fc functions in addition to Fab-mediated neutralization provides greater insight into vaccine efficacy for vulnerable populations, such as the elderly, against SARS-CoV-2 and novel variants.

BNT162b2 induced neutralizing and non-neutralizing antibody functions against SARSCoV-2 diminish with age.

Each novel SARS-CoV-2 variant renews concerns about decreased vaccine efficacy caused by evasion of vaccine induced neutralizing antibodies. However, accumulating epidemiological data show that while vaccine prevention of infection varies, protection from severe disease and death remains high. Thus, immune responses beyond neutralization could contribute to vaccine efficacy. Polyclonal antibodies function through their Fab domains that neutralize virus directly, and Fc domains that induce non-neutralizing host responses via engagement of Fc receptors on immune cells. To understand how vaccine induced neutralizing and non-neutralizing activities synergize to promote protection, we leverage sera from 51 SARS-CoV-2 uninfected health-care workers after two doses of the BNT162b2 mRNA vaccine. We show that BNT162b2 elicits antibodies that neutralize clinical isolates of wildtype and five variants of SARS-CoV-2, including Omicron BA.2, and, critically, induce Fc effector functions. FcγRIIIa/CD16 activity is linked to neutralizing activity and associated with post-translational afucosylation and sialylation of vaccine specific antibodies. Further, neutralizing and non-neutralizing functions diminish with age, with limited polyfunctional breadth, magnitude and coordination observed in those ≥65 years old compared to <65. Thus, studying Fc functions in addition to Fab mediated neutralization provides greater insight into vaccine efficacy for vulnerable populations such as the elderly against SARS-CoV-2 and novel variants.

Use of DFT Distance Metrics for Classification of SARS-CoV-2 Genomes.

In this work, we investigate using Fourier coefficients (FCs) for capturing useful information about viral sequences in a computationally efficient and compact manner. Specifically, we extract geographic submission location from SARS-CoV-2 sequence headers submitted to the GISAID Initiative, calculate corresponding FCs, and use the FCs to classify these sequences according to geographic location. We show that the FCs serve as useful numerical summaries for sequences that allow manipulation, identification, and differentiation via classical mathematical and statistical methods that are not readily applicable for character strings. Further, we argue that subsets of the FCs may be usable for the same purposes, which results in a reduction in storage requirements. We conclude by offering extensions of the research and potential future directions for subsequent analyses, such as the use of other series transforms for discreetly indexed signals such as genomes.

SeqWho: reliable, rapid determination of sequence file identity using k-mer frequencies in Random Forest classifiers.

MOTIVATION: With the vast improvements in sequencing technologies and increased number of protocols, sequencing is being used to answer complex biological problems. Subsequently, analysis pipelines have become more time consuming and complicated, usually requiring highly extensive prevalidation steps. Here, we present SeqWho, a program designed to assess heuristically the quality of sequencing files and reliably classify the organism and protocol type by using Random Forest classifiers trained on biases native in k-mer frequencies and repeat sequence identities. RESULTS: Using one of our primary models, we show that our method accurately and rapidly classifies human and mouse sequences from nine different sequencing libraries by species, library and both together, 98.32%, 97.86% and 96.38% of the time, respectively. Ultimately, we demonstrate that SeqWho is a powerful method for reliably validating the quality and identity of the sequencing files used in any pipeline. AVAILABILITY AND IMPLEMENTATION: https://github.com/DaehwanKimLab/seqwho. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Endovascular Aortic Repair in Patients of Advanced Age.

PURPOSE: Treatment decisions for the elderly with abdominal aortic aneurysms (AAAs) are challenging. With advancing age, the risk of endovascular aneurysm repair (EVAR) increases while life expectancy decreases, which may nullify the benefit of EVAR. The purpose of this study was to quantify the impact of EVAR on 1-year mortality in patients of advanced age. MATERIALS AND METHODS: The 2003-2020 Vascular Quality Initiative Database was utilized to identify patients who underwent EVAR for AAAs. Patients were included if they were 80 years of age or older. Exclusions included non-elective surgery or missing aortic diameter data. Predicted 1-year mortality of untreated AAAs was calculated based on a validated comorbidity score that predicts 1-year mortality (Gagne Index, excluding the component associated with AAAs) plus the 1-year aneurysm-related mortality without repair. The primary outcome for the study was 1-year mortality. RESULTS: A total of 11 829 patients met study criteria. The median age was 84 years [81, 86] with 9014 (76.2%) being male. Maximal AAA diameters were apportioned as follows: 39.6% were <5.5 cm, 28.6% were 5.5-5.9 cm, 21.3% were 6.0-6.9 cm, and 10.6% were ≥7.0 cm. The predicted 1-year mortality rate without EVAR was 11.9%, which was significantly higher than the actual 1-year mortality rate with EVAR (8.2%; p<0.001). The overall rate of perioperative MACE was 4.4% (n = 516). Patients with an aneurysm diameter <5.5cm had worse actual 1-year mortality rates with EVAR compared to predicted 1-year mortality rates without EVAR. In contrast, those with larger aneurysms (≥5.5cm) had better actual 1-year mortality rates with EVAR. The benefit from EVAR for those with Gagne Indices 2-5 was largely restricted to those with AAAs ≥ 7.0cm; whereas those with Gagne Indices 0-1 experience a survival benefit for AAAs larger than 5.5 cm. CONCLUSION: The current data suggest that EVAR decreases 1-year mortality rates for patients of advanced age compared to non-operative management in the elderly. However, the survival benefit is largely limited to those with Gagne Indices 0-1 with AAAs ≥ 5.5 cm and Gagne Indices 2-5 with AAAs ≥ 7.0 cm. Those of advanced age may benefit from EVAR, but realizing this benefit requires careful patient selection.

Rapid and accurate alignment of nucleotide conversion sequencing reads with HISAT-3N.

Sequencing technologies using nucleotide conversion techniques such as cytosine to thymine in bisulfite-seq and thymine to cytosine in SLAM seq are powerful tools to explore the chemical intricacies of cellular processes. To date, no one has developed a unified methodology for aligning converted sequences and consolidating alignment of these technologies in one package. In this paper, we describe hierarchical indexing for spliced alignment of transcripts-3 nucleotides (HISAT-3N), which can rapidly and accurately align sequences consisting of any nucleotide conversion by leveraging the powerful hierarchical index and repeat index algorithms originally developed for the HISAT software. Tests on real and simulated data sets show that HISAT-3N is faster than other modern systems, with greater alignment accuracy, higher scalability, and smaller memory requirements. HISAT-3N therefore becomes an ideal aligner when used with converted sequence technologies.

Risk Factors for Nonhome Discharge After Esophagectomy for Neoplastic Disease.

BACKGROUND: Esophagectomies are known to be technically challenging operations that create significant physiologic changes. These patients often require assisted care postoperatively that necessitates a nonhome discharge. The purpose of this study was to assess factors associated with nonhome discharge after esophagectomy for neoplastic disease. METHODS: The 2016 to 2017 American College of Surgeons National Surgical Quality Improvement Program Esophagectomy database was queried to identify patients who underwent esophagectomy for a neoplasm. Patients were excluded if they died within 30 days of their operation, the index operation was considered emergent, or had missing data for the variables of interest. Multivariable analysis was performed to identify which factors were predictive of nonhome discharge. RESULTS: One thousand seven patients were included. Of those, 121 (12.0%) had a nonhome discharge. Multivariable analysis showed that the following factors were associated with nonhome discharge: Modified Charlson comorbidity index (adjusted odds ratio [aOR], 2.04; 95% confidence interval [CI], 1.49-2.86), partially dependent preoperative functional status (aOR, 13.18; 95% CI, 1.07-315.67), urinary tract infection (aOR, 5.25; 95% CI, 1.32-20.41), and length of stay (aOR, 1.12; 95% CI, 1.08-1.16). CONCLUSIONS: We identified various factors associated with nonhome discharge. Early identification of patients who are at risk for nonhome discharge is important for early discharge planning, which may decrease nonmedical delays and healthcare costs.