Tumor mutational burden predictability in head and neck squamous cell carcinoma patients treated with immunotherapy: systematic review and meta-analysis.

BACKGROUND: Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. METHODS: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. RESULTS: The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74-3.94; p < 0.0001) and a survival advantage (HR = 0.53; 95% CI 0.39-0.71; p < 0.0001) after ICI treatment. CONCLUSION: This is the first meta-analysis to demonstrate a higher response and clinical benefit from ICI therapy in HNSCC patients with high TMB.

The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease.

Background: In 2014, the Affordable Care Act Medicaid Expansion (ME) increased Medicaid eligibility for adults with an income level up to 138% of the federal poverty level. In this study, we examined the impact of ME on mortality and amputation in patients with peripheral artery disease (PAD). Methods: The 100% MedPAR and Part-B Carrier files from 2011 to 2018 were queried to identify all fee-for-service Medicare beneficiaries with PAD using International Classification of Diseases codes. Our primary exposure was whether a state had adopted the ME on January 1, 2014. Our primary outcomes were the change in all-cause 1-year mortality and leg amputation. We used a state-level difference-in-differences (DID) analysis to compare the rates of the primary outcomes among patients who were in states (including the District of Columbia) who adopted ME (n = 25) versus those who were in states that did not (n = 26). We performed a subanalysis stratifying by sex, race, region, and dual-eligibility status. Results: Over the 8-year period, we studied 37,743,929 patients. The average unadjusted 1-year mortality decreased from 2011 to 2018 in both non-ME (9.5% to 8.7%, p < 0.001) and ME (9.1% to 8.3%, p < 0.001) states. The average unadjusted 1-year amputation rate did not improve in either the non-ME (0.86% to 0.87%, p = 0.17) or ME (0.69% to 0.69%, p = 0.65) states. Across the entire cohort, the DID model revealed that ME did not lead to a significant change in mortality (p = 0.15) or amputation (p = 0.34). Conclusion: Medicaid Expansion was not associated with reduced mortality or leg amputation in Medicare beneficiaries with PAD.

Engagement in GI Behavioral Health Is Associated with Reduced Portal Messages, Phone Calls, and ED Visits.

BACKGROUND AND AIMS: Chronic digestive disorders are associated with increased costs for healthcare systems and often require provision of both urgent care and non-face-to-face (non-F2F) care, such as responding to patient messages. Numerous benefits of integrated gastroenterology (GI) behavioral health have been identified; however, it is unclear if integrated care impacts healthcare utilization, including urgent care and non-F2F contact. We sought to investigate the association between patient engagement with GI behavioral health and healthcare utilization. METHODS: We performed a retrospective chart review study of adult patients who were referred for and completed at least one behavioral health appointment between January 1, 2019 and December 21, 2021 in the Gastroenterology and Hepatology department of a large academic medical center. Data on electronic medical record (EMR) messages, phone calls, and Emergency Department utilization were collected 6 months before and 9 months after patient engagement with GI behavioral health. RESULTS: 466 adult patients completed at least one behavioral health visit from 2019 to 2021. Overall, messages, phone calls, and ED visits all decreased significantly from the 6 months before behavioral health treatment to 6 months after (all P values < 0.001). CONCLUSION: Engagement with integrated GI behavioral health is associated with reduced non-F2F care and emergency department utilization in patients with chronic digestive disorders. Increasing access to GI behavioral health may result in reduced provider workload and healthcare system costs.

Perioperative Primary Care Utilization and Postoperative Readmission, Emergency Department Use, and Mortality in Older Surgical Patients.

BACKGROUND: Postdischarge primary care follow-up is associated with lower readmission rates after medical hospitalizations. However, the effect of primary care utilization on readmission has not been studied in surgical patients. METHODS: Retrospective cohort study of Medicare beneficiaries aged 65 and older undergoing major inpatient diagnostic or therapeutic procedures (n = 3,552,906) from 2017 through 2018, examining the association between postdischarge primary care visits within 14 days of discharge (primary exposure), and Annual Wellness Visits in the year prior (secondary exposure), with 30-day unplanned readmission (primary outcome), emergency department visits, and mortality (secondary outcomes). RESULTS: Overall, 9.5% (n = 336,837) had postdischarge visits within 14 days, 2.9% (n = 104,571) had Annual Wellness Visits in the year preceding the procedure, 9.5% (n = 336,401) were readmitted, 9% (n = 319,054) had emergency department visits, and 0.6% (n = 22,103) of the cohort died within 30 days. Our fully adjusted propensity-matched proportional hazards Cox regression analysis showed that postdischarge visits were associated with a 5% lower risk of readmission (hazard ratio [HR], 0.95, 95% confidence interval [CI], 0.93-0.97), 43% higher risk of emergency department use (HR, 1.43, 95% CI, 1.40-1.46) and no difference in mortality risk (HR, 0.98, 95% CI, 0.90-1.06), compared with not having a visit within 14 days of discharge. In a separate set of regression models, Annual Wellness Visits were associated with a 9% lower risk of readmission (HR, 0.91, 95% CI, 0.88-0.95), 45% higher risk of emergency department utilization (HR, 1.45, 95% CI, 1.40-1.49) and an 18% lower mortality risk (HR, 0.82, 95% CI, 0.75-0.89) compared with no Annual Wellness Visit in the year before the procedure. CONCLUSIONS: Both postdischarge visits and the Medicare Annual Wellness Visit appear to be extremely underutilized among the older surgical population. In those patients who do utilize primary care, compared with propensity-matched patients who do not, our study suggests primary care use is associated with modestly lower readmission rates. Prospective studies are needed to determine whether targeted primary care involvement can reduce readmission.

Clinical History Does Not Reliably Predict Clinical Outcomes With Pelvic Floor Physical Therapy to Treat Chronic Constipation.

Chronic constipation affects 10%-20% of the population and impacts quality-of-life similarly to rheumatoid arthritis or congestive heart failure.1 We recently showed in a prospective clinical trial that up-front, community-based pelvic floor physical therapy is effective to treat chronic constipation for patients seeking general gastroenterology care after failing a brief trial of osmotic laxative or soluble fiber supplementation2 and can be guided by anorectal function testing.3,4 In this post hoc analysis, we aimed to evaluate whether factors on clinical history including specific symptoms, work-productivity impairment, health-related quality-of-life impairment, and psychological factors are useful to inform patient selection on the expected likelihood of clinical response without using anorectal function tests.

An Office-Based, Point-of-Care Test Predicts Treatment Outcomes With Community-Based Pelvic Floor Physical Therapy in Patients With Chronic Constipation.

BACKGROUND & AIMS: Rectal evacuation disorders are common among constipated patients. We aimed to evaluate the accuracy of an investigational point-of-care test (rectal expulsion device [RED]) to predict outcomes with community-based pelvic floor physical therapy. METHODS: We enrolled patients meeting Rome IV criteria for functional constipation failing fiber/laxatives for more than 2 weeks. RED was inserted and self-inflated, and then time-to-expel was measured in a left lateral position. All patients underwent empiric community-based pelvic floor physical therapy in routine care with outcomes measured at 12 weeks. The primary end point was global clinical response (Patient Assessment of Constipation Symptoms score reduction, >0.75 vs baseline). Secondary end points included improvement in health-related quality-of-life (Patient Assessment of Constipation Quality of Life score reduction, >1.0) and complete spontaneous bowel movement frequency (Food and Drug Administration complete spontaneous bowel movement responder definition). RESULTS: Thirty-nine patients enrolled in a feasibility phase to develop the use-case protocol. Sixty patients enrolled in a blinded validation phase; 52 patients (mean, 46.9 y; 94.2% women) were included in the intention-to-treat analysis. In the left lateral position, RED predicted global clinical response (generalized area under the curve [gAUC], 0.67; 95% CI, 0.58-0.76]), health-related quality-of-life response (gAUC, 0.67; 95% CI, 0.58-0.77; P < .001), and complete spontaneous bowel movement response (gAUC, 0.63; 95% CI, 0.57-0.71; P < .001). As a screening test, a normal RED effectively rules out evacuation disorders (expected clinical response, 8.9%; P = .042). Abnormal RED in the left lateral position (defined as expulsion within 5 seconds or >120 seconds) predicted 48.9% clinical response to physical therapy. A seated maneuver enhanced the likelihood of clinical response (71.1% response with seated RED retained >13 seconds) but likely is unnecessary in most settings. CONCLUSIONS: RED offers an opportunity to disrupt the paradigm by offering a personalized approach to managing chronic constipation in the community (Clinicaltrials.gov: NCT04159350).

Utility of Anorectal Testing to Predict Outcomes With Pelvic Floor Physical Therapy in Chronic Constipation: Pragmatic Trial.

BACKGROUND & AIMS: We performed a clinical trial that aimed to inform the clinical utility of anorectal manometry (ARM) and balloon expulsion time (BET) as up-front tests to predict outcomes with community-based pelvic floor physical therapy as the next best step to address chronic constipation after failing an empiric trial of soluble fiber supplementation or osmotic laxatives. METHODS: We enrolled 60 treatment-naïve patients with Rome IV functional constipation failing 2 weeks of soluble fiber supplementation or osmotic laxatives. All patients underwent ARM/BET (London protocol) followed by community-based pelvic floor physical therapy. Outcomes were assessed at baseline and 12 weeks. The primary end point was clinical response (Patient Assessment of Constipation-Symptoms instrument). RESULTS: Fifty-three patients completed pelvic rehabilitation and the post-treatment questionnaire. Contemporary frameworks define dyssynergia on balloon expulsion time and dyssynergic patterns (ARM), but these parameters did not inform clinical outcomes (area under the curve [AUC], <0.6). Squeeze pressure (>192.5 mm Hg on at least 1 of 3 attempts; sensitivity, 47.6%; specificity, 83.9%) and limited squeeze duration (inability to sustain 50% of squeeze pressure for >20 seconds; sensitivity, 71.4%; specificity, 58.1%) were the strongest predictors of clinical outcomes. Combining BET with squeeze duration (BET greater than 6.5 seconds and limited squeeze duration) improved predictive accuracy (AUC, 0.75; 95% CI, 0.59-0.90). BET poorly predicted outcomes as a single test (AUC, 0.54; 95% CI, 0.38-0.69). CONCLUSIONS: Using ARM to evaluate squeeze profiles, rather than dyssynergia, appears useful to screen patients with chronic constipation for up-front pelvic floor physical therapy based on likelihood of response. BET appears noninformative as a single screening test (ClinicalTrials.gov: NCT04159350).

Circulating miR-133a-3p defines a low-risk subphenotype in patients with heart failure and central sleep apnea: a decision tree machine learning approach.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and central sleep apnea (CSA) are at a very high risk of fatal outcomes. OBJECTIVE: To test whether the circulating miRNome provides additional information for risk stratification on top of clinical predictors in patients with HFrEF and CSA. METHODS: The study included patients with HFrEF and CSA from the SERVE-HF trial. A three-step protocol was applied: microRNA (miRNA) screening (n = 20), technical validation (n = 60), and biological validation (n = 587). The primary outcome was either death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening of heart failure, whatever occurred first. MiRNA quantification was performed in plasma samples using miRNA sequencing and RT-qPCR. RESULTS: Circulating miR-133a-3p levels were inversely associated with the primary study outcome. Nonetheless, miR-133a-3p did not improve a previously established clinical prognostic model in terms of discrimination or reclassification. A customized regression tree model constructed using the Classification and Regression Tree (CART) algorithm identified eight patient subphenotypes with specific risk patterns based on clinical and molecular characteristics. MiR-133a-3p entered the regression tree defining the group at the lowest risk; patients with log(NT-proBNP) ≤ 6 pg/mL (miR-133a-3p levels above 1.5 arbitrary units). The overall predictive capacity of suffering the event was highly stable over the follow-up (from 0.735 to 0.767). CONCLUSIONS: The combination of clinical information, circulating miRNAs, and decision tree learning allows the identification of specific risk subphenotypes in patients with HFrEF and CSA.

Anaesthesia clinicians' perception of safety, workload, anxiety, and stress in a remote hybrid suite compared with the operating room.

BACKGROUND: Anaesthesia care outside of the standard operating room (OR) can be challenging. This prospective matched case-pair study describes the difference in anaesthesia clinicians' perception of safety, workload, anxiety, and stress in two settings by comparing similar neurosurgical procedures performed in either the OR or a remote hybrid room with intraoperative MRI (MRI-OR). METHODS: A visual numeric scale for safety perception and validated instruments for workload, anxiety, and stress were administered to enrolled anaesthesia clinicians after induction of anaesthesia and at the end of eligible cases. The difference in outcomes reported by the same clinician for unique pairs of similar operations performed in both settings (OR vs MRI-OR) was compared using the Student t-test with the general bootstrap algorithm to address the presence of clusters. RESULTS: Over 15 months, 37 clinicians provided data for 53 case pairs. Working in the remote MRI-OR vs OR was associated with lower perceived safety (7.3 [2.0] vs 8.8 [0.9]; P<0.001), higher scores in the workload subdomains effort and frustration (41.6 [24.1] vs 31.3 [21.6]; P=0.006 and 32.4 [22.9] vs 20.7 [17.2]; P=0.002, respectively), and higher anxiety (33.6 [10.1] vs 28.4 [9.2]; P=0.003) at the end of the case. Stress was rated higher in the MRI-OR after induction of anaesthesia (26.5 [15.5] vs 20.9 [13.4]; P=0.006). Effect sizes (Cohen's D) were moderate to good. CONCLUSIONS: Anaesthesia clinicians reported lower perceived safety and higher workload, anxiety, and stress in a remote MRI-OR compared with a standard OR. Improving non-standard work settings should benefit clinician well-being and patient safety. CLINICAL TRIAL REGISTRATION: .

Chronic Pain and Mood Disorders Are Not Barriers to Symptom Improvement Under Collaborative Co-managed Care (C3).

OBJECTIVES: Patients with comorbid chronic pain and mood disorders have more severe gastrointestinal disease and higher healthcare expenses than their peers. We sought to determine whether management under our innovative Collaborative Co-Managed Care (C3) general gastroenterology care model improved outcomes. METHODS: Patient questionnaires completed by outpatients at our GI Motility Center were analyzed alongside demographic information to determine predictors of response to treatment based on adequate relief of gastrointestinal symptoms and improvement in quality of life. RESULTS: These comorbidities did not significantly impair response and may be associated with improved response under our model. CONCLUSIONS: The C3 general gastroenterology care model anchors on setting expectations and team-based communication and improves outcomes of, and access to, care.

Tracking between cardiovascular-related measures at 4 and 8 years of age in the INMA-Asturias cohort.

Identifying cardiovascular-related measures that track from early childhood into later ages may help inform early prevention targets for cardiovascular disease. In this study, the tracking of triglycerides (TG), high-density cholesterol (HDL-c), atherogenic coefficient (AC), waist circumference to height ratio (WC/Height), mean arterial pressure (MAP), and homeostatic model assessment of insulin resistance (HOMA-IR) was examined in the INMA-Asturias cohort between 4 and 8 years of age. The analysis was conducted in 307 children who participated in the INMA-Asturias cohort (Spain) at 4 and at 8 years of age. Quantile regression models were used to evaluate tracking between measures at both ages, with each measure at 8 years as the dependent variable and the rank transformation of the same measure at 4 years as the independent variable. We found a positive association between HDL-c rank at 4 years and higher quantiles of the HDL-c distribution at 8 years, with an increase of 2.93 mg/dL (95% CI: 1.98, 3.87) per decile in the 0.9 quantile. A positive association was also found for WC/Height, with an increase of 0.008 (95% CI: 0.004, 0.012) per decile in the 0.9 quantile. We observed that tracking for AC increased in the higher quantiles of the distribution at 8 years, with an increase of 0.11 (95% CI: 0.09, 0.14) in the 0.6 quantile compared to an effect of 0.15 (95% CI: 0.09, 0.21) in the 0.9 quantile.  Conclusions: Adult markers of dyslipidemia and central obesity tracked between ages 4 and 8 years. For AC, tracking increased in the higher quantiles of the distribution. What is Known: • Atherosclerosis begins in early life, so preventive efforts that start in childhood may delay progression to clinical disease. Determine what cardiovascular risk factors track into time since childhood bring the opportunity to identified those subjects at risk for later cardiovascular disease. • The study of risk factors in health populations and, particularly in children, copes with not clear and/or controversial thresholds definition. This makes it challenging to study tracking in pediatric ages. What is New: • Quantile regression is a useful tool for assessing the tracking of risk factors for which there are no clinically meaningful thresholds. The increasing trend observed in the tracking of dyslipidemia suggests the possible difficulty that children with abnormal values at 4 years of age might have in normalizing them in future years. • The findings of this article may help to determine which cardiovascular-related measures could be screened and followed-up in children.

Distinct spectral dynamics of implanted cardiac defibrillator signals in spontaneous termination of polymorphic ventricular tachycardia and fibrillation in patients with electrical and structural diseases.

AIMS: To determine the spectral dynamics of early spontaneous polymorphic ventricular tachycardia and ventricular fibrillation (PVT/VF) in humans. METHODS AND RESULTS: Fifty-eight self-terminated and 173 shock-terminated episodes of spontaneously initiated PVT/VF recorded by Medtronic implanted cardiac defibrillators (ICDs) in 87 patients with various cardiac pathologies were analyzed by short fast Fourier transform of shifting segments to determine the dynamics of dominant frequency (DF) and regularity index (RI). The progression in the intensity of DF and RI accumulations further quantified the time course of spectral characteristics of the episodes. Episodes of self-terminated PVT/VF lasted 8.6 s [95% confidence interval (CI): 8.1-9.1] and shock-terminated lasted 13.9 s (13.6-14.3) (P < 0.001). Recordings from patients with primarily electrical pathologies displayed higher DF and RI values than those from patients with primarily structural pathologies (P < 0.05) independently of ventricular function or antiarrhythmic drug therapy. Regardless of the underlying pathology, the average DF and RI intensities were lower in self-terminated than shock-terminated episodes [DF: 3.67 (4.04-4.58) vs. 4.32 (3.46-3.93) Hz, P < 0.001; RI: 0.53 (0.48-0.56) vs. 0.63 (0.60-0.65), P < 0.001]. In a multivariate analysis controlled by the type of pathology and clinical variables, regularity remained an independent predictor of self-termination [hazard ratio: 0.954 (0.928-0.980)]. Receiver operating characteristic (ROC) curve analysis of DF and RI intensities demonstrated increased predictability for self-termination in time with 95% CI above the 0.5 cut-off limit at about t = 8.6 s and t = 6.95 s, respectively. CONCLUSION: Consistent with the notion that fast organized sources maintain PVT/VF in humans, reduction of frequency and regularity correlates with early self-termination. Our findings might help generate ICD methods aiming to reduce inappropriate shock deliveries.

A Processed Electroencephalogram-Based Brain Anesthetic Resistance Index Is Associated With Postoperative Delirium in Older Adults: A Dual Center Study.

BACKGROUND: Some older adults show exaggerated responses to drugs that act on the brain. The brain's response to anesthetic drugs is often measured clinically by processed electroencephalogram (EEG) indices. Thus, we developed a processed EEG-based measure of the brain's resistance to volatile anesthetics and hypothesized that low scores on it would be associated with postoperative delirium risk. METHODS: We defined the Duke Anesthesia Resistance Scale (DARS) as the average bispectral index (BIS) divided by the quantity (2.5 minus the average age-adjusted end-tidal minimum alveolar concentration [aaMAC] inhaled anesthetic fraction). The relationship between DARS and postoperative delirium was analyzed in 139 older surgical patients (age ≥65) from Duke University Medical Center (n = 69) and Mt Sinai Medical Center (n = 70). Delirium was assessed by geriatrician interview at Duke, and by research staff utilizing the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) instrument at Mt Sinai. We examined the relationship between DARS and delirium and used the Youden index to identify an optimal low DARS threshold (for delirium risk), and its associated 95% bootstrap confidence bounds. We used multivariable logistic regression to examine the relationship between low DARS and delirium risk. RESULTS: The relationship between DARS and delirium risk was nonlinear, with higher delirium risk at low DARS scores. A DARS threshold of 28.755 maximized the Youden index for the association between low DARS and delirium, with bootstrap 95% confidence bounds of 26.18 and 29.80. A low DARS (<28.755) was associated with increased delirium risk in multivariable models adjusting for site (odds ratio [OR] [95% confidence interval {CI}] = 4.30 [1.89-10.01]; P = .001), or site-plus-patient risk factors (OR [95% CI] = 3.79 [1.63-9.10]; P = .003). These associations with postoperative delirium risk remained significant when using the 95% bootstrap confidence bounds for the low DARS threshold (P < .05 for all). Further, a low DARS (<28.755) was associated with delirium risk after accounting for opioid, midazolam, propofol, phenylephrine, and ketamine dosage as well as site (OR [95% CI] = 4.21 [1.80-10.16]; P = .002). This association between low DARS and postoperative delirium risk after controlling for these other medications remained significant (P < .05) when using either the lower or the upper 95% bootstrap confidence bounds for the low DARS threshold. CONCLUSIONS: These results demonstrate that an intraoperative processed EEG-based measure of lower brain anesthetic resistance (ie, low DARS) is independently associated with increased postoperative delirium risk in older surgical patients.

The Effect of Antiseizure Medication Administration on Mortality and Early Posttraumatic Seizures in Critically Ill Older Adults with Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Older adults represent an understudied and growing TBI population. Current Brain Trauma Foundation guidelines support prophylactic antiseizure medication (ASM) administration to reduce the risk of early posttraumatic seizures (within 7 days of injury) in patients with severe TBI. Whether ASM decreases mortality or early seizure risk in this population remains unclear. This study addresses the knowledge gap regarding the impact of ASM administration on the risk of seizure or mortality after TBI in patients more than 65 years of age. METHODS: This retrospective cohort study used a publicly available data set from the Medical Information Mart for Intensive Care-III from the Massachusetts Institute of Technology. Our cohort included patients 65 years or older with a primary exposure of early ASM administration with TBI resulting in an intensive care unit (ICU) admission in a level I trauma center from 2001 to 2012. A double-robust inverse propensity scale weighted model on the basis of proportional hazard and logistic regression models was created to assess the association between ASM administration and risk of death within 7 days of admission to the ICU. Secondary outcomes included 30-day mortality and 1-year mortality, early posttraumatic seizures, ICU length of stay, and hospital length of stay. RESULTS: Of 1145 patients 65 years or older with TBI admitted to an ICU, 783 (68.4%) received ASM within the first 24 h. Patients meeting inclusion criteria were predominantly white (83.8%) and were male (52.3%), with a median (interquartile range) age of 81 (74-86) years. TBI severity, classified by Glasgow Coma Score, was predominantly mild (71.2%), followed by moderate (16.8%) and severe (11.3%). Patients who received ASM were less likely to have died at 7 days (adjusted death hazard ratio [HR] = 0.48 [95% confidence interval {CI} 0.28-0.88], P = 0.005), at 30 days (adjusted HR 0.67 [95% CI 0.45-0.99], P = 0.045), and at 1 year (adjusted HR 0.72 [95% CI 0.54-0.97], P = 0.029). Groups were not different in regard to seizure (adjusted seizure odds ratio 1.18 [95% CI 0.61-2.26]) compared with those who did not receive ASM. CONCLUSIONS: Early ASM administration was associated with reduced mortality at 7 days, 30 days, and 1 year but did not decrease the risk of early seizures among older adults who presented with TBI at an ICU. This benefit was observed in mild, moderate, and severe TBI assessed by Glasgow Coma Score on presentation among patients 65 years old and older and suggests broader recommendations for the use of ASM in older adults who present with TBI of any severity at an ICU.

Long-term Reintervention After Endovascular Abdominal Aortic Aneurysm Repair.

OBJECTIVE: To describe the long-term reintervention rate after endovascular abdominal aortic aneurysm repair (EVR), and identify factors predicting reintervention. SUMMARY OF BACKGROUND DATA: EVR is the most common method of aneurysm repair in America, and reintervention after EVR is common. Clinical factors predicting reintervention have not been described in large datasets with long-term follow-up. METHODS: We studied patients who underwent EVR using the Vascular Quality Initiative registry linked to Medicare claims. Our primary outcome was reintervention, defined as any procedure related to the EVR after discharge from the index hospitalization. We used classification and regression tree modeling to inform a multivariable Cox-regression model predicting reintervention after EVR. RESULTS: We studied 12,911 patients treated from 2003 to 2015. Mean age was 75.5 ±â€Š7.3 years, 79.9% were male, and 89.1% of operations were elective. The 3-year reintervention rate was 15%, and the 10-year rate was 33%. Five factors predicted reintervention: operative time ≥3.0 hours, aneurysm diameter ≥6.0 cm, an iliac artery aneurysm ≥2.0 cm, emergency surgery, and a history of prior aortic surgery. Patients with no risk factors had a 3-year reintervention rate of 12%, and 10-year rate of 26% (n = 7310). Patients with multiple risk factors, such as prior aortic surgery and emergent surgery, had a 3-year reintervention rate 72%, (n = 32). Modifiable factors including EVR graft manufacturer or supra-renal fixation were not associated with reintervention (P = 0.76 and 0.79 respectively). CONCLUSIONS: All patients retain a high likelihood of reintervention after EVR, but clinical factors at the time of repair can predict those at highest risk.

Plasma circular RNA hsa_circ_0001445 and coronary artery disease: Performance as a biomarker.

The role of circular RNAs (circRNAs) as biomarkers remains poorly characterized. Here, we investigated the performance of the circRNA hsa_circ_0001445 as a biomarker of coronary artery disease (CAD) in a real-world clinical practice setting. Plasma hsa_circ_0001445 was measured in a study population of 200 consecutive patients with suspected stable CAD who had undergone coronary computed tomographic angiography (CTA). Multivariable logistic models were constructed combining conventional risk factors with established biomarkers and hsa_circ_0001445. Model robustness was internally validated by the bootstrap technique. Biomarker accuracy was evaluated using the C-index. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were also calculated. Risk groups were developed via classification tree models. The stability of plasma hsa_circ_0001445 was evaluated under different clinical conditions. hsa_circ_0001445 levels were associated with higher coronary atherosclerosis extent and severity with a 2-fold increase across tertiles (28.4%-50.0%). Levels of hsa_circ_0001445 were proportional to coronary atherosclerotic burden, even after comprehensive adjustment for cardiovascular risk factors, medications, and established biomarkers (fully adjusted OR = 0.432 for hsa_circ_0001445 as a continuous variable and fully adjusted OR = 0.277 for hsa_circ_0001445 as a binary variable). The classification of patients was improved with the incorporation of hsa_circ_0001445 into a base clinical model (CM) composed of conventional cardiovascular risk factors, showing an IDI of 0.047 and NRI of 0.482 for hsa_circ_0001445 as a continuous variable and an IDI of 0.056 and NRI of 0.373 for hsa_circ_0001445 as a binary variable. A trend toward higher discrimination capacity was also observed (C-indexCM  = 0.833, C-indexCM+continuous hsa_circ_0001445  = 0.856 and C-indexCM+binary hsa_circ_0001445  = 0.855). Detailed analysis of stability showed that hsa_circ_0001445 was present in plasma in a remarkably stable form. In vitro, hsa_circ_0001445 was downregulated in extracellular vesicles secreted by human coronary smooth muscle cells upon exposure to atherogenic conditions. In patients with suspected stable CAD referred for coronary CTA, plasma hsa_circ_0001445 improves the identification of coronary artery atherosclerosis.

Time dependent hazard ratio estimation using instrumental variables without conditioning on an omitted covariate.

BACKGROUND: Estimation that employs instrumental variables (IV) can reduce or eliminate bias due to confounding. In observational studies, instruments result from natural experiments such as the effect of clinician preference or geographic distance on treatment selection. In randomized studies the randomization indicator is typically a valid instrument, especially if the study is blinded, e.g. no placebo effect. Estimation via instruments is a highly developed field for linear models but the use of instruments in time-to-event analysis is far from established. Various IV-based estimators of the hazard ratio (HR) from Cox's regression models have been proposed. METHODS: We extend IV based estimation of Cox's model beyond proportionality of hazards, and address estimation of a log-linear time dependent hazard ratio and a piecewise constant HR. We estimate the marginal time-dependent hazard ratio unlike other approaches that estimate the hazard ratio conditional on the omitted covariates. We use estimating equations motivated by Martingale representations that resemble the partial likelihood score statistic. We conducted simulations that include the use of copulas to generate potential times-to-event that have a given marginal structural time dependent hazard ratio but are dependent on omitted covariates. We compare our approach to the partial likelihood estimator, and two other IV based approaches. We apply it to estimation of the time dependent hazard ratio for two vascular interventions. RESULTS: The method performs well in simulations of a stepwise time-dependent hazard ratio, but illustrates some bias that increases as the hazard ratio moves away from unity (the value that typically underlies the null hypothesis). It compares well to other approaches when the hazard ratio is stepwise constant. It also performs well for estimation of a log-linear hazard ratio where no other instrumental variable approaches exist. CONCLUSION: The estimating equations we propose for estimating a time-dependent hazard ratio using an IV perform well in simulations. We encourage the use of our procedure for time-dependent hazard ratio estimation when unmeasured confounding is a concern and a suitable instrumental variable exists.

Adjusting for bias introduced by instrumental variable estimation in the Cox proportional hazards model.

Instrumental variable (IV) methods are widely used for estimating average treatment effects in the presence of unmeasured confounders. However, the capability of existing IV procedures, and most notably the two-stage residual inclusion (2SRI) algorithm recommended for use in non-linear contexts, to account for unmeasured confounders in the Cox proportional hazard model is unclear. We show that instrumenting an endogenous treatment induces an unmeasured covariate, referred to as an individual frailty in survival analysis parlance, which if not accounted for leads to bias. We propose a new procedure that augments 2SRI with an individual frailty and prove that it is consistent under certain conditions. The finite sample-size behavior is studied across a broad set of conditions via Monte Carlo simulations. Finally, the proposed methodology is used to estimate the average effect of carotid endarterectomy versus carotid stenting on the mortality of patients suffering from carotid artery disease. Results suggest that the 2SRI-frailty estimator generally reduces the bias of both point and interval estimators compared to traditional 2SRI.

Five-year reintervention after endovascular abdominal aortic aneurysm repair in the Vascular Quality Initiative.

OBJECTIVE: Patients who undergo endovascular abdominal aortic aneurysm repair (EVR) remain at risk for reintervention and rupture. We sought to define the 5-year rate of reintervention and rupture after EVR in the Vascular Quality Initiative (VQI). METHODS: We identified all patients in the VQI who underwent EVR from 2003 to 2015. We linked patients in the VQI to Medicare claims for long-term outcomes. We stratified patients on baseline clinical and procedural characteristics to identify those at risk for reintervention. Our primary outcomes were 5-year rates of reintervention and late aneurysm rupture after EVR. We assessed these with Kaplan-Meier survival estimation. RESULTS: We studied 12,911 patients who underwent EVR. The mean age was 75.5 years, 79.9% were male, 3.9% were black, and 89.1% of operations were performed electively. The 5-year rate of reintervention for the entire cohort was 21%, and the 5-year rate of late aneurysm rupture was 3%. Reintervention rates varied across categories of EVR urgency. Patients who underwent EVR electively had the lowest 5-year rate of reintervention at 20%. Those who underwent surgery for symptomatic aneurysms had higher rates of reintervention at 25%. Patients undergoing EVR emergently for rupture had the highest rate of reintervention, 27% at 4 years (log-rank across the three groups, P < .001). Black race and aneurysm size of 6.0 cm or greater were associated with significantly elevated reintervention rates (black, 31% vs white, 20% [log-rank, P < .001]; aneurysm size 6.0 cm or greater, 27% vs all others, <20% [log-rank, P < .001]). There were no significant associations between age or gender and the 5-year rate of reintervention. CONCLUSIONS: More than one in five Medicare patients undergo reintervention within 5 years after EVR in the VQI; late rupture remains low at 3%. Black patients, those with large aneurysms, and those who undergo EVR urgently and emergently have a higher likelihood of adverse outcomes and should be the focus of diligent long-term surveillance.

Peripheral, Interictal Serum S100B Levels are Not Increased in Chronic Migraine Patients.

BACKGROUND: The trigemino-vascular system (TVS) plays a key role in migraine pathophysiology. Glial cells are abundant in the TVS system and mainly in the trigeminal ganglion. S100B protein is a calcium-binding protein, found in the cytoplasm of glial cells in the central nervous system, which is released in response to inflammatory stimuli. Previous works analyzing S100B in migraineurs have offered contradictory results. OBJECTIVE: In this case-control study, we analyzed serum levels of S100B as a possible biomarker of the glial TVS activation in chronic migraine (CM). PATIENTS AND METHODS: The study group consisted of patients attending our clinic with CM and, as control groups, patients with episodic migraine (EM), cluster headache (CH) outside of a bout and healthy volunteers (HV) with no headache history. S100B levels were determined interictally in peripheral blood samples by ELISA. RESULTS: We assessed serum samples from 43 patients with CM, 19 with EM, 29 HV (mostly women), and 22 with (CH). S100B levels in CM (mean 22.9 ± 9.8 pg/mL) were not different (P = .727) when compared to EM patients (21.2 ± 9.3 pg/mL), difference of 1.7 (95% CI -5.7 to 8.9), CH patients (22.4 ± 7.8 pg/mL), difference of 0.5 (-5.7 to 6.7), and HV (20.6 ± 8.3 pg/mL), difference of 2.3 (-3.7 to 8.3). CONCLUSION: In contrast to other neuropeptides such as calcitonin gene-related-peptide and vasoactive intestinal peptide, which are increased in CM, interictal serum S100B levels are not elevated in these patients. According to our results, S100B levels do not seem to be a useful peripheral biomarker of the glial TVS activation in CM.