A clinical prediction model for 10-year risk of self-reported osteoporosis diagnosis in pre- and perimenopausal women.

A machine learning model using clinical, laboratory, and imaging data was developed to predict 10-year risk of menopause-related osteoporosis. The resulting predictions, which are sensitive and specific, highlight distinct clinical risk profiles that can be used to identify patients most likely to be diagnosed with osteoporosis. PURPOSE: The aim of this study was to incorporate demographic, metabolic, and imaging risk factors into a model for long-term prediction of self-reported osteoporosis diagnosis. METHODS: This was a secondary analysis of 1685 patients from the longitudinal Study of Women's Health Across the Nation using data collected between 1996 and 2008. Participants were pre- or perimenopausal women between 42 and 52 years of age. A machine learning model was trained using 14 baseline risk factors-age, height, weight, body mass index, waist circumference, race, menopausal status, maternal osteoporosis history, maternal spine fracture history, serum estradiol level, serum dehydroepiandrosterone level, serum thyroid-stimulating hormone level, total spine bone mineral density, and total hip bone mineral density. The self-reported outcome was whether a doctor or other provider had told participants they have osteoporosis or treated them for osteoporosis. RESULTS: At 10-year follow-up, a clinical osteoporosis diagnosis was reported by 113 (6.7%) women. Area under the receiver operating characteristic curve of the model was 0.83 (95% confidence interval, 0.73-0.91) and Brier score was 0.054 (95% confidence interval, 0.035-0.074). Total spine bone mineral density, total hip bone mineral density, and age had the largest contributions to predicted risk. Using two discrimination thresholds, stratification into low, medium, and high risk, respectively, was associated with likelihood ratios of 0.23, 3.2, and 6.8. At the lower threshold, sensitivity was 0.81, and specificity was 0.82. CONCLUSION: The model developed in this analysis integrates clinical data, serum biomarker levels, and bone mineral densities to predict 10-year risk of osteoporosis with good performance.

Key Thresholds and Relative Contributions of Knee Geometry, Anteroposterior Laxity, and Body Weight as Risk Factors for Noncontact ACL Injury.

Background: Limited data exist regarding the association of tibiofemoral bony and soft tissue geometry and knee laxity with risk of first-time noncontact anterior cruciate ligament (ACL) rupture. Purpose: To determine associations of tibiofemoral geometry and anteroposterior (AP) knee laxity with risk of first-time noncontact ACL injury in high school and collegiate athletes. Study Design: Cohort study; Level of evidence, 2. Methods: Over a 4-year period, noncontact ACL injury events were identified as they occurred in 86 high school and collegiate athletes (59 female, 27 male). Sex- and age-matched control participants were selected from the same team. AP laxity of the uninjured knee was measured using a KT-2000 arthrometer. Magnetic resonance imaging was taken on ipsilateral and contralateral knees, and articular geometries were measured. Sex-specific general additive models were implemented to investigate associations between injury risk and 6 features: ACL volume, meniscus-bone wedge angle in the lateral compartment of the tibia, articular cartilage slope at the middle region of the lateral compartment of the tibia, femoral notch width at the anterior outlet, body weight, and AP displacement of the tibia relative to the femur. Importance scores (in percentages) were calculated to rank the relative contribution of each variable. Results: In the female cohort, the 2 features with the highest importance scores were tibial cartilage slope (8.6%) and notch width (8.1%). In the male cohort, the 2 top-ranked features were AP laxity (5.6%) and tibial cartilage slope (4.8%). In female patients, injury risk increased by 25.5% with lateral middle cartilage slope becoming more posteroinferior from -6.2° to -2.0° and by 17.5% with lateral meniscus-bone wedge angle increasing from 27.3° to 28.2°. In males, an increase in AP displacement from 12.5 to 14.4 mm in response to a 133-N anterior-directed load was associated with a 16.7% increase in risk. Conclusion: Of the 6 variables studied, there was no single dominant geometric or laxity risk factor for ACL injury in either the female or male cohort. In males, AP laxity >13 to 14 mm was associated with sharply increased risk of noncontact ACL injury. In females, lateral meniscus-bone wedge angle >28° was associated with a sharply decreased risk of noncontact ACL injury.

Novel Arthrometer for Quantifying In Vivo Knee Laxity in Three Planes Following Total Knee Arthroplasty.

BACKGROUND: Knee instability is a leading cause of dissatisfaction following total knee arthroplasty (TKA). Instability can involve abnormal laxity in multiple directions including varus-valgus (VV) angulation, anterior-posterior (AP) translation, and internal-external rotation (IER). No existing arthrometer objectively quantifies knee laxity in all three of these directions. The study objectives were to verify the safety and assess reliability of a novel multiplanar arthrometer. METHODS: The arthrometer utilized a five degree-of-freedom instrumented linkage. Two examiners each conducted two tests on the leg that had received a TKA of 20 patients (mean age 65 years (range, 53-75); 9 men, 11 women), with nine and eleven distinct patients tested at 3-month and 1-year postoperative time points, respectively. AP forces from -10 to 30 Newtons, VV moments of ±3 Newton-meters, and IER moments of ±2.5 Newton-meters were applied to each subject's replaced knee. Severity and location of knee pain during testing were assessed using a visual analog scale. Intraexaminer and interexaminer reliabilities were characterized using intraclass correlation coefficients. RESULTS: All subjects successfully completed testing. Pain during testing averaged 0.7 (out of possible 10; range, 0-2.5). Intraexaminer reliability was >0.77 for all loading directions and examiners. Interexaminer reliability and 95% confidence intervals were 0.85 (0.66-0.94), 0.67 (0.35-0.85), and 0.54 (0.16-0.79) in the VV, IER, and AP directions, respectively. CONCLUSION: The novel arthrometer was safe for evaluating AP, VV, and IER laxities in subjects who had received TKA. This device could be used to examine relationships between laxity and patient perceptions of knee instability.

Does the Hospital Day of Surgery for Endovascular Repair of Symptomatic Abdominal Aortic Aneurysms Affect Outcomes?

OBJECTIVE: Symptomatic abdominal aortic aneurysms (sAAA) are considered surgically urgent. Recent data suggest delaying surgery allows for medical optimization without affecting outcomes. We investigated the association of the hospital day of surgery with 30 day outcomes. METHODS: Patients with infrarenal sAAA undergoing endovascular aortic repair (EVAR) between 2011 and 2018 in the American College of Surgeons National Surgery Quality Improvement Project database were included. The primary outcome was 30 day mortality. Additional outcomes included myocardial infarction, pulmonary complications, length of stay, and discharge disposition. Days-to-surgery were classified as the day of presentation (D0), day 1, day 2, days 3 and 4, days 5 to 7 (D5), and day 8 or more (D8). RESULTS: A total of 804 patients were identified. D8 patients had higher proportions of dyspnea on exertion, chronic obstructive pulmonary disease, congestive heart failure, and history of dialysis. D0 surgery appeared protective of mortality (odds ratio [OR] 0.34, p=0.0132). Each additional day increased the mortality risk (OR 1.23, p<0.001) although not within the first 4 days. There was increased mortality for patients having surgery at D5 (7.7%) and D8 (23.8%) compared with repair earlier (1%-4%, p=0.03). Bivariable analysis revealed no significant differences in secondary outcomes. Multivariable modeling revealed increased mortality for D8 versus D0 (adjusted OR of 6.8, 95% confidence interval 1.7-26.5). CONCLUSIONS: While D0 appears to have the lowest risk of mortality, EVAR for sAAA up to 4 days may not be associated with increased mortality. Further research should determine delay etiologies and whether they improve operative planning and optimization without impacting morbidity and mortality.

The order of surgery and chemotherapy matters: Multimodality therapy and stage-specific differences in survival in gastric cancer.

BACKGROUND AND OBJECTIVES: Multimodality treatment improves survival for gastric cancer (GC). However, the effect of treatment sequence by stage remains unclear. We aim to compare outcomes between patients receiving neoadjuvant(neoadj) and adjuvant chemotherapy (adj). METHODS: Nonmetastatic GC patients with clinical stage ≥ T2N0 who underwent both resection and neoadj or adj were identified using the National Cancer Database (2005-2014). Multivariable Cox regression analyses were performed on propensity score-matched (PSM) cohorts stratified by stage to compare overall survival (OS). RESULTS: We identified 11 984 patients; 55% stage I (SI), 76% stage II (SII) and 57% stage III (SIII) received neoadj. Unadjusted analysis showed worse survival among SI neoadj patients (hazard ratio [HR] 1.195, confidence interval [CI] 1.04-1.38) and improved survival for SII (HR 0.93 CI 0.87-0.998) and SIII (HR 0.75, CI 0.68-0.84). After PSM, SI patients with neoadj had worse OS with increased risk of death compared to Adj (HR 1.186, CI 1.004-1.402). SII patients had no difference in OS (HR 0.98, CI 0.91-1.07) and SIII patients had improved OS (HR 0.78, CI 0.69-0.90). CONCLUSIONS: In patients who received surgery and chemotherapy, the benefit of neoadj was limited to SIII with worse survival for SI. A clinical trial to examine the optimal sequence of chemotherapy is warranted.

Tumescent local anesthesia versus general anesthesia for subcutaneous implantable cardioverter-defibrillator implantation: A cost-effectiveness analysis.

BACKGROUND: General anesthesia (GA) is the standard anesthetic approach for subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation. Nonetheless, GA is expensive and can be associated with adverse events. Tumescent local anesthesia (TLA) has been shown to reduce in-room and procedural times and to decrease post-procedural pain, all of which could result in a reduction in procedure-related costs. OBJECTIVE: The purpose of this study is to compare the cost-effectiveness of GA and TLA in patients undergoing S-ICD implantation. METHODS: The present study is a prospective, nonrandomized, controlled study of patients who underwent S-ICD implantation between 2019 and 2022. Patients were allocated to either the TLA or the GA group. We performed a cost analysis for each intervention. As an effectiveness measure, the 0-10 point Numeric Pain Rating Scale at 1, 12, and 24 hours post-implantation was analyzed and compared between the groups. A score of 0 was considered no pain; 1-5, mild pain; 6-7, moderate pain; and 8-10, severe pain. Cost-effectiveness was calculated using incremental cost-effectiveness ratios. RESULTS: Seventy patients underwent successful S-ICD implantation. The total cost of the electrophysiology laboratory was higher in the GA group than in the TLA group (median ± interquartile range US$55,824 ± US$29,411 vs US$37,222 ± US$24,293; P < .001), with a net saving of $20,821 when compared with GA for each S-ICD implantation. There was a significant decrease in post-procedural pain scores in the TLA group when compared with the GA group (repeated measures analysis of variance, P = .009; median ± interquartile range 0 ± 3 vs 0 ± 5 at 1 hour, P = .058; 3 ± 4 vs 6 ± 8 at 12 hours, P = .030; 0 ± 4 vs 2 ± 6 at 24 hours, P = .040). CONCLUSION: TLA is a more cost-effective alternative to GA for S-ICD implantation, with both direct and indirect cost reductions. Importantly, these reduced costs are associated with reduced postprocedural pain.

Serum Pepsinogen as a Biomarker for Gastric Cancer in the United States: A Nested Case-Control Study Using the PLCO Cancer Screening Trial Data.

BACKGROUND: Gastric cancer lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, a gastric cancer precursor, and may be useful to detect persons at increased risk of gastric cancer. METHODS: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was conducted in the United States between 1993 and 2001. ELISA-based pepsinogen tests were conducted on prediagnostic serum samples of 105 PLCO participants who developed gastric cancer and 209 age, sex, and race-matched controls. Pepsinogen positive (PG+) was defined as pepsinogen I ≤ 70 µg/L and pepsinogen I/II ratio ≤3.0. Results of conditional logistic regression models, and sensitivity and specificity, of PG+ for gastric cancer are reported. RESULTS: Gastric cancer cases were more likely to be PG+ (31.4% vs. 5.5%, P < 0.001) at baseline than controls. Compared to PG-, PG+ was associated with an 8.5-fold increased risk for gastric cancer [95% confidence interval (CI) = 3.8-19.4]. This risk remained significant after adjusting for Helicobacter pylori, family history of gastric cancer, education, smoking, and BMI (aOR, 10.6; 95% CI, 4.3-26.2). In subgroup analysis, PG+ individuals were 11-fold more like to develop non-cardia gastric cancer (OR, 11.1; 95% CI, 4.3-28.8); conversely, they were not significantly more likely to develop cardia gastric cancer (OR, 2.0; 95% CI = 0.3-14.2). PG+ status yielded low sensitivity but high specificity for both noncardia (44.3%; 93.6%) and cardia gastric cancer (5.7%; 97.2%). CONCLUSIONS: Prediagnostic serum pepsinogen levels from a large, prospective cohort study were associated with risk of gastric cancer, particularly noncardia gastric cancer. IMPACT: PG status may identify individuals at higher risk of noncardia gastric cancer for targeted screening or interventions. See related commentary by Zhou and Huang, p. 1257.

Relation of Community-Level Socioeconomic Status to Delayed Diagnosis of Acute Type A Aortic Dissection.

Acute type A aortic dissection requires timely diagnosis and intervention. Previous studies have examined risk factors associated with delayed diagnosis; however, the effect of socioeconomic status (SES) has not been previously studied. Our study examined the impact of various SES measures on time to diagnosis. We examined time to diagnosis in consecutive cases of acute type A aortic dissection at a single institution. SES variables included race/ethnicity, Medicaid eligibility, and residence in a zip code with an increased Distressed Communities Index-an aggregate measure of community SES. Delayed diagnosis was defined as time to diagnosis in the upper quartile of the study population (>6.6 hours). A model predicting risk factors for delayed diagnosis was created using multivariable logistic regression. Our study included 124 patients with a median time to diagnosis of 3.36 hours (interquartile range [IQR] 1.83 to 6.63). A total of 92 patients were in the nondelayed cohort (median diagnosis time of 2.59 hours, IQR 1.49 to 4.18) and 32 patients were in the delayed cohort (median diagnosis time of 15.57 hours, IQR 9.34 to 28.75). In multivariable logistic regression, residence in a high-Distressed Communities Index zip code was associated with diagnostic delay (adjusted odds ratio [aOR] 5.108, p = 0.008). Patient age (aOR 0.944, p = 0.011), chest pain at presentation (aOR 0.099, p = 0.004), back pain at presentation (aOR 0.247, p = 0.012), evidence of malperfusion syndrome (aOR 0.040, p <0.001), history of hyperlipidemia (aOR 3.507, p = 0.026), and history of congestive heart failure (aOR 0.061, p = 0.036) were also significantly associated. In conclusion, our findings suggest community-level SES affects time to diagnosis in acute type A aortic dissection.

Concomitant Tricuspid Repair in Patients with Degenerative Mitral Regurgitation.

BACKGROUND: Tricuspid regurgitation is common in patients with severe degenerative mitral regurgitation. However, the evidence base is insufficient to inform a decision about whether to perform tricuspid-valve repair during mitral-valve surgery in patients who have moderate tricuspid regurgitation or less-than-moderate regurgitation with annular dilatation. METHODS: We randomly assigned 401 patients who were undergoing mitral-valve surgery for degenerative mitral regurgitation to receive a procedure with or without tricuspid annuloplasty (TA). The primary 2-year end point was a composite of reoperation for tricuspid regurgitation, progression of tricuspid regurgitation by two grades from baseline or the presence of severe tricuspid regurgitation, or death. RESULTS: Patients who underwent mitral-valve surgery plus TA had fewer primary-end-point events than those who underwent mitral-valve surgery alone (3.9% vs. 10.2%) (relative risk, 0.37; 95% confidence interval [CI], 0.16 to 0.86; P = 0.02). Two-year mortality was 3.2% in the surgery-plus-TA group and 4.5% in the surgery-alone group (relative risk, 0.69; 95% CI, 0.25 to 1.88). The 2-year prevalence of progression of tricuspid regurgitation was lower in the surgery-plus-TA group than in the surgery-alone group (0.6% vs. 6.1%; relative risk, 0.09; 95% CI, 0.01 to 0.69). The frequencies of major adverse cardiac and cerebrovascular events, functional status, and quality of life were similar in the two groups at 2 years, although the incidence of permanent pacemaker implantation was higher in the surgery-plus-TA group than in the surgery-alone group (14.1% vs. 2.5%; rate ratio, 5.75; 95% CI, 2.27 to 14.60). CONCLUSIONS: Among patients undergoing mitral-valve surgery, those who also received TA had a lower incidence of a primary-end-point event than those who underwent mitral-valve surgery alone at 2 years, a reduction that was driven by less frequent progression to severe tricuspid regurgitation. Tricuspid repair resulted in more frequent permanent pacemaker implantation. Whether reduced progression of tricuspid regurgitation results in long-term clinical benefit can be determined only with longer follow-up. (Funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research; ClinicalTrials.gov number, NCT02675244.).

Perioperative outcomes of carotid endarterectomy and transfemoral and transcervical carotid artery stenting in radiation-induced carotid lesions.

OBJECTIVE: Limited data are available to guide the choice of intervention for patients with radiation-induced carotid stenosis (RICS), either transcarotid artery revascularization (TCAR), transfemoral carotid artery stenting (TFCAS), or carotid endarterectomy (CEA). The purpose of the present study was to evaluate patients who had undergone these carotid artery interventions for RICS and the associated outcomes. METHODS: Patients in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) carotid artery stenting surveillance project registry and the SVS VQI CEA modules who had undergone carotid artery intervention (TCAR, TFCAS, or CEA) for RICS were included. Those aged >90 years and those with concomitant interventions (eg, coronary bypass) were excluded. A composite of death, myocardial infarction (MI), and stroke was the primary outcome. The secondary outcomes included death, MI, stroke, cranial nerve injury (CNI), and other local and systemic complications. Multivariable logistic regression controlling for presenting symptomatic status and comorbid medical conditions was conducted for the outcome variables, except for death, which was analyzed using Cox regression modeling. RESULTS: A total of 1927 patients with RICS had undergone CEA (n = 1172), TCAR (n = 253), or TFCAS (n = 502). The CEA group had a higher rate of diabetes (31% vs 25% for TCAR and 25% for TFCAS; P = .01), hypertension (85% vs 82% for TCAR and 79% for TFCAS; P < .01), and peripheral vascular disease (8% vs 4% for TCAR and 4% for TFCAS; P < .01). The TCAR and TFCAS groups had higher rates of coronary artery disease (21% for CEA vs 30% for TCAR and 29% for TFCAS; P < .01). The patients who had undergone TFCAS were more likely to have had symptomatic lesions (57% for TFCAS vs 47% for CEA and 41% for TCAR; P < .01) and prior stroke (55% for TFCAS vs 47% for CEA and 40% for TCAR; P < .001). The composite outcome occurred in 3.2% of TCAR patients, 11.2% of TFCAS patients, and 11.1% of CEA patients (P < .01) with an odds ratio of 0.27 for TCAR, 0.91 for TFCAS, and 1.00 for CEA. However, no differences in the individual outcomes were noted for any procedure. TCAR exhibited the lowest odds ratio for CNI (0.15) compared with TFCAS at 0.9, both relative to CEA (P = .03). CONCLUSIONS: RICS patients treated by TCAR in the SVS VQI had the lowest risk of the composite of stroke, death, and MI and CNI. Therefore, TCAR might be the preferred treatment modality. Further comparative studies are needed to evaluate the long-term outcomes in this population and to elucidate the relationship of these procedures to the individual outcomes of stroke, MI, and death.

Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia.

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = -0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = -0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

The Utility of Hepatobiliary Scintigraphy Scans in the Tokyo Guidelines Era for Acute Cholecystitis.

BACKGROUND: Hepatobiliary Scintigraphy (HIDA) aids the diagnosis of acute cholecystitis (AC) but has limitations. We sought to design a model based on the Tokyo Guidelines 2018 (TG18) to predict HIDA results. METHODS: A retrospective review of patients who underwent a HIDA scan during the evaluation of AC was performed. Using logistic regression techniques incorporating the TG18 criterion and additional readily available patient characteristics, a prediction model was created to identify patients likely to test negative for acute cholecystitis by HIDA scan. RESULTS: In 235 patients with suspected AC, a HIDA scan was performed. Variables associated with positive HIDA results were male gender (RR 2.0 (CI 1.33-2.99), age (OR 1.02 (CI 1.01-1.04), right upper quadrant tenderness (RR 1.7 (CI 1.1-2.8)), clinical Murphy's sign (RR 2.2 (CI 1.5-3.4)), ultrasound findings suggestive of AC by any of its components (RR 3.2 (CI 1.6-6.5)), gallbladder wall thickening (RR 2.0 (CI 1.3-3.1)), and gallbladder distention (RR 1.9 (CI 1.3-2.9)). These variables allowed for creation of a model to predict HIDA results. The model predicted HIDA results in 36.9% of patients with an area under the curve of 0.81. CONCLUSIONS: In the era of TG18, HIDA is probably over utilized. We developed an accurate, simple model based on TG18 that identifies a group of patients for whom a HIDA scan is unnecessary to establish the diagnosis of AC.

Admission Serum Bicarbonate Predicts Adverse Clinical Outcomes in Hospitalized Cirrhotic Patients.

A low serum bicarbonate (SB) level is predictive of adverse outcomes in kidney injury, infection, and aging. Because the liver plays an important role in acid-base homeostasis and lactic acid metabolism, we speculated that such a relationship would exist for patients with cirrhosis. To assess the prognostic value of admission SB on adverse hospital outcomes, clinical characteristics were extracted and analyzed from a large electronic health record system. Patients were categorized based on admission SB (mEq/L) into 7 groups based on the reference range (22-25) into mildly (18-21), moderately (14-17), and severely (<14) decreased groups and mildly (26-29), moderately (30-33), and severely (>30) increased groups, and the relationship of SB category with the frequency of complications (acute kidney injury/hepatorenal syndrome, portosystemic encephalopathy, gastrointestinal bleeding, ascites, and spontaneous bacterial peritonitis) and hospital metrics (length of stay [LOS], admission to an intensive care unit [ICU], and mortality) was assessed. A total of 2,693 patients were analyzed. Mean SB was 22.9 ± 4.5 mEq/L. SB was within the normal range (22-25 mEq/L) in 1,072 (39.8%) patients, and 955 patients (36%) had a low SB. As the SB category decreased, the incidence of complications progressively increased (p < 0.001). Increased MELD-Na score and low serum albumin also correlated with frequency of complications (p < 0.001). As the SB category decreased, LOS, ICU admission, and mortality progressively increased (p < 0.001). On multivariate analysis, the association of decreased SB with higher odds of complications, LOS, ICU admission, and mortality persisted. Conclusion. Low admission SB in patients with cirrhosis is associated with cirrhotic complications, longer LOS, increased ICU admissions, and increased hospital mortality.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

A Safe Anti-A2 Titer for a Successful A2 Incompatible Kidney Transplantation: A Single-center Experience and Review of the Literature.

BACKGROUND: Kidney allocation system allows blood type B candidates accept kidneys from A2/A2B donors. There is no mandate by UNOS on which the anti-A2 level is acceptable. We aimed to investigate the safety of kidney transplant in blood group B patients with anti-A2 titers ≤16. METHODS: We performed 41 A2-incompatible kidney transplants in blood group B recipients between May 2015 and September 2019. Clinical outcomes were compared with a control group of 75 blood group B recipients who received blood group compatible kidney transplantation at the same period. RESULTS: Of the 41 recipients, 85% were male, 48% African American, with a median age of 53 (20-73) y. Thirty-eight (93%) were deceased-donor and 3 (7%) were living-donor kidney transplant recipients. Pretransplant anti-A2 IgG titers were 2 in 16, 4 in 9, 8 in 6, and 16 in 5 and too weak to titer in 5 recipients. Eight patients had pretransplant donor-specific antibodies. During a median follow-up of 32.6 mo (6-57.3) patient and graft survival were 100% and 92% in the A2-incompatible kidney transplant group, and 91% and 92% in the blood group compatible group, respectively. Twelve A2-incompatible recipients underwent a 21 clinically indicated kidney biopsies at a median 28 d (6-390) after transplantation. None of the patients developed acute antibody-mediated rejection and 2 patients (5%) had acute T-cell-mediated rejection. Interestingly, peritubular capillary C4d positivity was seen in 7 biopsies which did not have any findings of acute rejection or microvascular inflammation but not in any of the rejection-free biopsies in the control group. C4d positivity was persistent in 5 of those patients who had follow-up biopsies. CONCLUSIONS: A2-incompatible transplantation is safe in patients with anti-A2 titers ≤16 with excellent short-term kidney allograft outcomes. C4d positivity is frequent in allograft biopsies without acute rejection.

Outcomes of Adrenalectomy and the Aldosteronoma Resolution Score in the Black and Hispanic Population.

BACKGROUND: Outcomes after adrenalectomy in patients with primary aldosteronism (PA) are variable. The aldosteronoma resolution score (ARS) uses preoperative variables to calculate a score that identifies those patients that are more likely to have resolution of hypertension after adrenalectomy. We aim to determine the efficacy of adrenalectomy and whether the ARS accurately predicts clinical success in a Black and Hispanic population. METHODS: We reviewed patients who underwent adrenalectomy for PA from 2004 to 2018 at two academic centers treating primarily Hispanic and Black patients. Postoperative outcomes were evaluated based on the primary aldosteronism surgical outcome consensus criterion. Retrospectively, the accuracy of ARS was determined by a receiver operating characteristic curve and the area under the curve (AUC). RESULTS: Forty-three Hispanic and 10 Black patients underwent adrenalectomy for PA. Twenty-two patients (41.5%) had complete clinical success. Variables associated with complete clinical success in the univariate analysis were female gender (p = 0.026), younger age (p = 0.001), lower preoperative aldosterone (p = 0.035), lower preoperative systolic blood pressure (p = 0.001), fewer number of preoperative antihypertensive medications (p = 0.007) and a higher ARS (p = 0.003). On multivariate analysis, only fewer number of preoperative antihypertensive medications was independently associated with complete clinical success (p = 0.026). The AUC of the ARS was 0.746. CONCLUSION: The rate of clinical success from adrenalectomy is good for Hispanic and Black patients with PA. Our analysis shows that the ARS is an accurate test of clinical success in Hispanic and Black patients. The ARS may be utilized preoperatively to frame expectations after adrenalectomy in these populations.

Tracheotomy Outcomes in 64 Ventilated COVID-19 Patients at a High-Volume Center in Bronx, NY.

OBJECTIVES/HYPOTHESIS: The COVID-19 pandemic has resulted in a dramatic increase in the number of patients requiring prolonged mechanical ventilation. Few studies have reported COVID-19 specific tracheotomy outcomes, and the optimal timing and patient selection criteria for tracheotomy remains undetermined. We delineate our outcomes for tracheotomies performed on COVID-19 patients during the peak of the pandemic at a major epicenter in the United States. METHODS: This is a retrospective observational cohort study. Mortality, ventilation liberation rate, complication rate, and decannulation rate were analyzed. RESULTS: Sixty-four patients with COVID-19 underwent tracheotomy between April 1, 2020 and May 19, 2020 at two tertiary care hospitals in Bronx, New York. The average duration of intubation prior to tracheotomy was 20 days ((interquartile range [IQR] 16.5-26.0). The mortality rate was 33% (n = 21), the ventilation liberation rate was 47% (n = 30), the decannulation rate was 28% (n = 18), and the complication rate was 19% (n = 12). Tracheotomies performed by Otolaryngology were associated with significantly improved survival (P < .05) with 60% of patients alive at the conclusion of the study compared to 9%, 12%, and 19% of patients undergoing tracheotomy performed by Critical Care, General Surgery, and Pulmonology, respectively. CONCLUSIONS: So far, this is the second largest study describing tracheotomy outcomes in COVID-19 patients in the United States. Our early outcomes demonstrate successful ventilation liberation and decannulation in COVID-19 patients. Further inquiry is necessary to determine the optimal timing and identification of patient risk factors predictive of improved survival in COVID-19 patients undergoing tracheotomy. LEVEL OF EVIDENCE: 4-retrospective cohort study Laryngoscope, 131:E1797-E1804, 2021.

Clinical Stage of Cancer Affects Perioperative Mortality for Gastrointestinal Cancer Surgeries.

BACKGROUND: The impact of the stage of cancer on perioperative mortality remains obscure. The purpose of this study was to investigate whether cancer stage influences 30-d mortality for gastric, pancreatic, and colorectal cancers. METHODS: Data were collected from the National Cancer Database for patients undergoing resections for cancers of the stomach, pancreas, colon, or rectum between 2004 and 2015. The main analysis was conducted among patients with cancer stages 1-3. A sensitivity analysis also included cancer stage 4. Descriptive statistics were used to compare the patients' baseline characteristics. Generalized linear mixed models were used to evaluate the relationship between stage and 30-d mortality, controlling for other disease-, patient- and hospital-level factors. Pseudo R2 statistics (%Δ pseudo R2) were used to quantify the relative explanatory capacity of the variables to the model for 30-d mortality. All analyses were performed using SAS 9.4. RESULTS: The cohort included 24,468, 28,078, 176,285, and 64,947 patients with stomach, pancreas, colon, and rectal cancers, respectively. After adjusting for other variables, 30-d mortality was different by stage for all cancer types examined. The factor most strongly associated with 30-d mortality was age (%Δ pseudo R2 range 14%-39%). The prognostic impact of cancer stage (Stages 1, 2, or 3) on 30-d mortality was comparable to that of the Charlson comorbidity index. CONCLUSIONS: Cancer stage contributes to explaining differences observed in short-term mortality for gastrointestinal cancers. Short-term mortality models would benefit by including more granular cancer stage, beyond disseminated status alone.

Understanding Racial Disparities in Gastrointestinal Cancer Outcomes: Lack of Surgery Contributes to Lower Survival in African American Patients.

BACKGROUND: Race/ethnicity-related differences in rates of cancer surgery and cancer mortality have been observed for gastrointestinal (GI) cancers. This study aims to estimate the extent to which differences in receipt of surgery explain racial/ethnic disparities in cancer survival. METHODS: The National Cancer Database was used to obtain data for patients diagnosed with stage I-III mid-esophageal, distal esophagus/gastric cardia (DEGC), noncardia gastric, pancreatic, and colorectal cancer in years 2004-2015. Mediation analysis was used to identify variables influencing the relationship between race/ethnicity and mortality, including surgery. RESULTS: A total of 600,063 patients were included in the study: 3.5% mid-esophageal, 12.4% DEGC, 4.9% noncardia gastric, 17.0% pancreatic, 40.1% colon, and 22.0% rectal cancers. The operative rates for Black patients were low relative to White patients, with absolute differences of 21.0%, 19.9%, 2.3%, 8.3%, 1.6%, and 7.7%. Adjustment for age, stage, and comorbidities revealed even lower odds of receiving surgery for Black patients compared with White patients. The observed HRs for Black patients compared with White patients ranged from 1.01 to 1.42. Mediation analysis showed that receipt of surgery and socioeconomic factors had greatest influence on the survival disparity. CONCLUSIONS: The results of this study indicate that Black patients appear to be undertreated compared with White patients for GI cancers. The disproportionately low operative rates contribute to the known survival disparity between Black and White patients. IMPACT: Interventions to reduce barriers to surgery for Black patients should be promoted to reduce disparities in GI cancer outcomes.See related commentary by Hébert, p. 438.

De Novo Renal Failure and Clinical Outcomes of Patients With Critical Coronavirus Disease 2019.

OBJECTIVES: To describe the characteristics and outcomes associated with concomitant renal and respiratory failure in patients with critical coronavirus disease 2019. DESIGN, SETTING, AND PATIENTS: This is a case series of patients from a U.S. healthcare system in New York City. All adult patients (≥ 18 yr) admitted to the hospital with positive coronavirus disease 2019 testing between March 10, 2020, and March 31, 2020, who required mechanical ventilatory support were included. Patients who remained hospitalized were followed through May 1, 2020. INTERVENTIONS: Renal replacement therapy included at least one session of dialysis, continued venovenous hemofiltration, or peritoneal dialysis. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics, laboratory markers, 30-day in-hospital outcomes, ventilator days, and survival to discharge were included. Multivariate predictors for mortality and need for renal replacement therapy were identified. A total of 330 patients were included in this analysis and were most commonly greater than or equal to 70 years (40%), male (61%), Black or African American (41%), and Hispanic or Latino (38%). Renal replacement therapy was required in 101 patients (29%), most commonly among Blacks or African Americans (50%). Elevated d-dimer, C-reactive protein, and procalcitonin were associated with renal replacement therapy, compared with the nondialysis cohort. Overall, 243 patients (74%) died and 56 (17%) were discharged from the hospital, of which 9 (3%) required renal replacement therapy. Male sex (odds ratio, 2.0; 1.1-3.5; p = 0.020), Black race (odds ratio, 1.8; 1.0-3.1; p = 0.453), and history of hypertension (odds ratio, 2.7; 1.3-5.4; p = 0.005) were predictors for requiring renal replacement therapy. Risk factors for in-hospital mortality included age greater than or equal to 60 years (odds ratio, 6.2; 3.0-13.0; p < 0.0001), male sex (odds ratio, 3.0; 1.4-6.4; p = 0.004), and body mass index greater than or equal to 30 kg/m2 (odds ratio, 2.1; 1.0-4.4; p = 0.039). Concomitant renal failure in critical coronavirus disease 2019 was not a significant predictor of death (odds ratio, 2.3; 0.98-5.5; p = 0.057). CONCLUSIONS: This case series concludes that respiratory failure conveys significant mortality risk in patients with coronavirus disease 2019 and that survival with concomitant renal failure is rare.