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BACKGROUND: Frailty assessment adds important prognostic information during preoperative decision-making but can be cumbersome to implement into routine clinical care. We developed and tested an abbreviated method of frailty assessment using variables routinely collected by the Vascular Quality Initiative (VQI) registry. METHODS: An abbreviated frailty score (the simple Vascular Quality Initiative-Frailty Score [VQI-FS]) was developed using 11 or fewer VQI variables (hypertension, congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes, chronic obstructive pulmonary disease, renal impairment, anemia, underweight, nonhome residence, and nonambulatory status) that map to recognized frailty domains in the Comprehensive Geriatric Assessment and the literature. Nonemergent cases registered in the VQI from 2010 to 2017 (n = 265,632) in seven registries (carotid endarterectomy, n = 77,111; carotid artery stenting, n = 13,215; endovascular abdominal aortic aneurysm repair, n = 29,607; open abdominal aortic aneurysm repair, n = 7442; infrainguinal bypass, n = 33,128; suprainguinal bypass, n = 10,661; and peripheral vascular intervention, n = 94,468) were analyzed using logistic regression models to determine the predictive power of the VQI-FS for perioperative and longer term (9-month) mortality. Nomograms were created using weighted regression coefficients to assist in individualized frailty assessment and estimation of 9-month mortality. RESULTS: The VQI-FS, using equal weighting of these 11 VQI variables, effectively predicted 9-month mortality with an area under the curve of 0.724 by receiver operating characteristic curve analysis. However, differential weighting of the variables allowed simplification of the model to only seven variables (congestive heart failure, renal impairment, chronic obstructive pulmonary disease, not living at home, not ambulatory, anemia, and underweight status); hypertension, coronary artery disease, peripheral vascular disease, and diabetes had relatively low predictive power. Adding procedure-specific risk further improved performance of the model with a final area under the curve on receiver operating characteristic curve analysis of 0.758. Model calibration was excellent with predicted/observed regression line slope of 0.991 and intercept of 5.449e-04. CONCLUSIONS: A differentially weighted abbreviated VQI-FS using seven variables in addition to procedure-specific risk has strong correlation with 9-month mortality. Nomograms incorporating patient- and procedure-adjusted risk can effectively predict 9-month mortality. Reliable estimates of longer term mortality should assist in preoperative decision-making for vascular procedures that often carry substantial risk of mortality.

ObjectiveDescribe dementia cases identified through International Classification of Diseases (ICD) coding in the Long-term Impact of Military-relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) multicenter prospective longitudinal study (PLS) of mild traumatic brain injury (mTBI).DesignDescriptive case series using cross-sectional data.MethodsVeterans Affairs (VA) health system data including ICD codes were obtained for 1563 PLS participants through the VA Informatics and Computing Infrastructure (VINCI). Demographic, injury, and clinical characteristics of Dementia positive and negative cases are described.ResultsFive cases of dementia were identified, all under 65 years old. The dementia cases all had a history of blast-related mTBI and all had self-reported functional problems and four had PTSD symptomatology at the clinical disorder range. Cognitive testing revealed some deficits especially in the visual memory and verbal learning and memory domains, and that two of the cases might be false positives.ConclusionsICD codes for early dementia in the VA system have specificity concerns, but could be indicative of cognitive performance and self-reported cognitive function. Further research is needed to better determine links to blast exposure, blast-related mTBI, and PTSD to early dementia in the military population.

Background & aimsResilience is the ability to adapt positively to stress and adversity. It is a potential therapeutic target as it is reduced in irritable bowel syndrome (IBS) compared to healthy controls and associated with worse symptom severity and poorer quality of life. The aim of this study was to examine if these findings are generalizable by comparing resilience between IBS versus the general population and other chronic gastrointestinal (GI) conditions.MethodsParticipants in the general population completed an online survey containing questionnaires measuring demographics, diagnosis of IBS and other GI conditions, symptom severity, psychological symptoms, resilience, and early adverse life events (EALs). IBS was defined as having a physician diagnosis of IBS and/or meeting Rome criteria without co-morbid GI disease. All others were included in the general population group. The chronic GI conditions group included those with inflammatory bowel disease, celiac disease and/or microscopic colitis.ResultsResilience was lower in IBS (n = 820) than the general population (n = 1026; p < 0.001) and associated with worse IBS symptom severity (p < 0.05). Global mental health affected resilience differently in IBS compared to the general population (all p's < 0.05). EALs were associated with decreased ability to bounce back from adversity in both IBS and the general population (p < 0.001). Resilience scores were similar in IBS and other chronic GI conditions that present with similar symptoms.ConclusionsResilience is lower compared to the general U.S. population but does not appear to be specific to IBS as it is comparable to other chronic GI conditions. Low resilience negatively affects symptom severity and mental health and thus, may serve as a novel therapeutic target.

BackgroundCurrent understanding of hematopoiesis is largely derived from mouse models that are physiologically distant from humans. Humanized mice provide the most physiologically relevant small animal model to study human diseases, most notably preclinical gene therapy studies. However, the clonal repopulation dynamics of human hematopoietic stem and progenitor cells (HSPC) in these animal models is only partially understood. Using a new clonal tracking methodology designed for small sample volumes, we aim to reveal the underlying clonal dynamics of human cell repopulation in a mouse environment.MethodsHumanized bone marrow-liver-thymus (hu-BLT) mice were generated by transplanting lentiviral vector-transduced human fetal liver HSPC (FL-HSPC) in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice implanted with a piece of human fetal thymus. We developed a methodology to track vector integration sites (VIS) in a mere 25 µl of mouse blood for longitudinal and quantitative clonal analysis of human HSPC repopulation in mouse environment. We explored transcriptional and epigenetic features of human HSPC for possible VIS bias.ResultsA total of 897 HSPC clones were longitudinally tracked in hu-BLT mice-providing a first-ever demonstration of clonal dynamics and coordinated expansion of therapeutic and control vector-modified human cell populations simultaneously repopulating in the same humanized mice. The polyclonal repopulation stabilized at 19 weeks post-transplant and the contribution of the largest clone doubled within 4 weeks. Moreover, 550 (~ 60%) clones persisted over 6 weeks and were highly shared between different organs. The normal clonal profiles confirmed the safety of our gene therapy vectors. Multi-omics analysis of human FL-HSPC revealed that 54% of vector integrations in repopulating clones occurred within ± 1 kb of H3K36me3-enriched regions.ConclusionsHuman repopulation in mice is polyclonal and stabilizes more rapidly than that previously observed in humans. VIS preference for H3K36me3 has no apparent negative effects on HSPC repopulation. Our study provides a methodology to longitudinally track clonal repopulation in small animal models extensively used for stem cell and gene therapy research and with lentiviral vectors designed for clinical applications. Results of this study provide a framework for understanding the clonal behavior of human HPSC repopulating in a mouse environment, critical for translating results from humanized mice models to the human settings.

BACKGROUND: Delirium is a deleterious condition affecting up to 60% of patients in the surgical ICU (SICU). Few SICU-focused delirium interventions have been implemented, including those addressing sleep-wake disruption, a modifiable delirium risk factor common in critically ill patients. RESEARCH QUESTION: What is the effect on delirium and sleep quality of a multicomponent nonpharmacologic intervention aimed at improving sleep-wake disruption in patients in the SICU setting? STUDY DESIGN AND METHODS: Using a staggered pre-post design, we implemented a quality improvement intervention in two SICUs (general surgery or trauma and cardiovascular) in an academic medical center. After a preintervention (baseline) period, a multicomponent unit-wide nighttime (ie, efforts to minimize unnecessary sound and light, provision of earplugs and eye masks) and daytime (ie, raising blinds, promotion of physical activity) intervention bundle was implemented. A daily checklist was used to prompt staff to complete intervention bundle elements. Delirium was evaluated twice daily using the Confusion Assessment Method for the Intensive Care Unit. Patient sleep quality ratings were evaluated daily using the Richards-Campbell Sleep Questionnaire (RCSQ). RESULTS: Six hundred forty-six SICU admissions (332 baseline, 314 intervention) were analyzed. Median age was 61 years (interquartile range, 49-70 years); 35% of the cohort were women and 83% were White. During the intervention period, patients experienced fewer days of delirium (proportion ± SD of ICU days, 15 ± 27%) as compared with the preintervention period (20 ± 31%; P = .022), with an adjusted pre-post decrease of 4.9% (95% CI, 0.5%-9.2%; P = .03). Overall RCSQ-perceived sleep quality ratings did not change, but the RCSQ noise subscore increased (9.5% [95% CI, 1.1%-17.5%; P = .02). INTERPRETATION: Our multicomponent intervention was associated with a significant reduction in the proportion of days patients experienced delirium, reinforcing the feasibility and effectiveness of a nonpharmacologic sleep-wake bundle to reduce delirium in critically ill patients in the SICU. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03313115; URL: www.clinicaltrials.gov.

BackgroundIrritable bowel syndrome (IBS) is a stress-sensitive disorder of brain-gut interactions associated with a higher prevalence of early adverse life events (EALs). However, it is incompletely understood how trauma severity or disclosure influence the risk of developing IBS or symptom severity.AimsTo determine whether (1) IBS patients report a greater number of EALs compared with healthy controls; (2) trauma severity and first age of EAL increase the odds of IBS; (3) confiding in others reduces the odds of IBS; (4) the number, trauma severity, and first age of EAL are associated with symptom severity; (5) sex differences exist.MethodsIn total, 197 IBS patients (72% women, mean age=30.28 y) and 165 healthy controls (59% women, mean age=30.77 y) completed the Childhood Traumatic Events Scale, measuring severity of EALs and degree of confiding in others. Regression analyses were used to predict IBS status from EALs and association between gastrointestinal symptoms and EALs.ResultsA greater number of EALs [odds ratio (OR)=1.36, 95% confidence interval (CI), 1.14-1.62; P

Background & aimsIrritable bowel syndrome (IBS) is a stress-sensitive disorder associated with dysregulation of the hypothalamic-pituitary-adrenal axis. We studied the cumulative effect of events during adulthood on this pathway in patients with IBS.MethodsWe studied 129 patients with IBS, based on Rome III criteria (mean age 28.1 years, 66% women), and 108 healthy individuals (controls; mean age 29.8 years, 60% women) who completed the Life Experiences Survey from August 2013 to September 2017. Data were collected on the presence and effects of events since age 18, IBS severity scores, and IBS-related quality of life. For a subset of subjects, we measured serum cortisol and adrenocorticotropic hormone (ACTH) production in response to administration of corticotropin-releasing factor and ACTH.ResultsCompared with controls, patients with IBS perceived more adulthood life events as negative and had a significantly higher negative life event impact score (14.17 ± 12.04 vs 10.83 ± 9.98; P=.022). In patients with IBS, the presence of more-negatively perceived adulthood life events was associated with worse IBS symptom severity (β = 1.53, 95% CI, 0.21-2.84; P = .025) and IBS-related quality of life (β = -0.70; 95% CI, -1.02 to -0.38; P < .001). Negatively perceived adulthood life events were associated with reduced production of ACTH in response to corticotropin-releasing factor in patients with IBS compared with controls (P < .05).ConclusionIn a study of more than 200 subjects, we associated more-negatively perceived events during adulthood with an increased risk for IBS, worse symptom severity and quality of life, and a dysregulated stress response. Understanding the effects of events that cause stress in adults and their perceived effects on IBS may help guide disease management.

BackgroundThe management of high-grade renal trauma (HGRT) and the indications for intervention are not well defined. The American Association for the Surgery of Trauma (AAST) renal grading does not incorporate some important clinical and radiologic variables associated with increased risk of interventions. We aimed to use data from a multi-institutional contemporary cohort to develop a nomogram predicting risk of interventions for bleeding after HGRT.MethodsFrom 2014 to 2017, data on adult HGRT (AAST grades III-V) were collected from 14 level 1 trauma centers. Patients with both clinical and radiologic data were included. Data were gathered on demographics, injury characteristics, management, and outcomes. Clinical and radiologic parameters, obtained after trauma evaluation, were used to predict renal bleeding interventions. We developed a prediction model by applying backward model selection to a logistic regression model and built a nomogram using the selected model.ResultsA total of 326 patients met the inclusion criteria. Mechanism of injury was blunt in 81%. Median age and injury severity score were 28 years and 22, respectively. Injuries were reported as AAST grades III (60%), IV (33%), and V (7%). Overall, 47 (14%) underwent interventions for bleeding control including 19 renal angioembolizations, 16 nephrectomies, and 12 other procedures. Of the variables included in the nomogram, a hematoma size of 12 cm contributed the most points, followed by penetrating trauma mechanism, vascular contrast extravasation, pararenal hematoma extension, concomitant injuries, and shock. The area under the receiver operating characteristic curve was 0.83 (95% confidence interval, 0.81-0.85).ConclusionWe developed a nomogram that integrates multiple clinical and radiologic factors readily available upon assessment of patients with HGRT and can provide predicted probability for bleeding interventions. This nomogram may help in guiding appropriate management of HGRT and decreasing unnecessary interventions.Level of evidencePrognostic and epidemiological study, level III.

Importance: Many women report inadequate symptom control after sacral neuromodulation (SNM), despite 50% reduction in urgency incontinence episodes (UUIE) after test stimulation. Objective: To determine the ideal percent UUIE reduction after test stimulation that predicts 24‐month success. Study Design: Using data from a multicenter SNM trial, we constructed receiver operating characteristic curves to identify an ideal threshold of percent UUIE reduction after test stimulation. We defined 24‐month success as Patient Global Impression of Improvement of "very much better" to "better." We compared predictive accuracy of two models predicting success: (1) percent UUIE reduction alone and (2) with baseline characteristics. Results: Of 149 women (median [IQR] baseline daily UUIE 4.7 [3.7, 6.0]), the ideal threshold for 24‐month success was 72% (95% confidence interval 64,76%) UUIE reduction with accuracy 0.54 (0.42, 0.66), sensitivity 0.71 (0.56, 0.86) and specificity 0.27 (0.05, 0.55). The accuracy of the 50% reduction threshold was 0.60 (0.49, 0.71), sensitivity 0.95 (0.88, 1.0) and specificity 0.04 (0.0, 0.12). Percent reduction in UUIE was not better than chance in predicting 24‐month success (concordance index [c‐index] 0.47 [0.46, 0.62]); adding age, body mass index, diabetes mellitus and visual or hearing impairment the c‐index was 0.68 (0.61, 0.78). Conclusions: Among women who received an internal pulse generator (IPG) due to ≥50% UUIE reduction after test stimulation, we found no ideal threshold that better predicted 24‐month success. Percent reduction in UUIE after test stimulation poorly predicts 24‐month success with or without clinical factors. Given this, re‐evaluating how we determine who should receive an IPG is needed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiogenic shock (CS) can stem from multiple causes and portends poor prognosis. Prior studies have focused on acute myocardial infarction-CS; however, acute decompensated heart failure (ADHF)-CS accounts for most cases. We studied patients suffering ADHF-CS to identify clinical factors, early in their trajectory, associated with a higher probability of successful outcomes. METHODS: Consecutive patients with CS were evaluated (N=1162). We studied patients who developed ADHF-CS at our hospital (N=562). Primary end point was native heart survival (NHS), defined as survival to discharge without receiving advanced HF therapies. Secondary end points were adverse events, survival, major cardiac interventions, and hospital readmissions within 1 year following index hospitalization discharge. Association of clinical data with NHS was analyzed using logistic regression. RESULTS: Overall, 357 (63.5%) patients achieved NHS, 165 (29.2%) died, and 41 (7.3%) were discharged post advanced HF therapies. Of 398 discharged patients (70.8%), 303 (53.9%) were alive at 1 year. Patients with NHS less commonly suffered cardiac arrest, underwent intubation or pulmonary artery catheter placement, or received temporary mechanical circulatory support, had better hemodynamic and echocardiographic profiles, and had a lower vasoactive-inotropic score at shock onset. Bleeding, hemorrhagic stroke, hemolysis in patients with mechanical circulatory support, and acute kidney injury requiring renal replacement therapy were less common compared with patients who died or received advanced HF therapies. After multivariable adjustments, clinical variables associated with NHS likelihood included younger age, history of systemic hypertension, absence of cardiac arrest or acute kidney injury requiring renal replacement therapy, lower pulmonary capillary wedge pressure and vasoactive-inotropic score, and higher tricuspid annular plane systolic excursion at shock onset (all P<0.05). CONCLUSIONS: By studying contemporary patients with ADHF-CS, we identified clinical factors that can inform clinical management and provide future research targets. Right ventricular function, renal function, pulmonary artery catheter placement, and type and timing of temporary mechanical circulatory support warrant further investigation to improve outcomes of this devastating condition. [ABSTRACT FROM AUTHOR]

BackgroundAlthough overlapping surgery is used to maximize efficiency, more empirical data are needed to guide patient safety. We conducted a retrospective cohort study to evaluate the safety of overlapping inpatient orthopaedic surgery, as judged by the occurrence of perioperative complications.MethodsAll inpatient orthopaedic surgical procedures performed at 5 academic institutions from January 1, 2015, to December 31, 2015, were included. Overlapping surgery was defined as 2 skin incisions open simultaneously for 1 surgeon. In comparing patients who underwent overlapping surgery with those who underwent non-overlapping surgery, the primary outcome was the occurrence of a perioperative complication within 30 days of the surgical procedure, and secondary outcomes included all-cause 30-day readmission, length of stay, and mortality. To determine if there was an association between overlapping surgery and a perioperative complication, we tested for non-inferiority of overlapping surgery, assuming a null hypothesis of an increased risk of 50%. We used an inverse probability of treatment weighted regression model adjusted for institution, procedure type, demographic characteristics (age, sex, race, comorbidities), admission type, admission severity of illness, and clustering by surgeon.ResultsAmong 14,135 cases, the frequency of overlapping surgery was 40%. The frequencies of perioperative complications were 1% in the overlapping surgery group and 2% in the non-overlapping surgery group. The overlapping surgery group was non-inferior to the non-overlapping surgery group (odds ratio [OR], 0.61 [90% confidence interval (CI), 0.45 to 0.83]; p < 0.001), with reduced odds of perioperative complications (OR, 0.61 [95% CI, 0.43 to 0.88]; p = 0.009). For secondary outcomes, there was a significantly lower chance of all-cause 30-day readmission in the overlapping surgery group (OR, 0.67 [95% CI, 0.52 to 0.87]; p = 0.003) and shorter length of stay (e, 0.94 [95% CI, 0.89 to 0.99]; p = 0.012). There was no difference in mortality.ConclusionsOur results suggest that overlapping inpatient orthopaedic surgery does not introduce additional perioperative risk for the complications that we evaluated. The suitability of this practice should be determined by individual surgeons on a case-by-case basis with appropriate informed consent.Level of evidenceTherapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

BackgroundPelvic fracture urethral injuries (PFUI) occur in up to 10% of pelvic fractures. It remains controversial whether initial primary urethral realignment (PR) after PFUI decreases the incidence of urethral obstruction and the need for subsequent urethral procedures. We present methodology for a prospective cohort study analyzing the outcomes of PR versus suprapubic cystostomy tube (SPT) after PFUI.MethodsA prospective cohort trial was designed to compare outcomes between PR (group 1) and SPT placement (group 2). Centers are assigned to a group upon entry into the study. All patients will undergo retrograde attempted catheter placement; if this fails a cystoscopy exam is done to confirm a complete urethral disruption and attempt at gentle retrograde catheter placement. If catheter placement fails, group 1 will undergo urethral realignment and group 2 will undergo SPT. The primary outcome measure will be the rate of urethral obstruction preventing atraumatic passage of a flexible cystoscope. Secondary outcome measures include: subsequent urethral interventions, post-injury complications, urethroplasty complexity, erectile dysfunction (ED) and urinary incontinence rates.ResultsPrior studies demonstrate PR is associated with a 15% to 50% reduction in urethral obstruction. Ninety-six men (48 per treatment group) are required to detect a 15% treatment effect (80% power, 0.05 significance level, 20% loss to follow up/death rate). Busy trauma centers treat complete PFUI approximately 1-6 times per year, thus our goal is to recruit 25 trauma centers and enroll patients for 3 years with a goal of 100 or more total patients with complete urethral disruption.ConclusionsThe proposed prospective multi-institutional cohort study should determine the utility of acute urethral realignment after PFUI.

Investigations of anti-HIV-1 human hematopoietic stem/progenitor cell (HSPC)-based gene therapy have been performed by HIV-1 challenge after the engraftment of gene-modified HSPCs in humanized mouse models. However, the clinical application of gene therapy is to treat HIV-1-infected patients. Here, we developed a new method to investigate an anti-HIV-1 HSPC-based gene therapy in humanized mice previously infected with HIV-1. First, humanized mice were infected with HIV-1. When plasma viremia reached >107 copies/mL 3 weeks after HIV-1 infection, the mice were myeloablated with busulfan and transplanted with anti-HIV-1 gene-modified CD34+ HSPCs transduced with a lentiviral vector expressing two short hairpin RNAs (shRNAs) against CCR5 and HIV-1 long terminal repeat (LTR), along with human thymus tissue under the kidney capsule. Anti-HIV-1 vector-modified human CD34+ HSPCs successfully repopulated peripheral blood and lymphoid tissues in HIV-1 previously infected humanized mice. Anti-HIV-1 shRNA vector-modified CD4+ T lymphocytes showed selective advantage in HIV-1 previously infected humanized mice. This new method will be useful for investigations of anti-HIV-1 gene therapy when testing in a more clinically relevant experimental setting.

BackgroundThe rarity of renal trauma limits its study and the strength of evidence-based guidelines. Although management of renal injuries has shifted toward a nonoperative approach, nephrectomy remains the most common intervention for high-grade renal trauma (HGRT). We aimed to describe the contemporary management of HGRT in the United States and also evaluate clinical factors associated with nephrectomy after HGRT.MethodsFrom 2014 to 2017, data on HGRT (American Association for the Surgery of Trauma grades III-V) were collected from 14 participating Level-1 trauma centers. Data were gathered on demographics, injury characteristics, management, and short-term outcomes. Management was classified into three groups-expectant, conservative/minimally invasive, and open operative. Descriptive statistics were used to report management of renal trauma. Univariate and multivariate logistic mixed effect models with clustering by facility were used to look at associations between proposed risk factors and nephrectomy.ResultsA total of 431 adult HGRT were recorded; 79% were male, and mechanism of injury was blunt in 71%. Injuries were graded as III, IV, and V in 236 (55%), 142 (33%), and 53 (12%), respectively. Laparotomy was performed in 169 (39%) patients. Overall, 300 (70%) patients were managed expectantly and 47 (11%) underwent conservative/minimally invasive management. Eighty-four (19%) underwent renal-related open operative management with 55 (67%) of them undergoing nephrectomy. Nephrectomy rates were 15% and 62% for grades IV and V, respectively. Penetrating injuries had significantly higher American Association for the Surgery of Trauma grades and higher rates of nephrectomy. In multivariable analysis, only renal injury grade and penetrating mechanism of injury were significantly associated with undergoing nephrectomy.ConclusionExpectant and conservative management is currently utilized in 80% of HGRT; however, the rate of nephrectomy remains high. Clinical factors, such as surrogates of hemodynamic instability and metabolic acidosis, are associated with nephrectomy for HGRT; however, higher renal injury grade and penetrating trauma remain the strongest associations.Level of evidencePrognostic/epidemiologic study, level III; Therapeutic study, level IV.

Author(s): Joseph E. Tonna [sup.1] [sup.2], Martin Urner [sup.3], Heather T. Keenan [sup.4], Daniel Brodie [sup.5], Eddy Fan [sup.3], Chong Zhang, Angela P. Presson Author Affiliations: Dear Editor, Exposure to [...]