Robert H. Hollis

Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA.

DYT1 dystonia, a common and severe primary dystonia, is caused by a 3-bp deletion in TOR1A which encodes torsinA, a protein found in the endoplasmic reticulum. Several cellular functions are altered by the mutant protein, but at a systems level the link between these and the symptoms of the disease is unclear. The most effective known therapy for DYT1 dystonia is the use of anticholinergic drugs. Previous studies have revealed that in mice, transgenic expression of human mutant torsinA under a non-selective promoter leads to abnormal function of striatal cholinergic neurons. To investigate what pathological role torsinA plays in cholinergic neurons, we created a mouse model in which the Dyt1 gene, the mouse homolog of TOR1A, is selectively deleted in cholinergic neurons (ChKO animals). These animals do not have overt dystonia, but do have subtle motor abnormalities. There is no change in the number or size of striatal cholinergic cells or striatal acetylcholine content, uptake, synthesis, or release in ChKO mice. There are, however, striking functional abnormalities of striatal cholinergic cells, with paradoxical excitation in response to D2 receptor activation and loss of muscarinic M2/M4 receptor inhibitory function. These effects are specific for cholinergic interneurons, as recordings from nigral dopaminergic neurons revealed normal responses. Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder.

Incorporation of Procedure-specific Risk Into the ACS-NSQIP Surgical Risk Calculator Improves the Prediction of Morbidity and Mortality After Pancreatoduodenectomy.

Objective: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Programs (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity. Background: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD – clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD. Methods: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score. Results: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001). Conclusions: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

Comparing the burden of pancreatic fistulas after pancreatoduodenectomy and distal pancreatectomy

BACKGROUND Differences in the behavior of postoperative pancreatic fistulas (POPF) have been described after various pancreatic resections. Here, we compare POPFs after pancreatoduodenectomy (PD) and distal pancreatectomy (DP) using the average complication burden (ACB), a quantitative measure of complication burden. METHODS From 2001 to 2014, 837 DPs and 1,533 PDs were performed by 14 surgeons at 4 institutions. POPFs were categorized by International Study Group on Pancreatic Fistula standards as biochemical (grade A) or clinically relevant (CR-POPF; grades B and C). ACB values were derived from fistula severity scores based on the Modified Accordion Severity Grading. The ACB of POPFs was compared between PD and DP. RESULTS POPFs were more common after DP compared with PD (34.5 vs 27.2%; P < .001); however, the incidence of any complication was greater after PD (64.9 vs 53.2%; P < .001). When POPFs occurred, they were more likely to be the highest-graded complication after DP compared with PD (65.1 vs 51.6%; P < .001). ACB significantly varied between PDs and DPs for grade C POPFs (0.804 vs 0.611; P < .001). POPFs accounted for 31.2% of the overall complication burden after DP compared with 17.5% of the burden after PD. ACB differed significantly across both institutions and surgeons in terms of POPFs, nonfistulous complications, and overall complications (all P < .05). CONCLUSION Although POPFs occur less frequently after PD, they are associated with a greater complication burden compared with DP. ACB varies significantly between health care providers, suggesting the need for risk-adjusted comparisons of complication severity. Using ACB to evaluate a distinct morbidity has the potential to aid in assessing the impact of procedure-specific complications.

Postoperative 30-day Readmission: Time to Focus on What Happens Outside the Hospital.

Objective: The aim of this study is to understand the relative contribution of preoperative patient factors, operative characteristics, and postoperative hospital course on 30-day postoperative readmissions. Background: Determining the risk of readmission after surgery is difficult. Understanding the most important contributing factors is important to improving prediction of and reducing postoperative readmission risk. Methods: National Veterans Affairs Surgical Quality Improvement Program data on inpatient general, vascular, and orthopedic surgery from 2008 to 2014 were merged with laboratory, vital signs, prior healthcare utilization, and postoperative complications data. Variables were categorized as preoperative, operative, postoperative/predischarge, and postdischarge. Logistic models predicting 30-day readmission were compared using adjusted R2 and c-statistics with cross-validation to estimate predictive discrimination. Results: Our study sample included 237,441 surgeries: 43% orthopedic, 39% general, and 18% vascular. Overall 30-day unplanned readmission rate was 11.1%, differing by surgical specialty (vascular 15.4%, general 12.9%, and orthopedic 7.6%, P < 0.001). Most common readmission reasons were wound complications (30.7%), gastrointestinal (16.1%), bleeding (4.9%), and fluid/electrolyte (7.5%) complications. Models using information available at the time of discharge explained 10.4% of the variability in readmissions. Of these, preoperative patient-level factors contributed the most to predictive models (R2 7.0% [c-statistic 0.67]); prediction was improved by inclusion of intraoperative (R2 9.0%, c-statistic 0.69) and postoperative variables (R2 10.4%, c-statistic 0.71). Including postdischarge complications improved predictive ability, explaining 19.6% of the variation (R2 19.6%, c-statistic 0.76). Conclusions: Postoperative readmissions are difficult to predict at the time of discharge, and of information available at that time, preoperative factors are the most important.

Association of the Modified Frailty Index With 30-Day Surgical Readmission

Importance Frail patients are known to have poor perioperative outcomes. There is a paucity of literature investigating how the Modified Frailty Index (mFI), a validated measure of frailty, is associated with unplanned readmission among military veterans following surgery. Objective To understand the association between frailty and 30-day postoperative unplanned readmission. Design, Setting, and Participants A retrospective cohort study was conducted among adult patients who underwent surgery and were discharged alive from Veterans Affairs hospitals for orthopedic, general, and vascular conditions between October 1, 2007, and September 30, 2014, with a postoperative length of stay between 2 and 30 days. Exposure Frailty, as calculated by the 11 variables on the mFI. Main Outcomes and Measures The primary outcome of interest is 30-day unplanned readmission. Secondary outcomes included any 30-day predischarge or postdischarge complication, 30-day postdischarge mortality, and 30-day emergency department visit. Results The study sample included 236 957 surgical procedures (among 223 877 men and 13 080 women; mean [SD] age, 64.0 [11.3] years) from high-volume surgical specialties: 101 348 procedures (42.8%) in orthopedic surgery, 92 808 procedures (39.2%) in general surgery, and 42 801 procedures (18.1%) in vascular surgery. The mFI was associated with readmission (odds ratio [OR], 1.11; 95% CI, 1.10-1.12; R2 = 10.3%; C statistic, 0.71). Unadjusted rates of overall 30-day readmission (26 262 [11.1%]), postdischarge emergency department visit (34 204 [14.4%]), any predischarge (13 855 [5.9%]) or postdischarge (14 836 [6.3%]) complication, and postdischarge mortality (1985 [0.8%]) varied by frailty in a dose-dependent fashion. In analysis by individual mFI components using Harrell ranking, impaired functional status, identified as nonindependent functional status (OR, 1.16; 95% CI, 1.11-1.21; P < .01) or having a residual deficit from a prior cerebrovascular accident (OR, 1.17; 95% CI, 1.11-1.22; P < .01), contributed most to the ability of the mFI to anticipate readmission compared with the other components. Acutely impaired sensorium (OR, 1.12; 95% CI, 0.99-1.27; P = .08) and history of a myocardial infarction within 6 months (OR, 0.93; 95% CI, 0.81-1.06; P = .28) were not significantly associated with readmission. Conclusions and Relevance The mFI is associated with poor surgical outcomes, including readmission, primarily due to impaired functional status. Targeting potentially modifiable aspects of frailty preoperatively, such as improving functional status, may improve perioperative outcomes and decrease readmissions.

Adverse cardiac events in patients with coronary stents undergoing noncardiac surgery: a systematic review

BACKGROUND When patients with drug-eluting stents (DES) present for surgery, current guidelines recommend delaying elective surgeries until 1 year of dual antiplatelet therapy has been completed. METHODS We performed a systematic literature review of the major adverse cardiac events (MACE) associated with noncardiac surgery in patients with DES. RESULTS Twenty-eight of 358 studies met inclusion criteria. Overall, MACE rates decreased as time to surgery increased and varied from 0% to 18% for surgeries within 1 year as compared with 0% to 12% for surgery more than 1 year after a stent. In addition, the current literature showed limited evidence for a protective effect of continuing perioperative dual antiplatelet therapy on MACE rates. CONCLUSIONS The current literature supports a significant decrease in MACE when surgery is performed 1 year after DES placement; however, the level of evidence is weak. Larger studies are needed to determine the safe interval for surgery after stent placement.

Association of Coronary Stent Indication With Postoperative Outcomes Following Noncardiac Surgery

IMPORTANCE Current guidelines for delaying surgery after coronary stent placement are based on stent type. However, the indication for the stent may be an important risk factor for postoperative major adverse cardiac events (MACE). OBJECTIVE To determine whether the clinical indication for a coronary stent is associated with postoperative MACE. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study in patients at US Veterans Affairs hospitals who had a coronary stent placed between January 1, 2000, and December 31, 2010, and underwent noncardiac surgery within the following 24 months. The association between the indication for stent and postoperative MACE rates was examined using logistic regression to control for patient and procedure factors. EXPOSURES Three subgroups of stent indication were examined: (1) myocardial infarction (MI); (2) unstable angina; and (3) revascularization not associated with acute coronary syndrome (non-ACS). MAIN OUTCOMES AND MEASURES Composite 30-day postoperative MACE rates including all-cause mortality, MI, or revascularization. RESULTS Among 26 661 patients (median [IQR] age, 68 [61.0-76.0] years; 98.4% male; 88.1% white) who underwent 41 815 surgical procedures within 24 months following coronary stent placement, the stent indication was MI in 32.8% of the procedures, unstable angina in 33.8%, and non-ACS in 33.4%. Postoperative MACE rates were significantly higher in the MI group (7.5%) compared with the unstable angina (2.7%) and non-ACS (2.6%) groups (P < .001). When surgery was performed within 3 months of percutaneous coronary intervention, adjusted odds of MACE were significantly higher in the MI group compared with the non-ACS group (odds ratio [OR] = 5.25; 95% CI, 4.08-6.75). This risk decreased over time, although it remained significantly higher at 12 to 24 months from percutaneous coronary intervention (OR = 1.95; 95% CI, 1.58-2.40). The adjusted odds of MACE for the unstable angina group were similar to those for the non-ACS group when surgery was performed within 3 months (OR = 1.11; 95% CI, 0.80-1.53) or between 12 and 24 months (OR = 1.08; 95% CI, 0.86-1.37) from stent placement. Stent type was not significantly associated with MACE regardless of indication. CONCLUSIONS AND RELEVANCE Surgery in patients with a coronary stent placed for MI was associated with increased postoperative MACE rates compared with other stent indications. The risk declined over time from PCI, and delaying surgery up to 6 months in this cohort of patients with stents may be important regardless of stent type.

Blood Transfusion and 30-Day Mortality in Patients With Coronary Artery Disease and Anemia Following Noncardiac Surgery

IMPORTANCE Although liberal blood transfusion thresholds have not been beneficial following noncardiac surgery, it is unclear whether higher thresholds are appropriate for patients who develop postoperative myocardial infarction (MI). OBJECTIVE To evaluate the association between postoperative blood transfusion and mortality in patients with coronary artery disease and postoperative MI following noncardiac surgery. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study involving Veterans Affairs facilities from January 1, 2000, to December 31, 2012. A total of 7361 patients with coronary artery disease who underwent inpatient noncardiac surgery and had a nadir postoperative hematocrit between 20% and 30%. Patients with significant bleeding, including any preoperative blood transfusion or transfusion of greater than 4 units during the intraoperative or postoperative setting, were excluded. Mortality rates were compared using both logistic regression and propensity score matching. Patients were stratified by postoperative nadir hematocrit and the presence of postoperative MI. EXPOSURE Initial postoperative blood transfusion. MAIN OUTCOMES AND MEASURES The 30-day postoperative mortality rate. RESULTS Of the 7361 patients, 2027 patients (27.5%) received at least 1 postoperative blood transfusion. Postoperative mortality occurred in 267 (3.6%), and MI occurred in 271 (3.7%). Among the 5334 patients without postoperative blood transfusion, lower nadir hematocrit was associated with an increased risk for mortality (hematocrit of 20% to <24%: 7.3%; 24% to <27%: 3.7%; and 27% to 30%: 1.6%; P < .01). In patients with postoperative MI, blood transfusion was associated with lower mortality, for those with hematocrit of 20% to 24% (odds ratio, 0.28; 95% CI, 0.13-0.64). In patients without postoperative MI, transfusion was associated with significantly higher mortality for those with hematocrit of 27% to 30% (odds ratio, 3.21; 95% CI, 1.85-5.60). CONCLUSIONS AND RELEVANCE These findings support a restrictive postoperative transfusion strategy in patients with stable coronary artery disease following noncardiac surgery. However, interventional studies are needed to evaluate the use of a more liberal transfusion strategy in patients who develop postoperative MI.

The Burden of the Fellowship Interview Process on General Surgery Residents and Programs.

OBJECTIVES This study evaluated the effect of the fellowship interview process in a cohort of general surgery residents. We hypothesized that the interview process would be associated with significant clinical time lost, monetary expenses, and increased need for shift coverage. DESIGN An online anonymous survey link was sent via e-mail to general surgery program directors in June 2014. Program directors distributed an additional survey link to current residents in their program who had completed the fellowship interview process. SETTING United States allopathic general surgery programs. PARTICIPANTS Overall, 50 general surgery program directors; 72 general surgery residents. RESULTS Program directors reported a fellowship application rate of 74.4%. Residents most frequently attended 8 to 12 interviews (35.2%). Most (57.7%) of residents reported missing 7 or more days of clinical training to attend interviews; these shifts were largely covered by other residents. Most residents (62.3%) spent over

Characterization and Optimal Management of High-Risk Pancreatic Anastomoses During Pancreatoduodenectomy

4000 on the interview process. Program directors rated fellowship burden as an average of 6.7 on a 1 to 10 scale of disruption, with 10 being a significant disruption. Most of the residents (57.3%) were in favor of change in the interview process. We identified potential areas for improvement including options for coordinated interviews and improved content on program websites. CONCLUSIONS The surgical fellowship match is relatively burdensome to residents and programs alike, and merits critical assessment for potential improvement.