Caitlin W. Hicks

Bace1 modulates myelination in the central and peripheral nervous system

Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the β-secretase site. Apart from this cleavage, the functional importance of Bace1 in other physiological events is unknown. We show here that Bace1 regulates the process of myelination and myelin sheath thickness in the central and peripheral nerves. In Bace1-null mice, the process of myelination was delayed and myelin thickness was markedly reduced, indicating that genetic deletion of Bace1 causes hypomyelination. Bace1-null mice also showed altered neurological behaviors such as elevated pain sensitivity and reduced grip strength. Further mechanistic studies showed an altered neuregulin-Akt signaling pathway in Bace1-null mice. Full-length neuregulin-1 was increased and its cleavage product was decreased in the CNS of Bace1-null mice. Furthermore, phosphorylated Akt was also reduced. Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells.

An overview of anthrax infection including the recently identified form of disease in injection drug users

PurposeBacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world.MethodsThis review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax.Results and conclusionsAnthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax.

Trends in Incident Hemodialysis Access and Mortality

IMPORTANCE Based on evidence of survival benefit when initiating hemodialysis (HD) via arteriovenous fistula (AVF) or arteriovenous graft (AVG) vs hemodialysis catheter (HC), the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative published practice guidelines in 1997 recommending 50% or greater AVF rates in incident HD patients. A decade after, lapses exist and the impact on HD outcomes is uncertain. OBJECTIVE To assess the achievement of the practice goals for incident vascular access and the effects on HD outcomes. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study was conducted using the US Renal Data System. All patients with end-stage renal disease in the United States without prior renal replacement therapy who had incident vascular access for HD created between January 1, 2006, and December 31, 2010 (N = 510 000) were included. MAIN OUTCOMES AND MEASURES Incident vascular access use rates and mortality. Relative mortality was quantified using multivariable Cox proportional hazard models. Coarsened exact matching and propensity score-matching techniques were used to better account for confounding by indication. RESULTS Of 510 000 patients included in this study, 82.6% initiated HD via HC, 14.0% via AVF, and 3.4% via AVG. Arteriovenous fistula use increased only minimally, from 12.2% in 2006 to 15.0% in 2010. Patients initiating HD with AVF had 35% lower mortality than those with HC (adjusted hazard ratio, 0.65; 95% CI, 0.64-0.66; P < .001). Those initiating HD with AVF had 23% lower mortality than those initiating with an HC while awaiting maturation of an AVF (adjusted hazard ratio, 0.77; 95% CI, 0.76-0.79; P < .001). CONCLUSIONS AND RELEVANCE Current incident AVF practice falls exceedingly short years after recommendations were made in 1997. The impact of this shortcoming on mortality for patients with end-stage renal disease is enormous. Functioning permanent access at initiation of HD confers lower mortality even compared with patients temporized with an HC while awaiting maturation of permanent access. A change of current policies and structured multidisciplinary efforts are required to establish matured fistulae prior to HD to ameliorate this deficit in delivering care.

Racial/Ethnic Disparities Associated With Initial Hemodialysis Access

IMPORTANCE Superior outcomes have been established with the use of an arteriovenous fistula (AVF) at first hemodialysis. However, considering the influence of comorbidities, medical insurance, and specialist care, racial/ethnic differences in the patterns of utilization of AVFs are unknown and deserve evaluation. OBJECTIVE To assess national trends in initial hemodialysis access with respect to race/ethnicity stratified by comorbid disease, nephrology care, and medical insurance status within the US Renal Data System. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of all patients with end-stage renal disease in the US Renal Data System who initiated hemodialysis between January 1, 2006, and December 31, 2010. Univariable statistics (χ² test and analysis of variance) and logistic regression were used to compare racial/ethnic groups (white vs black vs Hispanic). Multivariable logistic regression and propensity score-matching techniques were used to evaluate hemodialysis access rates between patients of different races/ethnicities with comparable characteristics. MAIN OUTCOMES AND MEASURES Utilization rates of AVF, arteriovenous graft, and intravascular hemodialysis catheter. RESULTS In this cohort of 396,075 patients, more white patients initiated hemodialysis with an AVF than black patients or Hispanic patients (18.3% vs 15.5% and 14.6%, respectively; P < .001). Black patients and Hispanic patients initiated hemodialysis with an AVF less frequently despite being younger and having less coronary artery disease, chronic obstructive pulmonary disease, and cancer than white patients with an AVF. When stratified by medical insurance status, black patients (odds ratios, 0.90 [95% CI, 0.82-0.98] for uninsured and 0.85 [95% CI, 0.84-0.87] for insured) and Hispanic patients (odds ratios, 0.72 [95% CI, 0.65-0.81] for uninsured and 0.81 [95% CI, 0.79-0.84] for insured) persistently initiated hemodialysis with an AVF less frequently than white patients (P < .05 for all). Arteriovenous fistula utilization at initial hemodialysis was lower among black patients (odds ratio, 0.81 [95% CI, 0.78-0.84]) and Hispanic patients (odds ratio, 0.86 [95% CI, 0.82-0.90]) compared with white patients within the category of patients who had nephrology care for longer than 1 year (P < .001 for all). CONCLUSIONS AND RELEVANCE Black patients and Hispanic patients tend to initiate hemodialysis with an AVF less frequently than white patients despite being younger and having fewer comorbidities. These disparities persisted independent of factors that drive health access for fistula placement, such as medical insurance status and nephrology care. The sociocultural underpinnings of these disparities deserve investigation and redress to maximize the benefits of initiating hemodialysis via fistula in patients with end-stage renal disease irrespective of race/ethnicity.

Possible Overuse of 3-Stage Procedures for Active Ulcerative Colitis

IMPORTANCE There is an assumption that patients treated with 3-stage procedures for active ulcerative colitis are undergoing a safer surgical approach and thus spared the complications associated with a 2-stage procedure. However, there is a paucity of data addressing the validity of this assumption, and the optimal staging approach for patients traditionally considered at high risk for anastomotic leak remains unclear. OBJECTIVES To identify factors associated with 3- vs 2-stage procedures and to determine their impact on surgical outcomes. DESIGN Retrospective analysis of patients who underwent 2-stage or 3-stage ileal pouch-anal anastomosis (IPAA) surgery for active ulcerative colitis due to failure of medical management over a 10.5-year period (September 1, 2000, to March 30, 2011). The mean (SEM) follow-up was 5.15 (0.24) years (range, 0.26-11.09 years). SETTING Single large academic medical center. PATIENTS One hundred forty-four patients treated with 3- or 2-stage IPAA surgery for active ulcerative colitis. Among these patients, 77 were male and 67 were female. The mean (SEM) age was 34.6 (1.0) years (range, 11-67 years). Of the 144 patients, 116 (80.6%) had a 2-stage procedure and 28 (19.4%) had a 3-stage procedure. INTERVENTIONS Two-stage vs 3-stage IPAA procedures for active ulcerative colitis. MAIN OUTCOMES AND MEASURES Factors leading to decision for 3-stage procedure, postoperative outcomes with 3-stage vs 2-stage procedures, and risks for complications in patients undergoing 3-stage vs 2-stage procedures. RESULTS Of 144 patients, only 19.4% had a 3-stage procedure. Decision to perform a 3-stage vs 2-stage procedure was affected by emergent status (P < .001) and hemodynamic instability (P = .04) but not by age, sex, body mass index, use of steroids, or use of anti-tumor necrosis factor agents. For patients with 2-stage procedures, multivariate regression revealed that the number of perioperative complications was affected by surgeon experience (P = .02) but not by emergent status, use of steroids, or use of anti-tumor necrosis factor agents. Two-stage procedures were associated with more perioperative complications on univariate analysis (P = .05), but multivariate regression suggested that this difference was due to surgeon experience (P = .02) rather than to creation of an IPAA at the first operation (P = .55). Importantly, 2-stage procedures did not change the risk of anastomotic leak when all operations were taken into account (odds ratio = 1.09; P = .94). In the long term (mean [SEM], 5.2 [0.2] years), patients who underwent 2-stage surgery had a lower risk of anal stricture (odds ratio = 8.21; P = .01) and no differences in fistula or abscess formation or in pouch failure. CONCLUSIONS AND RELEVANCE In patients with active ulcerative colitis, use of steroids and anti-tumor necrosis factor agents alone do not appear to justify the decision to avoid IPAA creation at the first operation provided that it is performed by a high-volume inflammatory bowel disease surgeon.

Improving Safety and Quality of Care With Enhanced Teamwork Through Operating Room Briefings

OBJECTIVES To describe the current state of the science for operating room (OR) briefings and debriefings, including an overview of key definitions, a review of the evidence of effectiveness, and a summary of our experiences as part of a comprehensive unit-based safety program. OVERVIEW Use of preoperative briefings has been shown to improve team communication, decrease disruptions to surgical workflow, improve compliance with antibiotic and deep vein thrombosis prophylaxis, and improve overall perceptions about the safety climate in the OR. Studies have demonstrated that an effective briefing can be performed in less than 2 minutes and reduce delays by more than 80%. Effective implementation involves changing workflows and expectations of interaction among OR team members, including participation from leaders at all levels. Briefings and debriefings are a strategy for revealing defects and facilitating adaptive change in the OR. CONCLUSIONS AND RELEVANCE Briefings and debriefings are a good method for improving teamwork and communication in the OR. Effective implementation may be associated with improved patient outcomes. Commitment by the participating providers is essential for effective briefings, which include discussion of relevant information pertaining to the procedure.

Mortality benefits of different hemodialysis access types are age dependent.

OBJECTIVE Risk of death in dialysis patients is lowest with arteriovenous fistulas (AVFs), followed by arteriovenous grafts (AVGs) and then intravenous hemodialysis catheters (HCs). Our aim was to analyze the effects of age at hemodialysis initiation on mortality across different access types. METHODS All patients ≥18 years in the United States Renal Data System between the years 2006 and 2010 were analyzed. Spline modeling and risk-adjusted Cox proportional hazard models were used to analyze the effect of age on mortality for first dialysis access with AVF vs AVG vs HC. RESULTS The study analyzed 507,791 patients (63.4 ± 0.02 years; 56.5% male; 40.9% mortality; follow-up, 1.57 ± 1.36 years). Increasing age was a significant predictor of overall mortality (adjusted hazard ratio [aHR], 1.03; P < .001). Compared with patients with HCs (n = 418,932), overall risk-adjusted mortality was lowest in patients with AVFs (n = 71,316; aHR, 0.63; P < .001) followed by AVGs (n = 17,543; aHR, 0.83; P < .001). AVF was superior to both HC and AVG for all age groups (P < .001). However, there was a significant change in the relative efficacy of AVG at ages 48 years and 89 years based on spline modeling; there were no significant differences comparing adjusted mortality with AVG vs HC for patients aged 18 to 48 years or for patients >89 years, but AVG was superior to HC for patients 49 to 89 years of age (aHR, 0.811; P < .001). The mortality benefit of AVF was consistently superior to that of AVG and HC for patients of all ages (all, P < .001). CONCLUSIONS AVF is superior to AVG and HC regardless of the patients age, including in octogenarians. In contrast, the mortality benefit of AVG over HC may not apply to younger (18-48 years) or older (>89 years) age groups. All patients 18 to 48 years should receive AVF for dialysis access whenever possible.

Rectal prolapse: an overview of clinical features, diagnosis, and patient-specific management strategies.

Rectal prolapse can present in a variety of forms and is associated with a range of symptoms including pain, incomplete evacuation, bloody and/or mucous rectal discharge, and fecal incontinence or constipation. Complete external rectal prolapse is characterized by a circumferential, full-thickness protrusion of the rectum through the anus, which may be intermittent or may be incarcerated and poses a risk of strangulation. There are multiple surgical options to treat rectal prolapse, and thus care should be taken to understand each patient’s symptoms, bowel habits, anatomy, and pre-operative expectations. Preoperative workup includes physical exam, colonoscopy, anoscopy, and, in some patients, anal manometry and defecography. With this information, a tailored surgical approach (abdominal versus perineal, minimally invasive versus open) and technique (posterior versus ventral rectopexy +/− sigmoidectomy, for example) can then be chosen. We propose an algorithm based on available outcomes data in the literature, an understanding of anorectal physiology, and expert opinion that can serve as a guide to determining the rectal prolapse operation that will achieve the best possible postoperative outcomes for individual patients.

Association Between Race and Age in Survival After Trauma

IMPORTANCE Racial disparities in survival after trauma are well described for patients younger than 65 years. Similar information among older patients is lacking because existing trauma databases do not include important patient comorbidity information. OBJECTIVE To determine whether racial disparities in trauma survival persist in patients 65 years or older. DESIGN, SETTING, AND PARTICIPANTS Trauma patients were identified from the Nationwide Inpatient Sample (January 1, 2003, through December 30, 2010) using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Injury severity was ascertained by applying the Trauma Mortality Prediction Model, and patient comorbidities were quantified using the Charlson Comorbidity Index. MAIN OUTCOMES AND MEASURES In-hospital mortality after trauma for blacks vs whites for younger (16-64 years of age) and older (≥65 years of age) patients was compared using 3 different statistical methods: univariable logistic regression, multivariable logistic regression with and without clustering for hospital effects, and coarsened exact matching. Model covariates included age, sex, insurance status, type and intent of injury, injury severity, head injury severity, and Charlson Comorbidity Index. RESULTS A total of 1,073,195 patients were included (502,167 patients 16-64 years of age and 571,028 patients ≥65 years of age). Most older patients were white (547,325 [95.8%]), female (406 158 [71.1%]), and insured (567,361 [99.4%]) and had Charlson Comorbidity Index scores of 1 or higher (323,741 [56.7%]). The unadjusted odds ratios (ORs) for death in blacks vs whites were 1.35 (95% CI, 1.28-1.42) for patients 16 to 64 years of age and 1.00 (95% CI, 0.93-1.08) for patients 65 years or older. After risk adjustment, racial disparities in survival persisted in the younger black group (OR, 1.21; 95% CI, 1.13-1.30) but were reversed in the older group (OR, 0.83; 95% CI, 0.76-0.90). This finding was consistent across all 3 statistical methods. CONCLUSIONS AND RELEVANCE Different racial disparities in survival after trauma exist between white and black patients depending on their age group. Although younger white patients have better outcomes after trauma than younger black patients, older black patients have better outcomes than older white patients. Exploration of this paradoxical finding may lead to a better understanding of the mechanisms that cause disparities in trauma outcomes.

Hospital-Level Factors Associated With Mortality After Endovascular and Open Abdominal Aortic Aneurysm Repair

IMPORTANCE Endovascular technology has become ubiquitous in the modern care of abdominal aortic aneurysm (AAA), yet broad estimates of its efficacy among variable hospital and regional settings is not known. OBJECTIVE To perform a preliminary analysis of hospital effects on mortality following open AAA repair (OAR) and endovascular AAA repair (EVAR). DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database was conducted on all patients undergoing OAR or EVAR from July 1, 2010, to November 30, 2012, using Current Procedural Terminology codes. MAIN OUTCOMES AND MEASURES Weight-adjusted 30-day observed to expected mortality ratios were compared based on hospital type (academic vs community) and size (100-299 beds vs 300-500 beds vs >500 beds). RESULTS Data on 11,250 patients (2466 underwent OAR and 8784 underwent EVAR) were analyzed. Endovascular AAA repair was performed more frequently than OAR at both academic (78.8%) and community (68.2%) hospitals. Overall 30-day mortality was 14.0% for OAR and 4.3% for EVAR (P < .001). Hospital size was significantly associated with mortality for OAR (observed to expected mortality ratio: >500 beds, 0.88 vs 300-500 beds, 1.11 vs 100-299 beds, 1.59; P = .01) but not for EVAR (P = .27). In contrast, hospital type was significantly associated with mortality for EVAR (observed to expected mortality ratio: academic, 0.60 vs community, 2.60; P < .001) but not OAR (P = .46). Multivariable analysis of hospital-level factors suggested that, for all outcomes, academic hospital type was the single most significant predictor of reduced mortality following AAA repair (observed to expected mortality ratio: academic, 0.91 vs community, 2.00; P = .05). CONCLUSIONS AND RELEVANCE Based on this preliminary report, outcomes for both OAR and EVAR appear to depend greatly on hospital-level effects. The relative safety of EVAR vs OAR may depend on appropriate patient selection and adequate access to multidisciplinary care in order to minimize failure to rescue rates and improve survival.