Christopher R. Roxbury

Challenges and strategies for generating therapeutic patient-specific hemangioblasts and hematopoietic stem cells from human pluripotent stem cells

Recent characterization of hemangioblasts differentiated from human embryonic stem cells (hESC) has further confirmed evidence from murine, zebrafish and avian experimental systems that hematopoietic and endothelial lineages arise from a common progenitor. Such progenitors may provide a valuable resource for delineating the initial developmental steps of human hemato-endotheliogenesis, which is a process normally difficult to study due to the very limited accessibility of early human embryonic/fetal tissues. Moreover, efficient hemangioblast and hematopoietic stem cell (HSC) generation from patient-specific pluripotent stem cells has enormous potential for regenerative medicine, since it could lead to strategies for treating a multitude of hematologic and vascular disorders. However, significant scientific challenges remain in achieving these goals, and the generation of transplantable hemangioblasts and HSC derived from hESC currently remains elusive. Our previous work has suggested that the failure to derive engraftable HSC from hESC is due to the fact that current methodologies for differentiating hESC produce hematopoietic progenitors developmentally similar to those found in the human yolk sac, and are therefore too immature to provide adult-type hematopoietic reconstitution. Herein, we outline the nature of this challenge and propose targeted strategies for generating engraftable human pluripotent stem cell-derived HSC from primitive hemangioblasts using a developmental approach. We also focus on methods by which reprogrammed somatic cells could be used to derive autologous pluripotent stem cells, which in turn could provide unlimited sources of patient-specific hemangioblasts and HSC.

Predictors of Complication after Percutaneous Ultrasound-Guided Kidney Biopsy in HIV-Infected Individuals: Possible Role of Hepatitis C and HIV Co-infection

BACKGROUND AND OBJECTIVES HIV-infected patients often undergo kidney biopsy. The risks of percutaneous ultrasound-guided kidney biopsy in this population are not well established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a case-control, single-center study of 1116 (243 with HIV infection and 873 without) consecutive ultrasound-guided biopsies from 1024 patients. The primary outcome was any major or minor complication. Major complications included biopsy-associated bleeding that required transfusion, angiography, or surgery; hypotension that required intervention; and death. Minor complications included development of a hematoma or gross hematuria. The odds of complication was assessed with logistic regression. RESULTS Overall complication rates (8.6 versus 7.2%) did not significantly differ between HIV-infected and noninfected individuals. HIV-positive status did not predict complication. In the entire cohort, hepatitis C infection was associated with a 2.08 (95% confidence interval [CI] 1.47 to 2.93) increased odds of complication, and each 10,000-cells/mm(3) decrease in prebiopsy platelet count a 1.05 (95% CI 1.02 to 1.08) increased odds of complication. In addition, prebiopsy hematocrit <30% and estimated GFR <30 ml/min per 1.73 m(2) were associated with major complication. Whereas the association of prebiopsy platelet count was not modified by HIV infection, hepatitis C/HIV co-infection was associated with a 5.71 (95% CI 1.89 to 17.2) increased odds of complication as compared with 1.27 (95% CI 0.73 to 2.19) in hepatitis C-positive/HIV-negative individuals. CONCLUSIONS Ultrasound-guided percutaneous kidney biopsy is a relatively safe, well-tolerated procedure in the HIV-infected population. HIV-infected individuals who are co-infected with hepatitis C seem to be at greatest risk.

Safety and Postoperative Adverse Events in Pediatric Otologic Surgery: Analysis of American College of Surgeons NSQIP-P 30-Day Outcomes.

Objectives Describe safety and postoperative sequelae of pediatric otologic surgery and identify predictive factors for postoperative events. Study Design Retrospective cohort study of the American College of Surgeons National Surgery Quality Improvement Program–Pediatric (NSQIP-P) database. Setting Data pooled from the 2012 NSQIP-P public use file (50 institutions). Subjects and Methods Current procedural terminology codes were used to identify children who underwent otologic surgery. Variables of interest included demographics and 30-day postoperative events grouped as reoperation, readmission, and complication. Event rates were determined and prevalence of events compared by procedure type and within patient subgroups according to chi-square analysis. Multivariate logistic regression evaluated predictive factors for postoperative events. Results Of 37,319 pediatric operations, 2556 (6.8%) were otologic procedures. The most common procedure was tympanoplasty (n = 893, 34.9%), followed by myringoplasty (n = 741, 30.0%), cochlear implantation (n = 464, 18.2%), and tympanomastoidectomy (n = 458, 17.9%). There were 9 reoperations (0.4%), 32 readmissions (1.3%), and 18 complications (0.7%). Children undergoing tympanomastoidectomy or cochlear implantation were more likely to be readmitted irrespective of other factors (odds ratio = 5.5, P = .010; odds ratio = 3.5, P = .083). Children <3 years old were 4 times more likely to be readmitted than older children (odds ratio = 4.4, P < .001). Conclusion Pediatric otologic procedures are common and have low rates of global 30-day postoperative events. Tympanomastoidectomy and cochlear implantation have the highest risk of 30-day readmission. Young children (<3 years) are more likely to be readmitted following these procedures. Further optimization of the NSQIP-P to include specialty and procedure-specific variables is necessary to assess complete, actionable outcomes of pediatric otologic surgery, however the present study provides a foundation to build upon for safety and quality improvement initiatives in pediatric otology.

Pain Reporting, Opiate Dosing, and the Adverse Effects of Opiates After Hip or Knee Replacement in Patients 60 Years Old or Older

Our goal was to determine whether there were age-related differences in pain, opiate use, and opiate side effects after total hip or knee arthroplasty in patients 60 years old or older. We hypothesized that there would be no significant differences between age groups in (1) mean pain score, (2) opiate use after adjusting for pain, or (3) opiate side effects after adjusting for opiate use and pain score. We retrospectively reviewed the electronic and paper charts of all patients undergoing total joint replacements at our institution over 3 years who met the following criteria: (1) 60 years old or older, (2) primary single total knee or total hip replacement, and (3) no preoperative dementia. Preoperative, intraoperative, and postoperative course data were collected using a customized data entry process and database. We divided the patients into 2 age groups, those 60 to 79 years old and those 80 years old or older. Using a marginal model with the panel variable of postoperative day, we investigated the associations between age group and pain, age group and pain adjusting for opiate use, and age group and complications (respiratory depression, naloxone usage as a measure of respiratory arrest, delirium, constipation, and urinary retention) adjusting for opiate use (Xtgee, Stata10, Stata Corp. LP, College Station, Texas). Significance was set at P < .05. We found no significant difference in pain scores between groups, but the older group had significantly fewer opiates prescribed yet significantly more side effects, including delirium (odds ratio 4.2), than did the younger group, even after adjusting for opiate dose and pain score.

Endonasal Endoscopic Surgery in the Management of Sinonasal and Anterior Skull Base Malignancies

Sinonasal malignancies represent a rare subset of tumors with a wide variety of histopathologic diagnoses and overall poor prognosis. These tumors tend to have an insidious onset with non-specific symptoms which often leads to delayed diagnosis and advanced local disease at presentation. The principal goal of surgery is to obtain a negative margin resection. Open craniofacial techniques are well established in the management of sinonasal malignancies and remain the treatment of choice for many advanced tumors. Over the past couple of decades, there has been tremendous application of endoscopic techniques to skull base pathologies including sinonasal malignancies. For selected cases, endonasal endoscopic techniques can be performed with curative intent and reduced surgical morbidity and mortality. Here we discuss principles of surgical management of sinonasal malignancies, review the techniques of endonasal endoscopic resection of sinonasal malignancies, and highlight the importance of pathology in the multi-disciplinary management of patients with these complex lesions.

Endoscopic Management of Esthesioneuroblastoma

Esthesioneuroblastoma is a rare malignant tumor of sinonasal origin. These tumors typically present with unilateral nasal obstruction and epistaxis, and diagnosis is confirmed on biopsy. Over the past 15 years, significant advances have been made in endoscopic technology and techniques that have made this tumor amenable to expanded endonasal resection. There is growing evidence supporting the feasibility of safe and effective resection of esthesioneuroblastoma via an expanded endonasal approach. This article outlines a technique for endoscopic resection of esthesioneuroblastoma and reviews the current literature on esthesioneuroblastoma with emphasis on outcomes after endoscopic resection of these malignant tumors.

Impact of crooked nose rhinoplasty on observer perceptions of attractiveness

To evaluate the impact of a crooked nose on observer perceptions of facial asymmetry and attractiveness and the ability of rhinoplasty to minimize it. We hypothesized that the presence of a crooked nose would penalize symmetry and attractiveness ratings as compared to normal faces. We further hypothesized that straightening rhinoplasty would restore symmetry and improve attractiveness.

Safety and postoperative adverse events in pediatric airway reconstruction: Analysis of ACS‐NSQIP‐P 30‐day outcomes

Prior research has shown that airway reconstructive procedures comprise significant composite morbidity compared to the whole of pediatric otolaryngologic cases evaluated in the American College of Surgeons National Surgery Quality Improvement Program‐Pediatric (ACS‐NSQIP‐P) platform. We describe postoperative sequelae of pediatric airway reconstructive procedures and identify predictive factors for adverse events.

Layered sellar reconstruction with avascular free grafts: Acceptable alternative to the nasoseptal flap for repair of low-volume intraoperative cerebrospinal fluid leak.

Background Although the nasoseptal flap has become the method of choice for reconstruction of intraoperative cerebrospinal fluid (CSF) leak in endoscopic minimally invasive surgery of the skull base, layered avascular graft techniques, including allografts and middle turbinate mucosal autografts, may provide comparable reconstructive success with decreased nasal morbidity. Objective To describe a method of reconstruction of intraoperative CSF leak in endoscopic surgery of the sella turcica and analyze its postoperative success rate and associated comorbidities. Methods A retrospective review of expanded endonasal sellar tumor resections from 2008-2014 was performed, and cases of layered intraoperative skull base reconstruction with avascular free grafts were identified. Demographic factors and comorbidities that predisposed to reconstruction failure (obstructive sleep apnea, obesity) were determined. Reconstruction-related nasal complications were also identified. Postoperative CSF leak rate was determined, and statistical analysis was performed to identify predictive factors for reconstructive failure. Results Seventy-three cases were identified. Layered closure with avascular free grafts was performed. There were five cases of postoperative CSF leak (6.85%). The mean follow-up was 19 months (range, 1-76 months). Intraoperative high-flow CSF leak was a significant predictor of reconstruction failure on univariate (odds ratio 22 [95% confidence interval, 2.26-214]; p = 0.008) and multivariate analysis (odds ratio 33.6 [95% confidence interval, 2.30-492]; p = 0.010). There were no significant differences in postoperative leak rates among bony overlay graft types. There were five patients (7.9%) who experienced persistent crusting after surgery. There were no significant differences in crusting rates between allografts and mucosal grafts. There were no postoperative mucoceles. Conclusion In cases of low-volume intraoperative CSF leak, layered skull base repair with avascular free grafts was an acceptable alternative to the nasoseptal flap, which may reduce prolonged sinonasal healing and donor-site morbidities.

Safety and Perioperative Adverse Events in Pediatric Endoscopic Sinus Surgery: An ACS‐NSQIP‐P Analysis

This study describes safety outcomes of pediatric endoscopic sinus surgery (ESS) to identify risk factors for 30‐day postoperative adverse events using the National Surgical Quality Improvement Program–Pediatric (NSQIP‐P) database.