It is well recognized that a certain component of surgical residency training has transitioned from the operating room to the surgical skills lab. Although a significant amount of important work has validated simulators as viable systems for teaching technical skills outside the operating room, the next step is integrating simulators into a comprehensive curriculum. Several frameworks for curricular design have been described in the literature; however, few curricula have been described or validated for minimally invasive surgical procedures. This study describes the design and validation of a comprehensive technical skills curriculum for laparoscopic colorectal surgery, an advanced laparoscopic procedure. The initial step in this project utilized the Delphi consensus methodology to develop a procedure-specific evaluation tool for laparoscopic colorectal surgery. This evaluation tool demonstrated reliability and validity in the context of expert and novice performance in the operating room. The next phase of the project also used the Delphi method to develop international consensus on a proficiency-based virtual reality program designed to teach the technical skills necessary to perform laparoscopic colorectal surgery. This virtual reality training program was then integrated into a comprehensive curriculum consisting of psychomotor training on the virtual reality simulator, as well as cognitive training and a cadaver lab. The final component of this project was a randomized single-blinded controlled trial that demonstrated that surgical residents who participated in the comprehensive curriculum exhibited superior technical skills in the operating room, and superior cognitive knowledge relating to laparoscopic colorectal surgery, compared to residents who received only conventional residency training.

HSV-2 may have adverse consequences in HIV. I evaluated the impact of HSV-2 co-infection on (highly active antiretroviral therapy)-untreated HIV infection in a systematic review of observational studies (study 1) and a retrospective cohort (study 2). I further evaluated whether HSV reactivation rates in co-infected persons differ by use of suppressive cART (study 3). Study 1 found modest evidence that HSV-2 seropositivity may be associated with accelerated progression to opportunistic infection or clinical AIDS, but not with increased HIV viral load. Some evidence suggests that HSV-2 disease activity is associated with increased HIV viral load and decreased CD4 counts. Study 2 compared rates of CD4 count change by HSV-2 status (Focus HerpeSelect ELISA) among 218 patients with a past period of ART-untreated follow-up using mixed linear regression models. No significant difference in the rate of CD4 count change was observed in HSV-2 seropositives at +13.6 cells/mm3/year (p=0.12) in univariate analysis, and -4.5 cells/mm3/year (p=0.68) in analysis adjusted for sex, HSV-1, oral and genital HSV symptoms, immigrant status, and immigrant*time interaction. These findings support the need for carefully designed and executed studies of HSV-2 suppression as an adjunctive management strategy for HIV disease, but raise questions regarding the exact mechanism of negative synergy between these viruses and the relative importance of HSV-2 latency and replication in driving these effects. In Study 3, 44 cART-naïve and 41 treated (HIV RNA<50 copies/mL) HIV+ adults with HSV-1 and/or 2 co-infection collected oral, genital and anal swabs daily for 28 days. Negative binomial models were used to quantify the relationship between cART and HSV shedding (Roche LightCycler HSV1/2). Overall HSV shedding was low, at a median (IQR) of 3.6% (0, 14.3%) of days. No relationship was seen between cART and HSV-1 or 2 shedding in univariate (RR=1.55, 95%CI=0.83,2.87) or multivariate analysis adjusted for sex, baseline CD4, recent immigrant status, and time since HIV diagnosis (aRR=1.05, 95%CI=0.43,2.58). Null results were also observed for HSV-1 and HSV-2 considered separately. That HSV shedding persists despite cART suggests that trials of anti-HSV drugs for improving HIV outcomes may be warranted in such patients.

Background: The incidence of inadequate empiric antibiotic therapy (IET) and its clinical importance as a risk factor for hospital mortality in Canadian solid-organ transplant patients remains unknown. Methods: This retrospective cohort study evaluated all patients admitted to a transplant unit from May/2002-April/2004. Therapy was considered adequate when the organism cultured was found to be susceptible to an antibiotic administered within 24 hours of the index sample collection time. Univariate and multivariate regression analyses were conducted to determine associations between potential determinants, IET, and mortality. Results: IET was administered in 169/312 (54%) transplant patients. Regression analysis demonstrated that an increasing duration of IET (adjusted OR at 24h, 1.33; p < 0.001), ICU-associated infections (adjusted OR, 6.27; p < 0.001), prior antibiotic use (adjusted OR, 3.56; p = 0.004), and increasing APACHE-II scores (adjusted OR, 1.26; p < 0.001), were independent determinants of hospital mortality. Conclusions: IET is common and appears to be an important determinant of hospital mortality in the Canadian transplant population.

Accumulating evidence suggests that volume overload in drug-resistant hypertension (RH) may contribute to the high prevalence of obstructive sleep apnea-hypopnea (OSAH). Upon recumbency, leg fluid volume moves rostrally causing an increase in nuchal and peripharyngeal fluid content, subsequently obstructing airflow. Rostral fluid displacement following lower body positive pressure (LBPP) application and occurring spontaneously overnight were evaluated in subjects with RH (n = 25) and controlled hypertension (n = 15). In both groups, the reduction in mean upper airway cross-sectional area with LBPP strongly related to the amount of fluid displaced from the legs (R2 = 0.41; p<0.0001), although its magnitude was greater in the RH group (p=0.001; adjusted for propensity score). In both groups, the apnea-hypopnea index strongly related to the amount of fluid spontaneously displaced from the legs during sleep (R2 = 0.56; p<0.0001), although its magnitude was greater in the RH group (p=0.01; adjusted for propensity score).

We conducted a retrospective review of discordant pathology for lymphoma patients treated at the Princess Margaret Hospital between 2000 and 2003. We identified 2818 lymphoma patients of which 1567 (38%) met inclusion criteria with 167 discordant cases (discordance rate 15.7%). Six reviewers blinded to clinical management rated potential for harm on a minimal to severe scoring. The majority (67.6%) received a rating of moderate to severe. Review of actual clinical management revealed unnecessary surgical procedures, incorrect chemotherapy and under or over treatment of patients. For discordant cases, 8.4% were identified as having severe actual harm. This means that 1/6 patients diagnosed with lymphoma may have a change in diagnosis after pathologic review, 1/9 will have discordance with the potential to cause moderate to severe consequences, and 1/75 will experience significant clinical harm. We conclude that pathologic discordance in lymphoma is common and can lead to patient harm.

Intractable epilepsy remains one of the top issues affecting the quality of living in Rett children. While several MeCP2-deficient mouse models of Rett Syndrome have been established, minimal information exists on how the loss of MeCP2 affects brain network activity. To address this issue, in vivo recordings of the hippocampus and somatosensory cortex of MeCP2-deficient mice were taken during exploration, immobility, and sleep. The frequency of hippocampal theta oscillations was significantly attenuated in MeCP2-deficient mice during exploration. A subset of MeCP2-heterozygotes displayed spontaneous, cortical epileptiform-like discharges in the immobile-awake state. Similar epileptiform-like discharges were observed in one of the four Mecp2-null mice recorded. Aside from these EEG abnormalities, basal network activity was preserved. Further, convulsive seizures were not seen. Collectively, these findings indicate that a deficiency of MeCP2 in mice leads to only subtle alterations in brain wave activity, contrasting the severely abnormal EEG observed in Rett girls.

The recombinant Hepatitis B surface antigen vaccine inadequately protects those living with HIV from Hepatitis B virus infection. This study utilized saved serum samples from a retrospective cohort of persons with HIV and documented vaccine-induced HBsAb seroconversion to determine factors associated with persistence of protective levels of HBsAb (≥10mIU/ml). HBsAb levels fell below 10mIU/ml in 27% of the cohort after a median follow-up of 43 months. HIV viral load suppression (<50copies/ml) at the time of vaccination was the major factor associated with persistence of protective levels of HBsAb (OR 3.83, p <0.01). Among individuals who lost protective levels of HBsAb, booster doses of vaccine re-instated the development of protective levels of HBsAb. Delaying or repeating HBV vaccination until after suppression of HIV viral load is achieved should be considered HBV antibody levels should be followed over time and boosters given with loss of protective levels of HBsAb.

Endogenously, VEGF initiates angiogenesis, then later Angiopoietin (Ang)-1 matures vessels. We hypothesized that multigene therapy of VEGF before Ang1 to ischemic hindlimb tissue would result in persistent angiogenesis. At 2, 4 and 8 wks after inducing ischemia, blood flow was assessed by contrast-enhanced ultrasound. Animals were treated with VEGF at 2 wks, VEGF/Ang1 at 2 wks, or VEGF at 2 wks and Ang1 at 4 wks. In untreated controls, blood flow remained reduced. After VEGF delivery, resting flow and vessel density increased; however, flow reserve remained reduced, and vasculature was capillary-rich and eventually regressed. After VEGF/Ang1 co-delivery, flow increased marginally, flow reserve improved and vascular architecture remained normal. After separated VEGF and Ang1 delivery, flow, vessel density and flow reserve increased and were sustained, while vascular architecture remained normal. In conclusion, temporally separated VEGF and Ang1 delivery promotes sustained angiogenesis and improved vessel functionality.

Airway hyperresponsiveness (AHR) is a cardinal feature of asthma that is aggravated by environmental air pollution (EAP). Splenocyte tyrosine kinase Syk has been associated with asthma pathogenesis. Therefore, we sought to investigate the effect of Syk inhibition on AHR and its exacerbation by EAP. For this purpose, we examined Syk protein expression in lung homogenates from three murine models of ovalbumin (OVA)-induced asthma expressing different pathophysiological features of the disease: airway inflammation, AHR and remodeling. Increased Syk expression was observed only in the chronic model of airway inflammation and remodeling. In vivo Syk inhibition attenuates AHR in this model, and further augmentation induced by EAP without affecting the underlying airway inflammation. We demonstrated, for the first time, that Syk inhibition effectively reverted AHR in an already established chronic model of asthma. These findings highlight the therapeutic potential of targeting Syk for the treatment of asthma and its exacerbations by EAP.

Intractable epilepsy remains one of the top issues affecting the quality of living in Rett children. While several MeCP2-deficient mouse models of Rett Syndrome have been established, minimal information exists on how the loss of MeCP2 affects brain network activity. To address this issue, in vivo recordings of the hippocampus and somatosensory cortex of MeCP2-deficient mice were taken during exploration, immobility, and sleep. The frequency of hippocampal theta oscillations was significantly attenuated in MeCP2-deficient mice during exploration. A subset of MeCP2-heterozygotes displayed spontaneous, cortical epileptiform-like discharges in the immobile-awake state. Similar epileptiform-like discharges were observed in one of the four Mecp2-null mice recorded. Aside from these EEG abnormalities, basal network activity was preserved. Further, convulsive seizures were not seen. Collectively, these findings indicate that a deficiency of MeCP2 in mice leads to only subtle alterations in brain wave activity, contrasting the severely abnormal EEG observed in Rett girls.