Sofosbuvir-Based Therapy in the Pre-Liver Transplant Setting: The Canadian National Experience.

INTRODUCTION AND AIM: Sofosbuvir (SOF)-based regimen has been shown to have high efficacy even in patients with decompensated cirrhosis. Treated patients may experience various degrees of hepatic recovery ranging from stabilization of liver function, to removal from liver transplant wait lists. The frequency of these occurrences in larger transplant eligible patient populations is unknown. The aim of this study was to assess the efficacy of SOF-based therapy in HCV infected transplant eligible patients and to evaluate short term changes in liver function and the effect on their liver transplant status. MATERIAL AND METHODS: A retrospective multicenter Canadian study of liver transplant candidates with advanced HCV cirrhosis treated with SOF-based therapy. Outcomes included sustained virologic response (SVR), and liver transplant status. RESULTS: 105 liver transplant candidates with advanced liver disease due to HCV were evaluated. The overall SVR was 83.8%. Hepatocellular carcinoma was diagnosed in 39 (37.1%) prior to transplant evaluation. In short term follow-up, 14 (13.3%) remained active on the list at the time of SVR12, 22 (20.9%) patients underwent liver transplantation, 7 (6.6%) patients were deactivated due to clinical improvement, 3 patients were delisted, and 10 deaths were reported. CONCLUSIONS: SOF-based therapy for patients progressing to liver transplantation leads to high SVR rates, short term stability in liver function, and deactivation from the transplant list .

Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.

BACKGROUND: The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slow-acting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease. OBJECTIVES: To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease. SEARCH METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015. SELECTION CRITERIA: Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically-induced remission were excluded. DATA COLLECTION AND ANALYSIS: At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20) of patients in the infliximab group (RR 1.02, 95% CI 0.74 to 1.40). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (29 events) and unclear risk of bias. One small study found no difference in maintenance of remission rates at one year between 6-MP (1 mg/day) and methotrexate (10 mg/week). Fifty per cent (8/16) of 6-MP patients maintained remission at one year compared to 53% (8/15) of methotrexate patients (RR 0.94, 95% CI 0.47 to 1.85). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (16 events) and high risk of bias. One study (147 participants) failed to show any significant benefit for early azathioprine treatment over a conventional management strategy. In the early azathioprine treatment group 67% (11-85%) of the trimesters were spent in remission compared to 56% (29-73%) in the conventional management group. AZA when compared to placebo had significantly increased risk of adverse events (RR 1.29, 95% CI 1.02 to 1.64), withdrawal due to adverse events (3.12, 95% CI 1.59 to 6.09) and serious adverse events (RR 2.45, 95% CI 1.22 to 4.90). AZA/6-MP also demonstrated a significantly higher risk of serious adverse events when compared to mesalazine or sulphasalazine (RR 9.37, 95% CI 1.84 to 47.7). AZA/6-MP did not differ significantly from other active therapies with respect to adverse event data. Common adverse events included pancreatitis, leukopenia, nausea, allergic reaction and infection. AUTHORS' CONCLUSIONS: Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease.

Using simplified blood pressure tables to avoid underdiagnosing childhood hypertension.

BACKGROUND: Recent studies have revealed that hypertension remains underdiagnosed in a significant number of children despite their recorded office blood pressure (OBP) exceeding the recommended fourth report OBP thresholds. Simplified OBP thresholds have been proposed to reduce this underdiagnosis of hypertension in children. In clinical practice, OBP screened as elevated according to the fourth report OBP thresholds are referred for ambulatory blood pressure (ABP) monitoring to rule out 'white coat' hypertension. OBJECTIVES: The present study tested the usefulness of simplified OBP thresholds to screen abnormal OBP for ABP monitoring referral. METHODS: A total of 155 subjects were retrospectively analyzed with paired OBP and ABP recordings obtained from an outpatient referral clinic. OBP recordings were classified as abnormal according to the simplified and fourth report OBP thresholds. ABP measurements were classified as abnormal according to the ABP reference tables. RESULTS: Simplified blood pressure (BP) tables correctly identified all OBP classified as abnormal according to fourth report BP thresholds (kappa [κ] 0.72 [95% CI 0.61 to 0.83]) for systolic OBP; κ 0.92 [95% CI 0.86 to 0.99] for diastolic OBP). OBP classified as abnormal by the simplified BP thresholds and by the fourth report BP thresholds performed similarly for correctly identifying abnormal ABP measurements as per ABP references (overlapping 95% CIs of the sensitivity, specificity and predictive values and likelihood ratios). CONCLUSIONS: Simplified BP tables, proposed to reduce the underdiagnosis of hypertension in children, can serve as a useful screening tool to decide a referral for ABP monitoring. Future prospective studies are needed to establish these findings.

HISTORIQUE: De récentes études ont démontré que l'hypertension demeure sous-diagnostiquée chez de nombreux enfants, même si leur tension artérielle prise en cabinet (TAC) dépassait les seuils recommandés pour la quatrième TAC enregistrée. Certains ont proposé des seuils simplifiés de TAC pour réduire ce sous-diagnostic. En pratique clinique, les TAC considérées comme élevées selon les seuils pour la quatrième TAC enregistrée sont dirigées vers une surveillance de la tension artérielle en milieu ambulatoire (TAA), pour écarter le « syndrome de la blouse blanche ¼. OBJECTIFS: La présente étude portait sur l'utilité des seuils simplifiés de TAC pour dépister les TAC anormales en vue de les aiguiller vers la surveillance de la TAA. MÉTHODOLOGIE: Au total, 155 sujets ont fait l'objet d'une analyse rétrospective par rapport à des enregistrements appariés de TAC et de TAA obtenues dans une clinique de consultation ambulatoire. Les enregistrements de TAC étaient classés comme anormaux d'après le seuil simplifié et le seuil de la quatrième TAC enregistrée. Les mesures de TAA étaient classées comme anormales en fonction des tableaux de référence de la TAA. RÉSULTATS: Les tableaux simplifiés de la tension artérielle (TA) ont permis de dépister toutes les TAC classées comme anormales selon les seuils de quatrième TA enregistrée (kappa [κ] 0,72 [95 % IC 0,61 à 0,83] pour la TAC systolique; κ 0,92 [95 % IC 0,86 à 0,99] pour la TAC diastolique). La TAC classée comme anormale selon les seuils simplifiés de la TA et les seuils de la quatrième TAC enregistrée ont permis de déterminer les mesures anormales de TAA conformément aux références de TAA (chevauchement 95 % IC de la sensibilité, de la spécificité et des valeurs prédictives ainsi que des ratios de probabilité). CONCLUSIONS: Les tableaux simplifiés de la TA proposés pour réduire le sous-diagnostic d'hypertension chez les enfants peuvent être utiles pour orienter ou non les patients vers une surveillance de la TAA. D'autres études prospectives s'imposent pour confirmer ces observations.

Nighttime blood pressure, systolic blood pressure variability, and left ventricular mass index in children with hypertension.

BACKGROUND: Nighttime blood pressure (BP) and systolic BP variability on ambulatory blood pressure monitoring (ABPM) have been strongly associated with target-organ damage in hypertensive adults. The clinical relevance of these variables in children with hypertension remains under-studied. METHODS: The study group included children aged 5-18 years old referred to the outpatient nephrology clinic for an elevated casual BP who underwent an ABPM and echocardiography (ECHO) study and did not have secondary hypertension. The interpretation of ABPM parameters and left ventricular mass index (LVMI) was based on normative references. RESULTS: Seventy-two children fulfilled the inclusion criteria. The association of various potential predictors including age, BMI z-score, casual BP z-score and ABPM parameters (BP z-score, BP load, nocturnal dipping and BP variability- within-subject standard deviation (SD) of BP) with LVMI was analyzed. On adjusted regression analysis, nighttime systolic BP load [standardized regression coefficient (ß) 0.23; p < 0.05] and daytime systolic BP variability (ß 0.37; p < 0.05) had significant association with LVMI. CONCLUSIONS: In children with primary hypertension, nighttime systolic BP load and daytime systolic BP variability had a stronger association with LVMI than casual BP and other ABPM parameters. Future longitudinal studies are needed to establish the causality among these variables.

KODA score: an updated and validated bowel preparation scale for patients undergoing small bowel capsule endoscopy.

Background and study aims A reliable outcome measure is needed for bowel preparation quality during capsule endoscopy. Currently, no scales are adequately validated. Our objective was to update an existing small bowel preparation score, create a standardized training module, then determine its inter-rater and intra-rater reliability. Patients and methods Modification to produce standardized scoring of an existing small bowel preparation score was performed followed by development of a training module and validation to create the new Korea-Canada (KODA) score. Twenty readers from a range of backgrounds, including capsule endoscopists, gastroenterology fellows, residents, medical students, and nurses rated bowel cleanliness in 25 capsule videos consisting of 1,233 images, in duplicate 4 weeks apart, after completing the training module. Sequential images selected in 5-minute intervals during small bowel transit were rated on a scale between 0-3 based on the amount of visualized mucosa and the degree of obstruction. Reliability was assessed using estimates of intraclass correlation coefficients (ICCs). Results Intraclass correlation coefficients for inter-rater (ICC 0.81, 95 % CI 0.70-0.87) and intra-rater (ICC 0.92, 95 % CI 0.87-0.94) reliability were almost perfect among the 20 readers. Inter-rater reliability ranged between 0.72 (95 % CI 0.57-0.81) and 0.89 (95 % CI 0.79-0.93) for nurses and residents, respectively. Intra-rater reliability was greater than 0.90 for all groups except for nurses, which was still almost perfect (ICC 0.86, 95 % CI 0.79-0.90). Conclusions Almost perfect inter-rater and intra-rater reliability was observed for the KODA score. This simple score could be used for future clinical trials after completion of the training module.

Repeat low-level blast exposure increases transient receptor potential vanilloid 1 (TRPV1) and endothelin-1 (ET-1) expression in the trigeminal ganglion.

Blast-associated sensory and cognitive trauma sustained by military service members is an area of extensively studied research. Recent studies in our laboratory have revealed that low-level blast exposure increased expression of transient receptor potential vanilloid 1 (TRPV1) and endothelin-1 (ET-1), proteins well characterized for their role in mediating pain transmission, in the cornea. Determining the functional consequences of these alterations in protein expression is critical to understanding blast-related sensory trauma. Thus, the purpose of this study was to examine TRPV1 and ET-1 expression in ocular associated sensory tissues following primary and tertiary blast. A rodent model of blast injury was used in which anesthetized animals, unrestrained or restrained, received a single or repeat blast (73.8 ± 5.5 kPa) from a compressed air shock tube once or daily for five consecutive days, respectively. Behavioral and functional analyses were conducted to assess blast effects on nocifensive behavior and TRPV1 activity. Immunohistochemistry and Western Blot were also performed with trigeminal ganglia (TG) to determine TRPV1, ET-1 and glial fibrillary associated protein (GFAP) expression following blast. Increased TRPV1, ET-1 and GFAP were detected in the TG of animals exposed to repeat blast. Increased nocifensive responses were also observed in animals exposed to repeat, tertiary blast as compared to single blast and control. Moreover, decreased TRPV1 desensitization was observed in TG neurons exposed to repeat blast. Repeat, tertiary blast resulted in increased TRPV1, ET-1 and GFAP expression in the TG, enhanced nociception and decreased TRPV1 desensitization.

Task-dependent effects of social attention on saccadic reaction times.

Previous research has shown that saccadic reaction times (SRTs) are shorter when a stimulus is flashed on the same side as the observed gaze direction of another individual. The gaze imitation hypothesis contends that observed gaze evokes the preparation of a saccade toward the same direction. Previous studies of this phenomenon have employed pro-saccade tasks in which the instructed saccade is directed toward the stimulus. In agreement with previous findings, we found that SRTs on pro-saccade trials were shorter when the stimulus appeared in the same direction as observed gaze. Here we also included anti-saccade trials in which subjects were required to look-away from a stimulus and toward its mirror position in the opposite visual field. The gaze imitation hypothesis predicts that subjects will have shorter SRTs on anti-saccade trials in which the stimulus appears opposite the observed gaze direction because they will have prepared already a saccade in that direction. However, contrary to the prediction of the gaze imitation hypothesis, we found that subjects had shorter SRTs on anti-saccade trials when the stimulus appeared in the same direction as observed gaze. Moreover, subjects also made more pro-saccade errors on anti-saccade trials in which the stimulus was presented opposite the observed gaze direction. The results of our study indicate that subjects prepared a saccade in the same direction as observed gaze on pro-saccade trials but opposite the observed gaze direction on anti-saccade trials. These findings suggest that the effect of social gaze cues on SRTs is task dependent.