"Interchangeability" of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy.

Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

Intravenous dextrose versus ondansetron for prevention of postoperative vomiting in children: a randomized non-inferiority trial.

BACKGROUND: Postoperative vomiting (POV) in children is frequent. Dextrose-containing intravenous fluids in the perioperative period have shown improvement of POV in adults. Similar studies have not been done in children. AIM: The primary purpose was to study the efficacy of intraoperative intravenous dextrose for antiemetic prophylaxis in children undergoing ambulatory surgery. METHODS: A non-inferiority randomized clinical trial of healthy children (three to nine years old) undergoing ambulatory dental surgery was conducted. The control group received dexamethasone (0.15 mg·kg-1 iv) and ondansetron (0.05 mg·kg-1 iv); the intervention group received dexamethasone (0.15 mg·kg-1 iv) and intravenous 5% dextrose in 0.9% normal saline according to a weight-based maintenance rate. The primary outcome was POV in the postanesthetic care unit (PACU) within two hr after surgery. Secondary outcomes included POV within 24 hr from discharge and unplanned hospital admission. A non-inferiority analysis was conducted on the primary outcome using an absolute risk difference of 7.5% as the non-inferiority margin. RESULTS: Data from 290 patients were analyzed. Demographics and intraoperative anesthetic management were similar between groups. Vomiting in the PACU occurred in 7.6% and 3.5% of the dextrose and ondansetron groups, respectively, with a risk difference of 4.2% (95% confidence interval [CI], -1.0 to 9.5). Given that the upper limit of the 95% CI exceeded our non-inferiority margin, non-inferiority of dextrose compared with ondansetron was not shown. CONCLUSION: These results do not support the use of intravenous dextrose as a satisfactory alternative to ondansetron to prevent POV in ambulatory pediatric dental surgery patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01912807); registered 18 July 2013.

RéSUMé: CONTEXTE: Les vomissements postopératoires (VPO) sont fréquents chez l'enfant. Il a été démontré qu'en période périopératoire, les solutés intraveineux contenant du dextrose entraînaient une diminution des VPO chez l'adulte, mais des études similaires n'ont pas été réalisées auprès de populations pédiatriques. OBJECTIF: L'objectif principal était d'évaluer l'efficacité du dextrose intraveineux peropératoire en tant que prophylaxie antiémétique chez les enfants subissant une chirurgie ambulatoire. MéTHODE: Une étude clinique randomisée de non-infériorité a été réalisée auprès d'enfants en bonne santé (de trois à neuf ans) devant subir une chirurgie dentaire en ambulatoire. Le groupe témoin a reçu de la dexaméthasone (0,15 mg·kg−1 iv) et de l'ondansétron (0,05 mg·kg−1 iv); le groupe intervention a reçu de la dexaméthasone (0,15 mg·kg−1 iv) et du dextrose intraveineux 5 % dans une solution de normal salin 0,9 % selon une échelle basée sur le poids. Le critère d'évaluation principal était la présence de VPO en salle de réveil au cours des deux heures suivant la chirurgie. Les critères d'évaluation secondaires comprenaient les VPO au cours des 24 h suivant le congé et une admission non planifiée à l'hôpital. L'analyse de non-infériorité a été réalisée pour le critère d'évaluation primaire en se fondant sur une différence de risque absolu de 7,5 % comme marge de non-infériorité. RéSULTATS: Les données de 290 patients ont été analysées. Les données démographiques et de prise en charge anesthésique peropératoire étaient semblables entre les deux groupes. Des vomissements sont survenus en salle de réveil chez 7,6 % et 3,5 % des groupes dextrose et ondansétron, respectivement, avec une différence de risque de 4,2 % (intervalle de confiance [IC] 95 %, -1,0 à 9,5). Étant donné que la limite supérieure de l'IC 95 % excédait notre marge de non-infériorité, la non-infériorité du dextrose comparativement à l'ondansétron n'a pas été démontrée. CONCLUSION: Ces résultats n'appuient pas l'utilisation de dextrose intraveineux en tant qu'alternative à l'ondansétron afin de prévenir les VPO chez les patients pédiatriques de chirurgie dentaire ambulatoire. ENREGISTREMENT DE L'éTUDE: www. CLINICALTRIALS: gov (NCT01912807); enregistrée le 18 juillet 2013.

Direction of the Biopsy Needle in Ultrasound-Guided Renal Biopsy Impacts Specimen Adequacy and Risk of Bleeding.

INTRODUCTION: Although medical factors such as hypertension and coagulopathy have been identified that are associated with hemorrhage after renal biopsy, little is known about the role of technical factors. The purpose of our study was to examine the effects of biopsy needle direction on renal biopsy specimen adequacy and bleeding complications. METHODS: Two hundred and forty-two patients who had undergone ultrasound-guided renal biopsies were included. A printout of the ultrasound picture taken at the time of the biopsy was used to measure the biopsy angle ("angle of attack" [AOA]) and to determine if the biopsy needle was aimed at the upper or lower pole and if the medulla was targeted or avoided. RESULTS: Of the 3 groups of biopsy angle, an AOA of between 50°-70° yielded the most glomeruli per core (P = .001) and the fewest inadequate specimens (4% vs 15% for > 70°, and 9% for < 50°, P = .038). Biopsy directed at a pole vs an interpolar region resulted in fewer inadequate specimens (8% vs 23%, P = .005), while biopsies that were medulla-avoiding resulted in fewer inadequate specimens (5% vs 16%, P = .004) and markedly reduced bleeding complications (12% vs 46%, P < .001) compared to biopsies where the medulla was entered. DISCUSSION: An AOA of approximately 60°, aiming at the poles, and avoiding the medulla were each associated with fewer inadequate biopsies and bleeding complications. While biopsy of the medulla is necessary for some diagnoses, the increased bleeding risk emphasizes the need for communication between nephrologist, pathologist, and radiologist.

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Health-related quality of life of patients on antiretroviral treatment in Botswana: A cross-sectional study.

OBJECTIVE: Antiretroviral therapy (ART) affords longevity to patients infected with the human immune deficiency virus (HIV). Since little is known about the health-related quality of life (HRQoL) of persons who have been on ART for at least five years, the present study investigated the HRQoL of these patients in Botswana. METHOD: Medical records, structured interviews, and the World Health Organization Quality of Life-BREF (WHOQoL-HIV-BREF) instrument were employed to obtain information from 456 respondents. RESULTS: Univariate and multivariate regression analyses showed that respondents' highest scores were in the "physical" domain (mean = 15.8, SD = 3.5), while the lowest scores were in the "environment" domain (mean = 12.9, SD = 2.5). Thus, the physical domain had the greatest impact on patients' overall HRQoL. Self-education about HIV-related issues was significantly correlated with all domains of HRQoL scores: physical (ρ = -2.32, CI 95% = -3.02, -1.61); psychological (ρ = -2.26, CI 95% = -2.87, -1.65); independence (ρ = -1.81, CI 95% = -2.54, -1.06); social relationships (ρ = -1.40, CI 95% = -2.13, -0.67); environment (ρ = -1.58, CI 95% = -2.13, -1.04); and spirituality (ρ = -1.70, CI 95% = -82.27, -1.13). SIGNIFICANCE OF RESULTS: HRQoL assessments can identify and address patients' needs, and it is important that guidelines be developed that will yield improved care to ART patients in Botswana.

Satisfaction and Quality of Life Related to Chemotherapy With an Arm Port: A Pilot Study.

PURPOSE: Placement of arm ports, or totally implanted venous access devices, is a common practice in our interventional radiology suite. We implant a miniaturized port in the upper arm for the provision of long-term chemotherapy. We hypothesized that there was general satisfaction with these arm ports and they have a minimal negative impact on quality of life. In this study we aimed to assess our hypotheses. METHODS: We surveyed subjects, who having previously received an arm port for chemotherapy to treat a malignancy, attended the interventional room for its removal. The survey assessed the port's effect on lifestyle, the degree of device-related pain, the acceptance of the port, and the willingness to have another port in the future. RESULTS: Survey responses from 77 subjects were reviewed. On a scale of 1 (most negative) to 10 (most positive), respondents indicated that the port system was a very positive enhancement to their treatment (satisfaction = 9.2 ± 2.0 and positivity = 8.8 ± 2.2). The port had little impact on daily activities. The mean score for the likelihood of choosing to have another port placed if additional treatment was required was 9.1 ± 2.1. DISCUSSION: The arm port in this study did not negatively impact subject satisfaction and quality of life for this cohort. Most subjects rated the device utility highly and felt that the port was a positive enhancement to their treatment, one that they would possibly utilise again in future, if need be.

Identifying factors associated with changes in CD4(+) count in HIV-infected adults in Saskatoon, Saskatchewan.

OBJECTIVE: To assess the impact of clinical and social factors unique to HIV-infected adults in Saskatoon, Saskatchewan, regarding the rate of CD4(+) count change, and to identify factors associated with a risk of CD4(+) count decline. METHODS: A retrospective longitudinal cohort study from medical chart reviews at two clinics was conducted in Saskatoon. Univariate and multivariate linear mixed effects models were used to assess the impact of selected factors on CD4(+) count change. RESULTS: Four hundred eleven HIV-infected patients were identified from January 1, 2003 to November 30, 2011. Two hundred eighteen (53%) were male, mean (± SD) age was 35.6 ±10.1 years, 257 (70.8%) were First Nations or Métis, 312 (80.2%) were hepatitis C virus (HCV) coinfected and 300 (73.3%) had a history of injection drug use (IDU). In univariate models, age, ethnicity, HCV, IDU, antiretroviral therapy and social assistance were significant. Using ethnicity, HCV and IDU, three multivariate models (models 1, 2, 3) were built due to high correlation. First Nations or Métis ethnicity, HCV coinfection and a history of IDU were associated with significantly lower CD4(+) counts in multivariate models. Older age and social assistance were associated with significantly lower CD4(+) counts in models 1 and 3. Age was marginally significant in model 2 (P=0.055). Not prescribed antiretroviral therapy was associated with a significantly negative CD4(+) count slope in all multivariate models. CONCLUSION: The unique epidemiology of this HIV-infected population may be contributing to CD4(+) count change. Increased attention and resources focused on this high-risk population are needed to prevent disease progression and to improve overall health and quality of life.

OBJECTIF: Évaluer les répercussions des facteurs cliniques et sociaux propres aux adultes infectés par le VIH de Saskatoon, en Saskatchewan, sur le taux de modifications de la numération de CD4+ et déterminer les facteurs associés à un risque de diminution de la numération de CD4+. MÉTHODOLOGIE: Les chercheurs ont réalisé une étude de cohorte longitudinale rétrospective des dossiers médicaux de deux cliniques de Saskatoon. Ils ont utilisé les modèles linéaires à effets mixtes univariés et multivariés pour évaluer les répercussions de certains facteurs associés aux modifications de la numération de CD4+. RÉSULTATS: Les chercheurs ont repéré 411 patients infectés par le VIH entre le 1er janvier 2003 et le 30 novembre 2011. Deux cent dix-huit d'entre eux (53 %) étaient de sexe masculin et avaient un âge moyen (± ÉT) de 35,6 ans ±10,1 ans, 257 (70,8 %) étaient Métis ou originaires des Premières nations, 312 (80,2 %) étaient co-infectés par le virus de l'hépatite C (VHC) et 300 (73,3 %) avaient des antécédents de consommation de drogues par injection (CDI). Dans les modèles univariés, l'âge, l'ethnie, le VHC, la CDI, l'antirétrovirothérapie et l'aide sociale étaient déterminants. À l'aide de l'ethnie, du VHC et de la CDI, les chercheurs ont formé trois modèles multivariés (modèles 1, 2, 3) en raison de leur forte corrélation. Le fait d'être Métis ou originaire des Premières nations, d'être co-infecté par le VHC et d'avoir des antécédents de CDI s'associait à des numérations de CD4+ beaucoup plus faibles dans les modèles multivariés. Le fait d'être plus âgé et de recevoir de l'aide sociale s'associait à une numération beaucoup plus faible de CD4+ dans les modèles 1 et 3. L'âge était légèrement significatif dans le modèle 2 (P=0,055). Dans tous les modèles multivariés, l'antirétrovirothérapie ne s'associait jamais à une pente négative de la numération de CD4+. CONCLUSION: L'épidémiologie unique de cette population infectée par le VIH contribue peut-être à une modification de la numération de CD4+. Il faudra se pencher sur ces patients à haut risque et y injecter plus de ressources pour prévenir l'évolution de leur maladie et améliorer leur santé et leur qualité de vie globales.

Reinventing Nuclear Histo-score Utilizing Inherent Morphologic Cutoffs: Blue-brown Color H-score (BBC-HS).

Immunohistochemistry (IHC) is a testing methodology that is widely used for large number of diagnostic, prognostic, and predictive biomarkers. Although IHC is a qualitative methodology, in addition to threshold-based stratification (positive vs. negative), the increasing levels of expression of some of these biomarkers often lead to more intense staining, which published evidence linked to specific diagnosis, prognosis, and responses to therapy. It is essential that the descriptive thresholds between positive and negative staining, as well as between frequently used graded categories of staining intensity (eg, 1+, 2+, 3+) are standardized and reproducible. Histo-score (H-score) is a frequently used scoring system that utilizes these categories. Our study introduces categorization of the cutoff points between positive and negative results and graded categories of staining intensity for nuclear IHC biomarker assays based on color interaction between hematoxylin and diaminobenzidine (DAB); the Blue-brown Color H-score (BBC-HS). Six cases of diffuse large B-cell lymphoma were stained for a nuclear marker MUM1. The staining was assessed by H-score by 12 readers. Short tutorial and illustrated instructions were provided to readers. The novel scoring system in this study uses the interaction between DAB (DAB, brown stain) and hematoxylin (blue counterstain) to set thresholds between "0" (negative nuclei), "1+" (weakly positive nuclei), "2+" (moderately positive nuclei), and "3+" (strongly positive nuclei). The readers recorded scores for 300 cells. Krippendorff alpha (K-alpha) and intraclass correlation coefficient (ICC) were calculated. We have also assessed if reliability improved when counting the first 100 cells, first 200 cells, and for the total 300 cells using K-alpha and ICC. To assess the performance of each individual reader, the mean H-score and percent positive score (PPS) for each case was calculated, and the bias was calculated between each reader's score and the mean. K-alpha was 0.86 for H-score and 0.76 for PPS. ICC was 0.96 for H-score and 0.92 for PPS. The biases for H-score ranged from -58 to 41, whereas for PPS it ranged from -27% to 33%. Overall, most readers showed very low bias. Two readers were consistently underscoring and 2 were consistently overscoring compared with the mean. For nuclear IHC biomarker assays, our newly proposed cutoffs provide highly reliable/reproducible results between readers for positive and negative results and graded categories of staining intensity using existing morphologic parameters. BBC-HS is easy to teach and is applicable to both human eye and image analysis. BBC-HS application should facilitate the development of new reliable/reproducible scoring schemes for IHC biomarkers.

A randomized double-blind controlled proof-of-concept study of alanyl-glutamine for reduction of post-myomectomy adhesions.

STUDY OBJECTIVE: To test the hypothesis that intraperitoneal instillation of a single bolus dose of l-alanyl-l-glutamine (AG) will reduce the incidence, extent and/or severity of adhesions following myomectomy and establish preliminary safety and tolerability of AG in humans. DESIGN: Phase 1,2 Randomized, double-blind, placebo-controlled study (DBRCT). SETTING: Tertiary care gynecology surgical centre. PATIENTS: Thirty-eight women who underwent myomectomies by laparoscopy (N = 38; AG-19 vs Placebo-19) or laparotomy (N = 10; AG-5 vs Placebo-5) with a scheduled second-look laparoscopy (SLL) 6-8 weeks later. Thirty-two patients in the laparoscopy arm completed SLL. INTERVENTIONS: Bolus dose of AG or normal saline solution control (0.9% NaCl) administered intraperitoneally immediately prior to suture closure of the laparoscopic ports. The average dose was 170 mL of AG or control based on a dosing scheme of 1 g/kg bodyweight. MEASUREMENTS: Digital recordings obtained for all procedures. The primary endpoint was reduction in the incidence, severity and extent of post-operative adhesions analyzed by intention-to-treat (ITT) approach. Three independent, blinded reviewers evaluated all operative video recordings to assess presence of adhesions. Post-hoc analysis assessed presence or absence of adhesions in the peritoneal cavity. Secondary endpoints assessed safety and tolerability of AG. MAIN RESULTS: Administration of AG reduced the incidence, severity and/or extent of post-operative adhesions (p = 0.046). The presence of adhesions in the AG group was lower than in the Control group (p = 0.041). Adhesion improvement was achieved in 15 of 15 (100%) in the AG group versus 5 of 17 (29.6%) in the placebo group. No serious adverse events were reported. No differences in safety parameters were observed. CONCLUSIONS: Intraperitoneal l-alanyl-l-glutamine reduced adhesion formation in all patients following laparoscopic myomectomy. Complete absence of adhesions was achieved at all abdominal sites in 93% of patients. Results confirm AG's known effects on cellular mechanisms of adhesiogenesis and lay the foundation for new adhesion prophylaxis research and treatment.

Beverage consumption patterns of Canadian adults aged 19 to 65 years.

OBJECTIVE: To investigate the beverage intake patterns of Canadian adults and explore characteristics of participants in different beverage clusters. DESIGN: Analyses of nationally representative data with cross-sectional complex stratified design. SETTING: Canadian Community Health Survey, Cycle 2.2 (2004). SUBJECTS: A total of 14 277 participants aged 19-65 years, in whom dietary intake was assessed using a single 24 h recall, were included in the study. After determining total intake and the contribution of beverages to total energy intake among age/sex groups, cluster analysis (K-means method) was used to classify males and females into distinct clusters based on the dominant pattern of beverage intakes. To test differences across clusters, χ2 tests and 95 % confidence intervals of the mean intakes were used. RESULTS: Six beverage clusters in women and seven beverage clusters in men were identified. 'Sugar-sweetened' beverage clusters - regular soft drinks and fruit drinks - as well as a 'beer' cluster, appeared for both men and women. No 'milk' cluster appeared among women. The mean consumption of the dominant beverage in each cluster was higher among men than women. The 'soft drink' cluster in men had the lowest proportion of the higher levels of education, and in women the highest proportion of inactivity, compared with other beverage clusters. CONCLUSIONS: Patterns of beverage intake in Canadian women indicate high consumption of sugar-sweetened beverages particularly fruit drinks, low intake of milk and high intake of beer. These patterns in women have implications for poor bone health, risk of obesity and other morbidities.

Early Single-Center Experience With Irreversible Electroporation for Stage 2, 3, and 4 Pancreatic Adenocarcinomas.

OBJECTIVES: Irreversible electroporation (IRE) is an ablation technology that uses electrical energy delivered between electrodes. If the electrodes are placed atraumatically, there is little to no risk of collateral injury, making IRE appealing for the treatment of pancreatic tumors. METHODS: We report on 20 patients with pancreatic adenocarcinoma (PAC) who underwent 21 IRE in our center. There were 6 IRE for stage 2 PAC, 11 for stage 3 PAC, 1 for stage 4 PAC, and 2 patients treated with IRE for recurrence after pancreaticoduodenectomy. One patient had local progression 18 months after IRE and received a second IRE treatment. Using propensity score matching (age, sex, stage, tumor size, and chemotherapy), cases were matched 2 to 1 with patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 7 cases experienced 8 complications; 4 complications were mild, and 4 were severe. Significant survival benefit was seen for patients with stage 3 PAC (27.5 vs 14.6 months for the matched group, P = 0.003); for stage 2, median survival was 15 months, and the single stage 4 patient survived 9 months after IRE treatment. CONCLUSIONS: Pancreatic cancers were safely and effectively treated with image-guided IRE in our medium-sized center.

Additive and multiplicative hazards modeling for recurrent event data analysis.

BACKGROUND: Sequentially ordered multivariate failure time or recurrent event duration data are commonly observed in biomedical longitudinal studies. In general, standard hazard regression methods cannot be applied because of correlation between recurrent failure times within a subject and induced dependent censoring. Multiplicative and additive hazards models provide the two principal frameworks for studying the association between risk factors and recurrent event durations for the analysis of multivariate failure time data. METHODS: Using emergency department visits data, we illustrated and compared the additive and multiplicative hazards models for analysis of recurrent event durations under (i) a varying baseline with a common coefficient effect and (ii) a varying baseline with an order-specific coefficient effect. RESULTS: The analysis showed that both additive and multiplicative hazards models, with varying baseline and common coefficient effects, gave similar results with regard to covariates selected to remain in the model of our real dataset. The confidence intervals of the multiplicative hazards model were wider than the additive hazards model for each of the recurrent events. In addition, in both models, the confidence interval gets wider as the revisit order increased because the risk set decreased as the order of visit increased. CONCLUSIONS: Due to the frequency of multiple failure times or recurrent event duration data in clinical and epidemiologic studies, the multiplicative and additive hazards models are widely applicable and present different information. Hence, it seems desirable to use them, not as alternatives to each other, but together as complementary methods, to provide a more comprehensive understanding of data.

A systematic review of intravenous ketamine for postoperative analgesia.

PURPOSE: Perioperative intravenous ketamine may be a useful addition in pain management regimens. Previous systematic reviews have included all methods of ketamine administration, and heterogeneity between studies has been substantial. This study addresses this issue by narrowing the inclusion criteria, using a random effects model, and performing subgroup analysis to determine the specific types of patients, surgery, and clinical indications which may benefit from perioperative ketamine administration. SOURCE: We included published studies from 1966 to 2010 which were randomized, double-blinded, and placebo-controlled using intravenous ketamine (bolus or infusion) to decrease postoperative pain. Studies using any form of regional anesthesia were excluded. No limitation was placed on the ketamine dose, patient age, or language of publication. PRINCIPAL FINDINGS: Ninety-one comparisons in seventy studies involving 4,701 patients met the inclusion criteria (2,652 in ketamine groups and 2,049 in placebo groups). Forty-seven of these studies were appropriate for evaluation in the core meta-analysis, and the remaining 23 studies were used to corroborate the results. A reduction in total opioid consumption and an increase in the time to first analgesic were observed across all studies (P < 0.001). The greatest efficacy was found for thoracic, upper abdominal, and major orthopedic surgical subgroups. Despite using less opioid, 25 out of 32 treatment groups (78%) experienced less pain than the placebo groups at some point postoperatively when ketamine was efficacious. This finding implies an improved quality of pain control in addition to decreased opioid consumption. Hallucinations and nightmares were more common with ketamine but sedation was not. When ketamine was efficacious for pain, postoperative nausea and vomiting was less frequent in the ketamine group. The dose-dependent role of ketamine analgesia could not be determined. CONCLUSION: Intravenous ketamine is an effective adjunct for postoperative analgesia. Particular benefit was observed in painful procedures, including upper abdominal, thoracic, and major orthopedic surgeries. The analgesic effect of ketamine was independent of the type of intraoperative opioid administered, timing of ketamine administration, and ketamine dose.

Effect of transfer, lifting, and repositioning (TLR) injury prevention program on musculoskeletal injury among direct care workers.

Musculoskeletal injuries among health care workers is very high, particularly so in direct care workers involved in patient handling. Efforts to reduce injuries have shown mixed results, and strong evidence for intervention effectiveness is lacking. The purpose of our study was to evaluate the effectiveness of a Transfer, Lifting and Repositioning (TLR) program to reduce musculoskeletal injuries (MSI) among direct health care workers. This study was a pre- and post-intervention design, utilizing a nonrandomized control group. Data were collected from the intervention group (3 hospitals; 411 injury cases) and the control group (3 hospitals; 355 injury cases) for periods 1 year pre- and post-intervention. Poisson regression analyses were performed. Of a total 766 TLR injury cases, the majority of injured workers were nurses, mainly with back, neck, and shoulder body parts injured. Analysis of all injuries and time-loss rates (number of injuries/100 full-time employees), rate ratios, and rate differences showed significant differences between the intervention and control groups. All-injuries rates for the intervention group dropped from 14.7 pre-intervention to 8.1 post-intervention. The control group dropped from 9.3 to 8.4. Time-loss injury rates decreased from 5.3 to 2.5 in the intervention group and increased in the control group (5.9 to 6.5). Controlling for group and hospital size, the relative rate of all-injuries and time-loss injuries for the pre- to post-period decreased by 30% (RR = 0.693; 95% CI = 0.60-0.80) and 18.6% (RR = 0.814; 95% CI = 0.677-0.955), respectively. The study provides evidence for the effectiveness of a multifactor TLR program for direct care health workers, especially in small hospitals.

Methods of competing risks analysis of end-stage renal disease and mortality among people with diabetes.

BACKGROUND: When a patient experiences an event other than the one of interest in the study, usually the probability of experiencing the event of interest is altered. By contrast, disease-free survival time analysis by standard methods, such as the Kaplan-Meier method and the standard Cox model, does not distinguish different causes in the presence of competing risks. Alternative approaches use the cumulative incidence estimator by the Cox models on cause-specific and on subdistribution hazards models. We applied cause-specific and subdistribution hazards models to a diabetes dataset with two competing risks (end-stage renal disease (ESRD) or death without ESRD) to measure the relative effects of covariates and cumulative incidence functions. RESULTS: In this study, the cumulative incidence curve of the risk of ESRD by the cause-specific hazards model was revealed to be higher than the curves generated by the subdistribution hazards model. However, the cumulative incidence curves of risk of death without ESRD based on those three models were very similar. CONCLUSIONS: In analysis of competing risk data, it is important to present both the results of the event of interest and the results of competing risks. We recommend using either the cause-specific hazards model or the subdistribution hazards model for a dominant risk. However, for a minor risk, we do not recommend the subdistribution hazards model and a cause-specific hazards model is more appropriate. Focusing the interpretation on one or a few causes and ignoring the other causes is always associated with a risk of overlooking important features which may influence our interpretation.

Hypersomnolence and sleep disorders in a rheumatic disease patient population.

OBJECTIVES: There is increasing awareness of the importance of sleep in health maintenance. Our primary objective was to evaluate prevalence of excess daytime sleepiness in a rheumatic disease patient population. Secondary objectives included evaluation of prevalence of abnormal sleep quality and primary sleep disorders. METHODS: Consecutive Rheumatology clinic patients were invited to participate in a self-administered questionnaire study. Included were measures for pain, fatigue, and global functioning, modified Health Assessment Questionnaire, Epworth Sleepiness Score (ESS), Pittsburgh Sleep Quality Index (PSQI), Berlin Score, diagnostic criteria for restless legs syndrome (RLS), Centre for Epidemiologic Studies Depression score (CES-D), stress scores, and the short form-36 quality of life instrument. RESULTS: Of 507 consecutive patients invited to participate, 423 agreed. Mean age was 52.1 years; 26% were male. Prevalence of excessive sleepiness (ESS >10) was 25.7%, abnormal sleep quality (PSQI >5) was 67.3%, high risk for obstructive sleep apnea Berlin scores were present in 35.2% and 24% of participants met criteria for RLS. Significantly worse pain, fatigue, global function, short form-36 summary scores, modified Health Assessment Questionnaire, depression, and stress scores were present in patients with higher ESS and PSQI scores. No significant differences in sleep assessment scores were observed between specific rheumatic disease groups. CONCLUSIONS: Our findings suggest a high prevalence of unrecognized hypersomnolence, poor sleep quality, and primary sleep disorders in rheumatology patients. We suggest evaluation of sleep health be incorporated into standard clinical assessments of all rheumatology patients. We would recommend this evaluation include the ESS and the criteria for RLS.

Barriers to Care in ACHD: A Study of Young Adults in Saskatchewan.

BACKGROUND: Adults with congenital heart disease (CHD) are living longer with more complex disease. Maintaining lifelong care prevents morbidity and mortality, but many patients remain lost to follow-up or experience care gaps. We sought to assess barriers to care for patients with adult CHD (ACHD) in Saskatchewan, a Canadian province with no local congenital cardiac surgical support and no clear framework for ACHD care. METHODS: We performed a telephone survey of patients with CHD transferred from pediatric to adult cardiology from 2007 to 2014. Our primary outcome was loss to follow-up > 2 years from last recommended cardiology appointment and/or multiple missed cardiology appointments. Secondary outcomes were guideline-based care (specialist training, adherence to appropriate endocarditis prophylaxis, pre-pregnancy counselling for women), presence or absence of previously described barriers to care in ACHD, and health care autonomy using the Krantz Health Opinion Survey. RESULTS: We interviewed 32 patients (30% response rate). One-quarter met the primary outcome: lost to follow-up > 2 years from last recommended cardiology appointment and/or self-report of missed cardiology appointments. Only 69% of young adults in Saskatchewan were receiving guideline-based care for their CHD (appropriate level of specialist expertise and frequency of follow-up). Only 72% of patients were adhering to endocarditis prophylaxis recommendations and 61% of women surveyed received counselling regarding pregnancy. Patients indicated a low preference for participating in decision making regarding their care on the Krantz Health Opinion Survey. CONCLUSIONS: With our survey, we have created a novel snapshot of CHD care in Saskatchewan and have identified significant deficits.

CONTEXTE: Les adultes souffrant d'une cardiopathie congénitale vivent de plus en plus longtemps avec une maladie complexe. Les soins qui leur sont prodigués toute leur vie aident à prévenir la morbidité et la mortalité, mais nombreux sont les patients qui sont perdus de vue en cours de route ou qui vivent des périodes sans recevoir de soins. Nous avons tenté d'évaluer les obstacles aux soins des patients adultes atteints d'une cardiopathie congénitale en Saskatchewan, une province canadienne où il n'existe aucun programme local de soutien en matière de chirurgie cardiaque pour les troubles congénitaux ni de cadre définissant clairement les soins à prodiguer aux adultes atteints d'une cardiopathie congénitale. MÉTHODOLOGIE: Nous avons interviewé par téléphone des patients atteints d'une cardiopathie congénitale qui sont passés d'un suivi en cardiologie en soins pédiatriques aux soins aux adultes entre 2007 et 2014. Le critère d'évaluation principal était la perte de vue pendant plus de 2 ans après le dernier rendez-vous de suivi en cardiologie recommandé et/ou plusieurs rendez-vous en cardiologie manqués. Les critères d'évaluation secondaires étaient les soins recommandés dans les lignes directrices (formation spécialisée, observance d'une prophylaxie endocardite appropriée, counseling préalable à la grossesse chez les femmes), la présence ou l'absence d'obstacles aux soins relatifs à la cardiopathie congénitale chez l'adulte cités antérieurement et l'autonomie en matière de soins de santé selon le sondage d'opinion sur la santé de Krantz. RÉSULTATS: Nous avons interviewé 32 patients (taux de réponse de 30 %). Le quart des patients interrogés répondaient au critère d'évaluation principal, soit la perte de vue pendant plus de 2 ans après le dernier rendez-vous de suivi en cardiologie recommandé et/ou plusieurs rendez-vous en cardiologie manqués autodéclarés. Seulement 69 % des jeunes patients adultes de la Saskatchewan recevaient les soins recommandés dans les lignes directrices en matière de cardiopathie congénitale (degré approprié d'expertise spécialisée du médecin et fréquence des consultations de suivi). Seulement 72 % des patients observaient les recommandations en matière de prophylaxie endocardite, et 61 % des femmes interrogées avaient reçu des services de counseling concernant la grossesse. Selon les résultats au sondage d'opinion sur la santé de Krantz, les patients étaient généralement peu disposés à participer aux décisions concernant leur programme de soins. CONCLUSIONS: Grâce à notre enquête, nous disposons maintenant d'un portrait à jour des soins aux patients atteints de cardiopathie congénitale en Saskatchewan; l'exercice nous a par ailleurs permis de cerner d'importantes lacunes à cet égard.

Canadian Multicenter Project on Standardization of Programmed Death-Ligand 1 Immunohistochemistry 22C3 Laboratory-Developed Tests for Pembrolizumab Therapy in NSCLC.

INTRODUCTION: The programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assay is used to select patients for first or second-line pembrolizumab monotherapy in NSCLC. The PD-L1 IHC 22C3 pharmDx assay requires an Autostainer Link 48 instrument. Laboratories without this stainer have the option to develop a highly accurate 22C3 IHC laboratory-developed test (LDT) on other instruments. The Canadian 22C3 IHC LDT validation project was initiated to harmonize the quality of PD-L1 22C3 IHC LDT protocols across 20 Canadian pathology laboratories. METHODS: Centrally optimized 22C3 LDT protocols were distributed to participating laboratories. The LDT results were assessed against results using reference PD-L1 IHC 22C3 pharmDx. Analytical sensitivity and specificity were assessed using cell lines with varying PD-L1 expression levels (phase 1) and IHC critical assay performance controls (phase 2B). Diagnostic sensitivity and specificity were assessed using whole sections of 50 NSCLC cases (phase 2A) and tissue microarrays with an additional 50 NSCLC cases (phase 2C). RESULTS: In phase 1, 80% of participants reached acceptance criteria for analytical performance in the first attempt with disseminated protocols. However, in phase 2A, only 40% of participants reached the desired diagnostic accuracy for both 1% and 50% tumor proportion score cutoff. In phase 2B, further protocol modifications were conducted, which increased the number of successful laboratories to 75% in phase 2C. CONCLUSIONS: It is possible to harmonize highly accurate 22C3 LDTs for both 1% and 50% tumor proportion score in NSCLC across many laboratories with different platforms. However, despite a centralized approach, diagnostic validation of predictive IHC LDTs can be challenging and not always successful.

Cyclophilin C-associated protein (CyCAP) knock-out mice spontaneously develop colonic mucosal hyperplasia and exaggerated tumorigenesis after treatment with carcinogen azoxymethane.

BACKGROUND: The discovery of a "serrated neoplasia pathway" has highlighted the role of hyperplastic lesions of the colon as the significant precursor of colorectal adenocarcinoma. In mice, hyperplasia of the colonic mucosa is a regular phenomenon after a challenge with colonic carcinogens indicating that mucosal hyperproliferation and thickening, even without cytological dysplasia, represents an early pre-malignant change. Cyclophilin C-associated protein (CyCAP) has been described to down-modulate endotoxin signaling in colorectal murine mucosa and is a murine orthologue of the tumor-associated antigen 90 K (TAA90K)/mac-2-binding protein. METHODS: Female Balb/c wild-type (WT) and CyCAP knock-out (KO) mice (6-8 weeks old) were administered 2 or 6 weekly subcutaneous injections of azoxymethane. The animals were evaluated post-injection at six weeks for aberrant crypt foci (ACF) study and at five months for colon tumor measurement. The thickness of the colon crypts was measured in microns and the number of colonocytes per crypt was also determined in well-oriented crypts. Morphometric analyses of the colon mucosa were also performed in untreated 6-8 weeks old KO and WT animals. Formalin-fixed/paraffin-embedded colon sections were also studied by immunohistochemistry to determine the Ki-67 proliferation fraction of the colon mucosa, beta-catenin cellular localization, cyclin D1, c-myc, and lysozyme in Paneth cells. RESULTS: Cyclophilin C-associated protein (CyCAP)-/- mice, spontaneously developed colonic mucosal hyperplasia early in life compared to wild-type mice (WT) (p < 0.0001, T-test) and crypts of colonic mucosa of the (CyCAP)-/- mice show higher proliferation rate (p = 0.039, Mann-Whitney Test) and larger number of cyclin D1-positive cells (p < 0.0001, Mann-Whitney Test). Proliferation fraction and cyclin D1 expression showed positive linear association (p = 0.019, Linear-by-Linear Association). The hyperplasia was even more pronounced in CyCAP-/- mice than in WT after challenge with azoxymethane (p = 0.005, T-test). The length of the crypts (r = 0.723, p = 0.018, Spearman Correlation) and the number of colonocytes per crypt (r = 0.863, p = 0.001, Spearman Correlation) in non-tumorous areas were positively associated with azoxymethane-induced number of tumors. CyCAP-/- developed larger numbers of tumors than WT animals (p = 0.003, T-Test) as well as overall larger tumor mass (p = 0.016, T-Test). Membranous beta-catenin was focally overexpressed in KO mice including proliferative zone of the crypts. CONCLUSION: CyCAP-/- represent the first described model of spontaneous colonic mucosal hyperplasia. We conclude that CyCAP-deficient mice spontaneously and after challenge with carcinogen develop significantly more colorectal mucosal hyperplasia, an early stage in murine colonic carcinogenesis.