PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. METHODS: R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. FINDINGS: We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. INTERPRETATION: This immunotherapy combination was found to be active and safe in this clinically challenging patient population.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Developing Guidance for Donor Intervention Randomized Controlled Trials: Initial Discussions From the Canada-United Kingdom 2022 Workshop.

BACKGROUND: Donor interventions, including medications, protocols, and medical devices administered to donors, can enhance transplantable organ quality and quantity and maximize transplantation success. However, there is paucity of high-quality evidence about their effectiveness, in part because of ethical, practical, and regulatory challenges, and lack of guidance about conduct of donor intervention randomized controlled trials (RCTs). METHODS: With the vision to develop authoritative guidance for conduct of donor intervention RCTs, we convened a workshop of Canadian-United Kingdom experts in organ donation and transplantation ethics, research, and policy to identify stakeholders, explore unique challenges, and develop research agenda to inform future work in this promising field. RESULTS: Donor intervention trials should consider perspectives of broad group of stakeholders including donors, transplant recipients, and their families; researchers in donation and transplantation; research ethics boards; and healthcare providers and administrators involved in donation and transplantation. Unique challenges include (1) research ethics (living versus deceased status of the donor at the time of intervention, intervention versus outcomes assessment in different individuals, harm-benefit analysis in donors versus recipients, consent, and impact on research bystanders); (2) outcome data standardization and linkage; and (3) regulatory and governance considerations. CONCLUSIONS: Donor intervention RCTs hold potential to benefit organ transplantation outcomes but face unique research ethics, outcome data, and regulatory challenges. By developing research agenda to address these challenges, our workshop was an important first step toward developing Canada-United Kingdom guidance for donor intervention RCTs that are poised to improve the quality and availability of transplantable organs.

Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial.

BACKGROUND: Metformin is increasingly being used during pregnancy, with potentially adverse long-term effects on children. We aimed to examine adiposity in children of women with type 2 diabetes from the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial, with and without in-utero exposure to metformin, up to 24 months of age. METHODS: MiTy Kids is a follow-up study that included infants of women who participated in the MiTy randomised controlled trial, receiving either oral 1000 mg metformin twice daily or placebo. Caregivers and researchers remained masked to the type of medication (metformin or placebo) mothers received during their pregnancy. Anthropometric measurements, including weight, height, and skinfold thicknesses, were taken at 3, 6, 12, 18, and 24 months. At 24 months, linear regression was used to compare the BMI Z score and sum of skinfolds in the metformin versus placebo groups, adjusted for confounders. Fractional polynomials were used to assess growth trajectories. This study is registered with ClinicalTrials.gov, NCT01832181. FINDINGS: Of the 465 eligible children, 283 (61%) were included from 19 centres in Canada and Australia. At 24 months, there was no difference between groups in mean BMI Z score (0·84 [SD 1·52] with metformin vs 0·91 [1·38] with placebo; mean difference 0·07 [95% CI -0·31 to 0·45], p=0·72) or mean sum of skinfolds (23·0 mm [5·2] vs 23·8 mm [5·4]; mean difference 0·8 mm [-0·7 to 2·3], p=0·31). Metformin was not a predictor of BMI Z score at 24 months of age (mean difference -0·01 [95% CI -0·42 to 0·37], p=0·92). There was no overall difference in BMI trajectory but, in males, trajectories were significantly different by treatment (p=0·048); BMI in the metformin group was higher between 6 and 24 months. Children of women with type 2 diabetes were approximately 1 SD heavier than the WHO reference population. INTERPRETATION: Anthropometrics were similar in children exposed and those not exposed to metformin in utero; hence, overall, data are reassuring with regard to the use of metformin during pregnancy in women with type 2 diabetes and the long-term health of their children. FUNDING: Canadian Institute for Health Research.

Gas-phase ambient air contaminants exhibit significant dioxin-like and estrogen-like activity in vitro.

Several adverse health effects, such as respiratory and cardiovascular morbidity, have been linked to exposure to particulate matter in ambient air; however, the biologic activity of gas-phase ambient organic air contaminants has not been examined as thoroughly. Using aryl hydrocarbon receptor (AHR)-based and estrogen receptor (ER)-based cell bioassay systems, we assessed the dioxin-like and estrogenic activities of gas-phase organic ambient air contaminants compared with those of particulate-phase contaminants using samples collected between seasons over 2 years from an urban and a rural location in the Greater Toronto Area, Canada. The concentration of the sum (Sigma) of polycyclic aromatic hydrocarbons, which was highest in the gas phase, was 10-100 times more abundant than that of Sigmapolychlorinated biphenyls, Sigmanitro-polycyclic aromatic hydrocarbons, and Sigmaorganochlorine pesticides, and 10(3) to 10(4) times more abundant than Sigmapolychlorinated dibenzo-p-dioxins/dibenzofurans. Gas-phase samples induced significant AHR- and ER-dependent gene expression. The activity of the gas-phase samples was greater than that of the particulate-phase samples in the estrogen assay and, in one case, in the AHR assay. We found no strong associations between either summer or winter seasons or urban or rural locations in the relative efficacy of the extracts in either the ER or AHR assay despite differences in chemical composition, concentrations, and abundance. Our results suggest that mechanistic studies of the health effects of ambient air must consider gas and particulate phases because chemicals present in both phases can affect AHR and ER signaling pathways.

Optimal collection technique and devices for a quality pap smear.

BACKGROUND: Collection technique is critical in the performance of the Papanicolaou (Pap) smear as an important screening tool for cervical cancer. While superior devices have been established, less effective devices continue to be used for both conventional and liquid-based Pap smears. Our aim is to determine the performance of collection devices currently used in obtaining conventional Pap smears and whether sequence of collection is important for higher quality results. METHODS: This prospective, blinded, cohort study used 2 cytology labs to analyze Pap smears done within a 1-year period. Study participants were 128 clinicians who practice in Dane County, Wis, who send their Pap smears to either of the 2 study cytology labs. Participants included advance practice nurses, family physicians, and obstetrician/gynecologists. Logistic regression was utilized for analysis. RESULTS: In conventional Pap smears, sequence of collection did not affect any quality indicators. The Cervex-brush (broom) was associated with absent endocervical cells (Odds Ratio = 3.12, P < .001), limited or unsatisfactory results (OR = 1.68, P < .01), and obscuring inflammation (OR = 2.01, P < .01). Of those clinicians who had high levels of absent endocervical cells on their Pap smears (defined as > 3/30 Pap smears), 47% used the broom alone. The Cytobrush optimized quality indicators, and the combination of the Cytobrush for the endocervix and spatula for the ectocervix was superior. Presence of infectious agents also contributed to the absence of endocervical cells (OR = 3.09, P < .001). CONCLUSIONS: The combination of the Cytobrush (endocervix) and spatula (ectocervix) is superior for a quality Pap smear. The sequence of collection was not important in conventional Pap smears. The broom alone performs poorly. Presence of infection decreases quality.

Current cervical cancer screening practices of Dane County, Wisconsin primary care clinicians.

PURPOSE: This study explores clinician Papanicolaou (Pap) smear collection and management strategies in light of current research, guidelines, and recommendations. METHODS: Two hundred thirty eligible obstetrician/gynecologists, family physicians, and advance practice nurses in Dane County, Wisconsin completed a survey. Descriptive statistics. RESULTS: The wooden spatula is most frequently (68%) used to collect ectocervical cells; the Cytobrush (75%) for endocervical cells. Most clinicians (63%) collect ectocervical cells first, endocervical cells second. Eighty-nine percent of clinicians are familiar with liquid-based Pap smears; 57% use them. Most clinicians (59%) prepare the cervix as needed prior to collecting a sample. Management of inflammation is variable. Forty-five percent of clinicians have no age limit in discontinuing Pap smears; 43% continue after benign hysterectomy. Training for doing Pap smears occurs primarily in residency (89%) or graduate nursing education (83%). CONCLUSIONS: Despite current research and guidelines, great variability exists among clinicians in Pap smear collection and management. Textbooks, articles, and clinician training must emphasize optimal collection technique and management to improve Pap smear quality and decrease unnecessary costs.

A community of practice for knowledge translation trainees: an innovative approach for learning and collaboration.

A growing number of researchers and trainees identify knowledge translation (KT) as their field of study or practice. Yet, KT educational and professional development opportunities and established KT networks remain relatively uncommon, making it challenging for trainees to develop the necessary skills, networks, and collaborations to optimally work in this area. The Knowledge Translation Trainee Collaborative is a trainee-initiated and trainee-led community of practice established by junior knowledge translation researchers and practitioners to: examine the diversity of knowledge translation research and practice, build networks with other knowledge translation trainees, and advance the field through knowledge generation activities. In this article, we describe how the collaborative serves as an innovative community of practice for continuing education and professional development in knowledge translation and present a logic model that provides a framework for designing an evaluation of its impact as a community of practice. The expectation is that formal and informal networking will lead to knowledge sharing and knowledge generation opportunities that improve individual members' competencies (eg, combination of skills, abilities, and knowledge) in knowledge translation research and practice and contribute to the development and advancement of the knowledge translation field.

Core competencies in the science and practice of knowledge translation: description of a Canadian strategic training initiative.

BACKGROUND: Globally, healthcare systems are attempting to optimize quality of care. This challenge has resulted in the development of implementation science or knowledge translation (KT) and the resulting need to build capacity in both the science and practice of KT. FINDINGS: We are attempting to meet these challenges through the creation of a national training initiative in KT. We have identified core competencies in this field and have developed a series of educational courses and materials for three training streams. We report the outline for this approach and the progress to date. CONCLUSIONS: We have prepared a strategy to develop, implement, and evaluate a national training initiative to build capacity in the science and practice of KT. Ultimately through this initiative, we hope to meet the capacity demand for KT researchers and practitioners in Canada that will lead to improved care and a strengthened healthcare system.