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To determine invasive group A Streptococcus trends in Canada, we characterized emm1 isolates collected during 2018–2023. The percentage of hypervirulent M1UK lineage isolates increased significantly, from 22.1% in 2018 to 60.2% in 2023. Genomic analysis identified geographically and temporally associated clusters and genes associated with virulent bacteriophage acquisition.

Abstract Fentanyl test strips (FTS) are lateral flow immunoassays that were originally designed and validated for detecting low concentrations of fentanyl in urine. Some FTS are now being marketed for the harm reduction purpose of testing street drugs for the presence of fentanyl. This manuscript provides a simple protocol to assess whether different brands and lots of fentanyl test strips perform adequately for use in drug checking. The results gathered from this protocol will document problems with particular lots or brands of FTS, help buyers choose from among the array of products, provide feedback to manufacturers to improve their products, and serve as an early warning system for ineffective products.

Abstract Background Fentanyl test strips (FTS) are lateral flow immunoassay strips designed for detection of ng/mL levels of fentanyl in urine. In 2021, the US Centers for Disease Control and the Substance Abuse and Mental Health Administration stated that federal funds could be used for procurement of FTS for harm reduction strategies approved by the government such as drug checking. The market for FTS has expanded rapidly in the US and Canada. However, there is no regulatory oversight by either government to ensure proper function of FTS that are being marketed for drug checking. Main body Many brands of FTS have rapidly entered the harm reduction market, creating concerns about the reproducibility and accuracy of their performance from brand to brand and lot to lot. Some examples are provided in this Comment. Similar problems with product quality were observed in the mid 2000’s when lateral flow immunoassays for malaria were funded in many countries and again in 2020, when COVID-19 tests were in huge demand. The combination of high demand and low levels of regulation and enforcement led some manufacturers to join the goldrush without adequate field testing or quality assurance. We argue that the harm reduction community urgently needs to set a lot checking program in place. A set of simple protocols for conducting the tests and communicating the results have been developed, and are described in the following Perspectives paper in this issue. Conclusion In the absence of governmental regulation and enforcement, the harm reduction community should implement a FTS lot checking program. Based on previous experience with the malaria diagnostic lot checking program, this inexpensive effort could identify products that are not suitable for harm reduction applications and provide valuable feedback to manufacturers. Dissemination of the results will help harm reduction organizations to ensure that FTS they use for drug checking are fit for the purpose.

Abstract Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7–97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1–2 vomiting OR 1.87 [95% CI 1.37–2.56] and OR 2.27 [95% CI 1.59–3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3–4 diarrhea OR 118.06 [95% CI 7.28–1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3–4 infections. Abemaciclib had significantly less grade 3–4 transaminitis and grade 3–4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.

Abstract Approval of drugs is based on randomized trials observing statistically significant superiority of an experimental agent over a standard. Statistical significance results from a combination of effect size and sampling, with larger effect size more likely to translate to population effectiveness. We assess sample size justification in trials supporting cancer drug approvals. We identified US FDA anti-cancer drug approvals for solid tumors from 2015 to 2019. We extracted data on study characteristics, statistical plan, accrual, and outcomes. Observed power (P obs ) was calculated based on completed study characteristics and observed hazard ratio (HR obs ). Studies were considered over-sampled if P obs > expected with HR obs similar or worse than expected or if P obs was similar to expected with HR obs worse than expected. We explored associations with over-sampling using logistic regression. Of 75 drug approvals (reporting 94 endpoints), 21% (20/94) were over-sampled. Over-sampling was associated with immunotherapy (OR: 5.5; p = 0.04) and associated quantitatively but not statistically with targeted therapy (OR: 3.0), open-label trials (OR: 2.5), and melanoma (OR: 4.6) and lung cancer (OR: 2.17) relative to breast cancer. Most cancer drug approvals are supported by trials with justified sample sizes. Approximately 1 in 5 endpoints are over-sampled; benefit observed may not translate to clinically meaningful real-world outcomes.

Despite being an embodied medium, virtual reality (VR) prioritizes vision and sound over the other senses. While touch has been demonstrated to foster a sense of presence and embodiment, most haptic research in VR focuses on uncanny vibration motors or limited experiences of touch with simple props. Meanwhile, immersive performances such as Eve 3.0 incorporate performer-facilitated touch in novel ways to evoke a complete and social experience of human touch in VR. In response, we conducted a mixed-methods study to investigate the experience of performer-facilitated touch in a 360° video segment from the immersive performance Eve 3.0. Using a 3 × 2 factorial design, we compared touch from a diary prop and performer in festival and laboratory settings. We found that performer-facilitated touch increased realistic behaviours and questionnaire measures of social presence, embodiment, and tactile realism. The setting also had a significant effect with festival participants demonstrating significantly more behaviours indicating presence, particularly in the no-touch condition. Participant descriptions reveal that in addition to touch, a rich narrative and vivid visuals of social interaction were just as important in immersing participants in the experience and making them feel present. We find that participant experiences are a co-creation situated at the intersection of artefact and context that require a willing suspension of disbelief. The authentic setting and performance artefact afforded a deep understanding of the rich and complex experience of human touch in immersive performance.

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

Abstract Background Canadian and US Task Forces recommend against routine mammography screening for women age 40–49 at average breast cancer risk as harms outweigh benefits. Both suggest individualized decisions based on the relative value women place on potential screening benefits and harms. Population-based data reveal variation in primary care professionals (PCPs) mammography rates in this age group after adjusting for sociodemographic factors, highlighting the need to explore PCP screening perspectives and how this informs clinical behaviours. Results from this study will inform interventions that can improve guideline concordant breast screening for this age group. Methods Qualitative semi-structured interviews were performed with PCPs in Ontario, Canada. Interviews were structured using the theoretical domains framework (TDF) to explore determinants of breast cancer screening best-practice behaviours: (1) risk assessment; (2) discussion regarding benefits and harms; and (3) referral for screening. Analysis Interviews were transcribed and analyzed iteratively until saturation. Transcripts were coded deductively by behaviour and TDF domain. Data that did not fit within a TDF code were coded inductively. The research team met repeatedly to identify potential themes that influenced or were important consequences of the screening behaviours. The themes were tested against further data, disconfirming cases, and different PCP demographics. Results Eighteen physicians were interviewed. The theme of perceived guideline clarity (a lack of clarity on guideline-concordant practices) influenced all behaviours and moderated the extent to which the risk assessment and discussion occurred. Many were unaware of how risk-assessment factored into the guidelines and/or did not perceive that a shared-care discussion was guideline-concordant. Deferral to patient preference (screening referral without a complete discussion of benefits and harms) occurred when the PCPs had low knowledge regarding harms and/or if they experienced regret (TDF domain: emotion) resulting from prior clinical experiences. Older providers described patient’s influence impacting their decisions and physicians trained outside Canada, practicing in higher-resourced areas, and female physicians described being influenced by beliefs about consequences of benefits of screening. Conclusion Perceived guideline clarity is an important driver of physician behaviour. Improving guideline concordant care should start by clarifying the guideline itself. Thereafter, targeted strategies include building skills in identifying and overcoming emotional factors and communication skills important for evidence-based screening discussions.

Patients with oligometastatic breast cancer (BC) are candidates of choice for metastasis-directed therapy (MDT). This paper summarizes the opinions of an expert committee about the management of oligometastatic BC. The experts could complete the questionnaire from 13 September 2021, to 10 October 2021, followed by a discussion. The experts were physicians working in the Province of Quebec (Canada) and specialized in BC care, including surgical oncologists, medical oncologists, and radiation oncologists. The experts provided their opinions about the context of the disease and therapeutic approach, local and systemic therapies, and the prognosis of oligometastatic BC. In addition to the expert panel’s opinions about the management of oligometastatic disease per se, the experts stated that a prospective data registry should be implemented to collect data about oligometastatic BC to improve knowledge about oligometastatic BC and implement data-driven MDT. These data could also allow for the design of treatment algorithms. In conclusion, this paper presents the expert panel’s opinions about the management of oligometastatic BC and highlights the needs to be met to improve the care of this condition.

We present a rare case of meningoradiculitis occurring after mRNA COVID-19 vaccination.This patient, with a history of inflammatory arthritis following rubella vaccination, presented to the emergency department 4 days after her vaccination with both central and radicular nervous system symptoms. Symptoms included pain, sensory and motor deficits in L5 roots distribution, along with signs of central irritation, such as headache, difficulty concentrating and a Babinski sign. MRI showed bilateral L5 nerve roots enhancement. Lumbar puncture showed elevated protein and IgG, and relevant serologies excluded common causes. Prednisone and physical therapy helped the patient to achieve near complete recovery nine weeks after presentation.We concluded that this patient presented meningoradiculitis probably secondary to her vaccination in a context of possible overactive immune system. While such presentations might be rare, and do not constitute a general reason to abstain from vaccination, they must be well recognized and treated.

Abstract Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.

Abstract Disease-free survival (DFS) comprises both breast cancer and non-breast cancer events. DFS has not been validated as a surrogate endpoint for overall survival (OS) in most breast cancer subtypes. We assessed changes to the type of events contributing to DFS over time. We identified adjuvant studies in breast cancer (BC) from 2000 to 2020 where the endpoint was DFS. We examined change in distant DFS events and the BC-related DFS using univariable and multivariable linear regression. Data were reported quantitatively using the Burnand criteria irrespective of statistical significance. We included 84 studies (88 cohorts), comprising 212,191 participants, 41,604 DFS events and 23,205 distant DFS events. The DFS event rate/100 participants/year has declined modestly over time (ß − 0.34, p = 0.001). Start year was negatively associated with distant DFS events (ß − 0.58, p

Abstract PARP inhibitors (PARPi) have modest antitumor activity in patients with advanced breast cancer and mutation in BRCA. It is unclear whether some subgroups derive greater benefit from treatment. MEDLINE and EMBASE were searched from inception to March 2021 to identify trials of PARPi in patients with metastatic breast cancer. Objective response rate (ORR) and clinical benefit rate (CBR) to PARPi were extracted and pooled in a meta-analysis using the Mantel Haenszel random effects model. Meta-regression explored the influence of patient and tumor characteristics on ORR and CBR. For randomized trials, hazard ratio comparing PARPi to control therapy were pooled using inverse variance and random effects. Analysis included 43 studies comprising 2409 patients. Among these, 1798 (75%) patients had BRCA mutations and 1146 (48%) were triple negative. In 10 studies (28%; n = 680 patients), the PARPi was given in combination with platinum-based chemotherapy. Weighted mean ORR was 45%; 64% when combined with platinum vs 37% with PARPi monotherapy (p

Respiratory syncytial virus (RSV) is a leading cause of hospitalization among young children. Historically, American Indian and Alaska Native (AI/AN) children have experienced high rates of RSV-associated hospitalization. In August 2023, a preventive monoclonal antibody (nirsevimab) was recommended for all infants aged <8 months (born during or entering their first RSV season) and for children aged 8-19 months (entering their second RSV season) who have increased risk for severe RSV illness, including all AI/AN children. This evaluation in Alaska's Yukon-Kuskokwim Delta region estimated nirsevimab effectiveness among AI/AN children in their first or second RSV seasons during 2023-2024. Among 472 children with medically attended acute respiratory illness (ARI), 48% overall had received nirsevimab ≥7 days earlier (median = 91 days before the ARI-related visit). For children in their first RSV season (292), nirsevimab effectiveness was 76% (95% CI = 42%-90%) against medically attended RSV illness and 89% (95% CI = 32%-98%) against RSV hospitalization. For children in their second RSV season (180), effectiveness against medically attended RSV illness was 88% (95% CI = 48%-97%). Nirsevimab is effective for preventing severe RSV illness among infants entering their first RSV season and children entering their second season with increased risk for severe RSV, including all AI/AN children. [ABSTRACT FROM AUTHOR]

To determine invasive group A Streptococcus trends in Canada, we characterized emm1 isolates collected during 2018-2023. The percentage of hypervirulent M1UK lineage isolates increased significantly, from 22.1% in 2018 to 60.2% in 2023. Genomic analysis identified geographically and temporally associated clusters and genes associated with virulent bacteriophage acquisition. [ABSTRACT FROM AUTHOR]