Extraction of redox extracellular vesicles using exclusion-based sample preparation.

Studying specific subpopulations of cancer-derived extracellular vesicles (EVs) could help reveal their role in cancer progression. In cancer, an increase in reactive oxygen species (ROS) happens which results in lipid peroxidation with a major product of 4-hydroxynonenal (HNE). Adduction by HNE causes alteration to the structure of proteins, leading to loss of function. Blebbing of EVs carrying these HNE-adducted proteins as a cargo or carrying HNE-adducted on EV membrane are methods for clearing these molecules by the cells. We have referred to these EVs as Redox EVs. Here, we utilize a surface tension-mediated extraction process, termed exclusion-based sample preparation (ESP), for the rapid and efficient isolation of intact Redox EVs, from a mixed population of EVs derived from human glioblastoma cell line LN18. After optimizing different parameters, two populations of EVs were analyzed, those isolated from the sample (Redox EVs) and those remaining in the original sample (Remaining EVs). Electron microscopic imaging was used to confirm the presence of HNE adducts on the outer leaflet of Redox EVs. Moreover, the population of HNE-adducted Redox EVs shows significantly different characteristics to those of Remaining EVs including smaller size EVs and a more negative zeta potential EVs. We further treated glioblastoma cells (LN18), radiation-resistant glioblastoma cells (RR-LN18), and normal human astrocytes (NHA) with both Remaining and Redox EV populations. Our results indicate that Redox EVs promote the growth of glioblastoma cells, likely through the production of H2O2, and cause injury to normal astrocytes. In contrast, Remaining EVs have minimal impact on the viability of both glioblastoma cells and NHA cells. Thus, isolating a subpopulation of EVs employing ESP-based immunoaffinity could pave the way for a deeper mechanistic understanding of how subtypes of EVs, such as those containing HNE-adducted proteins, induce biological changes in the cells that take up these EVs.

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

A randomized, embedded, pragmatic, Bayesian clinical trial examining clinical decision support for high flow nasal cannula management in children with bronchiolitis: design and statistical analysis plan.

BACKGROUND: High flow nasal cannula (HFNC) has been increasingly adopted in the past 2 decades as a mode of respiratory support for children hospitalized with bronchiolitis. The growing use of HFNC despite a paucity of high-quality data regarding the therapy's efficacy has led to concerns about overutilization. We developed an electronic health record (EHR) embedded, quality improvement (QI) oriented clinical trial to determine whether standardized management of HFNC weaning guided by clinical decision support (CDS) results in a reduction in the duration of HFNC compared to usual care for children with bronchiolitis. METHODS: The design and summary of the statistical analysis plan for the REspiratory SupporT for Efficient and cost-Effective Care (REST EEC; "rest easy") trial are presented. The investigators hypothesize that CDS-coupled, standardized HFNC weaning will reduce the duration of HFNC, the trial's primary endpoint, for children with bronchiolitis compared to usual care. Data supporting trial design and eventual analyses are collected from the EHR and other real world data sources using existing informatics infrastructure and QI data sources. The trial workflow, including randomization and deployment of the intervention, is embedded within the EHR of a large children's hospital using existing vendor features. Trial simulations indicate that by assuming a true hazard ratio effect size of 1.27, equivalent to a 6-h reduction in the median duration of HFNC, and enrolling a maximum of 350 children, there will be a > 0.75 probability of declaring superiority (interim analysis posterior probability of intervention effect > 0.99 or final analysis posterior probability of intervention effect > 0.9) and a > 0.85 probability of declaring superiority or the CDS intervention showing promise (final analysis posterior probability of intervention effect > 0.8). Iterative plan-do-study-act cycles are used to monitor the trial and provide targeted education to the workforce. DISCUSSION: Through incorporation of the trial into usual care workflows, relying on QI tools and resources to support trial conduct, and relying on Bayesian inference to determine whether the intervention is superior to usual care, REST EEC is a learning health system intervention that blends health system operations with active evidence generation to optimize the use of HFNC and associated patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05909566. Registered on June 18, 2023.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Wastewater Surveillance for Xylazine in Kentucky.

Introduction: In the U.S., xylazine, the veterinary non-opioid sedative, has emerged as a major threat to people who use illicitly manufactured fentanyl and other drugs. The aim of this study was to compare wastewater detection of xylazine with other public health and safety surveillance data from 2019 to 2023 in Kentucky. Methods: Wastewater samples from 5 rest areas, 2 truck weigh stations, and 4 wastewater treatment plants were tested for xylazine. Wastewater xylazine positivity rates were compared with xylazine-positive submission rates from the National Forensic Laboratory Information System and Kentucky's fatal overdoses in 6-month periods (Period 1=January-June; Period 2=July-December). Results: Xylazine was detected in 61.6% (424 of 688) of daily wastewater samples from roadway sites/wastewater treatment plants. For roadways, detection increased from 55% (Period 1, 2021) to 94% (Period 1, 2023), and wastewater treatment plants had an overall detection of 25.8% (n=66 samples, Periods 1 and 2, 2022). Increasing roadway positivity corresponded to trends in National Forensic Laboratory Information System xylazine-positive submission rates: from 0.19 per 1,000 submissions (Period 1, 2019) to 2.9 per 1,000 (Period 2, 2022, latest available). No deaths from xylazine were reported publicly in Kentucky, although this study's authors identified 1-4 deaths (true count suppressed) in the overdose surveillance system, which, in back-of-the-envelope comparisons with other states, is far fewer than expected. Conclusions: Wastewater signals indicate broad geographic exposure to xylazine in Kentucky, yet health outcomes data suggest otherwise. These findings may inform regional, national, and international efforts to incorporate wastewater-based drug surveillance. Harm-reduction activities along roadways and other suitable locations may be needed.

Correction: Gill et al. Report from the 24th Annual Western Canadian Gastrointestinal Cancer Consensus Conference on Colorectal Cancer, Richmond, British Columbia, 28-29, October 2022. Curr. Oncol. 2023, 30, 7964-7983.

Karen Mulder was not included as an author in the original publication [...].

Optimal sample size division in two-stage seamless designs.

Inferentially seamless 2/3 designs are increasingly popular in clinical trials. It is important to understand their relative advantages compared with separate phase 2 and phase 3 trials, and to understand the consequences of design choices such as the proportion of patients included in the phase 2 portion of the design. Extending previous work in this area, we perform a simulation study across multiple numbers of arms and efficacy response curves. We consider a design space crossing the choice of a separate versus seamless design with the choice of allocating 0%-100% of available patients in phase 2, with the remainder in phase 3. The seamless designs achieve greater power than their separate trial counterparts. Importantly, the optimal seamless design is more robust than the optimal separate program, meaning that one range of values for the proportion of patients used in phase 2 (30%-50% of the total phase 2/3 sample size) is nearly optimal for a wide range of response scenarios. In contrast, a percentage of patients used in phase 2 for separate trials may be optimal for some alternative scenarios but decidedly inferior for other alternative scenarios. When operationally and scientifically viable, seamless trials provide superior performance compared with separate phase 2 and phase 3 trials. The results also provide guidance for the implementation of these trials in practice.

The differential needs and expectations from general practitioners in oncology between high-income countries and low- and-middle-income countries: results from a survey of Canadian and Nepali oncologists.

Background: To address the shortage of oncologists in the wake of the rapidly increasing global cancer burden, general practitioners of oncology (GPOs) have been added to cancer care teams worldwide. GPOs are family physicians with additional training in oncology and their roles differ by both country and region. In this study, we aimed to learn about the roles and expectations of GPOs from the perspective of oncologists in Canada and Nepal. Methods: A survey was designed and administered to Canadian and Nepali Oncologists between February and November 2022 using Research Electronic Data Capture, a secure web-based software platform hosted at Queen's University in Kingston, Ontario, Canada. Participants were recruited through personal networks/social media in Nepal and the survey was distributed through an email list provided by the Canadian Association of Medical Oncologists. Results: The survey received 48 responses from Canadian and 7 responses from Nepali oncologists. Canadian respondents indicated that in terms of educational content delivery, clinics with oncologists followed by didactic lectures by oncologists were thought to be the most effective, followed by a small group learning and online education. Nepali oncologists also indicated didactic lectures by oncologists and small group learning would be the most effective teaching techniques, followed by online education and clinics with oncologists. Critical knowledge domains and skills most relevant for GPO training identified by Canadian respondents were managing pain and other common symptoms of cancers, as well as treatment of common side effects, followed by goals of care discussion, post-treatment surveillance for recurrence, and the management of long-term complications from treatment. Respondents from Nepal, however, suggested an approach to diagnosis to patient with increased risk of cancer, and cancer staging were the most critical knowledge domains and skills. The majority of oncologists in both countries thought a training program of 6-12 months was optimal. Conclusion: We found many similarities in oncologist's opinions of GPOs between the two countries, however, there were also some notable differences such as the need to provide cancer screening services in Nepal. This highlights the need to tailor GPO training programs based on local context.

Global control of RNA polymerase II.

RNA polymerase II (Pol II) is the multi-protein complex responsible for transcribing all protein-coding messenger RNA (mRNA). Most research on gene regulation is focused on the mechanisms controlling which genes are transcribed when, or on the mechanics of transcription. How global Pol II activity is determined receives comparatively less attention. Here, we follow the life of a Pol II molecule from 'assembly of the complex' to nuclear import, enzymatic activity, and degradation. We focus on how Pol II spends its time in the nucleus, and on the two-way relationship between Pol II abundance and activity in the context of homeostasis and global transcriptional changes.

Wastewater Surveillance for Identifying SARS-CoV-2 Infections in Long-Term Care Facilities, Kentucky, USA, 2021-2022.

Persons living in long-term care facilities (LTCFs) were disproportionately affected by COVID-19. We used wastewater surveillance to detect SARS-CoV-2 infection in this setting by collecting and testing 24-hour composite wastewater samples 2-4 times weekly at 6 LTCFs in Kentucky, USA, during March 2021-February 2022. The LTCFs routinely tested staff and symptomatic and exposed residents for SARS-CoV-2 using rapid antigen tests. Of 780 wastewater samples analyzed, 22% (n = 173) had detectable SARS-CoV-2 RNA. The LTCFs reported 161 positive (of 16,905) SARS-CoV-2 clinical tests. The wastewater SARS-CoV-2 signal showed variable correlation with clinical test data; we observed the strongest correlations in the LTCFs with the most positive clinical tests (n = 45 and n = 58). Wastewater surveillance was 48% sensitive and 80% specific in identifying SARS-CoV-2 infections found on clinical testing, which was limited by frequency, coverage, and rapid antigen test performance.

Breast Cancer-Related Financial Toxicity in Sri Lanka: Insights From a Lower Middle-Income Country With Free Universal Public Healthcare.

Financial toxicity (FT) describes either objective or perceived excess financial strain due to a cancer diagnosis on the well-being of patients, families, and society. The consequences of FT have been shown to span countries of varied economic tiers and diverse healthcare models. This study attempts to describe FT and its effects in a lower- to middle-income country delivering predominantly public nonfee-levying healthcare. This was a cross-sectional study involving 210 patients with breast cancer of any stage (I to IV), interviewed between 6 and 18 months from the date of diagnosis. Financial toxicity was highly prevalent with 81% reporting 3 or more on a scale of 1 to 5. Costs incurred for travelling (94%), out-of-hospital investigations (87%), and consultation fees outside the public system (81%) were the most common contributors to FT. Daily compromises for food and education were made by 30% and 20%, respectively, with loss of work seen in over one-third. Greater FT was seen with advanced cancer stage and increasing distance to the nearest radiotherapy unit (P = .008 and .01, respectively). Family and relatives were the most common form of financial support (77.6%). In conclusion, FT is substantial in our group, with many having to make daily compromises for basic needs. Many opt to visit the fee-levying private sector for at least some part of their care, despite the availability of an established public nonfee-levying healthcare.

Simple SARS-CoV-2 concentration methods for wastewater surveillance in low resource settings.

Wastewater-based epidemiology (WBE) measures pathogens in wastewater to monitor infectious disease prevalence in communities. Due to the high dilution of pathogens in sewage, a concentration method is often required to achieve reliable biomarker signals. However, most of the current concentration methods rely on expensive equipment and labor-intensive processes, which limits the application of WBE in low-resource settings. Here, we compared the performance of four inexpensive and simple concentration methods to detect SARS-CoV-2 in wastewater samples: Solid Fraction, Porcine Gastric Mucin-conjugated Magnetic Beads, Calcium Flocculation-Citrate Dissolution (CFCD), and Nanotrap® Magnetic Beads (NMBs). The NMBs and CFCD methods yielded the highest concentration performance for SARS-CoV-2 (∼16-fold concentration and âˆ¼ 41 % recovery) and require <45 min processing time. CFCD has a relatively low consumable cost (<$2 per four sample replicates). All methods can be performed with basic laboratory equipment and minimal electricity usage which enables further application of WBE in remote areas and low resource settings.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention: Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

REMAP Periop: a randomised, embedded, multifactorial adaptive platform trial protocol for perioperative medicine to determine the optimal enhanced recovery pathway components in complex abdominal surgery patients within a US healthcare system.

INTRODUCTION: Implementation of enhanced recovery pathways (ERPs) has resulted in improved patient-centred outcomes and decreased costs. However, there is a lack of high-level evidence for many ERP elements. We have designed a randomised, embedded, multifactorial, adaptive platform perioperative medicine (REMAP Periop) trial to evaluate the effectiveness of several perioperative therapies for patients undergoing complex abdominal surgery as part of an ERP. This trial will begin with two domains: postoperative nausea/vomiting (PONV) prophylaxis and regional/neuraxial analgesia. Patients enrolled in the trial will be randomised to arms within both domains, with the possibility of adding additional domains in the future. METHODS AND ANALYSIS: In the PONV domain, patients are randomised to optimal versus supraoptimal prophylactic regimens. In the regional/neuraxial domain, patients are randomised to one of five different single-injection techniques/combination of techniques. The primary study endpoint is hospital-free days at 30 days, with additional domain-specific secondary endpoints of PONV incidence and postoperative opioid consumption. The efficacy of an intervention arm within a given domain will be evaluated at regular interim analyses using Bayesian statistical analysis. At the beginning of the trial, participants will have an equal probability of being allocated to any given intervention within a domain (ie, simple 1:1 randomisation), with response adaptive randomisation guiding changes to allocation ratios after interim analyses when applicable based on prespecified statistical triggers. Triggers met at interim analysis may also result in intervention dropping. ETHICS AND DISSEMINATION: The core protocol and domain-specific appendices were approved by the University of Pittsburgh Institutional Review Board. A waiver of informed consent was obtained for this trial. Trial results will be announced to the public and healthcare providers once prespecified statistical triggers of interest are reached as described in the core protocol, and the most favourable interventions will then be implemented as a standardised institutional protocol. TRIAL REGISTRATION NUMBER: NCT04606264.

Breaking Down Barriers to Detection and Care in Early-Age-Onset Colorectal Cancer in Canada.

The second Early-Age-Onset Colorectal Cancer Symposium, convened in October 2022, sought solutions to the barriers to early detection and care for colorectal cancer in Canada. This meeting built on a previous symposium, held in 2021 and reported in this journal. Early-age-onset colorectal cancer (EAOCRC) affects increasing numbers of people under the age of 50 in Canada and throughout the developed world. Two main themes emerged from the meeting: the importance of timely detection, and the need for a tailored approach to the care of EAOCRC. Early detection is crucial, especially in light of the later stage at diagnosis and unique tumour characteristics. Symposium participants were strongly in favour of reducing the age of eligibility for screening from 50 to 45, and promoting the development of non-invasive screening techniques such as testing for circulating tumour DNA and biomarkers. Leading approaches to care were described and discussed, which meet the unique treatment needs of younger CRC patients. Multidisciplinary practices within and outside Canada address such factors as fertility, family roles, education, careers and financial responsibilities. These models can be applied in treatment centres across the country.

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. Objective: To determine whether vitamin C improves outcomes for patients with COVID-19. Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Oncoplastic Breast Reduction: A Systematic Review of Postoperative Complications.

Background: Breast-conserving therapy with oncoplastic reduction is a useful strategy for partial mastectomy defect reconstruction. The most recently published systematic review of oncoplastic breast reduction outcomes from 2015 showed wound dehiscence in 4.3%, hematoma in 0.9%, infection in 2.8%, and nipple necrosis in 0.9% of patients. We performed a systematic review of oncoplastic breast reduction literature, comparing outcomes and complication rates reported over the past 8 years. Methods: Studies describing the use of oncoplastic breast reduction and discussion of postoperative complications were included. The primary outcome assessed was the postoperative complication rate; secondary outcomes analyzed were rates of margin expansion, completion mastectomy, and delays in adjuvant therapy due to complications. Results: Nine articles met inclusion criteria, resulting in 1715 oncoplastic breast reduction patients. The mean rate of hematoma was 3%, nipple necrosis was 2%, dehiscence was 4%, infection was 3%, and seroma was 2%. The need for re-excision of margins occurred in 8% of patients, and completion mastectomy in 2%. Finally, delay in adjuvant treatment due to a postoperative complication occurred in 4% of patients. Conclusions: Oncoplastic breast reduction is an excellent option for many patients undergoing breast-conserving therapy; however, postoperative complications can delay adjuvant radiation therapy. Results of this systematic literature review over the past 8 years showed a slight increase in complication rate compared to the most recent systematic review from 2015. With increased popularity and surgeon familiarity, oncoplastic breast reduction remains a viable option for reconstruction of partial mastectomy defects despite a slight increase in complication rate.