Trends and Prescriber Variation in the Duration of Oxaliplatin-Containing Adjuvant Chemotherapy for Stage III Colon Cancer From 2007 to 2019: A Population-Based Retrospective Cohort Study.

INTRODUCTION: The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration in 2017 established 3 months of adjuvant therapy as an alternative to 6 months of therapy for stage III colon cancer. We determined the association between the IDEA publication, changes in clinical practice, and prescriber variation. PATIENTS AND METHODS: Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019 who received oxaliplatin-containing adjuvant therapy. The outcome was duration of therapy, categorized as ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% of a 6-month course of therapy to approximate treatment durations in the IDEA collaboration. We examined trends in duration over time using an interrupted time series regression model. We analyzed treatment duration after accounting for patient and prescriber characteristics, using multivariable mixed effects logistic regression models to quantify between-prescriber variation. RESULTS: We included 4695 patients with stage III colon cancer who received oxaliplatin-containing adjuvant chemotherapy, of whom 77.5% initiated treatment pre-IDEA and 22.5% initiated treatment post-IDEA. Post-IDEA, there was a 16.4% (95% CI, 12.5%-20.3%) absolute increase in the proportion of patients treated with ≤50% of a maximal course of therapy. This trend was greatest among patients with low-risk tumors. Prescriber variation increased pre-IDEA to 15.6% post-IDEA (variance partition coefficient 5.4% pre-IDEA and 15.6% post-IDEA). CONCLUSION: The publication of IDEA was associated with increases in short duration adjuvant therapy and prescriber-level practice variation for stage III colon cancer. Clinicians should be better supported to make consistent recommendations about adjuvant duration under conditions of uncertainty and trade-offs.

The Association of Oxaliplatin-Containing Adjuvant Chemotherapy Duration with Overall and Cancer-Specific Mortality in Individuals with Stage III Colon Cancer: A Population-Based Retrospective Cohort Study.

PURPOSE: Few studies have examined the relationship between duration of oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer and mortality in routine practice. We examined the association between treatment with 50% versus >85% of a maximal course of adjuvant therapy (eight cycles of CAPOX, twelve cycles of FOLFOX) and mortality in stage III colon cancer. METHODS: Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019. In the primary comparison, we compared patients who received 50% or >85% of a maximal course of adjuvant therapy; in a secondary comparison, we evaluated a dose effect across patients who received FOLFOX in one-cycle increments from six to ten cycles against >85% (more than ten cycles) of a maximal course of FOLFOX. The main outcomes were overall and cancer-specific mortality. Follow-up began 270 days after adjuvant treatment initiation and terminated at the first of the outcome of interest, loss of eligibility for Ontario's Health Insurance Program, or study end. Overlap propensity score weights accounted for baseline between-group differences. We determined the hazard ratio, estimating the association between mortality and treatment. Non-inferiority was concluded in the primary comparison for either outcome if the upper limit of the two-sided 95% CI was ≤1.11, which is the margin used in the International Duration Evaluation of Adjuvant Chemotherapy Collaboration. RESULTS: We included 3546 patients in the analysis of overall mortality; 486 (13.7%) received 50% and 3060 (86.3%) received >85% of a maximal course of therapy. Median follow-up was 5.4 years, and total follow-up was 20,510 person-years. There were 833 deaths. Treatment with 50% of a maximal course of adjuvant therapy was associated with a hazard ratio of 1.13 (95% CI 0.88 to 1.47) for overall mortality and a subdistribution hazard ratio of 1.31 (95% CI 0.91 to 1.87) for cancer-specific mortality versus >85% of a maximal course of therapy. In the secondary comparison, there was a trend toward higher overall mortality in patients treated with shorter durations of therapy, though confidence intervals overlapped considerably. CONCLUSION: We could not conclude that treatment with 50% of a maximal course is non-inferior to >85% of a maximal course of adjuvant therapy for mortality in stage III colon cancer. Clinicians and patients engaging in decision-making around treatment duration in this context should carefully consider the trade-off between treatment effectiveness and adverse effects of treatment.

Randomised controlled trials of non-pharmacological interventions to improve patient-reported outcomes of colonoscopy: a scoping review.

BACKGROUND AND AIMS: Non-pharmacological interventions to improve patient-reported outcomes of colonoscopy may be effective at mitigating negative experiences and perceptions of the procedure, but research to characterise the extent and features of studies of these interventions is limited. METHODS: We conducted a scoping review searching multiple databases for peer-reviewed publications of randomised controlled trials conducted in adults investigating a non-pharmacological intervention to improve patient-reported outcomes of colonoscopy. Study characteristics were tabulated and summarised narratively and graphically. RESULTS: We screened 5939 citations and 962 full texts, and included 245 publications from 39 countries published between 1992 and 2022. Of these, 80.8% were full publications and 19.2% were abstracts. Of the 41.9% of studies reporting funding sources, 11.4% were unfunded. The most common interventions were carbon dioxide and/or water insufflation methods (33.9%), complementary and alternative medicines (eg, acupuncture) (20.0%), and colonoscope technology (eg, magnetic scope guide) (21.6%). Pain was as an outcome across 82.0% of studies. Studies most often used a patient-reported outcome examining patient experience during the procedure (60.0%), but 42.9% of studies included an outcome without specifying the time that the patient experienced the outcome. Most intraprocedural patient-reported outcomes were measured retrospectively rather than contemporaneously, although studies varied in terms of when outcomes were assessed. CONCLUSION: Research on non-pharmacological interventions to improve patient-reported outcomes of colonoscopy is unevenly distributed across types of intervention and features high variation in study design and reporting, in particular around outcomes. Future research efforts into non-pharmacological interventions to improve patient-reported outcomes of colonoscopy should be directed at underinvestigated interventions and developing consensus-based guidelines for study design, with particular attention to how and when outcomes are experienced and measured. PROSPERO REGISTRATION NUMBER: 42020173906.

Clinical Delays and Comparative Outcomes in Younger and Older Adults with Colorectal Cancer: A Systematic Review.

Outcome disparities between adults <50 with colorectal cancer (CRC) and older adults may be explained by clinical delays. This study synthesized the literature comparing delays and outcomes between younger and older adults with CRC. Databases were searched until December 2021. We included studies published after 1990 reporting delay in adults <50 that made comparisons to older adults. Comparisons were described narratively and stage between age groups was meta-analyzed. 39 studies were included representing 185,710 younger CRC patients and 1,422,062 older patients. Sixteen delay intervals were compared. Fourteen studies (36%) found significantly longer delays among younger adults, and nine (23%) found shorter delays among younger patients. Twelve studies compared time from symptom onset to diagnosis (N younger = 1538). Five showed significantly longer delays for younger adults. Adults <50 years also had higher odds of advanced stage (16 studies, pooled OR for Stage III/IV 1.76, 95% CI 1.52-2.03). Ten studies compared time from diagnosis to treatment (N younger = 171,726) with 4 showing significantly shorter delays for younger adults. All studies showing longer delays for younger adults examined pre-diagnostic intervals. Three studies compared the impact of delay on younger versus older adult. One showed longer delays were associated with advanced stage and worse survival in younger but not older adults. Longer delays among younger adults with CRC occur in pre-diagnostic intervals.

Time to diagnosis and treatment in younger adults with colorectal cancer: A systematic review.

BACKGROUND: The incidence of colorectal cancer is rising in adults <50 years of age. As a primarily unscreened population, they may have clinically important delays to diagnosis and treatment. This study aimed to review the literature on delay intervals in patients <50 years with colorectal cancer (CRC), and explore associations between longer intervals and outcomes. METHODS: MEDLINE, Embase, and LILACS were searched until December 2, 2021. We included studies published after 1990 reporting any delay interval in adults <50 with CRC. Interval measures and associations with stage at presentation or survival were synthesized and described in a narrative fashion. Risk of bias was assessed using the Newcastle-Ottawa Scale, Institute of Health Economics Case Series Quality Appraisal Checklist, and the Aarhus Checklist for cancer delay studies. RESULTS: 55 studies representing 188,530 younger CRC patients were included. Most studies used primary data collection (64%), and 47% reported a single center. Sixteen unique intervals were measured. The most common interval was symptom onset to diagnosis (21 studies; N = 2,107). By sample size, diagnosis to treatment start was the most reported interval (12 studies; N = 170,463). Four studies examined symptoms onset to treatment start (total interval). The shortest was a mean of 99.5 days and the longest was a median of 217 days. There was substantial heterogeneity in the measurement of intervals, and quality of reporting. Higher-quality studies were more likely to use cancer registries, and be population-based. In four studies reporting the relationship between intervals and cancer stage or survival, there were no clear associations between longer intervals and adverse outcomes. DISCUSSION: Adults <50 with CRC may have intervals between symptom onset to treatment start greater than 6 months. Studies reporting intervals among younger patients are limited by inconsistent results and heterogeneous reporting. There is insufficient evidence to determine if longer intervals are associated with advanced stage or worse survival. OTHER: This study's protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42020179707).

CD26 Induces Colorectal Cancer Angiogenesis and Metastasis through CAV1/MMP1 Signaling.

CD26 has been reported as a marker for colorectal cancer stem cells endowed with tumor-initiating properties and capable of colorectal cancer (CRC) metastasis. In this study, we investigated the functional effect of CD26 on CRC angiogenesis and metastasis, and the potential underlying mechanism. The functional effects of CD26 overexpression or repression were determined by a wound healing experiment, and cell migration and invasion assays in vitro and in mouse models. Differentially expressed genes regulated by CD26 were identified by genome-wide mRNA expression array and validated by quantitative PCR. CD26 functionally regulated CRC cell migration and invasion in vitro and angiogenesis and metastasis in vivo. Genome-wide mRNA expression array and qPCR showed that MMP1 was up-regulated in CD26+ subpopulation, and a subsequent experiment demonstrated the regulatory effect of CD26 on MMP1 in CRC cell lines with CD26 repression or overexpression. Furthermore, overexpression of CAV1 abrogated the CD26-regulated MMP1 induction in CRC cell lines. This study demonstrated the functional roles of CD26 in inducing CRC migration, invasion, angiogenesis and metastasis and identified the potential involvement of MMP1 and CAV1 in such process. CD26 is an attractive therapeutic target for combating tumor progression to improve the prognosis of CRC patients.

Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi.

BACKGROUND: Cerebral malaria is still a major cause of death in children in sub-Saharan Africa. Among survivors, debilitating neurological sequelae can leave children with permanent cognitive impairments and societal stigma, resulting in taxing repercussions for their families. This study investigated the effect of delay in presentation to medical care on outcome in children with cerebral malaria in Malawi. METHODS: This retrospective study included participants enrolled in a longstanding study of cerebral malaria between 2001 and 2021 and considered coma duration prior to arrival at hospital (with or without anti-malarial treatment), HIV status, blood lactate levels at admission and age as factors that could affect clinical outcome. Outcomes were categorized as full recovery, sequelae at the time of discharge, or death. A multinomial regression was fit and run controlling for coma duration, HIV status, lactate levels and age, to determine the association between each explanatory variable and outcome. RESULTS: A total of 1663 children with cerebral malaria, aged 6 months to 14 years were included. Longer coma duration (in hours) was associated with greater odds of developing sequelae (OR = 1.023, 95% CI 1.007-1.039, p = 0.006) but not death (OR = 1.00, 95% CI 0.986-1.015, p = 0.961). Younger age (in months) was also correlated with higher rates of sequelae, (OR = 0.990, 95% CI 0.983-0.997, p = 0.004) but not with increased mortality (OR = 0.998, 95% CI 0.993-1.003, p = 0.335). Blood lactate levels on admission were correlated with mortality (OR = 1.125, 95% CI 1.090-1.161, p < 0.001) but not associated with increased rates of sequelae (OR = 1.016, 95% CI 0.973-1.060, p = 0.475). Positive HIV status and treatment with an anti-malarial (artemisinin or non-artemisinin-based) prior to arrival at the hospital were not significantly associated with either adverse outcome. CONCLUSIONS: In Malawian children with cerebral malaria, higher rates of sequelae were significantly associated with extended coma duration prior to admission and younger age. Mortality rates were correlated with increased lactate levels on admission. The differential effects of variables on clinical outcomes suggest that there may be different pathogenic pathways leading to sequelae and death. Actions taken by parents and health care professionals are critical in defining when patients arrive at hospital and determining their ultimate outcome.

Building Environmentally Sustainable Health Systems in Canada: The Time Is Now for Emergent and Strategic Leadership.

Canada's healthcare sector produces the third highest healthcare-related emissions per capita globally. However, Canada has no national strategy toward environmentally sustainable healthcare. Transforming Canada's health systems to be environmentally sustainable requires leadership from many stakeholders and collaboration between trainees and health leaders. This article provides an overview of student and trainee leadership among health-related fields in response to the climate crisis and highlights the formation of a trainee-led organization focused on building capacity among emerging leaders in healthcare. We share key lessons learned by this group that are essential for all leaders seeking to leverage interdisciplinary action toward sustainable health systems in Canada.

A population-based analysis of the impact of the COVID-19 pandemic on common abdominal and gynecological emergency department visits.

BACKGROUND: Reduced use of the emergency department during the COVID-19 pandemic may result in increased disease acuity when patients do seek health care services. We sought to evaluate emergency department visits for common abdominal and gynecologic conditions before and at the beginning of the pandemic to determine whether changes in emergency department attendance had serious consequences for patients. METHODS: We conducted a population-based analysis using administrative data to evaluate the weekly rate of emergency department visits pre-COVID-19 (Jan. 1-Mar. 10, 2020) and during the beginning of the COVID-19 pandemic (Mar. 11-June 30, 2020), compared with a historical control period (Jan. 1-July 1, 2019). All residents of Ontario, Canada, presenting to the emergency department with appendicitis, cholecystitis, ectopic pregnancy or miscarriage were included. We evaluated weekly incidence rate ratios (IRRs) of emergency department visits, management strategies and clinical outcomes. RESULTS: Across all study periods, 39 691 emergency department visits met inclusion criteria (40.2 % appendicitis, 32.1% miscarriage, 21.3% cholecystitis, 6.4% ectopic pregnancy). Baseline characteristics of patients presenting to the emergency department did not vary across study periods. After an initial reduction in emergency department visits, presentations for cholecystitis and ectopic pregnancy quickly returned to expected levels. However, presentations for appendicitis and miscarriage showed sustained reductions (IRR 0.61-0.80), with 1087 and 984 fewer visits, respectively, after the start of the pandemic, relative to 2019. Management strategies, complications and mortality rates were similar across study periods for all conditions. INTERPRETATION: Although our study showed evidence of emergency department avoidance in Ontario during the first wave of the COVID-19 pandemic, no adverse consequences were evident. Emergency care and outcomes for patients were similar before and during the pandemic.

Hyaluronate carboxymethylcellulose sheets for the prevention of adhesive complications: a model-based cost-utility analysis.

AIM: Clinical trials suggest that hyaluronate carboxymethylcellulose (HA/CMC) prevents adhesion-related complications after intra-abdominal surgery, but at a high upfront cost. This study evaluated the cost-effectiveness of HA/CMC for patients undergoing curative-intent open colorectal cancer surgery. METHODS: Using a Markov Monte Carlo microsimulation model, we conducted a cost-utility analysis comparing the cost-effectiveness of HA/CMC at curative-intent open colorectal cancer surgery versus standard management. We considered a scenario where HA/CMC was used at the index operation only, as well as where it was used at the index operation and any subsequent operations. The perspective was that of the third-party payer. Costs and utilities were discounted 1.5% annually, with a 1-month cycle length and 5-year time horizon. Model input data were obtained from a literature review. Outcomes included cost, quality-adjusted life-years (QALYs), small bowel obstructions (SBOs) and operations for SBO. RESULTS: Using HA/CMC at the index operation results in an incremental cost increase of CA$316 and provides 0.001 additional QALYs, for an incremental cost-effectiveness ratio of CA$310,000 per QALY compared to standard management. In our simulated cohort of 10,000 patients, HA/CMC prevented 460 SBOs and 293 surgeries for SBO. Probabilistic sensitivity analysis found that HA/CMC was cost-effective in 18.5% of iterations, at a cost-effectiveness threshold of CA$50,000 per QALY. Results of the scenario analysis where HA/CMC was used at the index operation and any subsequent operations were similar. CONCLUSIONS: Hyaluronate carboxymethylcellulose prevents adhesive bowel obstruction after open colorectal cancer surgery but is unlikely to be cost-effective given minimal long-term impact on healthcare costs and QALYs.

A Tail Fiber Engineering Platform for Improved Bacterial Transduction-Based Diagnostic Reagents.

Bacterial transduction particles were critical to early advances in molecular biology and are currently experiencing a resurgence in interest within the diagnostic and therapeutic fields. The difficulty of developing a robust and specific transduction reagent capable of delivering a genetic payload to the diversity of strains constituting a given bacterial species or genus is a major impediment to their expanded utility as commercial products. While recent advances in engineering the reactivity of these reagents have made them more attractive for product development, considerable improvements are still needed. Here, we demonstrate a synthetic biology platform derived from bacteriophage P1 as a chassis to target transduction reagents against four clinically prevalent species within the Enterobacterales order. Bacteriophage P1 requires only a single receptor binding protein to enable attachment and injection into a target bacterium. By engineering and screening particles displaying a diverse array of chimeric receptor binding proteins, we generated a potential transduction reagent for a future rapid phenotypic carbapenem-resistant Enterobacterales diagnostic assay.

Non-pharmacological interventions to improve the patient experience of colonoscopy under moderate or no sedation: a systematic review protocol.

INTRODUCTION: The patient experience is a critical dimension of colonoscopy quality. Sedative and analgesic drugs are commonly used to improve the patient experience of colonoscopy, with predominant regimens being deep sedation, typically achieved with propofol, and moderate sedation, typically achieved with an opioid and a benzodiazepine. However, non-pharmacological interventions exist that may be used to improve patient experience. Furthermore, by identifying non-pharmacological interventions to increase the quality of patient experience under moderate sedation, jurisdictions facing rising use of deep sedation for colonoscopy and its significant associated costs may be better able to encourage patients and clinicians to adopt moderate sedation. Advancing either of these aims requires synthesising the evidence and raising awareness around these non-pharmacological interventions to improve the patient experience of colonoscopy. METHODS AND ANALYSIS: A systematic review will be conducted that searches multiple electronic databases from inception until 2020 to identify randomised controlled trials evaluating what, if any, non-pharmacological interventions are effective compared with placebo or usual care for improving the patient experience of routine colonoscopy under moderate or no sedation. Two reviewers will independently perform a three-stage screening process and extract all study data using piloted forms. Study quality will be assessed using the Cochrane Risk of Bias Tool V.2.0. Where multiple studies evaluate a single intervention, evidence will be quantitatively synthesised using pairwise meta-analysis, otherwise narrative syntheses will be undertaken. ETHICS AND DISSEMINATION: This is a review of existing literature not requiring ethics approval. The review findings will be included in future efforts to develop an implementation strategy to reduce the use of deep sedation for routine colonoscopy. They will also be published in a peer-reviewed journal, presented at conferences and contribute to a doctoral thesis. PROSPERO REGISTRATION NUMBER: CRD42020173906.

Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA).

Parkinson disease (PD) is an age-related neurodegenerative disorder associated with misfolded SNCA/α-synuclein accumulation in brain. Impaired catabolism of SNCA potentiates formation of its toxic oligomers. LRRK2 (leucine-rich repeat kinase-2) mutations predispose to familial and sporadic PD. Mutant LRRK2 perturbs chaperone-mediated-autophagy (CMA) to degrade SNCA. We showed greater age-dependent accumulation of oligomeric SNCA in striatum and cortex of aged LRRK2R1441G knockin (KI) mice, compared to age-matched wildtype (WT) by 53% and 31%, respectively. Lysosomal clustering and accumulation of CMA-specific LAMP2A and HSPA8/HSC70 proteins were observed in aged mutant striatum along with increased GAPDH (CMA substrate) by immunohistochemistry of dorsal striatum and flow cytometry of ventral midbrain cells. Using our new reporter protein clearance assay, mutant mouse embryonic fibroblasts (MEFs) expressing either SNCA or CMA recognition 'KFERQ'-like motif conjugated with photoactivated-PAmCherry showed slower cellular clearance compared to WT by 28% and 34%, respectively. However, such difference was not observed after the 'KFERQ'-motif was mutated. LRRK2 mutant MEFs exhibited lower lysosomal degradation than WT indicating lysosomal dysfunction. LAMP2A-knockdown reduced total lysosomal activity and clearance of 'KFERQ'-substrate in WT but not in mutant MEFs, indicating impaired CMA in the latter. A CMA-specific activator, AR7, induced neuronal LAMP2A transcription and lysosomal activity in MEFs. AR7 also attenuated the progressive accumulation of both intracellular and extracellular SNCA oligomers in prolonged cultures of mutant cortical neurons (DIV21), indicating that oligomer accumulation can be suppressed by CMA activation. Activation of autophagic pathways to reduce aged-related accumulation of pathogenic SNCA oligomers is a viable disease-modifying therapeutic strategy for PD.Abbreviations: 3-MA: 3-methyladenine; AR7: 7-chloro-3-(4-methylphenyl)-2H-1,4-benzoxazine; CMA: chaperone-mediated autophagy; CQ: chloroquine; CSF: cerebrospinal fluid; DDM: n-dodecyl ß-D-maltoside; DIV: days in vitro; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GWAS: genome-wide association studies; HSPA8/HSC70: heat shock protein 8; KFERQ: CMA recognition pentapeptide; KI: knockin; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LDH: lactate dehydrogenase; LRRK2: leucine-rich repeat kinase 2; MEF: mouse embryonic fibroblast; NDUFS4: NADH:ubiquinone oxidoreductase core subunit S4; NE: novel epitope; PD: Parkinson disease; RARA/RARα: retinoic acid receptor, alpha; SNCA: synuclein, alpha; TUBB3/TUJ1: tubulin, beta 3 class III; WT: wild-type.

Theoretical Study of Diastereoselective NHC-Catalyzed Cross-Benzoin Reactions between Furfural and N-Boc-Protected α-Amino Aldehydes.

The mechanism and origins of syn and anti selectivity of cross-benzoin reactions between furfural and α-amino aldehydes, catalyzed by a triazolium-based NHC, were investigated using density functional theory calculations. N-Boc-α-amino aldehydes were found to react with anti selectivity, while N-Bn-N-Boc-α-amino aldehydes react with syn selectivity. We find that the anti product is more thermodynamically favored than the syn product for reactions with N-Boc-α-amino aldehydes, and that the formation of the syn product for reactions involving N-Bn-N-Boc-α-amino aldehydes is kinetically favored. The switch in selectivity is a result of an intramolecular hydrogen bond in the N-Boc-α-amino aldehyde, whereas switching to N-Bn-N-Boc-α-amine removes the hydrogen bond. The steric and electronic interactions in the transition state are rationalized by a Felkin-Anh model.