The Canadian VirusSeq Data Portal & Duotang: open resources for SARS-CoV-2 viral sequences and genomic epidemiology.

The COVID-19 pandemic led to a large global effort to sequence SARS-CoV-2 genomes from patient samples to track viral evolution and inform public health response. Millions of SARS-CoV-2 genome sequences have been deposited in global public repositories. The Canadian COVID-19 Genomics Network (CanCOGeN - VirusSeq), a consortium tasked with coordinating expanded sequencing of SARS-CoV-2 genomes across Canada early in the pandemic, created the Canadian VirusSeq Data Portal, with associated data pipelines and procedures, to support these efforts. The goal of VirusSeq was to allow open access to Canadian SARS-CoV-2 genomic sequences and enhanced, standardized contextual data that were unavailable in other repositories and that meet FAIR standards (Findable, Accessible, Interoperable and Reusable). The Portal data submission pipeline contains data quality checking procedures and appropriate acknowledgement of data generators that encourages collaboration. Here we also highlight Duotang, a web platform that presents genomic epidemiology and modeling analyses on circulating and emerging SARS-CoV-2 variants in Canada. Duotang presents dynamic changes in variant composition of SARS-CoV-2 in Canada and by province, estimates variant growth, and displays complementary interactive visualizations, with a text overview of the current situation. The VirusSeq Data Portal and Duotang resources, alongside additional analyses and resources computed from the Portal (COVID-MVP, CoVizu), are all open-source and freely available. Together, they provide an updated picture of SARS-CoV-2 evolution to spur scientific discussions, inform public discourse, and support communication with and within public health authorities. They also serve as a framework for other jurisdictions interested in open, collaborative sequence data sharing and analyses.

Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR-T therapies in autoimmunity.

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and CD20 therapies had minimal effects. These data both confirm that the autoreactome is comprised of autoantibodies secreted by plasma cells, and strongly suggest that BCMA or other plasma cell targeting therapies may be highly effective in treating currently refractory autoantibody mediated diseases.

Sensitivity of the African neuropsychology battery memory subtests and learning slopes in discriminating APOE 4 and amyloid pathology in adult individuals in the Democratic Republic of Congo.

Background: The current study examined the sensitivity of two memory subtests and their corresponding learning slope metrics derived from the African Neuropsychology Battery (ANB) to detect amyloid pathology and APOEε4 status in adults from Kinshasa, the Democratic Republic of the Congo. Methods: 85 participants were classified for the presence of ß-amyloid pathology and based on allelic presence of APOEε4 using Simoa. All participants were screened using CSID and AQ, underwent verbal and visuospatial memory testing from ANB, and provided blood samples for plasma Aß42, Aß40, and APOE proteotype. Pearson correlation, linear and logistic regression were conducted to compare amyloid pathology and APOEε4 status with derived learning scores, including initial learning, raw learning score, learning over trials, and learning ratio. Results: Our sample included 35 amyloid positive and 44 amyloid negative individuals as well as 42 without and 39 with APOEε4. All ROC AUC ranges for the prediction of amyloid pathology based on learning scores were low, ranging between 0.56-0.70 (95% CI ranging from 0.44-0.82). The sensitivity of all the scores ranged between 54.3-88.6, with some learning metrics demonstrating good sensitivity. Regarding APOEε4 prediction, all AUC values ranged between 0.60-0.69, with all sensitivity measures ranging between 53.8-89.7. There were minimal differences in the AUC values across learning slope metrics, largely due to the lack of ceiling effects in this sample. Discussion: This study demonstrates that some ANB memory subtests and learning slope metrics can discriminate those that are normal from those with amyloid pathology and those with and without APOEε4, consistent with findings reported in Western populations.

Plasma SOMAmer proteomics of postoperative delirium.

BACKGROUND: Postoperative delirium is prevalent in older adults and has been shown to increase the risk of long-term cognitive decline. Plasma biomarkers to identify the risk for postoperative delirium and the risk of Alzheimer's disease and related dementias are needed. METHODS: This biomarker discovery case-control study aimed to identify plasma biomarkers associated with postoperative delirium. Patients aged ≥65 years undergoing major elective noncardiac surgery were recruited. The preoperative plasma proteome was interrogated with SOMAmer-based technology targeting 1433 biomarkers. RESULTS: In 40 patients (20 with vs. 20 without postoperative delirium), a preoperative panel of 12 biomarkers discriminated patients with postoperative delirium with an accuracy of 97.5%. The final model of five biomarkers delivered a leave-one-out cross-validation accuracy of 80%. Represented biological pathways included lysosomal and immune response functions. CONCLUSION: In older patients who have undergone major surgery, plasma SOMAmer proteomics may provide a relatively non-invasive benchmark to identify biomarkers associated with postoperative delirium.

Real-world diagnostic outcomes and cost-effectiveness of genome-wide sequencing for developmental and seizure disorders: Evidence from Canada.

PURPOSE: To determine real-world diagnostic rates, cost trajectories, and cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children with developmental and/or seizure disorders in British Columbia, Canada. METHODS: Based on medical records review, we estimated real-world costs and outcomes for 491 patients who underwent standard of care (SOC) diagnostic testing at British Columbia Children's Hospital. Results informed a state-transition Markov model examining cost-effectiveness of 3 competing diagnostic strategies: (1) SOC with last-tier access to ES, (2) streamlined ES access, and (3) first-tier GS. RESULTS: Through SOC, 49.4% (95% CI: 40.6, 58.2) of patients were diagnosed at an average cost of C$11,683 per patient (95% CI: 9200, 14,166). Compared with SOC, earlier ES or GS access yielded similar or improved diagnostic rates and shorter times to genetic diagnosis, with 94% of simulations demonstrating cost savings for streamlined ES and 60% for first-tier GS. Net benefit from the perspective of the health care system was C$2956 (95% CI: -608, 6519) for streamlined ES compared with SOC. CONCLUSION: Using real-world data, we found earlier access to ES may yield more rapid genetic diagnosis of childhood developmental and seizure disorders and cost savings compared with current practice in a Canadian health care system.

Scalable plasma and digital cognitive markers for diagnosis and prognosis of Alzheimer's disease and related dementias.

INTRODUCTION: With emergence of disease-modifying therapies, efficient diagnostic pathways are critically needed to identify treatment candidates, evaluate disease severity, and support prognosis. A combination of plasma biomarkers and brief digital cognitive assessments could provide a scalable alternative to current diagnostic work-up. METHODS: We examined the accuracy of plasma biomarkers and a 10-minute supervised tablet-based cognitive assessment (Tablet-based Cognitive Assessment Tool Brain Health Assessment [TabCAT-BHA]) in predicting amyloid ß positive (Aß+) status on positron emission tomography (PET), concurrent disease severity, and functional decline in 309 older adults with subjective cognitive impairment (n = 49), mild cognitive impairment (n = 159), and dementia (n = 101). RESULTS: Combination of plasma pTau181, Aß42/40, neurofilament light (NfL), and TabCAT-BHA was optimal for predicting Aß-PET positivity (AUC = 0.962). Whereas NfL and TabCAT-BHA optimally predicted concurrent disease severity, combining these with pTau181 and glial fibrillary acidic protein was most accurate in predicting functional decline. DISCUSSION: Combinations of plasma and digital cognitive markers show promise for scalable diagnosis and prognosis of ADRD. HIGHLIGHTS: The need for cost-efficient diagnostic and prognostic markers of AD is urgent. Plasma and digital cognitive markers provide complementary diagnostic contributions. Combination of these markers holds promise for scalable diagnosis and prognosis. Future validation in community cohorts is needed to inform clinical implementation.

Isolation and characterization of ZK002, a novel dual function snake venom protein from Deinagkistrodon acutus with anti-angiogenic and anti-inflammatory properties.

Introduction: Pathological angiogenesis, the abnormal or excessive generation of blood vessels, plays an important role in many diseases including cancer, diabetic retinopathy, psoriasis, and arthritis. Additionally, increasing evidence supports the close linkage between angiogenesis and inflammation. Snake venoms are a rich natural source of biologically active molecules and carry rich potential for the discovery of anti-angiogenic and anti-inflammatory modulators. Methods: Here, we isolated and purified a novel protein, ZK002, from the venom of the snake Deinagkistrodon acutus, and investigated its anti-angiogenic and anti-inflammatory activities and mechanisms. Results: ZK002 was identified as a 30 kDa heterodimeric protein of α and ß chains, which exhibited anti-angiogenic activity in various in vitro assays. Mechanistically, ZK002 inhibited activation of VEGF signaling and related mediators including eNOS, p38, LIMK, and HSP27. ZK002 also upregulated the metalloproteinase inhibitor TIMP3 and inhibited components of the VEGF-induced signaling cascade, PPP3R2 and SH2D2A. The anti-angiogenic activity of ZK002 was confirmed in multiple in vivo models. ZK002 could also inhibit the in vitro expression of pro-inflammatory cytokines, as well as in vivo inflammation in the carrageenin-induced edema rat model. Conclusion: Our findings highlight the potential for further development of ZK002 as a dual function therapeutic against diseases with involvement of pathogenic angiogenesis and chronic inflammation.

Genetic matching for time-dependent treatments: a longitudinal extension and simulation study.

BACKGROUND: Longitudinal matching can mitigate confounding in observational, real-world studies of time-dependent treatments. To date, these methods have required iterative, manual re-specifications to achieve covariate balance. We propose a longitudinal extension of genetic matching, a machine learning approach that automates balancing of covariate histories. We examine performance by comparing the proposed extension against baseline propensity score matching and time-dependent propensity score matching. METHODS: To evaluate comparative performance, we developed a Monte Carlo simulation framework that reflects a static treatment assigned at multiple time points. Data generation considers a treatment assignment model, a continuous outcome model, and underlying covariates. In simulation, we generated 1,000 datasets, each consisting of 1,000 subjects, and applied: (1) nearest neighbour matching on time-invariant, baseline propensity scores; (2) sequential risk set matching on time-dependent propensity scores; and (3) longitudinal genetic matching on time-dependent covariates. To measure comparative performance, we estimated covariate balance, efficiency, bias, and root mean squared error (RMSE) of treatment effect estimates. In scenario analysis, we varied underlying assumptions for assumed covariate distributions, correlations, treatment assignment models, and outcome models. RESULTS: In all scenarios, baseline propensity score matching resulted in biased effect estimation in the presence of time-dependent confounding, with mean bias ranging from 29.7% to 37.2%. In contrast, time-dependent propensity score matching and longitudinal genetic matching achieved stronger covariate balance and yielded less biased estimation, with mean bias ranging from 0.7% to 13.7%. Across scenarios, longitudinal genetic matching achieved similar or better performance than time-dependent propensity score matching without requiring manual re-specifications or normality of covariates. CONCLUSIONS: While the most appropriate longitudinal method will depend on research questions and underlying data patterns, our study can help guide these decisions. Simulation results demonstrate the validity of our longitudinal genetic matching approach for supporting future real-world assessments of treatments accessible at multiple time points.

Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study.

Amnestic mild cognitive impairment (aMCI) is a predementia stage of Alzheimer's disease associated with dysfunctional episodic memory and limited treatment options. We aimed to characterize feasibility, clinical, and biomarker effects of noninvasive neurostimulation for aMCI. 13 individuals with aMCI received eight 60-minute sessions of 40-Hz (gamma) transcranial alternating current stimulation (tACS) targeting regions related to episodic memory processing. Feasibility, episodic memory, and plasma Alzheimer's disease biomarkers were assessed. Neuroplastic changes were characterized by resting-state functional connectivity (RSFC) and neuronal excitatory/inhibitory balance. Gamma tACS was feasible and aMCI participants demonstrated improvement in multiple metrics of episodic memory, but no changes in biomarkers. Improvements in episodic memory were most pronounced in participants who had the highest modeled tACS-induced electric fields and exhibited the greatest changes in RSFC. Increased RSFC was also associated with greater hippocampal excitability and higher baseline white matter integrity. This study highlights initial feasibility and the potential of gamma tACS to rescue episodic memory in an aMCI population by modulating connectivity and excitability within an episodic memory network.

Presence of Preoperative Neurodegeneration Biofluid Markers in Patients with Postoperative Delirium.

BACKGROUND: The pathophysiology of delirium is incompletely understood, including what molecular pathways are involved in brain vulnerability to delirium. This study examined whether preoperative plasma neurodegeneration markers were elevated in patients who subsequently developed postoperative delirium through a retrospective case-control study. METHODS: Inclusion criteria were patients of 65 yr of age or older, undergoing elective noncardiac surgery with a hospital stay of 2 days or more. Concentrations of preoperative plasma P-Tau181, neurofilament light chain, amyloid ß1-42 (Aß42), and glial fibrillary acidic protein were measured with a digital immunoassay platform. The primary outcome was postoperative delirium measured by the Confusion Assessment Method. The study included propensity score matching by age and sex with nearest neighbor, such that each patient in the delirium group was matched by age and sex with a patient in the no-delirium group. RESULTS: The initial cohort consists of 189 patients with no delirium and 102 patients who developed postoperative delirium. Of 291 patients aged 72.5 ± 5.8 yr, 50.5% were women, and 102 (35%) developed postoperative delirium. The final cohort in the analysis consisted of a no-delirium group (n = 102) and a delirium group (n = 102) matched by age and sex using the propensity score method. Of the four biomarkers assayed, the median value for neurofilament light chain was 32.05 pg/ml for the delirium group versus 23.7 pg/ml in the no-delirium group. The distribution of biomarker values significantly differed between the delirium and no-delirium groups (P = 0.02 by the Kolmogorov-Smirnov test) with the largest cumulative probability difference appearing at the biomarker value of 32.05 pg/ml. CONCLUSIONS: These results suggest that patients who subsequently developed delirium are more likely to be experiencing clinically silent neurodegenerative changes before surgery, reflected by changes in plasma neurofilament light chain biomarker concentrations, which may identify individuals with a preoperative vulnerability to subsequent cognitive decline.

Nocturnal respiratory abnormalities among ward-level postoperative patients as detected by the Capnostream 20p monitor: A blinded observational study.

PURPOSE: This prospective observational study aimed to establish the frequency of postoperative nocturnal respiratory abnormalities among patients undergoing major surgery who received ward-level care. These abnormalities may have implications for postoperative pulmonary complications (PPCs). METHODS: Eligible patients underwent blinded noninvasive continuous capnography with pulse oximetry using the Capnostream™ 20p monitor over the first postoperative night. All patients received oxygen supplementation and patient-controlled opioid analgesia. The primary outcome was the number of prolonged apnea events (PAEs), defined as end-tidal carbon dioxide (EtCO2) ≤5 mmHg for 30-120 seconds or EtCO2 ≤5 mmHg for >120 seconds with oxygen saturation (SpO2) <85%. Secondary outcomes were the proportion of recorded time that physiological indices were aberrant, including the apnea index (AI), oxygen desaturation index (ODI), integrated pulmonary index (IPI), and SpO2. Exploratory analysis was conducted to assess the associations between PAEs, PPCs, and pre-defined factors. RESULTS: Among 125 patients who had sufficient data for analysis, a total of 1800 PAEs occurred in 67 (53.4%) patients. The highest quartile accounted for 89.1% of all events. Amongst patients who experienced any PAEs, the median (IQR) number of PAE/patient was four (2-12). As proportions of recorded time (median (IQR)), AI, ODI, and IPI were aberrant for 12.4% (0-43.2%), 19.1% (2.0-57.1%), and 11.5% (3.1-33.3%) respectively. Only age, ARISCAT, and opioid consumption/kg were associated with PPCs. CONCLUSIONS: PAE and aberrant indices were frequently detected on the first postoperative night. However, they did not correlate with PPCs. Future research should investigate the significance of detected aberrations.

Unveiling the autoreactome: Proteome-wide immunological fingerprints reveal the promise of plasma cell depleting therapy.

The prevalence and burden of autoimmune and autoantibody mediated disease is increasing worldwide, yet most disease etiologies remain unclear. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leverage advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of proteome-wide autoantibody profiles in both health and disease. We demonstrate that each individual, regardless of disease state, possesses a distinct set of autoreactivities constituting a unique immunological fingerprint, or "autoreactome", that is remarkably stable over years. In addition to uncovering important new biology, the autoreactome can be used to better evaluate the relative effectiveness of various therapies in altering autoantibody repertoires. We find that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly alter an individual's autoreactome, while anti-CD19 and CD-20 therapies have minimal effects, strongly suggesting a rationale for BCMA or other plasma cell targeted therapies in autoantibody mediated diseases.

Hepatic and renal function impact concentrations of plasma biomarkers of neuropathology.

Introduction: The impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis. Methods: Plasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression. Results: p-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (ß = 0.75, P < .01), NfL (ß = 0.32, P < .01), and t-tau (ß = 0.31, P < .01), but not GFAP (ß = -0.01, P = .88) or UCHL1 (ß = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (ß = -0.18, P < .01), NfL (ß = -0.22, P < .01), GFAP (ß = -0.17, P < .05), t-tau (ß = -0.20, P = .02), and UCHL1 (ß = -0.15, P = .09). Conclusions: Elevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.

Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis.

BACKGROUND: Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored. METHODS: Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial's participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period. RESULTS: NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=-0.035 [-0.068 to -0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [-0.0004 to 0.007], p=0.081). Based on a Cohen's d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power. CONCLUSIONS: In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination. TRIAL REGISTRATION NUMBER: NCT02040298.

Lactobacillus casei Strain Shirota Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Increasing Taurine-Conjugated Bile Acids and Inhibiting NF-κB Signaling via Stabilization of IκBα.

Inflammatory bowel disease (IBD) is a chronic progressive intestinal inflammatory disease, characterized by an altered gut microbiota composition and accompanying alterations in circulatory bile acids. Increasing evidence supports the beneficial effect of probiotics intake on health. Introduction of probiotics to the intestines can modulate gut microbiota composition and in turn regulate the host immune system and modify the inflammatory response. Probiotics can also improve intestinal barrier function and exhibit a positive impact on host physiological and pathological conditions via gut microbiota-derived metabolites. Previous studies have demonstrated that Lactobacillus casei strain Shirota (LcS) treatment could inhibit clinical manifestation of colitis in dextran sulfate sodium (DSS)-induced mice, however, the underlying mechanisms remain unknown. In this study, we employed the DSS-induced acute colitis mouse model to investigate the anti-inflammatory effects of LcS and related mechanisms. Administration of LcS ameliorated the severity of DSS-induced colitis and enhanced intestinal integrity via induction of mucin-2 and occludin expression in colons. Fecal microbiota analysis showed that LcS increased the relative abundance of beneficial bacterial species in colitic mice, whereas the relative abundance of pathobionts was reduced. Additionally, LcS treatment modulated circulating bile acid profiles in colitic mice. In mice treated with LcS, we identified increased levels of primary taurine-conjugated bile acids, including taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA). LcS treatment also increased the levels of secondary taurine-conjugated bile acids, including taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). Moreover, LcS treatment exhibited a suppressive effect on the hydroxylated primary bile acids α-muricholic acid (α-MCA) and ß-muricholic acid (ß-MCA). We further demonstrated that LcS treatment suppressed the expression of pro-inflammatory mediators interferon-gamma (IFN-γ) and nitric oxide (NO), and increased the expression of the anti-inflammatory mediator interleukin-10 (IL-10) in colon tissues, potentially as a result of altered bile acid profiles. Mechanistically, we showed that LcS treatment suppressed the activation of nuclear factor-kappa B (NF-κB) signaling via stabilization of inhibitor of NF-κB alpha (IκBα). Altogether, we have demonstrated the therapeutic effects of LcS in DSS-induced colitis, providing new insights into its effect on bile acid metabolism and the related anti-inflammatory mechanisms. Our findings provide support for the application of LcS in the treatment of IBD.

1,1,3,3-Tetramethylguanidine-Mediated Zwitterionic Ring-Opening Polymerization of Sarcosine-Derived N-Thiocarboxyanhydride toward Well-Defined Polysarcosine.

Zwitterionic ring-opening polymerization (ZROP) of sarcosine-derived N-thiocarboxyanhydrides (Me-NNTAs) can be induced by using 1,1,3,3-tetramethylguanidine (TMG) initiators in CH2Cl2 at 25 °C, rapidly producing well-defined polysarcosine polymers with controlled molecular weights (M n = 1.9-37 kg/mol) and narrow molecular weight distributions (D = 1.01-1.12). The reaction exhibits characteristics of a living polymerization, evidenced by pseudo-first-order polymerization kinetics, the linear increase of polymer molecular weight (M n) with conversion, and the successful chain extension experiments. The polymerization is proposed to proceed via propagating macro-zwitterions bearing a cationic 1,1,3,3-tetramethylguanidinium and an anionic thiocarbamate chain end. The TMG not only initiates the polymerization but also serves to stabilize the thiocarbamate chain end where the monomer addition occurs. Because of the enhanced hydrolytic stability of Me-NNTA, the polymerization can be conducted without the rigorous exclusion of moisture, further enhancing the appeal of the method to access well-defined polysarcosine.

Use of a buprenorphine-based pain management protocol is associated with reduced opioid requirements and pain on swallowing in oral mucositis: a retrospective cohort study.

OBJECTIVE: The aim of this study is to ascertain the analgesic efficacy and total oral morphine equivalent daily dose (OMEDD) effect of a buprenorphine-based analgesic protocol in the treatment of severe Oral Mucositis (OM). DESIGN: This is a retrospective cohort study. SETTING: This study was done in a single Quaternary Referral Centre, Haematology Unit. SUBJECTS: Fifty-four stem cell transplant patients suffering at least grade 3 oral mucositis (OM), 24 prior to [Pr-I] and 30 subsequent to [Po-I] a buprenorphine-based OM analgesic protocol. METHODS: We analysed data from the above subjects with the primary outcome measure of difference in total OMEDDs from all opioid types and administration routes, and secondary outcome measures of area under the curve (AUC) of 11-point Numerical Rating Scale (NRS-11) pain assessments, sedation scores and respiratory rate. RESULTS: Post-protocol patients' total OMEDD requirements were significantly reduced [Pr-I: 1961 (1365)mg; Po-I: 928 (625)mg, p = 0.02], as were total NRS-11:hours AUC on swallowing [Pr-I: 54(24) score-hours; Po-I: 41(18) score-hours, p < 0.001]. There were no significant differences in objective measures of OM severity between groups (Number of Grade 3 or 4 OM severity assessments [mean (SD)] Pr-I: 5 (6.2); Po-I: 7 (5.1) or number of days Neutrophil count 0.0 or 0.1 × 109/L; Pr-I: 13 (5.4); Po-I: 15 (4.7)). 5 Pr-I and 4 Po-I patients required ketamine infusions, with 1 Pr-I patient also requiring IV lignocaine. CONCLUSIONS: Use of Buprenorphine via transdermal, sublingual and intravenous Patient Controlled Analgesia (PCA) delivery as part of an analgesic protocol for severe post stem cell transplant oral mucositis in adult patients appears to significantly reduce opioid requirements and pain on swallowing. Further randomised prospective work is required to confirm these associations.

Cost-Effectiveness of Molecularly Guided Treatment in Diffuse Large B-Cell Lymphoma (DLBCL) in Patients under 60.

BACKGROUND: Classifying diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subtypes could allow for personalized cancer control. Evidence suggests that subtype-guided treatment may be beneficial in the activated B-cell (ABC) subtype of DLBCL, among patients under the age of 60. METHODS: We estimated the cost-effectiveness of age- and subtype-specific treatment guided by gene expression profiling (GEP). A probabilistic Markov model examined costs and quality-adjusted life-years gained (QALY) accrued to patients under GEP-classified COO treatment over a 10-year time horizon. The model was calibrated to evaluate the adoption of ibrutinib as a first line treatment among patients under 60 years with ABC subtype DLBCL. The primary data source for efficacy was derived from published estimates of the PHOENIX trial. These inputs were supplemented with patient-level, real-world data from BC Cancer, which provides comprehensive cancer services to the population of British Columbia. RESULTS: We found the cost-effectiveness of GEP-guided treatment vs. standard care was $77,806 per QALY (24.3% probability of cost-effectiveness at a willingness-to-pay (WTP) of $50,000/QALY; 53.7% probability at a WTP of $100,000/QALY) for first-line treatment. Cost-effectiveness was dependent on assumptions around decision-makers' WTP and the cost of the assay. CONCLUSIONS: We encourage further clinical trials to reduce uncertainty around the implementation of GEP-classified COO personalized treatment in this patient population.

Defining a Core Data Set for the Economic Evaluation of Precision Oncology.

OBJECTIVES: Precision oncology is generating vast amounts of multiomic data to improve human health and accelerate research. Existing clinical study designs and attendant data are unable to provide comparative evidence for economic evaluations. This lack of evidence can cause inconsistent and inappropriate reimbursement. Our study defines a core data set to facilitate economic evaluations of precision oncology. METHODS: We conducted a literature review of economic evaluations of next-generation sequencing technologies, a common application of precision oncology, published between 2005 and 2018 and indexed in PubMed (MEDLINE). Based on this review, we developed a preliminary core data set for informal expert feedback. We then used a modified-Delphi approach with individuals involved in implementation and evaluation of precision medicine, including 2 survey rounds followed by a final voting conference to refine the data set. RESULTS: Two authors determined that variation in published data elements was reached after abstraction of 20 economic evaluations. Expert consultation refined the data set to 83 unique data elements, and a multidisciplinary sample of 46 experts participated in the modified-Delphi process. A total of 68 elements (81%) were selected as required, spanning demographics and clinical characteristics, genomic data, cancer treatment, health and quality of life outcomes, and resource use. CONCLUSIONS: Cost-effectiveness analyses will fail to reflect the real-world impacts of precision oncology without data to accurately characterize patient care trajectories and outcomes. Data collection in accordance with the proposed core data set will promote standardization and enable the generation of decision-grade evidence to inform reimbursement.

Characteristics of Older Adults Accessing Medical Assistance in Dying (MAiD): a Descriptive Study.

BACKGROUND: Medical Assistance in Dying (MAiD) is an end-of-life option for Canadians accounting for 2% of all deaths in Canada in 2019. Adults over 80 years old represent a significant proportion of these deaths, yet little is known about how they compare with their younger counterparts. METHODS: This study retrospectively reviewed our tertiary care institution's MAiD database to compare MAiD recipients <65, 65-80, and >80 years of age. Extracted data included basic demographics, illness characteristics, functional status, social living arrangements/contacts, and outcomes of MAiD assessments. RESULTS: Of 267 patients assessed for MAiD, 38.2% were over 80. Compared to the younger groups, those over 80 were more likely to be female, to live alone, and to be widowed; however, they did not self-identify as 'socially isolated'. The majority fit into the illness categories of malignancy, cardiopulmonary or neurologic diseases, but those over 80 were more likely to have other more chronic/subacute conditions leading to the MAiD request. CONCLUSIONS: Older adults accessing MAiD are distinct in that they tend to be increasingly frail and without a predominant underlying diagnosis as compared with younger adults, but rather have an accumulation of losses resulting in global functional decline and subsequent loss of autonomy and independence.