Mathematical modelling for pandemic preparedness in Canada: Learning from COVID-19.

Background: The COVID-19 pandemic underlined the need for pandemic planning but also brought into focus the use of mathematical modelling to support public health decisions. The types of models needed (compartment, agent-based, importation) are described. Best practices regarding biological realism (including the need for multidisciplinary expert advisors to modellers), model complexity, consideration of uncertainty and communications to decision-makers and the public are outlined. Methods: A narrative review was developed from the experiences of COVID-19 by members of the Public Health Agency of Canada External Modelling Network for Infectious Diseases (PHAC EMN-ID), a national community of practice on mathematical modelling of infectious diseases for public health. Results: Modelling can best support pandemic preparedness in two ways: 1) by modelling to support decisions on resource needs for likely future pandemics by estimating numbers of infections, hospitalized cases and cases needing intensive care, associated with epidemics of "hypothetical-yet-plausible" pandemic pathogens in Canada; and 2) by having ready-to-go modelling methods that can be readily adapted to the features of an emerging pandemic pathogen and used for long-range forecasting of the epidemic in Canada, as well as to explore scenarios to support public health decisions on the use of interventions. Conclusion: There is a need for modelling expertise within public health organizations in Canada, linked to modellers in academia in a community of practice, within which relationships built outside of times of crisis can be applied to enhance modelling during public health emergencies. Key challenges to modelling for pandemic preparedness include the availability of linked public health, hospital and genomic data in Canada.

A Retrospective Cohort Study Examining the Validation of the Modified Duke Activity Status Index in the Non-cardiac Surgical Population.

PURPOSE: We aimed to ascertain if the Duke Activity Status Index (DASI) and its simplified variants predict 30-day mortality and myocardial injury after major non-cardiac surgery in at-risk patients. DESIGN: Retrospective cohort study. METHODS: We included 4,199 patients to validate the DASI and its variants in predicting the same composite outcome in patients with risk factors for coronary artery disease. Additional outcomes included 30-day severe complications, 1-year survival, and the effect of the Area Deprivation Index (ADI) on the DASI score and subsequent outcomes. FINDINGS: Patients were a median of 66 years old (interquartile range 57.0, 73.0), 47.9% were male, predominantly Caucasian (71.9%), with an American Society of Anesthesiologists score of 3 or greater (80.7%) and a median National ADI of 54.0 (interquartile range 33.0 to 74.0). The 30-day composite outcome was predicted by the original DASI (area under the curve [AUC] 0.82 [CI 0.73, 0.91], P < .001); modified 4-question DASI (AUC 0.82 [CI 0.73, 0.91], P < .048). The original DASI also predicted the 1-year composite outcome (hazard ratio 0.88 [CI 0.84, 0.93], P < .001), as did the modified 4-question DASI (hazard ratio 0.78 [CI 0.69, 0.89], P < .001), but not severe complications (P = .400 and P = .332 respectively). The ADI showed an inverse relationship with all versions of the DASI; there was a 0.8-point DASI decrease ([95% confidence interval -0.96 to -0.59], P < .001) for every 10-point increase in the National ADI. CONCLUSIONS: The DASI is a reliable predictor of long-term postoperative outcomes.

A global, propensity-score matched analysis of patients receiving inflatable penile prostheses and the risk of complications, infections, and re-interventions.

Background: Over 25,000 men undergo inflatable penile prosthesis (IPP) placement yearly to treat erectile dysfunction (ED). Although various comorbidities are hypothesized risk factors for complications, this remains incompletely understood. Our objective was to utilize multi-institutional data to characterize risk for reintervention, complications, and infections in patients with common suspected risk factors undergoing IPP placement. Methods: We queried the TriNetX database for adult men who underwent IPP placement from 2003-2023 utilizing Current Procedural Terminology (CPT) codes. We examined the impact of diabetes mellitus (DM), hypertension (HTN), nicotine use, radiation therapy (RT), radical prostatectomy (RP), and urethral surgery [urethroplasty, artificial urinary sphincter (AUS), male urethral sling (MS)] on clinical outcomes defined by International Classification of Diseases 10th Revision (ICD-10) codes. Our primary outcome was need for reintervention based on CPT codes. Secondary outcomes included overall rates of complication and infection utilizing ICD-10 codes. Analytics were performed using TriNetX to calculate risk ratios (RRs) and Kaplan-Meier (KM) survival. We evaluated outcomes overall and for each individual comparison cohort using the remaining demographic variables to perform propensity score matching (PSM). Results: In a total of 11,026 patients there was an overall 13.5% risk of undergoing at least one reintervention, with some undergoing multiple based on CPT codes. KM analysis showed a median IPP survival of 18.2 years and a projected 10- and 20-year survival probability at 70.6% and 48.4% respectively. Overall complication rate was 19.3% with a 5.2% rate of infection based on ICD codes. Patients with history of urethral surgery were at higher risk of both IPP complication and re-intervention. When further analyzing type of re-intervention, patients with a history of smoking, prior RP, and prior AUS/MS placement had higher rates of device removal. Patients with a history of diabetes were less likely to undergo IPP replacement at the time of explant. There were no identified risk factors for IPP infection. Conclusions: This is the largest cohort of patients ever evaluated and can help guide patient selection and counseling. There was a higher rate of IPP complications than previously reported, but this may be due to different reporting parameters. History of prior urethral surgery conferred a higher risk of complications and re-intervention. These results can help guide patient selection and counseling.

State of Head and Neck Microvascular Reconstruction: Current and Future Directions.

Since its inception, microvascular free tissue transfer has broadened possibilities for oncologic ablation and restoration of form and function. Developments throughout recent decades have resulted in increasing flap success rates and complexity. Advances in technology and knowledge gained from past experiences will continue to improve surgical efficiency, flap success rates, and ultimately, patient outcomes.

Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study.

BACKGROUND AND AIMS: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports. METHODS: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates. RESULTS: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials.

Evaluating the effectiveness of large language models in abstract screening: a comparative analysis.

OBJECTIVE: This study aimed to evaluate the performance of large language models (LLMs) in the task of abstract screening in systematic review and meta-analysis studies, exploring their effectiveness, efficiency, and potential integration into existing human expert-based workflows. METHODS: We developed automation scripts in Python to interact with the APIs of several LLM tools, including ChatGPT v4.0, ChatGPT v3.5, Google PaLM 2, and Meta Llama 2, and latest tools including ChatGPT v4.0 turbo, ChatGPT v3.5 turbo, Google Gemini 1.0 pro, Meta Llama 3, and Claude 3. This study focused on three databases of abstracts and used them as benchmarks to evaluate the performance of these LLM tools in terms of sensitivity, specificity, and overall accuracy. The results of the LLM tools were compared to human-curated inclusion decisions, gold standard for systematic review and meta-analysis studies. RESULTS: Different LLM tools had varying abilities in abstract screening. Chat GPT v4.0 demonstrated remarkable performance, with balanced sensitivity and specificity, and overall accuracy consistently reaching or exceeding 90%, indicating a high potential for LLMs in abstract screening tasks. The study found that LLMs could provide reliable results with minimal human effort and thus serve as a cost-effective and efficient alternative to traditional abstract screening methods. CONCLUSION: While LLM tools are not yet ready to completely replace human experts in abstract screening, they show great promise in revolutionizing the process. They can serve as autonomous AI reviewers, contribute to collaborative workflows with human experts, and integrate with hybrid approaches to develop custom tools for increased efficiency. As technology continues to advance, LLMs are poised to play an increasingly important role in abstract screening, reshaping the workflow of systematic review and meta-analysis studies.

Steroid profiling in human primary teeth via liquid chromatography-tandem mass spectrometry for long-term retrospective steroid measurement.

Steroid hormones are important modulators of many physiological processes, and measurements of steroids in blood, saliva, and urine matrices are widely used to assess endocrine pathologies and stress. However, these matrices cannot be used to retrospectively assess early-life stress and developmental endocrine pathologies, because they do not integrate steroid levels over the long term. A novel biological matrix in which to measure steroids is primary teeth (or "baby teeth"). Primary teeth develop early in life and accumulate various endogenous molecules during their gradual formation. Here, we developed and validated the first assay to measure steroids in human primary teeth using liquid chromatography-tandem spectrometry (LC-MS/MS). Our assay is highly sensitive, specific, accurate, and precise. It allows for the simultaneous quantification of 17 steroids in primary teeth (16 of which have not been examined previously in primary teeth). Overall, steroid levels in primary teeth were relatively low, and 8 steroids were quantifiable. Levels of dehydroepiandrosterone, cortisol, and progesterone were the highest of the 17 steroids examined. Next, we used this assay to perform steroid profiling in primary teeth from males and females. The same 8 steroids were quantifiable, and no sex differences were found. Levels of androgens (androstenedione and testosterone) were positively correlated, and levels of glucocorticoids (cortisol, cortisone, corticosterone, 11-dehydrocorticosterone) were also positively correlated. These data demonstrate that multiple steroids can be quantified by LC-MS/MS in human primary teeth, and this method potentially provides a powerful new way to retrospectively assess early-life stress and developmental endocrine pathologies.

Canada's provincial COVID-19 pandemic modelling efforts: A review of mathematical models and their impacts on the responses.

SETTING: Mathematical modelling played an important role in the public health response to COVID-19 in Canada. Variability in epidemic trajectories, modelling approaches, and data infrastructure across provinces provides a unique opportunity to understand the factors that shaped modelling strategies. INTERVENTION: Provinces implemented stringent pandemic interventions to mitigate SARS-CoV-2 transmission, considering evidence from epidemic models. This study aimed to summarize provincial COVID-19 modelling efforts. We identified modelling teams working with provincial decision-makers, through referrals and membership in Canadian modelling networks. Information on models, data sources, and knowledge translation were abstracted using standardized instruments. OUTCOMES: We obtained information from six provinces. For provinces with sustained community transmission, initial modelling efforts focused on projecting epidemic trajectories and healthcare demands, and evaluating impacts of proposed interventions. In provinces with low community transmission, models emphasized quantifying importation risks. Most of the models were compartmental and deterministic, with projection horizons of a few weeks. Models were updated regularly or replaced by new ones, adapting to changing local epidemic dynamics, pathogen characteristics, vaccines, and requests from public health. Surveillance datasets for cases, hospitalizations and deaths, and serological studies were the main data sources for model calibration. Access to data for modelling and the structure for knowledge translation differed markedly between provinces. IMPLICATION: Provincial modelling efforts during the COVID-19 pandemic were tailored to local contexts and modulated by available resources. Strengthening Canadian modelling capacity, developing and sustaining collaborations between modellers and governments, and ensuring earlier access to linked and timely surveillance data could help improve pandemic preparedness.

RéSUMé: CONTEXTE: La modélisation mathématique a joué un rôle de premier plan dans les ripostes sanitaires à la COVID-19 au Canada. Les différentes trajectoires épidémiques provinciales, leurs approches de modélisation et infrastructures de données représentent une occasion unique de comprendre les facteurs qui ont influencé les stratégies de modélisation provinciales. INTERVENTION: Les provinces ont mis en place des mesures de santé publique strictes afin d'atténuer la transmission du SRAS-CoV-2 en tenant compte des données probantes provenant des modèles épidémiques. Notre étude vise à décrire et résumer les efforts provinciaux de modélisation de la COVID-19. Nous avons identifié les équipes de modélisation travaillant avec les décideurs provinciaux parmi les réseaux Canadiens de modélisation et par référence. Les informations sur les modèles, leurs sources de données et les approches de mobilisation des connaissances ont été obtenues à l'aide d'instruments standardisés. RéSULTATS: Nous avons colligé les informations provenant de six provinces. Pour les provinces qui ont eu de la transmission communautaire soutenue, les efforts de modélisation initiaux se sont concentrés sur la projection des trajectoires épidémiques et des demandes de soins de santé et sur l'évaluation des impacts des interventions proposées. Dans les provinces où la transmission communautaire a été faible, les modèles visaient à quantifier les risques d'importation. La plupart des équipes ont développé des modèles à compartiments déterministes avec des horizons de projection de quelques semaines. Les modèles ont été régulièrement mis à jour ou remplacés par de nouveaux, s'adaptant aux dynamiques locales, à l'arrivée de nouveaux variants, aux vaccins et aux demandes des autorités de santé publique. Les données de surveillance des cas, des hospitalisations et des décès, ainsi que les études sérologiques, ont constitué les principales sources de données pour calibrer les modèles. L'accès aux données pour la modélisation et la structure de mobilisation des connaissances différaient considérablement d'une province à l'autre. IMPLICATION: Les efforts de modélisation provinciaux pendant la pandémie de la COVID-19 ont été adaptés aux contextes locaux et modulés par les ressources disponibles. Le renforcement de la capacité canadienne de modélisation, le développement et le maintien de collaborations entre les modélisateurs et les gouvernements, ainsi qu'un accès rapide et opportun aux données de surveillance individuelles et liées pourraient contribuer à améliorer la préparation aux futures pandémies.

Butyrate and tributyrin reduce LPS-induced inflammatory cytokine production from human visceral fat.

INTRODUCTION: The current obesity crisis has resulted in many people with excess adipose tissue suffering from chronic inflammation. This inflammation is largely due to the release of cytokines and chemokines from visceral fat. The aim of this study was to identify potential anti-inflammatory agents that might alleviate obesity-induced chronic inflammation. METHODS: To identify agents that might alleviate this obesity-induced chronic inflammation we have developed a simple protocol for incubating intact pieces of human visceral adipose tissue in 35 mm tissue culture plates, in the presence of low-dose lipopolysaccharide (LPS) and co-incubating these samples with potential anti-inflammatory agents. RNA-Seq analysis was performed to identify enriched gene expression signatures among the most significantly differentially expressed genes. RESULTS: From this screen, we have identified the short-chain fatty acid (SCFA) sodium butyrate and its triacylglyceride form, tributyrin, as effective agents, significantly reducing the production of LPS-induced inflammatory cytokines and chemokines from all adipose tissue samples tested. As well, these agents appear to be non-toxic at the concentrations tested. RNA-Seq analysis has revealed that IL36γ is one of the most upregulated genes in response to LPS and one of the most downregulated when sodium butyrate is added to human fat samples stimulated with LPS. IL-36γ ELISAs confirmed this holds true at the protein level as well. CONCLUSIONS: These studies suggest that the short-chain fatty acid, sodium butyrate, and its triacylglyceride form, tributyrin, might alleviate the chronic inflammation that is associated with many individuals with obesity.

HER2-CD3-Fc Bispecific Antibody-Encoding mRNA Delivered by Lipid Nanoparticles Suppresses HER2-Positive Tumor Growth.

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor and tumor-associated antigen abnormally expressed in various types of cancer, including breast, ovarian, and gastric cancer. HER2 overexpression is highly correlated with increased tumor aggressiveness, poorer prognosis, and shorter overall survival. Consequently, multiple HER2-targeted therapies have been developed and approved; however, only a subset of patients benefit from these treatments, and relapses are common. More potent and durable HER2-targeted therapies are desperately needed for patients with HER2-positive cancers. In this study, we developed a lipid nanoparticle (LNP)-based therapy formulated with mRNA encoding a novel HER2-CD3-Fc bispecific antibody (bsAb) for HER2-positive cancers. The LNPs efficiently transfected various types of cells, such as HEK293S, SKOV-3, and A1847, leading to robust and sustained secretion of the HER2-CD3-Fc bsAb with high binding affinity to both HER2 and CD3. The bsAb induced potent T-cell-directed cytotoxicity, along with secretion of IFN-λ, TNF-α, and granzyme B, against various types of HER2-positive tumor cells in vitro, including A549, NCI-H460, SKOV-3, A1847, SKBR3, and MDA-MB-231. The bsAb-mediated antitumor effect is highly specific and strictly dependent on its binding to HER2, as evidenced by the gained resistance of A549 and A1847 her2 knockout cells and the acquired sensitivity of mouse 4T1 cells overexpressing the human HER2 extracellular domain (ECD) or epitope-containing subdomain IV to the bsAb-induced T cell cytotoxicity. The bsAb also relies on its binding to CD3 for T-cell recruitment, as ablation of CD3 binding abolished the bsAb's ability to elicit antitumor activity. Importantly, intratumoral injection of the HER2-CD3-Fc mRNA-LNPs triggers a strong antitumor response and completely blocks HER2-positive tumor growth in a mouse xenograft model of human ovarian cancer. These results indicate that the novel HER2-CD3-Fc mRNA-LNP-based therapy has the potential to effectively treat HER2-positive cancer.

Extended lifespan in female Drosophila melanogaster through late-life calorie restriction.

Calorie restriction has many beneficial effects on healthspan and lifespan in a variety of species. However, how late in life application of caloric restriction can extend fly life is not clear. Here we show that late-life calorie restriction increases lifespan in female Drosophila melanogaster aged on a high-calorie diet. This shift results in rapid decrease in mortality rate and extends fly lifespan. In contrast, shifting female flies from a low- to a high-calorie diet leads to a rapid increase in mortality and shorter lifespan. These changes are mediated by immediate metabolic and physiological adaptations. One of such adaptation is rapid adjustment in egg production, with flies directing excess energy towards egg production when shifted to a high diet, or away from reproduction in females shifted to low-caloric diet. However, lifelong female fecundity reveals no associated fitness cost due to CR when flies are shifted to a high-calorie diet. In view of high conservation of the beneficial effects of CR on physiology and lifespan in a wide variety of organisms, including humans, our findings could provide valuable insight into CR applications that could provide health benefits later in life.

Immunotherapy for hepatocellular carcinoma: The next evolution in expanding access to liver transplantation.

Immunotherapy has revolutionised the treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in combination with surgical or locoregional therapies for early-to intermediate-stage HCC have recently reported positive results, and other phase III trials in the same patient population are currently in progress. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarise key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients.

Examining ethnic identity, school climate, and academic futility among minoritized students.

The present causal-comparative study examined the relation between school climate, ethnic identity, and academic futility among racially and ethnically minoritized students. The sample included 1721 racially and ethnically minoritized students identifying as Black, Asian, Latine, and Multiracial from 11 schools in the northeastern region of the United States. Regression models indicated a direct relation between the school climate subscales including School Connectedness, Safety, Character, Peer Support, Adult Support, Cultural Acceptance, Physical Environment, and Order and Discipline and academic futility for all groups in the study. Ethnic identity moderated the relation between school climate subscales and academic futility, although the impact differed across racial and ethnic groups. The present study's results highlight the similarities and differences in the educational experiences of minoritized students. The discussion provides recommendations for cultivating educational environments that are culturally affirming and informed to meet the needs of an increasingly diverse student population. Limitations and future directions are discussed.

Caregiver-reported symptom burden and preferences for therapeutic goals in pediatric primary sclerosing cholangitis.

This study analyzed qualitative and quantitative survey responses from 51 pediatric primary sclerosing cholangitis (PSC) patients and caregivers using the PSC Partners Patient Registry-Our Voices survey. The most common symptoms reported by children/caregivers include: fatigue (71%), abdominal pain (69%), anxiety (59%), appetite loss (51%), insomnia (49%), and pruritus (45%). When experiencing symptoms at their worst, over half of patients/caregivers reported limitations in physically demanding activities (67%), work/school duties (63%), social life activities (55%), and activities for fun or exercise (53%). Over half of patients/caregivers expressed willingness to participate in clinical trials, however none reported ever participating in trials for new or investigational PSC drugs. This study revealed a substantial patient/caregiver-reported symptom burden for children with PSC that impacts quality of life and limits access to clinical trials. Future efforts should focus on developing patient-centered clinical endpoints for PSC trials, increasing trial availability for pediatric PSC patients, and reducing logistical barriers to trial involvement.

Extended observation of reduced methamphetamine use with combined naltrexone plus bupropion in the ADAPT-2 trial.

BACKGROUND AND AIMS: A 12-week placebo-controlled, sequential parallel Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial evaluated the effects of extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN) on methamphetamine (MA) use over two stages. This study reports on the previously unpublished stage 2 MA use in participants randomized at stage 1 to receive NTX + BUPN through both stages compared with those assigned to placebo. DESIGN: This is a secondary analysis of the US National Institute on Drug Abuse (NIDA) ADAPT-2 network trial. SETTING: The parent ADAPT-2 trial was carried out across multiple NIDA Clinical Trials Network (CTN) sites in the United States. PARTICIPANTS: This analysis includes 403 people with MA use disorder who participated in the ADAPT-2 CTN trial. INTERVENTION AND COMPARATOR: NTX + BUPN was compared with placebo over the course of the trial. MEASUREMENT: MA use was measured by urine drug screens conducted twice weekly for 12 weeks, then once in week 13 and once in week 16 post-treatment follow-up. FINDINGS: Participants on NTX + BUPN in stage 1 showed an additional 9.2% increase [95% confidence interval (CI), 0.09%-17.9%, P = 0.038] during stage 2 in their probability of testing negative for MA, with a total increase of 27.1% (95% CI, 13.2%-41.1%, P < 0.001) over the full 12 weeks of treatment. In contrast, participants on placebo in both stages increased in probability of testing MA-negative by a total of 11.4% (95% CI, 4.1%-18.6%, P = 0.002) over all 12 weeks. The 12-week increase among participants on NTX + BUPN was significantly greater-by 15.8% (95% CI, 4.5%-27.0%, P = 0.006)-than the increase among those on placebo. CONCLUSION: For people with methamphetamine (MA) use disorder receiving treatment with extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN), continued treatment with NTX + BUPN after 6 weeks is associated with additional reductions in MA use up to 12 weeks.

Patient-focused drug development in primary sclerosing cholangitis: Insights on patient priorities and involvement in clinical trials.

BACKGROUND: According to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC's rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials. METHODS: PSC Partners Seeking a Cure developed the "Our Voices" survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development. RESULTS: Of 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09-2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19-0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42-0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50-3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials. CONCLUSIONS: Most patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.

Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).

TRAF3 loss-of-function reveals the noncanonical NF-κB pathway as a therapeutic target in diffuse large B cell lymphoma.

Here, we report recurrent focal deletions of the chr14q32.31-32 locus, including TRAF3, a negative regulator of NF-κB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between TRAF3 copy number loss with accumulation of NIK, the central noncanonical (NC) NF-κB kinase, and increased NC NF-κB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF-κB downstream signaling. Knockdown or pharmacological inhibition of NIK in TRAF3-deficient cells differentially impaired their proliferation and survival, suggesting an acquired onco-addiction to NC NF-κB. TRAF3 ablation also led to exacerbated secretion of the immunosuppressive cytokine IL-10. Coculturing of TRAF3-deficient DLBCL cells with CD8+ T cells impaired the induction of Granzyme B and interferon (IFN) γ, which were restored following neutralization of IL-10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF-κB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL.

Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. AIM: To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. METHODS: We searched Cochrane and PubMed databases for articles published through August 2023. RESULTS: Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. CONCLUSIONS: Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.