Post-mRNA vaccine flares in autoimmune inflammatory rheumatic diseases: Results from the COronavirus National Vaccine registry for ImmuNe diseases SINGapore (CONVIN-SING).

BACKGROUND: Studies of flares of autoimmune inflammatory rheumatic diseases (AIIRD) after COVID-19 mRNA vaccination are limited by small sample size, short follow up or at risk of selection bias. METHODS: A national retrospective cohort study of consecutive AIIRD patients ≥12 years old, across 8 hospitals who received at least one dose of a COVID-19 mRNA vaccine. Patients were included from the date of 1st vaccine dose and censored at the time of flare or on the date of the clinic visit at least 3 months from cohort entry, whichever came first. Predictors of flare were determined by Cox proportional hazards analysis. FINDINGS: 4627 patients (73% Chinese, 71% female) of median (IQR) age 61 (48, 70) years were included; 42% Rheumatoid arthritis, 14% Systemic lupus erythematosus and 11% Psoriatic arthritis. 47% were in remission, 41% low disease activity, 10% moderate disease activity and 1% in high disease activity. 18% patients flared, of which 11.7% were within the 3-month period of interest. 11.8% patients improved. Median (IQR) time-to-flare was 60 (30, 114) days. 25% flares were self-limiting, 61% mild-moderate and 14% severe. Older patients (53-65 years and >66 years) had a lower risk of flare [HR 0.6 (95% CI 0.5-0.8) and 0.7 (0.6-0.8) respectively]. Patients with inflammatory arthritis and with active disease had a higher risk of flare [HR 1.5 (1.2-2.0) and 1.4 (1.2-1.6), respectively]. Treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), immunosuppression and prednisolone was also associated with an increased risk of flare [HR 1.5 (1.1-2), 1.2 (1.1-1.4) and 1.5 (1.2-1.8) for prednisolone ≤7.5 mg respectively]. INTERPRETATION: There was a moderately high rate of AIIRD flares after mRNA vaccination but also improvement in several patients. Severe flares and hospitalisation were rare. Thus, vaccination remains safe and highly recommended.

Assessing the effects of a mentoring program on professional identity formation.

BACKGROUND: Medical education has enjoyed mixed fortunes nurturing professional identity formation (PIF), or how medical students think, feel and act as physicians. New data suggests that structured mentoring programs like the Palliative Medicine Initiative (PMI) may offer a means of developing PIF in a consistent manner. To better understand how a well-established structured research mentoring program shapes PIF, a study of the experiences of PMI mentees is proposed. METHODOLOGY: Acknowledging PIF as a sociocultural construct, a Constructivist approach and Relativist lens were adopted for this study. In the absence of an effective tool, the Ring Theory of Personhood (RToP) and Krishna-Pisupati Model (KPM) model were used to direct this dual Systematic Evidence-Based Approach (Dual-SEBA) study in designing, employing and analysing semi-structured interviews with PMI mentees and mentoring diaries. These served to capture changes in PIF over the course of the PMI's mentoring stages. Transcripts of the interviews and mentoring diaries were concurrently analysed using content and thematic analysis. Complementary themes and categories identified from the Split Approach were combined using the Jigsaw Approach and subsequently compared with mentoring diaries in the Funnelling Process. The domains created framed the discussion. RESULTS: A total of 12 mentee interviews and 17 mentoring diaries were analysed, revealing two domains-PMI as a Community of Practice (CoP) and Identity Formation. The domains confirmed the centrality of a structured CoP capable of facilitating longitudinal mentoring support and supporting the Socialisation Process along the mentoring trajectory whilst cultivating personalised and enduring mentoring relationships. CONCLUSION: The provision of a consistent mentoring approach and personalised, longitudinal mentoring support guided along the mentoring trajectory by structured mentoring assessments lay the foundations for more effective mentoring programs. The onus must now be on developing assessment tools, such as a KPM-based tool, to guide support and oversight of mentoring relationships.

Professional identity formation amongst peer-mentors in a research-based mentoring programme.

BACKGROUND: Mentoring plays a pivotal yet poorly understood role in shaping a physician's professional identity formation (PIF) or how they see, feel and act as professionals. New theories posit that mentoring nurtures PIF by functioning as a community of practice through its structured approach and its support of a socialisation process made possible by its assessment-directed personalized support. To test this theory and reshape the design, employ and support of mentoring programs, we evaluate peer-mentor experiences within the Palliative Medicine Initiative's structured research mentoring program. METHODS: Semi-structured interviews with peer mentors under the Palliative Medicine Initiative (PMI) at National Cancer Centre Singapore were conducted and triangulated against mentoring diaries to capture longitudinal data of their PMI experiences. The Systematic Evidence-Based Approach (SEBA) was adopted to enhance the trustworthiness of the data. SEBA employed concurrent content and thematic analysis of the data to ensure a comprehensive review. The Jigsaw Perspective merged complementary themes and categories identified to create themes/categories. The themes/categories were compared with prevailing studies on mentoring in the Funnelling Process to reaffirm their accuracy. RESULTS: Twelve peer-mentors participated in the interviews and eight peer-mentors completed the mentoring diaries. The domains identified were community of practice and identity work. CONCLUSIONS: The PMI's structured mentoring program functions as a community of practice supporting the socialisation process which shapes the peer-mentor's belief system. Guided by a structured mentoring approach, stage-based assessments, and longitudinal mentoring and peer support, peer-mentors enhance their detection and evaluation of threats to their regnant belief system and adapt their self-concepts of identity and personhood to suit their context. These insights will help structure and support mentoring programs as they nurture PIF beyond Palliative Medicine.

The role of mentoring, supervision, coaching, teaching and instruction on professional identity formation: a systematic scoping review.

BACKGROUND: Mentoring's pivotal role in nurturing professional identity formation (PIF) owes much to its combined use with supervision, coaching, tutoring, instruction, and teaching. However the effects of this combination called the 'mentoring umbrella' remains poorly understood. This systematic scoping review thus aims to map current understanding. METHODS: A Systematic Evidence-Based Approach guided systematic scoping review seeks to map current understanding of the 'mentoring umbrella' and its effects on PIF on medical students and physicians in training. It is hoped that insights provided will guide structuring, support and oversight of the 'mentoring umbrella' in nurturing PIF. Articles published between 2000 and 2021 in PubMed, Scopus, ERIC and the Cochrane databases were scrutinised. The included articles were concurrently summarised and tabulated and concurrently analysed using content and thematic analysis and tabulated. The themes and categories identified were compared with the summaries of the included articles to create accountable and reproducible domains that guide the discussion. RESULTS: A total of 12201 abstracts were reviewed, 657 full text articles evaluated, and 207 articles included. The three domains identified were definitions; impact on PIF; and enablers and barriers. The mentoring umbrella shapes PIF in 3 stages and builds a cognitive base of essential knowledge, skills and professional attitudes. The cognitive base informs thinking, conduct and opinions in early supervised clinical exposure in Communities of practice (COP). The COPs' individualised approach to the inculcation of desired professional characteristics, goals, values, principles and beliefs reshapes the individual's identity whilst the socialisation process sees to their integration into current identities. CONCLUSION: The mentoring umbrella's provides personalised longitudinal support in the COP and socialisation process. Understanding it is key to addressing difficulties faced and ensuring holistic and timely support.

Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling.

X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active ß-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos. Although XIAPT180A ubiquitylates TLE3 at wild-type levels in vitro, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAPT180A binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.

Projected effects of nonpharmaceutical public health interventions to prevent resurgence of SARS-CoV-2 transmission in Canada.

BACKGROUND: Continual efforts to eliminate community transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will be needed to prevent additional waves of infection. We explored the impact of nonpharmaceutical interventions on projected SARS-CoV-2 transmission in Canada. METHODS: We developed an age-structured agent-based model of the Canadian population simulating the impact of current and projected levels of public health interventions on SARS-CoV-2 transmission. Interventions included case detection and isolation, contact tracing and quarantine, physical distancing and community closures, evaluated alone and in combination. RESULTS: Without any interventions, 64.6% (95% credible interval [CrI] 63.9%-65.0%) of Canadians will be infected with SARS-CoV-2 (total attack rate) and 3.6% (95% CrI 2.4%-3.8%) of those infected and symptomatic will die. If case detection and contact tracing continued at baseline levels without maintained physical distancing and reimplementation of restrictive measures, this combination brought the total attack rate to 56.1% (95% CrI 0.05%-57.1%), but it dropped to 0.4% (95% CrI 0.03%-23.5%) with enhanced case detection and contact tracing. Combining the latter scenario with maintained physical distancing reduced the total attack rate to 0.2% (95% CrI 0.03%-1.7%) and was the only scenario that consistently kept hospital and intensive care unit bed use under capacity, prevented nearly all deaths and eliminated the epidemic. Extending school closures had minimal effects but did reduce transmission in schools; however, extending closures of workplaces and mixed-age venues markedly reduced attack rates and usually or always eliminated the epidemic under any scenario. INTERPRETATION: Controlling SARS-CoV-2 transmission will depend on enhancing and maintaining interventions at both the community and individual levels. Without such interventions, a resurgent epidemic will occur, with the risk of overwhelming our health care systems.

Blood vessel epicardial substance reduces LRP6 receptor and cytoplasmic ß-catenin levels to modulate Wnt signaling and intestinal homeostasis.

Blood vessel epicardial substance (BVES, otherwise known as POPDC1) is an integral membrane protein known to regulate tight junction formation and epithelial-mesenchymal transition. BVES is underexpressed in a number of malignancies, including colorectal cancer. BVES loss leads to activation of the Wnt pathway, suggesting that decreased BVES expression functionally contributes to tumorigenesis. However, the mechanism by which BVES modulates Wnt signaling is unknown. Here, we confirm that BVES loss increases ß-catenin protein levels, leads to Wnt pathway activation in a ligand-independent fashion and coordinates with Wnt ligand to further increase Wnt signaling. We show that BVES loss increases levels and activation of the Wnt co-receptor, LRP6, in cell lines, murine adenoma tumoroids and human-derived colonoids. We also demonstrate that BVES interacts with LRP6. Finally, murine tumor modeling using a Wnt-driven genetic model and a chemically induced model of colorectal carcinogenesis demonstrate that BVES loss increases tumor multiplicity and dysplasia. Together, these results implicate BVES as an inhibitor of Wnt signaling, provide one of the first examples of a tight junction-associated protein regulating Wnt receptor levels, and expand the number of putative molecular targets for therapeutic intervention in colorectal cancer.

A Novel Bvg-Repressed Promoter Causes vrg-Like Transcription of fim3 but Does Not Result in the Production of Serotype 3 Fimbriae in Bvg- Mode Bordetella pertussis.

In Bordetella pertussis, two serologically distinct fimbriae, FIM2 and FIM3, undergo on/off phase variation independently of each other via variation in the lengths of C stretches in the promoters for their major subunit genes, fim2 and fim3 These two promoters are also part of the BvgAS virulence regulon and therefore, if in an on configuration, are activated by phosporylated BvgA (BvgA~P) under normal growth conditions (Bvg+ mode) but not in the Bvg- mode, inducible by growth in medium containing MgSO4 or other compounds, termed modulators. In the B. pertussis Tohama I strain (FIM2+ FIM3-), the fim3 promoter is in the off state. However, a high level of transcription of the fim3 gene is observed in the Bvg- mode. In this study, we provide an explanation for this anomalous behavior by defining a Bvg-repressed promoter (BRP), located approximately 400 bp upstream of the Pfim3 transcriptional start. Although transcription of the fim3 gene in the Bvg- mode resulted in Fim3 translation, as measured by LacZ translational fusions, no accumulation of Fim3 protein was detectable. We propose that Fim3 protein resulting from translation of mRNA driven by BRP in the Bvg- mode is unstable due to a lack of the fimbrial assembly apparatus encoded by the fimBC genes, located within the fha operon, and therefore is not expressed in the Bvg- mode.IMPORTANCE In Bordetella pertussis, the promoter Pfim3-15C for the major fimbrial subunit gene fim3 is activated by the two-component system BvgAS in the Bvg+ mode but not in the Bvg- mode. However, many transcriptional profiling studies have shown that fim3 is transcribed in the Bvg- mode even when Pfim3 is in a nonpermissive state (Pfim3-13C), suggesting the presence of a reciprocally regulated element upstream of Pfim3 Here, we provide evidence that BRP is the cause of this anomalous behavior of fim3 Although BRP effects vrg-like transcription of fim3 in the Bvg- mode, it does not lead to stable production of FIM3 fimbriae, because expression of the chaperone and usher proteins FimB and FimC occurs only in the Bvg+ mode.

Activation of Bvg-Repressed Genes in Bordetella pertussis by RisA Requires Cross Talk from Noncooperonic Histidine Kinase RisK.

The two-component response regulator RisA, encoded by open reading frame BP3554 in the Bordetella pertussis Tohama I genomic sequence, is a known activator of vrg genes, a set of genes whose expression is increased under the same environmental conditions (known as modulation) that result in repression of the bvgAS virulence regulon. Here we demonstrate that RisA is phosphorylated in vivo and that RisA phosphorylation is required for activation of vrg genes. An adjacent histidine kinase gene, risS, is truncated by frameshift mutation in B. pertussis but not in Bordetella bronchiseptica or Bordetella parapertussis Neither deletion of risS' or bvgAS nor phenotypic modulation with MgSO4 affected levels of phosphorylated RisA (RisA∼P) in B. pertussis However, RisA phosphorylation did require the histidine kinase encoded by BP3223, here named RisK (cognate histidine kinase of RisA). RisK was also required for expression of the vrg genes. This requirement could be obviated by the introduction of the phosphorylation-mimicking RisAD60E mutant, indicating that an active conformation of RisA, but not phosphorylation per se, is crucial for vrg activation. Interestingly, expression of vrg genes is still modulated by MgSO4 in cells harboring the RisAD60E mutation, suggesting that the activated RisA senses additional signals to control vrg expression in response to environmental stimuli.IMPORTANCE In B. pertussis, the BvgAS two-component system activates the expression of virulence genes by binding of BvgA∼P to their promoters. Expression of the reciprocally regulated vrg genes requires RisA and is also repressed by the Bvg-activated BvgR. RisA is an OmpR-like response regulator, but RisA phosphorylation was not expected because the gene for its presumed, cooperonic, histidine kinase is inactivated by mutation. In this study, we demonstrate phosphorylation of RisA in vivo by a noncooperonic histidine kinase. We also show that RisA phosphorylation is necessary but not sufficient for vrg activation but, importantly, is not affected by BvgAS status. Instead, we propose that vrg expression is controlled by BvgAS through its regulation of BvgR, a cyclic di-GMP (c-di-GMP) phosphodiesterase.

Effets projetés des mesures de santé publique non pharmacologiques visant à prévenir la recrudescence de la transmission du SRAS-CoV-2 au Canada.

CONTEXTE: Il faudra prendre des mesures continues contre la transmission communautaire du coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2) pour prévenir d'autres vagues d'infection. Nous avons exploré les effets des interventions non pharmacologiques sur la transmission projetée du SRAS-CoV-2 au Canada. MÉTHODES: Nous avons créé un modèle de la population canadienne à base d'agents intégrant l'âge qui simule les effets des mesures de santé publique, selon leur intensité actuelle et projetée, sur la transmission du SRAS-CoV-2. Les mesures étudiées sont le dépistage et l'isolement des cas, la recherche de contacts et la mise en quarantaine, l'éloignement sanitaire et la fermeture des espaces partagés. Nous avons évalué l'effet des mesures prises individuellement et celui des mesures combinées. RÉSULTATS: En l'absence de mesures, 64,6 % (intervalle de crédibilité [ICr] à 95 % : 63,9 %­65,0 %) des Canadiens contracteraient le SRAS-CoV-2 (taux d'attaque global), et 3,6 % (ICr à 95 % 2,4 %­3,8 %) des personnes infectées en mourraient. En poursuivant le dépistage et la recherche de contacts à la même intensité que pendant la période de référence, sans maintenir l'éloignement sanitaire ou refermer certains endroits, le pays connaîtrait un taux d'attaque global de 56,1 % (ICr à 95 % 0,05 %­57,1 %); si ces mesures étaient accrues, le taux d'attaque chuterait à 0,4 % (ICr à 95 % 0,03 %­23,5 %). En combinant ce dernier scénario et le maintien de l'éloignement sanitaire, le taux tomberait à 0,2 % (ICr à 95 % 0,03 %­1,7 %). Ce scénario est le seul qui garderait la demande en soins hospitaliers et intensifs sous la capacité, qui préviendrait presque tous les décès et qui mettrait fin à l'épidémie. La prolongation de la fermeture des écoles aurait un effet minime, mais réduirait la transmission en milieu scolaire. Par contre, la prolongation de la fermeture des lieux de travail et des lieux publics réduirait de manière marquée le taux d'attaque et mettait habituellement ou toujours fin à l'épidémie, selon les différents scénarios simulés. INTERPRÉTATION: Le contrôle de la transmission du SRAS-CoV-2 passera par l'amélioration et le maintien des mesures, tant communautaires qu'individuelles. Autrement, il y aura une recrudescence de l'épidémie, et un risque de surcharger le système de santé.

A Scoping Review on the Epidemiology of Orthobunyaviruses of Canadian Public and Animal Health Relevance in the Context of Vector Species.

Background: Mosquito-borne orthobunyaviruses are a growing priority for public and animal health in Canada. It is anticipated that disease incidence will increase due to a warming climate, given that habitats are expanding for reservoir hosts and vectors, particularly in Canada. Little is known about the ecology of primary vectors that perpetuate these orthobunyaviruses, including the viral transmission cycle and the impact of climatic and landscape factors. Methods: A scoping review was conducted to describe the current state of knowledge on the epidemiology of orthobunyaviruses relevant to Canada. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines was used to characterize studies focused on vector species. A literature search was conducted in six databases and gray literature. Eligible studies characterized orthobunyavirus epidemiology related to vector species, including viral competency, geospatial distributions, seasonal trends, and/or risk factors. Results: A total of 1734 unique citations were identified. Screening of these citations revealed 172 relevant studies, from which 87 studies presented primary data related to vectors. The orthobunyaviruses included Cache Valley virus (CVV), Jamestown Canyon virus (JCV), Snowshoe Hare virus (SHV), and La Crosse virus (LACV). Surveillance was the predominant study focus, with most citations representing the United States, specifically, LACV surveillance in Tennessee, followed by CVV and JCV in Connecticut. Orthobunyaviruses were detected in many mosquito species across multiple genera, with high vector specificity only being reported for LACV, which included Aedes triseriatus, Aedes albopictus, and Aedes japonicus. Peridomestic areas were positively associated with infected mosquitoes compared with dense forests. Orthobunyavirus infections, coinfections, and gut microbiota affected mosquito feeding and breeding behavior. Conclusion: Knowledge gaps included Canadian surveillance data, disease modeling, and risk projections. Further research in these areas, especially accounting for climate change, is needed to guide health policy for prevention of orthobunyaviral disease.

Forecasting seasonal influenza activity in Canada-Comparing seasonal Auto-Regressive integrated moving average and artificial neural network approaches for public health preparedness.

INTRODUCTION: Public health preparedness is based on timely and accurate information. Time series forecasting using disease surveillance data is an important aspect of preparedness. This study compared two approaches of time series forecasting: seasonal auto-regressive integrated moving average (SARIMA) modelling and the artificial neural network (ANN) algorithm. The goal was to model weekly seasonal influenza activity in Canada using SARIMA and compares its predictive accuracy, based on root mean square prediction error (RMSE) and mean absolute prediction error (MAE), to that of an ANN. METHODS: An initial SARIMA model was fit using automated model selection by minimizing the Akaike information criterion (AIC). Further inspection of the autocorrelation function and partial autocorrelation function led to 'manual' model improvements. ANNs were trained iteratively, using an automated process to minimize the RMSE and MAE. RESULTS: A total of 378, 462 cases of influenza was reported in Canada from the 2010-2011 influenza season to the end of the 2019-2020 influenza season, with an average yearly incidence risk of 20.02 per 100,000 population. Automated SARIMA modelling was the better method in terms of forecasting accuracy (per RMSE and MAE). However, the ANN correctly predicted the peak week of disease incidence while the other models did not. CONCLUSION: Both the ANN and SARIMA models have shown to be capable tools in forecasting seasonal influenza activity in Canada. It was shown that applying both in tandem is beneficial, SARIMA better forecasted overall incidence while ANN correctly predicted the peak week.

A Scoping Review on the Epidemiology of Orthobunyaviruses in Canada, in the Context of Human, Wildlife, and Domestic Animal Host Species.

Background: Mosquito-borne orthobunyaviruses in Canada are a growing public health concern. Orthobunyaviral diseases are commonly underdiagnosed and in Canada, likely underreported as surveillance is passive. No vaccines or specific treatments exist for these disease agents. Further, climate change is facilitating habitat expansion for relevant reservoirs and vectors, and it is likely that the majority of the Canadian population is susceptible to these viruses. Methods: A scoping review was conducted to describe the current state of knowledge on orthobunyavirus epidemiology in Canada. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guideline was used. Literature searches were conducted in six databases and in gray literature. The epidemiology of orthobunyaviruses was characterized for studies focusing on host species, including spatiotemporal patterns, risk factors, and climate change impact. Results: A total of 172 relevant studies were identified from 1734 citations from which 95 addressed host species, including humans, wildlife, and domestic animals including livestock. The orthobunyaviruses-Cache Valley virus (CVV), Jamestown Canyon virus (JCV), Snowshoe Hare virus (SHV), and La Crosse virus (LACV)-were identified, and prevalence was widespread across vertebrate species. CVV, JCV, and SHV were detected across Canada and the United States. LACV was reported only in the United States, predominantly the Mid-Atlantic and Appalachian regions. Disease varied by orthobunyavirus and was associated with age, environment, preexisting compromised immune systems, or livestock breeding schedule. Conclusion: Knowledge gaps included seroprevalence data in Canada, risk factor analyses, particularly for livestock, and disease projections in the context of climate change. Additional surveillance and mitigation strategies, especially accounting for climate change, are needed to guide future public health efforts to prevent orthobunyavirus exposure and disease.

The role of glucagon-like peptide 1 receptor agonists for weight control in individuals with acquired hypothalamic obesity-A systematic review.

Hypothalamic obesity does not respond well to conventional interventions for obesity. GLP-1 receptor agonists have mechanisms independent of the hypothalamus which may be potentially beneficial for managing hypothalamic obesity. This systematic review summarizes the efficacy and safety of GLP-1 receptor agonists use in hypothalamic obesity. A PRISMA-compliant systematic review was performed. Data was extracted from included studies and analysed based on change in weight, body mass index, glycaemic control, satiety, and safety profile with GLP-1 receptor agonist use. Ten studies comprising 5 case reports, 4 case series and 1 randomized-controlled trial included 54 patients (24 males, 30 females) with mean age of 25.2 (range 13-71) years with hypothalamic obesity who had received GLP-1 receptor agonists (exenatide = 48, liraglutide = 5 and dulaglutide = 1) over a mean duration of treatment of 12 (range 3-51) months. Mean weight reduction of 7.4 (SD 7.92) kg was observed in patients in whom weight was reported, with 85.7% of patients experiencing weight loss. All patients on liraglutide had weight reduction post-therapy. The sole trial had reported a non-significant reduction in BMI post-exenatide. Glycaemic control had either improved/maintained in all patients in whom this was measured. The main side effects of GLP-1 receptor agonist in individuals with hypothalamic obesity were nausea and vomiting; there were no major safety concerns. Based on limited published experience, GLP-1RA may be effective and safe for weight control in hypothalamic obesity, with the added benefit of improved glycaemic control in those with concurrent diabetes mellitus.

Cache a Killer: Cache Valley virus seropositivity and associated farm management risk factors in sheep in Ontario, Canada.

Cache Valley virus (CVV) disease is a mosquito-borne zoonosis endemic to North America. CVV disease is reported most often in sheep, causing lethal congenital deformities. There are limited data on CVV in Ontario, which is the largest sheep producing province in Canada. This study aimed to determine CVV seroprevalence in Ontario sheep flocks and investigate farm management factors associated with CVV exposure. A cross-sectional study was performed including 364 mature ewes across 18 farms selected from the five largest sheep districts in the province. A questionnaire was administered at each farm to determine farm management practices pertinent to the flock and ewes specifically sampled. Mixed multivariable logistic regression with a random effect for farm was conducted to assess associations between CVV seropositivity (outcome variable) and farm management risk factors (predictor variables). CVV seroprevalence was 33.2% in individual ewes (95% CI: 28.4%-38.1%) as determined by a virus neutralization assay with a titre > 4. Sixteen of the eighteen flocks (88.9%) had at least one CVV seropositive ewe. Increased age, smaller flock size, and sheep housing near wetlands, lakes, or ponds were found to be significantly associated with higher odds of CVV seropositivity. These findings are valuable in guiding breeding practices and housing during mosquito season to minimize infection and, ultimately, CVV disease in the flock.

Large Decrease in the Melting Point of Benzoquinones via High-n Eutectic Mixing Predicted by a Regular Solution Model.

Decreasing the melting point (Tm) of a mixture is of interest in cryopreservatives, molten salts, and battery electrolytes. One general strategy to decrease Tm, exemplified by deep eutectic solvents, is to mix components with favorable (negative) enthalpic interactions. We demonstrate a complementary strategy to decrease Tm by mixing many components with neutral or slightly positive enthalpic interactions, using the number of components (n) to increase the entropy of mixing and decrease Tm. In theory, under certain conditions this approach could achieve an arbitrarily low Tm. Furthermore, if the components are small redox-active molecules, such as the benzoquinones studied here, this approach could lead to high energy density flow battery electrolytes. Finding the eutectic composition of a high-n mixture can be challenging due to the large compositional space yet is essential for ensuring the existence of a purely liquid phase. We reformulate and apply fundamental thermodynamic equations to describe high-n eutectic mixtures of small redox-active molecules (benzoquinones and hydroquinones). We illustrate a novel application of this theory by tuning the entropy of melting, rather than the enthalpy, in systems highly relevant to energy storage. We demonstrate with differential scanning calorimetry measurements that 1,4-benzoquinone derivatives exhibit eutectic mixing that decreases their Tm, despite slightly positive enthalpies of mixing (0-5 kJ/mol). By rigorously investigating all 21 binary mixtures of a set of seven 1,4-benzoquinone derivatives with alkyl substituents (Tm's between 44 and 120 °C), we find that the eutectic melting point of a mixture of all seven achieves a large decrease in Tm to -6 °C. We further determine that the regular solution model shows improvement over an ideal solution model in predicting the eutectic properties for this newly investigated type of mixture composed of many small redox-active organic molecules.

Quantifying the economic gains associated with COVID-19 vaccination in the Canadian population: A cost-benefit analysis.

Background: Vaccination has been a key part of Canada's coronavirus disease 2019 (COVID-19) pandemic response. Although the clinical benefits of vaccination are clear, an understanding of the population-level benefits of vaccination relative to the programmatic costs is of value. The objective of this article is to quantify the economic impact of COVID-19 vaccination in the Canadian population between December 2020 and March 2022. Methods: We conducted a model-based cost-benefit analysis of Canada's COVID-19 vaccination program. We used an epidemiological model to estimate the number of COVID-19 symptomatic cases, hospitalizations, post-COVID condition (PCC) cases, and deaths in the presence and absence of vaccination. Median, lower and upper 95% credible interval (95% CrI) outcome values from 100 model simulations were used to estimate the direct and indirect costs of illness, including the value of health. We used a societal perspective and a 1.5% discount rate. Results: We estimated that the costs of the vaccination program were far outweighed by the savings associated with averted infections and associated downstream consequences. Vaccination increased the net benefit by CAD $298.1 billion (95% CrI: 27.2-494.6) compared to the no vaccination counterfactual. The largest benefits were due to averted premature mortality, resulting in an estimated $222.0 billion (95% CrI: 31.2-379.0) benefit. Conclusion: Our model-based economic evaluation provides a retrospective assessment of COVID-19 vaccination during the first 16 months of the program in Canada and suggests that it was welfare-improving, considering the decreased hospitalizations and use of healthcare resources, deaths averted and lower morbidity from conditions such as PCC.

USP47 deubiquitylates Groucho/TLE to promote Wnt-ß-catenin signaling.

The Wnt-ß-catenin signal transduction pathway is essential for embryonic development and adult tissue homeostasis. Wnt signaling converts TCF from a transcriptional repressor to an activator in a process facilitated by the E3 ligase XIAP. XIAP-mediated monoubiquitylation of the transcriptional corepressor Groucho (also known as TLE) decreases its affinity for TCF, thereby allowing the transcriptional coactivator ß-catenin to displace it on TCF. Through a genome-scale screen in cultured Drosophila melanogaster cells, we identified the deubiquitylase USP47 as a positive regulator of Wnt signaling. We found that USP47 was required for Wnt signaling during Drosophila and Xenopus laevis development, as well as in human cells, indicating evolutionary conservation. In human cells, knockdown of USP47 inhibited Wnt reporter activity, and USP47 acted downstream of the ß-catenin destruction complex. USP47 interacted with TLE3 and XIAP but did not alter their amounts; however, knockdown of USP47 enhanced XIAP-mediated ubiquitylation of TLE3. USP47 inhibited ubiquitylation of TLE3 by XIAP in vitro in a dose-dependent manner, suggesting that USP47 is the deubiquitylase that counteracts the E3 ligase activity of XIAP on TLE. Our data suggest a mechanism by which regulated ubiquitylation and deubiquitylation of TLE enhance the ability of ß-catenin to cycle on and off TCF, thereby helping to ensure that the expression of Wnt target genes continues only as long as the upstream signal is present.

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions.

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.

The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6.

The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/ß-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.