A Case Report on Primary Collapsing Glomerulopathy in a Filipino Post-partum Female and An Updated Review of Literature.

Collapsing Glomerulopathy (CG) is a rare entity presenting as nephrotic syndrome and rapidly progressive renal deterioration. It has been first identified among African-American patients and subsequently dubbed HIV-associated nephropathy after a number of patients with HIV were found to have CG. It has re-emerged recently among patients with COVID-19. To our knowledge, this is the first case of primary collapsing glomerulopathy in the country to be published. The case is a 36-year-old Filipino female admitted due to bipedal edema which started 2 weeks post-partum. She has no comorbidities and social history was negative for illicit drug use. Initial work up showed hypoalbuminemia and diffuse hepatic disease on ultrasound. She was referred to a gastroenterologist where albumin infusion and paracentesis was done but with no improvement. She developed anasarca and was admitted. Paracentesis obtained minimal ascitic fluid. Serum ascites albumin gradient was low and baseline laboratories showed high creatinine, hypoalbuminemia, and albuminuria. 24-hour urine protein was 11 grams, ANA and anti-DsDNA were negative and c3 and c4 levels were normal. Hepatitis profile was negative for infection. Abdominal CT scan revealed multiple hypoenhancing lesions. Tumor markers CA-125, CA 19-9 and CA 15-3 were high. Breast ultrasound showed simple breast cyst. Gynecology consult was called where pap smear was negative for atypical cells. Surgery service recommended monitoring for the pancreatic and breast lesions. Kidney biopsy was delayed due to new onset bacterial pneumonia. COVID-19 RT-PCR test was negative. Patient was discharged improved with no edema. On follow up, the kidney biopsy result came out to be collapsing glomerulopathy. HIV test was then done and was negative. Bipedal edema and albuminuria recurred. She was started on tacrolimus. She has been on regular follow up and currently has no edema, no proteinuria and normal creatinine level. This is an interesting case as the primary glomerular disease has been masked by the earlier laboratory findings which led us to think of liver disease then a paraneoplastic nephrotic syndrome. Ultimately, the renal biopsy revealed the diagnosis. This serves as an index case for primary collapsing glomerulopathy in a Filipino patient on remission after being treated with tacrolimus.

Optimizing Morbidity in Unplanned Soft Tissue Sarcoma Excisions: Should We Skip the Reconstructive Ladder?

INTRODUCTION: Soft tissue sarcomas (STSs) are rare and diverse primary malignant tumors that comprise approximately 1% of all malignancies. Misdiagnoses and unplanned excisions of STSs are common due to the tumor's rarity, leading to secondary tumor bed excisions (TBEs). Reconstructive outcomes for TBEs remain poorly understood, prompting this study to address the knowledge gap and inform preoperative discussions. METHODS: This was a retrospective cohort study of patients who underwent STS excisions at a quaternary cancer center. Patients were categorized into mass excision (ME) and TBE groups. Reconstructive approaches were divided into simple (primary closure, complex repair, skin grafts, local flaps) and advanced (pedicled or free flaps). The groups were compared for postoperative outcomes, including complications, recurrence, and death. RESULTS: When simple reconstructive techniques were used, TBEs exhibited higher rates of overall and major complications, whereas MEs had higher rates of overall and minor complications. Intergroup analysis revealed that with simple reconstruction, rates of overall and major complications were higher in TBEs than in MEs, and rates of minor complications were higher in MEs than in TBEs. Regression analyses revealed that simple reconstruction of TBEs had 90% and 180% higher odds of major complications and reoperation compared to simple reconstruction of MEs (P < 0.05). CONCLUSION: TBEs, despite their smaller size, exhibited a heightened susceptibility to overall and major complications, challenging the notion that simpler techniques suffice in these cases. Our findings encourage the consideration of advanced reconstructive techniques for TBEs that may seem amenable to simple reconstructive techniques.

Prostate cancer reshapes the secreted and extracellular vesicle urinary proteomes.

Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.

Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.

Climate extremes in Svalbard over the last two millennia are linked to atmospheric blocking.

Arctic precipitation in the form of rain is forecast to become more prevalent in a warmer world but with seasonal and interannual changes modulated by natural modes of variability. Experiencing rapid hydroclimatic changes in the Arctic, Svalbard serves as an ideal study location due to its exposure to oceanic and atmospheric variability in the North Atlantic region. Here we use climate data from paleoproxies, observations, and a climate model to demonstrate that wet and warm extremes in Svalbard over the last two millennia are linked to the presence of atmospheric blocking regimes over Scandinavia and the Ural mountain region. Rainfall episodes lead to the deposition of coarse sediment particles and high levels of calcium in Linnévatnet, a lake in southwest Svalbard, with the coarsest sediments consistently deposited during atmospheric blocking events. A unique annually resolved sediment record from Linnévatnet confirms that this linkage has been persistent over the past 2000 years. Our record also shows that a millennial-scale decline in Svalbard precipitation ended around the middle of the 19th century, followed by several unprecedented extreme events in recent years. As warming continues and sea ice recedes, future Svalbard floods will become more intense during episodes of Scandinavian and Ural blocking.

Structured bubbling in vibrated gas-fluidized beds of binary granular particles: experiments and simulations.

Mixing and segregation of granular particles on the basis of size and density from vertical vibration or upward gas flow is critical to a wide range of industrial, agricultural and natural processes. Recently, combined vibration and gas flow under certain conditions has been shown to create periodically repeating structured bubbling patterns within a fluidized bed of spherical, monodisperse particles. Here, we demonstrate with experiments and simulations that structured bubbling can form in binary mixtures of particles with different size and density, but with similar minimum fluidization velocities. Structured bubbling leads to particles mixing regardless of initial particle configuration, while exciting particles with only gas flow produces smaller unstructured bubbles which act to segregate particles. Discrete particle simulations match the experimental results qualitatively and, in some regards quantitatively, while continuum particle simulations do not predict mixing in the case of structured bubbling, highlighting areas for future model improvement.

Teprotumumab for the treatment of Thyroid eye disease.

Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves' disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED: chemosis, lid swelling, proptosis and diplopia are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that one of the major drivers of this molecular signature is the over-expression of the insulin like growth factor-1 receptor (IGF-1R) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the US for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia and burden on quality of life, in patients who were treated. Post introduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, over 5, 800 patients have been treated with teprotumumab and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first line therapy for patients with moderate to severe TED, who display features of proptosis and diplopia.

Structure-Dependent Water Responsiveness of Protein Block Copolymers.

Biological water-responsive (WR) materials are abundant in nature, and they are used as mechanical actuators for seed dispersal by many plants such as wheat awns and pinecones. WR biomaterials are of interest for applications as high-energy actuators, which can be useful in soft robotics or for capturing energy from natural water evaporation. Recent work on WR silk proteins has shown that ß-sheet nanocrystalline domains with high stiffness correlate with the high WR actuation energy density, but the fundamental mechanisms to drive water responsiveness in proteins remain poorly understood. Here, we design, synthesize, and study protein block copolymers consisting of two α-helical domains derived from cartilage oligomeric matrix protein coiled-coil (C) flanking an elastin-like peptide domain (E), namely, CEC. We use these protein materials to create WR actuators with energy densities that outperform mammalian muscle. To elucidate the effect of structure on WR actuation, CEC was compared to a variant, CECL44A, in which a point mutation disrupts the α-helical structure of the C domain. Surprisingly, CECL44A outperformed CEC, showing higher energy density and less susceptibility to degradation after repeated cycling. We show that CECL44A exhibits a higher degree of intermolecular interactions and is stiffer than CEC at high relative humidity (RH), allowing for less energy dissipation during water responsiveness. These results suggest that strong intermolecular interactions and the resulting, relatively steady protein structure are important for water responsiveness.

Erythropoietin hyporesponsiveness in non-alcoholic fatty liver disease.

Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness. To test our hypothesis, we evaluated the effect of EPO in healthy rats and rats with NAFLD induced by a high-fat, high-carbohydrate (HFHC) diet. After 12 weeks on the HFHC diet, NAFLD rats showed lower erythroid response to EPO treatment than healthy rats. We, then, determined that the primary cause of EPO hyporesponsiveness could be iron deficiency associated with inflammation, which reduces erythroid cell production. Specifically, the concentrations of hepcidin, ferritin, transferrin and white blood cells in NAFLD rats were 12.8-, 16.4-, 2.51- and 1.40-fold higher than those in healthy rats, respectively. However, erythroid cell types in the bone marrow of NAFLD rats were significantly reduced. In conclusion, our data suggest that NAFLD could be a risk factor for EPO responsiveness, which is attributed to functional iron deficiency associated with inflammation.

Why Should Pharmacy Students Take Biochemistry?

The role of biochemistry in the pharmacy curriculum has recently been questioned based on its relevance to the career of a working pharmacist. This commentary explores the historical background of pharmacy education and the central role of chemistry since the 19th century. Reasons for the importance of biochemistry and other sciences are introduced to demonstrate their role in the practice of pharmacy.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Noticing Voluntary E-Cigarette Warning Labels and Associations With Harm Perceptions and Use Intentions: A Baseline Cross-Sectional Analysis of Wave 4 of the Population Assessment of Tobacco and Health Study Prior to the Food and Drug Administration Mandate.

PURPOSE: To examine the effect of e-cigarette warning labels (EWLs) prior to the August 2018 FDA-warning label mandate to establish a baseline for future research. DESIGN: Cross-sectional survey. SETTING: United States. PARTICIPANTS: A cohort of adult participants in the Population Assessment of Tobacco and Health (PATH) study (n = 30,004) at Wave 4 (Dec 2016-Jan 2018). MEASURES: Correlates (e.g., sociodemographics, substance use, social influence, cigarette warnings, and mental health) of noticing EWLs in the past 30-days (noticed vs did not notice), perceived harm of e-cigarettes/nicotine (from 1 = not at all harmful to 5 = extremely harmful), relative harm of e-cigarettes (from 1 = less harmful to 3 = more harmful than cigarettes), intention to quit (yes/no) and intention to try e-cigarettes (from 1 = definitely not to 4 = definitely yes). RESULTS: The prevalence of noticing EWLs was 22.1%. Those who currently use electronic nicotine products, established and experimentally, were more likely to notice EWLs relative to never users (aOR = 3.55; 95% CI: 2.96-4.25; P < .001 and aOR = 2.42; 95% CI: 1.88-3.10; P < .001, respectively). Those with past 30-day alcohol and cigarette use were less likely to notice EWLs (aOR = .27; 95% CI: .24-.31 and aOR = .91; 95% CI: .83-.99; respectively). Those who noticed cigarette warnings were more likely to notice EWLs (aOR = 12.00; 95% CI: 10.46-13.77; P < .001). Among those who noticed EWLs, there were higher odds of perceiving e-cigarettes to be equally or more harmful than cigarettes (aOR = 1.15; 95% CI: 1.02-1.30), but no association was found between noticing EWLs and perceived harm of e-cigarettes/nicotine or use intentions. CONCLUSION: Noticing voluntary EWLs was not associated with increased perceived harm of e-cigarettes and nicotine harm, or e-cigarette use intentions. Future research is warranted to examine the effect of the FDA mandated EWLs.

When to ditch the ladder and take the elevator: The Anderson SArcoma Risk of Complications (A-SARC) score to guide reconstructive decision-making in extremity soft tissue sarcoma patients.

BACKGROUND: The reconstructive ladder relies mostly on defect size and depth to determine reconstructive technique, however, in actuality, many more variables ultimately inform reconstructive decision making, especially regarding extremity soft tissue sarcoma (eSTS) defects. The purpose of this study was to describe eSTS patients who will most optimally benefit from an advanced method of reconstruction (defined as a pedicled regional flap or free flap) and to create a simple risk assessment scale that can be employed in clinical practice. STUDY DESIGN: A single-institution retrospective cohort study examined patients undergoing resection of soft tissue sarcoma affecting the upper or lower extremities between 2016 and 2021. We categorized patients who required a pedicled or free flap as having had advanced reconstruction, and all other techniques were considered simple reconstruction. A regression was used to create a risk scale to guide reconstructive decision-making. RESULTS: The following variables were identified as independent predictors of complications and used to create our risk scale: lower extremity tumor location, preoperative radiotherapy, tumor bed excision, male sex, hypertension, and tumor volume. Intermediate and high-risk patients reconstructed using simple techniques had significantly greater overall complication rates compared to those reconstructed with advanced techniques. Major complications were significantly greater in low-risk patients reconstructed with advanced techniques. CONCLUSIONS: To minimize postoperative wound complications, low-risk patients should receive simple methods of reconstruction, whereas high-risk patients should be reconstructed using advanced techniques.

Microdissected tumor cuboids: a microscale cancer model that retains a complex tumor microenvironment.

Present cancer disease models - typically based on cell cultures and animal models that lack the human tumor microenvironment (TME) - are extremely poor predictors of human disease outcomes. Microscale cancer models that combine the micromanipulation of tissues and fluids offer the exciting possibility of miniaturizing the drug testing workflow, enabling inexpensive, more efficient tests of high clinical biomimicry that maximize the use of scarce human tissue and minimize animal testing. Critically, these microscale models allow for precisely addressing the impact of the structural features of the heterogeneous TME to properly target and understand the contributions of these unique zones to therapeutic response. We have recently developed a precision slicing method that yields large numbers of cuboidal micro-tissues ("cuboids", ∼ (400 µm) 3 ) from a single tumor biopsy. Here we evaluate cuboids from syngeneic mouse tumor models and human tumors, which contain native immune cells, as models for drug and immunotherapy evaluation. We characterize relevant TME parameters, such as their cellular architecture (immune cells and vasculature), cytokine secretion, proteomics profiles, and their response to drug panels in multi-well arrays. Despite the cutting procedure and the time spent in culture (up to 7 days), the cuboids display strong functional responses such as cytokine and drug responses. Overall, our results suggest that cuboids make an excellent model for applications that require the TME, such as immunotherapy drug evaluations, including for clinical trials and personalized oncology approaches.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

Teprotumumab improves light sensitivity in patients with thyroid eye disease.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody, has been shown to significantly reduce the signs of acute and chronic Thyroid Eye Disease (TED). Light sensitivity is a reported symptom in patients with TED. There is a lack of a prospective study that has explored the effects on light sensitivity in a large cohort of patients with acute and chronic TED following treatment with teprotumumab. METHODS: Consecutive patients who were diagnosed with TED and reported light sensitivity at baseline were considered for study eligibility. All patients had measurements of Visual Light Sensitivity Questionnaire-8 (VLSQ-8), proptosis, clinical activity score (CAS), and MRD1 (distance between the upper eyelid margin and corneal reflex, mm) and MRD2 (distance between the lower eyelid margin and corneal reflex, mm) before and after treatment. RESULTS: Ninety patients (41 acute, 49 chronic) met the inclusion criteria. The mean (SD) age was 47.3 (14.3). Eighty-six (95.6%) patients completed all 8 infusions. There was a significant reduction in the total score and across all categories of the VLSQ-8 (p <  0.01 for all). Seventy-two (80%) patients had a clinically significant improvement (≥2 reduction) in at least one category. There was no significant difference in the total VLSQ-8 score between the acute and chronic group (p = 0.8). CONCLUSION: Teprotumumab improves light sensitivity in patients with acute and chronic TED. The results of this study highlight that the improvements in light sensitivity following treatment are not directly related to the mechanical changes in TED, suggesting another underlying mechanism is potentially involved.

Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents.

BACKGROUND AND PURPOSE: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. KEY RESULTS: The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. CONCLUSIONS AND IMPLICATIONS: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.

Temporal variations in the serogroup distribution of invasive meningococcal disease in Quebec, Canada, due to emerging unique clade of serogroup Y strain belonging to the Sequence Type-23 clonal complex.

OBJECTIVE: To identify recent trends in invasive meningococcal diseases (IMD) in Quebec, Canada, with a focus on MenY cases and MenY strains. METHODS: IMD cases and MenY strains from January 1, 2015 to August 11, 2023 were analyzed for clonal analysis and prediction of susceptibility to MenB vaccines. MenY strains of ST-23 CC from Quebec were analyzed with global MenY strains by core-genomic multi-locus sequence typing (cg-MLST). RESULTS: Since 2015 the serogroup distribution of IMD in Quebec has shifted from predominantly MenB to mainly MenY, with most (80.9 %) of the latter belonging to ST-23 CC. The median age of MenY cases due to ST-23 CC were statistically younger than MenY cases due to non-ST-23 CC. MenY of ST-23 CC showed genetic diversity and the major genetic cluster were similar to the Swedish Y1 strain. The increase in invasive MenY disease in Quebec was due to a sub-clade of Lineage 23.1 which caused an elevated proportion of severe disease in young adults. CONCLUSION: The increase in invasive MenY disease in Quebec, Canada was driven by the expansion of a sub-clade of Lineage 23.1 in young adults. Currently available quadrivalent A,C,W,Y-conjugate meningococcal vaccines were predicted to provide protection against these strains.