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The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Chronic kidney disease (CKD) is common and ranks among the leading causes of mortality and morbidity. This analysis aimed to present global CKD estimates using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 to inform evidence-based policies for CKD identification and treatment. This analysis focused on adults aged 20 years and older over the period 1990 to 2023, from 204 countries and territories. Data sources used were published literature, vital registration systems, kidney failure treatment registries, and household surveys. Estimates of CKD burden, including deaths, incidence, prevalence, and disability-adjusted life-years (DALYs), were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool. A comparative risk assessment approach estimated the proportion of cardiovascular deaths attributable to impaired kidney function and estimated risk factors for CKD. Globally, in 2023, 788 million (95% uncertainty interval 743-843) people aged 20 years and older were estimated to have CKD, up from 378 million (354-407) in 1990. The global age-standardised prevalence of CKD in adults was 14·2% (13·4-15·2), a relative rise of 3·5% (2·7-4·1) from 1990. The region with the highest age-standardised prevalence was north Africa and the Middle East (18·0%; 16·9-19·4). Most people had stage 1-3 CKD, with a combined prevalence of 13·9% (13·1-15·0). In 2023, CKD was the ninth leading cause of death globally, accounting for 1·48 million (1·30-1·65) deaths, and the 12th leading cause of DALYs, with an age-standardised DALY rate of 769·2 (691·8-857·4) per 100 000. Impaired kidney function as a risk factor accounted for 11·5% (8·4-14·5) of cardiovascular deaths. High fasting plasma glucose, body-mass index, and systolic blood pressure were all leading risk factors for CKD DALYs. CKD is a major global health issue, with rising prevalence and increasing importance as a cause of death and as a risk factor for cardiovascular death. A better understating of aetiology, appropriate screening, and implementation programmes are needed to translate advances in CKD treatment into improved patient outcomes. Gates Foundation, Wellcome, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.
Obesity, type 2 diabetes (T2D), and cardiovascular disease are closely related conditions contributing to the global rise in cardiometabolic disease. Incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have emerged as critical regulators of glucose metabolism, pancreatic function, and cardiovascular physiology. However, despite increasing clinical use of GLP-1 receptor agonists and dual GLP-1/GIP agonists, the precise mechanisms by which endogenous incretins influence cardiovascular tissues remain incompletely understood, particularly in the context of obesity and T2D. This review explores the signalling mechanisms and physiological actions of natural endogenous GLP-1 and GIP, with a focus on cardiovascular physiology. Endogenous GLP-1 promotes insulin secretion, β-cell survival, and appetite suppression, and exerts protective effects on the endothelium. GLP-1 also reduces inflammation, enhances nitric oxide production, and improves myocardial glucose utilization during ischemia. Endogenous GIP is involved in insulin secretion, β-cell survival, and adipogenesis. In obesity and T2D, incretin secretion and insulinotropic effects are altered. The therapeutic potential of GLP-1 receptor agonists and emerging dual GLP-1/GIP agonists has been shown to aid in managing metabolic dysfunction and, more recently, in preventing cardiovascular complications.
Despite restoration of systemic and pulmonary circulation and normalized oxygen saturation, patients with Fontan circulation experience frailty, exercise intolerance, and impaired exercise hemodynamics. Altered cytokine-chemokine profiles have been reported, but their relationship with Fontan pathophysiology remains poorly defined. Adult Fontan patients and matched controls were assessed for frailty, cardiopulmonary exercise capacity, and resting/exercise-augmented hemodynamics. Plasma cytokine-chemokine concentrations were measured using multiplex ELISA. Twenty Fontan patients (mean age 28.8 ± 9.8 years; 35% female) and 20 controls (29.7 ± 6.0 years; 30% female) were studied. Fontan patients had longer 5 × sit-to-stand test (9.6 ± 3.1 vs. 5.7 ± 1.3 s; p < 0.0001), lower VO2max (% predicted), and reduced stroke index, cardiac index, and cardiac power index. TNF-α, IL-1β, IL-6, IFN-γ, IL-8, IP-10, MCP-1, and SDF-1α were elevated in Fontan patients, while IL-10 and MIP-1α were not different. SDF-1α and IP-10 correlated with frailty, impaired oxygen uptake, and hemodynamic parameters. Elevated SDF-1α and IP-10 are associated with frailty and impaired exercise hemodynamics in Fontan patients. These novel findings suggest a role for inflammation in Fontan-associated dysfunction and warrant further investigation.
Alzheimer's disease is the most common form of dementia, primarily affecting the elderly population. It is a progressive neurodegenerative disease with key pathogenesis hallmarks being amyloid-beta plaque accumulation, and neurofibrillary tangles of tau protein. With an increasingly aging population and rising numbers of surgical procedures, growing interest has been directed towards the potential impact of inhalational anesthetics, particularly isoflurane, sevoflurane and desflurane, in contributing to the neurodegenerative process. Evidence supporting anesthetic-related modulation of Alzheimer's disease pathways is derived predominantly from in vitro and animal models, with comparatively limited and heterogeneous human biomarker and clinical data. This review will explore the various mechanisms by which these volatile anesthetics contribute to the pathogenesis of neurodegeneration in the context of AD. This includes upregulation of beta-secretase 1 resulting in the formation of amyloid-beta oligomers and inhibition of tau dephosphorylation. While certain studies point towards a neuroprotective effect of these anesthetics, the evidence remains inconsistent. Collectively, these findings support perioperative strategies focused on maintenance of normothermia, optimization of oxygenation, and judicious anesthetic exposure as practical measures to mitigate vulnerability in at-risk populations.
Management of metabolic dysfunction-associated steatotic liver disease (MASLD) remains a significant clinical challenge. This study evaluated the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapy to metformin in the treatment of MASLD using an experimentally induced type 2 diabetes (T2D) rat model. T2D was induced in 18 rats through a high-fat diet combined with a low dose of streptozotocin. The diabetic rats were then randomly allocated into three equal groups: untreated, metformin-treated, and metformin/CoQ10-treated. An additional six rats maintained on a normal chow diet served as the control group. Development of MASLD was confirmed through biochemical assays and histopathological analyses. Liver histology and electron microscopy were performed, along with immunohistochemistry for BAX and CD68 markers. Our results demonstrated that T2D rats exhibited impaired glucose and lipid profiles, elevated liver enzymes, and reduced adiponectin levels. These alterations were accompanied by hepatic oxidative stress, histopathological features of MASLD, fibrosis, and increased expression of BAX and CD68. Treatment with either metformin monotherapy or metformin/CoQ10 combination therapy significantly ameliorated the biochemical and histopathological manifestations of MASLD, as well as reduced the expression of BAX and CD68 in the liver. Importantly, combined metformin/CoQ10 therapy exerted a stronger hepatoprotective effect than metformin alone.
The aim of the study was to follow the impact of cystectomy and compare bipolar and laser electrocoagulation on prooxidative stress biomarkers and antioxidative capacity. A total of 60 women with diagnosed endometriosis were included in the study and divided in two groups according to laparoscopy treatment with different energy sources for electrocoagulation. Prooxidative parameters (superoxide anion radical (O2-), nitrites (NO2-), hydrogen peroxide (H2O2), index of lipid peroxidation measured as thiobarbituric acid reactive substances) and antioxidative defence system parameters (reduced glutathione (GSH), activity of superoxide dismutase (SOD), and activity of catalase (CAT)) were determined spectrophotometrically before and after the surgery. The value of H2O2 was decreased in group treated with biporal electrocoagulation, while the value of GSH was increased in both groups. The value of O2- was significantly decreased in the group treated with laser, while SOD activity was increased in the same group. Both methods had a similar effect on index of lipid peroxidase and reduced glutathione, but when it comes to the decreasing of harmful superoxide anion radical and increasing of SOD activity, laser electrocoagulation showed better outcome. The role of oxidative stress in both understanding the pathogenesis of this disease and as a potential therapeutic target is certainly of great importance.
Cognitive performance in people with epilepsy (PwE) and the optimal approach to cognitive testing requires further investigation. The primary objective of this study was to assess the feasibility of using Creyos in PwE, a reliable and validated online cognitive battery. Our exploratory secondary analyses included comparing PwE's performance to age- and sex-matched norms and their performance on the online battery to performance on the Telephone Interview for Cognitive Status (TICS), functioning scales, and the Quality of Life in Neurological Disorders (Neuro-QOL) questionnaire. Participants (N = 48; 94% with drug-resistant epilepsy) underwent the battery on a tablet, which met feasibility criteria (93% consent rate, 94% completion rate). Participants performed worse than matched norms on 11 of the 12 battery's tests and its three domains: short-term memory, reasoning abilities and verbal processing (p < 0.01). Scores on the overall battery and TICS were moderately correlated (r = 0.50, p < 0.001) but there was negligible agreement (κ = 0.19, 95% CI = -0.04-0.41). There were no associations between patient characteristics and mild (Z ≤ -1) or marked (Z ≤ -1.5) impairment on the battery or International Classification for Cognitive Disorders in Epilepsy domains, except for executive functioning and age of epilepsy onset (p < 0.05). On the Neuro-QOL, participants (N = 42) scored significantly worse than the reference population on satisfaction with social roles/activities, subjective cognitive functioning, and anxiety. Most participants (64%) underestimated their cognitive abilities. Overall, this study was the first to establish feasibility of this online cognitive battery in PwE and provided further insight into the cognitive performance and QOL of people with drug-resistant epilepsy.
Allergic rhinitis (AR) impacts quality of life, work and school productivity. Over the last years, an important body of evidence resulting from mHealth data has led to a better understanding of AR. Such advances have motivated an EAACI-endorsed update of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (ARIA 2024-2025). This manuscript presents the ARIA 2024-2025 recommendations for intranasal treatments, one of the mainstays for AR management. The ARIA 2024-2025 guideline panel issued recommendations following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework. Several sources of evidence were used to inform panel judgments and recommendations, including systematic reviews, evaluation of mHealth and pharmacovigilance data, as well as a survey of experts on costs. Eleven guideline questions concerning intranasal treatments for AR were prioritized, leading to recommendations. Overall, these questions concern the choice between different classes of intranasal medications-most notably, intranasal corticosteroids (INCS), antihistamines (INAH), fixed combinations of INAH+INCS and decongestants-or between different individual medications within each class. Four questions had not been evaluated in previous ARIA guidelines, while for the other three there was a change in the strength or directionality of recommendations. Overall, recommendations point to the suggested use of INAH+INCS over INAH or INCS and INCS over INAH. This ARIA 2024-2025 article supports patients, their caregivers, and healthcare professionals in choosing an intranasal treatment. However, decisions on AR treatment should consider the clinical variability of the disease, patients' values, and the affordability of medications.
Caenorhabditis elegans has many traits that make it a valuable model for human neurobiology, including the study of pain-related processes. In particular, its genetic tractability can help uncover novel genetic factors involved in pain-related signal transduction. This can be beneficial for studying pain medications, such as cannabinoids and opioids. Here, we review how the pain-related impacts of cannabinoids/opioids have been assessed using behavioural assays (e.g., measuring feeding, locomotion, and nociception). Reviewed studies identified genetic factors responsible for both cannabinoid (e.g., endocannabinoid receptor npr-19) and opioid (e.g., opioid receptor npr-17) signalling, which were in turn used to characterize neurotransmission (e.g., monoaminergic, neuropeptidergic, and Hedgehog signalling) and complex modulators (e.g., TRP channels involved in cannabinoid signalling) contributing to cannabinoid/opioid signalling. Additionally, studies using these models were able to discover novel genetic components, including frpr-13 (orthologous to human GRP139), involved in opioid sensitivity, and ptr-25 (orthologous to human PTCHD1), involved in opioid tolerance. The pathways highlighted in this review represent clear paths for further investigation of the genetic mechanisms underlying individual differences in pain sensitivity, pain relief, and drug tolerance. Overall, this review demonstrates the value of C. elegans as a model for uncovering the genetic underpinnings of pain and its management.
The treatment of metabolic syndrome (MS), characterized by type 2 diabetes, obesity, dyslipidemias, and cardiovascular problems, requires integral treatment. In addition to its central activity, serotonin also has peripheral effects, implying regulation of blood glucose and insulin levels. Indorenate is a serotonin analog with antihypertensive properties and possible activity on the metabolism of carbohydrates. However, its effect on glucose levels has not been explored, which is relevant in searching for the indorenate's potential as an alternative to treatment of MS. This investigation aimed to study the effects of indorenate on glycemia through in vivo and in silico assays. In normal rats, indorenate was co-administrated with two serotoninergic antagonists: pelanserin (5-HT2a antagonist) and WAY-100635 (5-HT1a antagonist). Indorenate caused a hypoglycemic effect in normal rats. Pelanserin and WAY-100635 inhibited this effect. In diabetic rats, indorenate increased insulin levels. In addition, indorenate decreased glycemia in an euglycemic clamp test, while pelanserin inhibited this effect. In silico, indorenate exhibited a higher affinity and interactions than serotonin for 5-HT2a and 5HT1a receptors. The data suggest that the hypoglycemic effect of indorenate requires the participation of the 5-HT2a receptor and partially of the 5-HT1a receptor. Finding drugs with beneficial multimodal effects for blood pressure and glycemic control, such as indorenate, might be relevant for treating MS and its associated pathologies.
Incretin therapies have emerged as key interventions for glycemic control and weight reduction and are now among Canada's costliest outpatient drug classes. This review synthesizes current clinical and economic evidence on the cost-effectiveness of incretin-based therapies. These include glucagon-like peptide-1 receptor agonists (GLP-1RAs; e.g., semaglutide) and dual agonists (e.g., tirzepatide) targeting both glucose-dependent insulinotropic polypeptide and GLP-1 receptors, in patients with type 2 diabetes mellitus or for weight loss. We review data from clinical trials and recent Canadian and international economic models, identify emerging indications, and discuss limitations in current health-technology assessment frameworks. Implications for Canadian reimbursement are highlighted, with attention to price, patient selection, and outcome considerations.
Cardiovascular autonomic dysfunction (CVAD) is a prevalent yet underrecognized nonmotor manifestation of Parkinson's disease (PD) that adversely affects morbidity, prognosis, and quality of life. Framed by the heart-brain axis, this review examines bidirectional interactions between neurodegeneration and cardiovascular control, synthesizing clinical and preclinical evidence from 2015 to 2025. We searched PubMed for English-language studies addressing autonomic involvement in PD and cardiovascular outcomes; of 1035 records identified, more than 240 met inclusion criteria following removal of duplicates, commentaries, and off-topic articles. Consistent clinical observations include orthostatic hypotension, diminished heart rate variability, impaired baroreflex sensitivity, and blood pressure lability, though heterogeneity in acquisition protocols and analytics limits comparability. Experimental models reveal mechanistic leads but often lack integration of central and peripheral endpoints, sex-inclusive cohorts, aging variables, and longitudinal designs. We highlight methodological constraints, particularly the interpretive limits of HRV, anesthesia effects in preclinical work, and inconsistent preprocessing, and outline priorities for standardized, multimodal approaches that couple neural markers with cardiovascular readouts. Advancing an integrative, translational framework may enable earlier diagnosis, robust autonomic biomarkers, risk stratification across "body-first" and "brain-first" trajectories, and targeted interventions, including neuromodulation and metabolic strategies, aimed at mitigating CVAD and potentially modifying PD progression.
In view of the well-known anti-inflammatory property of roxithromycin, the present study was carried out to evaluate its efficacy in ameliorating prostate inflammation-induced chronic pelvic pain in rat model. Inflammation was induced by single intraprostatic injection of carrageenan where a time course study revealed a peak histology score on day 14. The efficacy study was carried out in four sets of rats, each comprising five groups, which included respective normal and experimental controls (NC, EC). The drugs (roxithromycin 5 and 20 mg/kg, diclofenac 5 mg/kg) were given daily orally and pain score and body weight were evaluated at different time intervals. The prostatic index, vascular permeability, tissue levels of TNF-α and PGE2, thiobarbituric acid reactive substances, glutathione and superoxide dismutase, histology score, and immunoreactivity of COX-2 and iNOS were evaluated on day 14. Like diclofenac, roxithromycin decreased pain score and the rats gained weight during the study period as compared to the EC group. The beneficial effect of roxithromycin was also evident from the dose-dependent restoration of markers of inflammation and oxidative stress. This study shows that by alleviating pain and suppressing inflammation and oxidative stress, roxithromycin has a potential to provide relief in prostatitis.
Human genome- and transcriptome-wide analyses revealed that 56% of heart failure cases have unknown causes. Interestingly, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is one of those causes. Previously, we have shown a robust increase in the degradation of a disintegrin and metalloproteinase (ADAM) and connexin-43 (Cx43) in human end-stage heart failure with reduced ejection fraction (HFrEF). We also observed Cx43 degradation and blood-heart barrier leakage during HFrEF in mice. Although Cx43 coordinates mitochondrial fusion-fission with myocyte contraction-relaxation, respectively, the mechanism is unclear. Interestingly, inhibition of mitochondrial ATP citrate lyase (ACYLi, a lipid-lowering agent) causes HFpEF, but its role in HFrEF is unknown. We hypothesize that during HFrEF, activation of ADAMTS1 degrades Cx43, causing dyssynchronous endothelial-myocyte-mitochondrial contraction coupling, as well as myocyte slippage during contraction and HFrEF. Because HFrEF is more prevalent in males than females, we created chronic cardiopulmonary volume overload by aorta-vena cava fistula (AVF) below the kidney in male wild-type (C57BL/6J) mice aged 12 weeks. By serial echocardiography, we observed HFrEF after 16 weeks. The ADAMTS1 inhibitor (epigallocatechin gallate) or ACYLi (hydroxycitric acid lactone) was administered in drinking water at the same time as AVF. Also, to assess interoceptive inhibition via Piezo channels, we ganglionally denervated the heart prior to AVF. By gel-specific substrate zymography, we measured NGAL, MMP2, MMP9, ADAMTS1, ADAMTS14, and TMPRSS2. The levels of Cx43, ADAMTS1, mitochondrial Drp1 (fission protein), and ACYL were measured by Western blot analysis. The results suggest that ADAMTS1 is activated during HFrEF. Connexin-43 degradation and mitochondrial mitophagy were increased by an increase in Drp1. The therapeutic effects of ADAMTS1 and ACYL inhibitors for systolic HFrEF are suggested.
We previously showed that male rats develop more severe cardiac hypertrophy than female rats following abdominal aortic constriction (AAC) and highlighted corresponding changes in cardiac cytochrome P450 (CYP) enzymes and their arachidonic acid (AA) metabolites. In this study, we report sex-specific changes in renal CYP enzymes and AA metabolites after AAC. Kidneys were isolated from adult male and female Sprague-Dawley rats 5 weeks after sham or AAC surgeries. Renal CYP, lipoxygenase, and epoxide hydrolase enzyme levels were measured by PCR and Western blot, and renal microsomal formation of hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) was measured by liquid chromatography-tandem mass spectrometry. Protein levels of CYP2E1 and CYP4F were significantly elevated post-AAC only in female rats, paralleled by a significant increase in their respective metabolites, 19(R)-HETE and 20-HETE. On the other hand, CYP2C23 mRNA levels were significantly decreased only in male rats, with no significant decrease in EETs. Our findings indicate that renal CYP-mediated AA metabolism undergoes sex-specific reprogramming in response to cardiac pressure overload, which may contribute to the observed divergent cardiac remodeling. This research highlights the importance of the kidney-heart axis and supports the potential for sex-specific metabolic targets in the treatment of cardiovascular diseases.
This study evaluated the presence of bacterial species in the placenta of women with pre-eclampsia and compared with that of normotensive women. One hundred and twenty participants, comprising 60 pre-eclamptic (30 early- and late-onset, respectively) and 60 age-matched normotensive women (30 early and late-gestation normotensive, respectively) were recruited. After informed consent was obtained, the placenta were obtained through caesarean section with sterile and standardized clinical procedures. DNA was extracted from each tissue, and the samples were pooled into six libraries and sequenced on Illumina NextSeq500 using a shotgun metagenomic approach. Bioinformatics was used to analyse the reads with the implementation of Kraken2/MetaPhlAn classification methods and complemented by multi-layered contamination assessment strategy that included frequency-based decontam filtering. Most reads were classified as belonging to the phyla Cutibacterium acnes, Staphylococcus epidermidis, and various Bradyrhizobium species. PE samples showed notable Corynebacterium tuberculostearicum and Pseudomonas species, while Bradyrhizobium and Cutibacterium acnes dominated normotensive samples. Further analysis showed no significant difference between bacterial species of pre-eclamptic and normotensive placental samples. The results show very low levels of bacteria in the placental samples. In addition, a little difference was observed between the bacterial compositions of pre-eclamptic and age-matched normotensive placental tissues, but not statistically significant.
Opioid agonist treatment (OAT) is the recommended first-line therapy for individuals with opioid use disorder. The availability of different products and prescribing guidance for OAT has rapidly evolved in recent years. Therefore, we conducted a repeated cross-sectional study using pharmacy dispensing data from six Canadian provinces to examine trends in methadone and buprenorphine use between January 2018 and December 2022. Monthly population-adjusted rates of OAT recipients were calculated by province, and annual cohorts were stratified by demographic characteristics and OAT type. Prevalence of OAT use varied across provinces, ranging from 1.03 per 1000 in Quebec to 3.59 per 1000 in British Columbia. Increases in OAT use between 2018 and 2022 were observed in Alberta (3.00-3.75 per 1000) and Manitoba (1.68-2.39 per 1000), while rates remained relatively stable elsewhere. OAT use was highest among adults aged 25-44 years, males, and residents of lower-income neighbourhoods. A notable shift toward buprenorphine prescribing was observed across all provinces, with 45%-74% of OAT recipients dispensed a buprenorphine product in 2022. These cross-provincial differences in OAT rates likely reflect variations in opioid use disorder prevalence, prescribing practices, and access to care.
Breast cancer affects one in eight Canadian women over their lifetime. Triple-negative breast cancer (TNBC) represents 10%-20% of all advanced stage breast cancers, often developing multidrug resistance (MDR), commonly resulting in treatment failure. Jadomycin B (JB), a natural product of Streptomyces venezuelae, maintains cytotoxicity against MDR TNBCs, and its activity is enhanced when combined with selective cyclooxygenase-2 inhibitor, celecoxib (CXB) in vitro. Our objectives were to evaluate the toxicity and anticancer effects of JB combined with CXB using zebrafish larval xenografts as a model system. Fluorescent human TNBC MDA-MB-231 cells (231-enhanced green fluorescent protein (EGFP)) were generated and characterized for zebrafish larval xenografts. A maximum tolerated dose (MTD) in zebrafish larvae were determined for JB (20 µM) and CXB (5 µM). Zebrafish embryos were xenotransplanted with 50-100 231-EGFP cells and treated with the MTDs of JB and CXB alone or in combination. The combination of JB and CXB resulted in a 75% reduction in 231-EGFP fluorescence intensity, significantly higher than reductions caused by either drug alone (39% for JB, 15% for CXB) (p < 0.05). This study demonstrates that combining JB with CXB enhances anticancer activity in a zebrafish larval xenograft model of human TNBC, validating effects previously determined in vitro.
Hypertrophic cardiomyopathy (HCM) is a relatively common heritable cardiac condition (∼1 in 500), which poses significant morbidity and mortality. Severe symptoms are often from dynamic left ventricular outflow tract (LVOT) obstruction which may result in dyspnea, chest pain, fatigue, and (pre)syncope. This obstructive phenotype is present in more than half of cases. Traditional pharmacological therapies used to treat symptomatic LVOT obstruction are ineffective in many patients thereby necessitating septal reduction therapy in the form of alcohol septal ablation or surgical myectomy. In recent years, the demand for improved HCM treatment without surgical intervention has led to the development of a new class of drugs called cardiac myosin inhibitors. Mavacamten represents the first-in-class cardiac myosin inhibitor, which is now approved in Canada, available for special authorization cost coverage in most provinces, and is increasingly being prescribed in both specialized HCM programs and general cardiology clinics. As such, many general cardiologists, internists, and family physicians will need to be familiar with these agents. This review on the myosin inhibitors, particularly mavacamten, provides a perspective for more general cardiovascular providers by summarizing the key mechanisms, clinical trials, expected outcomes, and potential impacts on the Canadian healthcare system.