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INTRODUCTION: We aimed to describe rates and toxicological findings of unintentional opioid and stimulant toxicity deaths, 2012-2021. METHODS: The dataset included accidental deaths determined by the Coroner to be due to opioids or stimulants. We calculated annual crude mortality rates and described combinations of drugs identified in toxicological examinations of these deaths. We described temporal trends in the detection of specific opioids, stimulants, benzodiazepines (including novel benzodiazepines), gabapentinoids and z-drugs in deaths due to opioids and stimulants. RESULTS: Mortality rates increased over time, reaching their peak in 2020 and remaining high in 2021. In deaths due to opioids, there was a decline in the proportion of deaths involving pharmaceutical opioids after 2019, and a corresponding increase in the proportion of deaths with fentanyl detected. Benzodiazepines were often present in deaths due to opioids, with novel benzodiazepines increasing rapidly from 2019 onwards. Cocaine was the most frequently detected drug in deaths due to stimulants, but amphetamine/methamphetamine was detected in around half of all stimulant deaths from 2016 onwards. DISCUSSION AND CONCLUSIONS: Despite availability of a multitude of overdose prevention interventions, mortality rates due to drug toxicity have increased in Québec. Toxicological findings of these deaths suggest concerning shifts in the illicit drug market, with Québec potentially having entered a new era of elevated overdose mortality. Intervention scale-up is essential, but unlikely to be sufficient, to reduce drug-related mortality. Policy reform to address the root causes of drug toxicity deaths, including an unpredictable drug supply, strained health systems and socio-economic precarity, is essential.
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Analgésicos Opioides , Estimulantes del Sistema Nervioso Central , Sobredosis de Droga , Humanos , Analgésicos Opioides/envenenamiento , Quebec/epidemiología , Sobredosis de Droga/mortalidad , Estimulantes del Sistema Nervioso Central/envenenamiento , Estimulantes del Sistema Nervioso Central/efectos adversos , Femenino , Masculino , Adulto , Drogas Ilícitas/envenenamiento , BenzodiazepinasRESUMEN
BACKGROUND: Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients. METHODS: We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival. RESULTS: Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up. CONCLUSION: PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.
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Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Trasplante de Riñón , Complicaciones Posoperatorias , Tumor de Músculo Liso , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Masculino , Femenino , Tumor de Músculo Liso/virología , Tumor de Músculo Liso/etiología , Tumor de Músculo Liso/patología , Tumor de Músculo Liso/diagnóstico , Adulto , Estudios de Seguimiento , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/aislamiento & purificación , Pronóstico , Francia/epidemiología , Adolescente , Adulto Joven , Niño , Complicaciones Posoperatorias/diagnóstico , Rechazo de Injerto/etiología , Fallo Renal Crónico/cirugía , Supervivencia de Injerto , Factores de Riesgo , Pruebas de Función Renal , Tasa de Filtración Glomerular , Tasa de SupervivenciaRESUMEN
BACKGROUND: Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. OBJECTIVE: To describe blood and BM eosinophil characteristics in SM. METHODS: A large collection of BM biopsies was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining, and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. RESULTS: Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in non-advanced-SM (n=37 BM biopsies) compared to both controls (n=8, p=0.0003) and to advanced SM (n=24, p=0.014). In non-advanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r=0.38, p=0.038), eosinophils count in BM biopsies (r=0.45, p=0.007), EPX staining (r=0.37, p=0.035) and eosinophil degranulation (r=0.39, p=0.023). Eosinophil counts in BM biopsies also correlated with MC counts (r=0.47, p=0.006) and KIT staining surface (r=0.49, p=0.003). BM MCs expressed interleukin-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils display several increased surface markers compared to controls, suggesting an activated state. CONCLUSION: Our data suggest a possible crosstalk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in non-advanced-SM not fully controlled by other therapies.
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Introduction: Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs. Methods: We evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, n = 14) or chronic infection (SR/CI, n = 8). Results: Both groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4+CXCR5+PD-1+ICOS+FoxP3-) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19+CD27+IgM-E2-Tet+) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3+CCR6-) subset correlated with the neutralization breadth and potency of NAbs. Conclusion: These results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.
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Hepacivirus , Hepatitis C , Células B de Memoria , Reinfección , Células T Auxiliares Foliculares , Humanos , Hepacivirus/inmunología , Células T Auxiliares Foliculares/inmunología , Masculino , Femenino , Hepatitis C/inmunología , Hepatitis C/virología , Células B de Memoria/inmunología , Adulto , Persona de Mediana Edad , Reinfección/inmunología , Reinfección/virología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Memoria Inmunológica , Anticuerpos contra la Hepatitis C/inmunología , Anticuerpos contra la Hepatitis C/sangre , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Activación de Linfocitos/inmunologíaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) infection is a significant global health burden, particularly among people who inject drugs. Rapid point-of-care HCV testing has emerged as a promising approach to improve HCV detection and linkage to care in harm reduction organizations such as needle and syringe programs. The objective of this study was to use an intersectionality lens to explore the barriers and enablers to point-of-care HCV testing in a needle and syringe program. METHODS: A qualitative study was conducted using semi-structured interviews with clients (people who inject drugs) and service providers in a large community organization focused on the prevention of sexually transmitted and blood borne infections and harm reduction in Montreal, Canada. An intersectionality lens was used alongside the Theoretical Domains Framework to guide the formulation of research questions as well as data collection, analysis, and interpretation. RESULTS: We interviewed 27 participants (15 clients, 12 providers). For clients, four themes emerged: (1) understanding and perceptions of HCV testing, (2) the role of an accessible and inclusive environment, (3) the interplay of emotions and motivations in decision-making, and (4) the impact of intersectional stigma related to HCV, behaviors, and identities. For providers, five themes emerged: (1) knowledge, skills, and confidence for HCV testing, (2) professional roles and their intersection with identity and lived experience, (3) resources and integration of services, (4) social and emotional factors, and (5) behavioral regulation and incentives for HCV testing. Intersectional stigma amplified access, emotional and informational barriers to HCV care for clients. In contrast, identity and lived experience acted as powerful enablers for providers in the provision of HCV care. CONCLUSION: The application of an intersectionality lens provides a nuanced understanding of multilevel barriers and enablers to point-of-care HCV testing. Findings underscore the need for tailored strategies that address stigma, improve provider roles and communication, and foster an inclusive environment for equitable HCV care. Using an intersectionality lens in implementation research can offer valuable insights, guiding the design of equity-focused implementation strategies.
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Hepatitis C , Pruebas en el Punto de Atención , Investigación Cualitativa , Abuso de Sustancias por Vía Intravenosa , Humanos , Hepatitis C/psicología , Femenino , Masculino , Abuso de Sustancias por Vía Intravenosa/psicología , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Persona de Mediana Edad , Programas de Intercambio de Agujas , Accesibilidad a los Servicios de Salud , Canadá , Personal de Salud/psicología , Entrevistas como Asunto , Reducción del Daño , Estigma SocialRESUMEN
Background: Cannabidiol (CBD) has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders, including substance use disorders. Pre-clinical evidence suggests that CBD can increase anandamide (AEA) plasma concentration, possibly mediating some of its therapeutic properties. Whether CBD exerts such an effect on AEA in individuals with cocaine use disorder (CUD) remains unknown. Aims: To explore the sustained effects of daily CBD administration on AEA plasma concentrations compared with placebo in CUD. Methods: We used data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy in CUD. Seventy-eight individuals were randomized to receive a daily oral dose of 800 mg CBD (n = 40) or a placebo (n = 38). Participants stayed in an inpatient detoxification setting for 10 days, after which they were followed in an outpatient setting for 12 weeks. AEA plasma concentration was measured at baseline and at 23-h post CBD ingestion on day 8 and week 4. A generalized estimating equation model was used to assess CBD's effects on AEA, and sensitivity analyses were computed using Bayesian linear regressions. Results: Sixty-four participants were included in the analysis. Similar mean AEA plasma concentrations in both treatment groups (p = 0.357) were observed. At day 8, mean AEA plasma concentrations (± standard deviation) were 0.26 (± 0.07) ng/mL in the CBD group and 0.29 (± 0.08) ng/mL in the placebo group (p = 0.832; Bayes factor [BF] = 0.190). At week 4, they were 0.27 (± 0.09) ng/mL in the CBD group and 0.30 (± 0.09) ng/mL in the placebo group (p = 0.181; BF = 0.194). Conclusion: While not excluding any potential acute and short-term effect, daily CBD administration did not exert a sustained impact on AEA plasma concentrations in individuals with CUD compared with placebo. Registration: clinicaltrials.gov (NCT02559167).
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FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
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Células Asesinas Naturales , Proteínas de la Membrana , Animales , Femenino , Humanos , Masculino , Ratones , Linfocitos B/metabolismo , Linfocitos B/citología , Médula Ósea/metabolismo , Linaje de la Célula , Células Dendríticas/metabolismo , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Células de Langerhans/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Monocitos/metabolismo , Piel/metabolismo , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Limited data exists on psychological impacts of the COVID-19 pandemic among people who use drugs (PWUD). This study aimed to determine the prevalence and correlates of severe psychological distress (PD) among PWUD in Montreal around the beginning of the pandemic. METHODS: We conducted a rapid assessment study from May to December 2020 among PWUD recruited via a community-based cohort of people who inject drugs in Montreal (Hepatitis C cohort [HEPCO], N = 128) and community organisations (N = 98). We analysed self-reported data on changes in drug use behaviours and social determinants since the declaration of COVID-19 as a public health emergency, and assessed past-month PD using the Kessler K6 scale. Multivariable logistic regression was conducted to examine correlates of PD distress (score ≥13). RESULTS: Of 226 survey participants, a quarter (n = 56) were screened positive for severe PD. In multivariable analyses, age (1-year increment) (adjusted odds ratio = 0.94, 95% confidence interval [0.90, 0.98]) and a decrease in non-injection drug use versus no change (0.26 [0.07, 0.92]) were protective against severe PD, while positive associations were found for any alcohol use in the past 6 months (3.73 [1.42, 9.78]), increased food insecurity (2.88 [1.19, 6.93]) and both moving around between neighbourhoods more (8.71 [2.63, 28.88]) and less (3.03 [1.18, 7.74]) often compared to no change. DISCUSSION AND CONCLUSIONS: This study documented a high prevalence of severe PD among PWUD during the COVID-19 pandemic compared with pre-COVID-19 data. Social determinants such as food insecurity and mobility issues, alongside demographic and substance use-related factors, were linked to distress. Evidence-based risk mitigation strategies for this population could reduce negative consequences in future pandemics or disruptions.
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Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.
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Inhibidores mTOR , Mastocitosis Sistémica , Sirolimus , Humanos , Mastocitosis Sistémica/tratamiento farmacológico , Proyectos Piloto , Femenino , Masculino , Persona de Mediana Edad , Adulto , Francia , Anciano , Sirolimus/uso terapéutico , Sirolimus/efectos adversos , Inhibidores mTOR/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Everolimus/uso terapéutico , Everolimus/efectos adversos , Resultado del Tratamiento , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Anciano de 80 o más AñosRESUMEN
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (â¼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition.
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Cromosomas Humanos X , Linfoma Extranodal de Células NK-T , Humanos , Masculino , Femenino , Cromosomas Humanos X/genética , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/virología , Linfoma Extranodal de Células NK-T/patología , Linfoma Extranodal de Células NK-T/metabolismo , Variaciones en el Número de Copia de ADN , Mutación , Persona de Mediana Edad , Animales , Adulto , Ratones , Pronóstico , Anciano , Perfilación de la Expresión Génica , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Adulto Joven , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicacionesRESUMEN
Background: People who inject drugs (PWID) are a priority population in HCV elimination programming. Overcoming sex and gender disparities in HCV risk, prevention, and the cascade of care is likely to be important to achieving this goal, but these have not yet been comprehensively reviewed. Methods: Systematic review and meta-analysis. We searched Pubmed, EMBASE and the Cochrane Database of Systematic Reviews 1 January 2012-22 January 2024 for studies of any design reporting sex or gender differences among PWID in at least one of: sharing of needles and/or syringes, incarceration history, injection while incarcerated, participation in opioid agonist treatment or needle and syringe programs, HCV testing, spontaneous HCV clearance, direct-acting antiviral (DAA) treatment initiation or completion, and sustained virological response (SVR). Assessment of study quality was based on selected aspects of study design. Additional data were requested from study authors. Data were extracted in duplicate and meta-analysed using random effects models. PROSPERO registration CRD42022342806. Findings: 9533 studies were identified and 92 studies were included. Compared to men, women were at greater risk for receptive needle and syringe sharing (past 6-12 months: risk ratio (RR) 1.12; 95% confidence interval (CI) 1.01-1.23; <6 months: RR 1.38; 95% CI 1.09-1.76), less likely to be incarcerated (lifetime RR 0.64; 95% CI 0.57-0.73) more likely to be tested for HCV infection (lifetime RR 1.07; 95% CI 1.01, 1.14), more likely to spontaneously clear infection (RR1.58; 95% CI 1.40-1.79), less likely to initiate DAA treatment (0.84; 95% CI 0.78-0.90), and more likely to attain SVR after completing DAA treatment (RR 1.02; 95% CI 1.01-1.04). Interpretation: There are important differences in HCV risk and cascade of care indicators among people who inject drugs that may impact the effectiveness of prevention and treatment programming. Developing and assessing the effectiveness of gender-specific and gender-responsive HCV interventions should be a priority in elimination programming. Funding: Réseau SIDA-MI du Québec.
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To achieve hepatitis C virus (HCV) elimination, high uptake along the care cascade steps for all will be necessary. We mapped engagement with the care cascade overall and among priority groups in the post-direct-acting antivirals (DAAs) period and assessed if this changed relative to pre-DAAs. We created a population-based cohort of all reported HCV diagnoses in Quebec (1990-2018) and constructed the care cascade [antibody diagnosed, RNA tested, RNA positive, genotyped, treated, sustained virologic response (SVR)] in 2013 and 2018. Characteristics associated with RNA testing and treatment initiation were investigated using marginal logistic models via generalized estimating equations. Of the 31,439 individuals HCV-diagnosed in Quebec since 1990 and alive as of 2018, there was significant progress in engagement with the care cascade post- vs. pre-DAAs; 86% vs. 77% were RNA-tested, and 64% vs. 40% initiated treatment. As of 2018, a higher risk of not being RNA-tested or treated was observed among individuals born <1945 vs. >1965 [hazard ratio (HR); 95% CI; 1.35 (1.16-1.57)], those with material and social deprivation [1.21 (1.06-1.38)], and those with alcohol use disorder [1.21 (1.08-1.360]. Overall, non-immigrants had lower rates of RNA testing [0.76 (0.67-0.85)] and treatment initiation [0.63 (0.57-0.70)] than immigrants. As of 2018, PWID had a lower risk of not being RNA tested [0.67 (0.61-0.85)] but a similar risk of not being treated, compared to non-PWID. Engagement in the HCV care cascade have improved in the post-DAA era, but inequities remain. Vulnerable subgroups, including certain older immigrants, were less likely to have received RNA testing or treatment as of 2018 and would benefit from focused interventions to strengthen these steps.
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Hepatitis C Crónica , Hepatitis C , Humanos , Hepacivirus/genética , Antivirales/uso terapéutico , Estudios Retrospectivos , Hepatitis C Crónica/tratamiento farmacológico , Estudios de Cohortes , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Canadá/epidemiología , ARNRESUMEN
BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.
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Hepatomegalia , Hígado , Mastocitosis Sistémica , Humanos , Mastocitosis Sistémica/patología , Mastocitosis Sistémica/complicaciones , Estudios Retrospectivos , Femenino , Hígado/patología , Masculino , Persona de Mediana Edad , Adulto , Biopsia , Hepatomegalia/patología , Hepatomegalia/etiología , Anciano , Hipertensión Portal/patología , Hipertensión Portal/etiología , Francia , Cirrosis Hepática/patología , Mastocitos/patología , Fosfatasa Alcalina/sangre , PronósticoRESUMEN
BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.
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Metadona , Trastornos Relacionados con Opioides , Humanos , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Combinación Buprenorfina y Naloxona/uso terapéutico , Tratamiento de Sustitución de Opiáceos/métodos , Estado de Salud , Analgésicos Opioides/uso terapéuticoRESUMEN
PURPOSE: This study aimed to identify opioid consumption trajectories among persons living with chronic pain (CP) and put them in relation to patient-reported outcomes 6 months after initiating multidisciplinary pain treatment. METHODS: This study used data from the Quebec Pain Registry (2008-2014) linked to longitudinal Quebec health insurance databases. We included adults diagnosed with CP and covered by the Quebec public prescription drug insurance plan. The daily cumulative opioid doses in the first 6 months after initiating multidisciplinary pain treatment were transformed into morphine milligram equivalents. An individual-centered approach involving principal factor and cluster analyses applied to longitudinal statistical indicators of opioid use was conducted to classify trajectories. Multivariate regression models were applied to evaluate the associations between trajectory group membership and outcomes at 6-month follow-up (pain intensity, pain interference, depression, and physical and mental health-related quality of life). RESULTS: We identified three trajectories of opioid consumption: "no or very low and stable" opioid consumption (n = 2067, 96.3%), "increasing" opioid consumption (n = 40, 1.9%), and "decreasing" opioid consumption (n = 39, 1.8%). Patients in the "no or very low and stable" trajectory were less likely to be current smokers, experience polypharmacy, use opioids or benzodiazepine preceding their first visit, or experience pain interference at treatment initiation. Patients in the "increasing" opioid consumption group had significantly greater depression scores at 6-month compared to patients in the "no or very low and stable" trajectory group. CONCLUSION: Opioid consumption trajectories do not seem to be important determinants of most PROs 6 months after initiating multidisciplinary pain treatment.
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Dolor Crónico , Trastornos Relacionados con Opioides , Adulto , Humanos , Analgésicos Opioides/uso terapéutico , Calidad de Vida , Trastornos Relacionados con Opioides/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/epidemiología , Medición de Resultados Informados por el PacienteRESUMEN
BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.
Asunto(s)
Anafilaxia , Mastocitosis Sistémica , Mastocitosis , Humanos , Mastocitosis Sistémica/epidemiología , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Estudios Retrospectivos , Prevalencia , Mastocitosis/epidemiología , Mastocitosis/genética , Mastocitosis/patología , Anafilaxia/patología , Mastocitos/patología , Triptasas/genéticaRESUMEN
IMPORTANCE: Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) can control virus replication and prolong the life of people living with HIV (PLWH). However, the virus remains dormant within immune cells in what is called the HIV reservoir. Furthermore, 2.3 million PLWH are also coinfected with hepatitis C virus (HCV) and are at risk of developing chronic liver disease and cancer. HCV treatment with direct acting antivirals (DAA) can completely cure the infection in more than 95% of treated individuals and improve their long-term health outcomes. In this study, we investigated how HCV treatment and cure affect the HIV reservoir. We demonstrate the beneficial impact of DAA treatment as it reduces the HIV reservoirs in particular in people infected with HCV before HIV. These results support the need for early ART and DAA treatment in HIV/HCV coinfections.
Asunto(s)
Antivirales , Coinfección , Infecciones por VIH , Hepatitis C Crónica , Hepatitis C , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Hepacivirus/fisiología , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , VIH/fisiología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: Detecting hepatitis C virus (HCV) reinfection among key populations helps prevent ongoing transmission. This systematic review aims to determine the association between different testing intervals during post-SVR follow-up on the detection of HCV reinfection among highest risk populations. METHODS: We searched electronic databases between January 2014 and February 2023 for studies that tested individuals at risk for HCV reinfection at discrete testing intervals and reported HCV reinfection incidence among key populations. Pooled estimates of reinfection incidence were calculated by population and testing frequency using random-effects meta-analysis. RESULTS: Forty-one single-armed observational studies (9453 individuals) were included. Thirty-eight studies (8931 individuals) reported HCV reinfection incidence rate and were included in meta-analyses. The overall pooled estimate of HCV reinfection incidence rate was 4.13 per 100 per person-years (py) (95% confidence interval [CI]: 3.45-4.81). The pooled incidence estimate among people who inject drugs (PWID) was 2.84 per 100 py (95% CI: 2.19-3.50), among men who have sex with men (MSM) 7.37 per 100 py (95% CI: 5.09-9.65) and among people in custodial settings 7.23 per 100 py (95% CI: 2.13-16.59). The pooled incidence estimate for studies reporting a testing interval of ≤6 months (4.26 per 100 py; 95% CI: 2.86-5.65) was higher than studies reporting testing intervals >6 months (5.19 per 100 py; 95% CI: 3.92-6.46). CONCLUSIONS: HCV reinfection incidence was highest in studies of MSM and did not appear to change with retesting interval. Shorter testing intervals are likely to identify more reinfections, help prevent onward transmission where treatment is available and enable progress towards global HCV elimination, but additional comparative studies are required.