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Lung megakaryocytes (Mks) are largely extravascular with an immune phenotype (1). Because bone marrow (BM) Mks are short lived, it has been assumed that extravascular lung Mks are constantly 'seeded' from the BM. To investigate lung Mk origins and how origin affects their functions, we developed methods to specifically label lung Mks using CFSE dye and biotin delivered via the oropharyngeal route. Labeled lung Mks were present for up to 4 months, while BM Mks had a lifespan of less than 1 week. In a parabiosis model, lung Mks were partially replaced over 1 month from a circulating source. Unlike tissue-resident macrophages, using [MDS1.sup.-Cre-ERT2] TdTomato mice, we found that lung Mks arose from hematopoietic stem cells. However, studies with FlkSwitch mTmG mice showed that lung Mks were derived from a Flt3-independent lineage that did not go through a multipotent progenitor. CFSE labeling to track lung Mk-derived platelets showed that approximately 10% of circulating platelets were derived from lung-resident Mks at steady state, but in sterile thrombocytopenia this was doubled (~20%). Lung-derived platelets were similarly increased in a malaria infection model (Plasmodium yoelii) typified by thrombocytopenia. These studies indicate that lung Mks arise from a Flt3- BM source, are long-lived, and contribute more platelets during thrombocytopenia., Introduction Platelets serve dual roles as a critical component of clot formation and as regulators of immune responses (1, 2). Activated platelets promote inflammation, while circulating resting platelets limit inflammation [...]

Introdução O emicizumabe é um anticorpo biespecífico recomendado para profilaxia contra sangramentos em pessoas com hemofilia A sem (PcHA) ou com inibidores (PcHAi). No Brasil, o emicizumabe foi incorporado pela CONITEC em 2019 para profilaxia de PcHAi que falharam à terapia de imunotolerância. A incorporação, no entanto, envolveu algumas incertezas, tendo em vista que o ensaio pivoral do medicamento não apresentava comparador ativo e o tempo de acompanhamento foi restrito. A avaliação de desempenho de tecnologias em saúde é uma importante ferramenta para a análise pós-incorporações, em especial para avaliar se os resultados de eficácia, provenientens dos estudos pivotais, se traduzem em efetividade, em cenário de mundo real. Objetivo: Avaliar o desempenho do emicizumabe, considerando como desfecho a taxa anualizada de sangramentos tratados (TAS) um ano antes e durante o primeiro ano de profilaxia com emicizumabe, para PcHAi que falharam a imunotolerância, conforme estabelecido pelo Protocolo Clínico do Ministério da Saúde. Métodos O Registro Brasileiro de Emicizumabe (Projeto EmCase) é uma coorte retrospectiva e prospectiva, que acompanha PcHAi desde o início do uso do medicamento, além de avaliar os dados clínicos de 12 meses anteriores ao uso de emicizumabe. Participam do estudo, até o momento, 63 PcHA de 19 Centros de Tratamento de Hemofilia (CTH) de todo o Brasil. Dados clínicos do tratamento anterior (12 meses) e durante (12 meses) a profilaxia com emicizumabe foram coletados. Avaliaram-se as TAS para sangramento total e espontâneo. Também foi avaliada a frequência de PcHAi com sangramento zero. Resultados No momento da escrita deste resumo, 32 PcHAi registradas em 11 CTH tinham pelo menos 1 ano de profilaxia com emicizumabe. Desse total, 22/32 (69%) tinham hemofilia A grave. Antes de iniciar o emicizumabe, 27/32 (85%) PcHAi estavam em profilaxia, 5/32 (15%) recebiam exclusivamente tratamento episódico e todos recebiam agentes de bypass. A idade mediana no início do emicizumabe foi 10 anos (intervalo 1-71). O ataque de emicizumabe prescrito foi 3 mg/kg/semana ao longo de 4 semanas. O esquema de manutenção mais prescrito foi 1,5 mg/kg/semana (18/32; 56%). A duração mediana da profilaxia com emicizumabe foi 651 dias (intervalo 627- 686). Entre as PcHAi tratadas com profilaxia com agente de bypass antes de iniciar emicizumabe (n = 27), as medianas (intervalos interquartis; intervalo) da TAS-total reduziram de 3 (0,3-4; 0-16) para 0 (0-0; 0-2) e da TAS- espontânea reduziram de 0 (0-1; 0-10) para 0 (0-0; 0-1), entre o período pré-emicizumabe e o primeiro ano de uso de emicizumabe, respectivamente. O número de PcHA com zero sangramento aumentou de 7/26 (27%) para 21/26 (81%), respectivamente. Entre as PcHAi tratadas exclusivamente sob demanda e antes de iniciar emicizumabe (n = 5), as medianas (intervalos interquartis; intervalo) da TAS-total reduziram de 2 (1-12; 0-12) para 0 (0- 0; 0-1) e da TAS-espontânea reduziram de 1 (0-0; 0-12) para 0 (0-0; 0-0), entre o período pré-emicizumabe e no primeiro ano de uso de emicizumabe, respectivamente. O número de PcHA com zero após uso profilático de emicizumabe foi de 4/5 (80%). Nenhuma das PcHAi que utilizaram by pass sob demanda não apresentaram número de sangramentos zero. Não foram relatados eventos adversos ao emicizumabe no primeiro ano de acompanhamento. Discussão e conclusões TAS-total e TAS-espontânea foram reduzidas e o número de PcHAi com sangramentos zero aumentou durante a profilaxia com emicizumabe, em comparação com a profilaxia anterior, entre PcHAi. A avaliação de desempenho do emicizumabe tem mostrado bons resultados entre PcHAi. Houve, em 2023, a ampliação do grupo elegível para uso do medicamento e, com isso, faz-se neessária a continuidade do estudo, para a avaliação do uso em cenário de mundo real.

ABSTRACTIndonesia has an abundance of pigmented rice cultivars with high nutritional value. The purpose of this study was to identify and characterize the phytochemical profiles, anthocyanin properties, and biological activities of endogenous Indonesian black rice (Oryza sativa L.) cultivars from Java and East Nusa Tenggara (NTT) Islands. Thirteen black rice cultivars from eastern Nusa Tenggara and West, Central, and East Java were examined. The secondary metabolites of the black rice samples included flavonoids, tannins, phenolics, quinones, glycosides, anthraquinones, leucoanthocyanidins, alkaloids, and proteins. According to the FRAP (ferric reducing antioxidant power) assay, various levels of antioxidant activity were present. The results of an alpha amylase inhibition assay indicated that the black rice samples might have antidiabetic properties. We conclude that the Java and NTT endogenous black rice cultivars have rich phytochemical compounds with high nutritional value, and that their antioxidant and antidiabetic biological activities can promote a healthy life.

Abstract Background British Columbia (BC) has been facing a public health emergency of overdose since 2016, with rural regions of the province facing the highest rates of death. Peers (in this case, people with lived experience of substance use) are known to be effective patient navigators in health systems and can play a role in connecting patients to care and reducing overdose risk. Case presentation We outline a peer-led program focused on opioid agonist treatment and prescribed safe supply medication delivery that began in March 2020 at a clinic in rural BC. The peer takes an Indigenous harm reduction approach and is focused on meeting the needs of the whole person. The peer has regular contact with approximately 50 clients and navigates medication delivery and appointments for approximately 10–15 people each day. Clients have been retained on the medication, and experienced improvement in other outcomes, including securing housing, employment and managing acute and chronic health conditions. The peer has established contact with clients since March 2020 to support engagement with health care and continuity of medication access. This program highlights the importance and value of peer-led work and need for further investments in peer-led programs to respond to the unregulated drug poisoning crisis. Conclusions This peer-led intervention is a promising approach to engaging people who remain disconnected from health services in care in a rural community. This model could be adapted to other settings to support patient contact with the health system and medication access and continuity, with the ultimate goal of reducing overdose risk.

Abstract Background Encephalopathy can occur from a non-fatal toxic drug event (overdose) which results in a partial or complete loss of oxygen to the brain, or due to long-term substance use issues. It can be categorized as a non-traumatic acquired brain injury or toxic encephalopathy. In the context of the drug toxicity crisis in British Columbia (BC), Canada, measuring the co-occurrence of encephalopathy and drug toxicity is challenging due to lack of standardized screening. We aimed to estimate the prevalence of encephalopathy among people who experienced a toxic drug event and examine the association between toxic drug events and encephalopathy. Methods Using a 20% random sample of BC residents from administrative health data, we conducted a cross-sectional analysis. Toxic drug events were identified using the BC Provincial Overdose Cohort definition and encephalopathy was identified using ICD codes from hospitalization, emergency department, and primary care records between January 1st 2015 and December 31st 2019. Unadjusted and adjusted log-binomial regression models were employed to estimate the risk of encephalopathy among people who had a toxic drug event compared to people who did not experience a toxic drug event. Results Among people with encephalopathy, 14.6% (n = 54) had one or more drug toxicity events between 2015 and 2019. After adjusting for sex, age, and mental illness, people who experienced drug toxicity were 15.3 times (95% CI = 11.3, 20.7) more likely to have encephalopathy compared to people who did not experience a drug toxicity event. People who were 40 years and older, male, and had a mental illness were at increased risk of encephalopathy. Conclusions There is a need for collaboration between community members, health care providers, and key stakeholders to develop a standardized approach to define, screen, and detect neurocognitive injury related to drug toxicity.

Abstract Background Stimulant use has been rising among people with opioid use disorder in recent years in North America, alongside a parallel rise in illicit drug toxicity (overdose) deaths. This study aimed to examine the association between stimulant use and overdose mortality. Methods Data from a universal health insurance client roster were used to identify a 20% random general population sample (aged ≥12) in British Columbia, Canada between January 1 2015 and December 31 2018 (N = 1,089,682). Provincial health records were used to identify people who used opioids and/or stimulants. Fatal overdose observed during follow-up (January 12,015- December 312,018) was retrieved from Vital Statistics Death Registry and BC Coroners Service Data. Potential confounders including age, sex, health region, comorbidities and prescribed medications were retrieved from the provincial client roster and health records. Results We identified 7460 people who used stimulants and or opioids. During follow-up there were 272 fatal overdose events. People who used both opioids and stimulants had more than twice the hazard of fatal overdose (HR: 2.02, 95% CI: 1.47-2.78, p

Abstract Background Concurrent opioid and stimulant use is on the rise in North America. This increasing trend of use has been observed in the general population, and among people released from prison in British Columbia (BC), who face an elevated risk of overdose post-release. Opioid agonist treatment is an effective treatment for opioid use disorder and reduces risk of overdose mortality. In the context of rising concurrent stimulant use among people with opioid use disorder, this study aims to investigate the impact of stimulant use disorder on opioid agonist treatment dispensation following release from prison in BC. Methods Linked health and corrections records were retrieved for releases between January 1st 2015 and December 29th 2018 (N = 13,380). Hospital and primary-care administrative health records were used to identify opioid and stimulant use disorder and mental illness. Age, sex, and health region were derived from BC’s Client Roster. Incarceration data were retrieved from provincial prison records. Opioid agonist treatment data was retrieved from BC’s provincial drug dispensation database. A generalized estimating equation produced estimates for the relationship of stimulant use disorder and opioid agonist treatment dispensation within two days post-release. Results Cases of release among people with an opioid use disorder were identified (N = 13,380). Approximately 25% (N = 3,328) of releases ended in opioid agonist treatment dispensation within two days post-release. A statistically significant interaction of stimulant use disorder and mental illness was identified. Stratified odds ratios (ORs) found that in the presence of mental illness, stimulant use disorder was associated with lower odds of obtaining OAT [(OR) = 0.73, 95% confidence interval (CI) = 0.64–0.84)] while in the absence of mental illness, this relationship did not hold [OR = 0.89, 95% CI = 0.70–1.13]. Conclusions People with mental illness and stimulant use disorder diagnoses have a lower odds of being dispensed agonist treatment post-release compared to people with mental illness alone. There is a critical need to scale up and adapt opioid agonist treatment and ancillary harm reduction, and treatment services to reach people released from prison who have concurrent stimulant use disorder and mental illness diagnoses.

BackgroundThe NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been described in both immune cells and platelets, but its role in the megakaryocyte (MK) lineage remains elusive.ObjectiveThe aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets.MethodsWe generated Nlrp3A350V/+/Gp1ba-CreKI/+ mice carrying a mutation genetically similar to the one observed in human Muckle–Wells syndrome, which leads to hyperactivity of NLRP3 specifically in MK and platelets.ResultsPlatelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome. Nlrp3A350V/+/Gp1ba-CreKI/+ mice developed normally and had normal platelet counts. Expression of major platelet receptors, platelet aggregation, platelet deposition on collagen under shear, and deep vein thrombosis were unchanged. Nlrp3A350V/+/Gp1ba-CreKI/+ mice had mild anemia, reduced Ter119+ cells in the bone marrow, and splenomegaly. A mild increase in MK TGF-β1 might be involved in the anemic phenotype. Intraperitoneal injection of zymosan in Nlrp3A350V/+/Gp1ba-CreKI/+ mice induced increased neutrophil egression and elevated levels of a set of proinflammatory cytokines, alongside IL-10 and G-CSF, in the peritoneal fluid as compared with control animals.ConclusionMK/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.

Abstract Introduction Canada and the United States continue to experience increasing overdose deaths attributed to highly toxic illicit substances, driven by fentanyl and its analogues. Many bystanders report being hesitant to call 9-1-1 at an overdose due to fears around police presence and arrests. In Canada, a federal law was enacted in 2017, the Good Samaritan Drug Overdose Act (GSDOA), to provide protection from simple drug possession and related charges when 9-1-1 is called to an overdose. There is limited evidence, however, that the GSDOA has improved rates of intention to call 9-1-1 at overdose events. We therefore sought to examine intent to call 9-1-1 among persons who received GSDOA education and were at risk of witnessing an overdose. Methods A cross-sectional survey was conducted with people at risk of witnessing an overdose recruited at 19 Take Home Naloxone (THN) program sites across British Columbia as well as online through Foundry from October 2020 to April 2021. Descriptive statistics were used to examine intention to call 9-1-1 at future overdoses. Multivariable logistic regression models were built in hierarchical fashion to examine factors associated with intention to call 9-1-1. Results Overall, 89.6% (n = 404) of the eligible sample reported intention to call 9-1-1. In the multivariable model, factors positively associated with intention to call 9-1-1 included identifying as a cisgender woman (adjusted odds ratio [AOR]: 3.37; 95% CI: 1.19–9.50) and having previous GSDOA awareness ([AOR]: 4.16; 95% CI: 1.62–10.70). Having experienced a stimulant overdose in the past 6 months was negatively associated with intention to call 9-1-1 ([AOR]: 0.24; 95% CI: 0.09–0.65). Conclusion A small proportion of the respondents reported that, despite the enactment of GSDOA, they did not intend to call 9-1-1 and those who were aware of the act were more likely to report an intention to call at future overdose events. Increasing GSDOA awareness and/or additional interventions to support the aims of the GSDOA could address ongoing reluctance to seek emergency medical care by people who use drugs.