RESUMO
Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor approved as continuous monotherapy and in combination with rituximab as fixed-treatment duration for relapsed and refractory chronic lymphocytic leukemia (R/R CLL). DEVOTE was a 24-week, multicenter observational study (NCT03310190) evaluating the safety, healthcare resource utilization (HCRU) and health-related quality of life (HRQoL) of patients initiating venetoclax for R/R CLL in Canada. Overall, 89 patients received 1 dose of venetoclax; 80% had prior exposure (42% resistant) to ibrutinib. Biochemical tumor lysis syndrome (TLS) occurred in five patients. We observed differences in hospitalization across Canadian provinces including in patients at low risk for TLS with no clear impact on TLS incidence. Additionally, a rapid and sustained improvement in several domains of HRQoL was observed during venetoclax initiation. Early adoption of venetoclax was mainly for R/R CLL patients with few treatment options; nonetheless, acceptable toxicity and a positive impact on HRQoL were observed.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Linfocítica Crônica de Células B , Qualidade de Vida , Sulfonamidas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Gerenciamento Clínico , Recursos em Saúde/estatística & dados numéricos , Adulto , Síndrome de Lise Tumoral/etiologia , Resultado do Tratamento , Canadá/epidemiologiaAssuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Humanos , Rituximab/uso terapêutico , Tiotepa/uso terapêutico , Metotrexato/uso terapêutico , Citarabina/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Sistema Nervoso Central , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Exercise is a non-pharmacological intervention that may benefit elderly patients with depression, but the effects of an exercise intervention in geriatric psychiatry outpatients have yet to be tested. METHOD: Outpatients in a geriatric psychiatry clinic participated in a structured exercise intervention of 50 minutes, twice-weekly, over twelve weeks. Depressive symptoms were assessed at baseline and post-intervention using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Nine participants had baseline and post-intervention PHQ-9 scores. Mean scores were 5.9 and 2.8 at baseline and post-intervention, respectively (p = 0.03). CONCLUSIONS: Exercise intervention for geriatric psychiatry outpatients may improve depressive symptoms. Evidence from controlled interventions is warranted.
Assuntos
Depressão , Psiquiatria Geriátrica , Humanos , Idoso , Depressão/terapia , Depressão/diagnóstico , Pacientes Ambulatoriais , Exercício Físico , Terapia por Exercício/métodosRESUMO
OBJECTIVE: Compare a telephone version and full version of the Montreal Cognitive Assessment (MoCA). METHODS: Cross-sectional analysis of a prospective study. A 20-point telephone version of MoCA (Tele-MoCA) was compared to the Full-MoCA and Mini Mental State Examination. RESULTS: Total of 140 participants enrolled. Mean scores for language were significantly lower with Tele-MoCA than with Full-MoCA (P = .003). Mean Tele-MoCA scores were significantly higher for participants with over 12 years of education (P < .001). Cutoff score of 17 for the Tele-MoCA yielded good specificity (82.2%) and negative predictive value (84.4%), while sensitivity was low (18.2%). CONCLUSIONS: Remote screening of cognition with a 20-point Tele-MoCA is as specific for defining normal cognition as the Full-MoCA. This study shows that telephone evaluation is adequate for virtual cognitive screening. Our sample did not allow accurate assessment of sensitivity for Tele-MoCA in detecting MCI or dementia. Further studies with representative populations are needed to establish sensitivity.
Assuntos
Disfunção Cognitiva , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Estudos Transversais , Humanos , Testes Neuropsicológicos , Estudos Prospectivos , Sensibilidade e Especificidade , TelefoneRESUMO
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.
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Glicemia/metabolismo , Remodelação Óssea/fisiologia , Túbulos Renais Proximais/efeitos dos fármacos , Osteoporose/metabolismo , Animais , Canabinoides/farmacologia , Nefropatias Diabéticas , Glucose/farmacologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos Endogâmicos C57BLRESUMO
The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.
When the human body has stored enough energy from food, it releases a hormone called leptin that travels to the brain and stops feelings of hunger. This hormone moves through the bloodstream and can affect other organs, such as the liver, which also help control our body's energy levels. Most people with obesity have very high levels of leptin in their blood, but are resistant to its effects and will therefore continue to feel hungry despite having stored enough energy. One of the proteins that controls the levels of leptin is a receptor called sOb-R, which is released by the liver and binds to leptin as it travels in the blood. Individuals with high levels of this receptor often have less free leptin in their bloodstream and a lower body weight. Another protein that helps the body to regulate its energy levels is the cannabinoid-1 receptor, or CB1R for short. In people with obesity, this receptor is overactive and has been shown to contribute to leptin resistance, which is when the brain becomes less receptive to leptin. Previous work in mice showed that blocking CB1R reduced the levels of leptin and allowed mice to react to this hormone normally again, but it remained unclear whether CB1R affects how other organs, such as the liver, respond to leptin. To answer this question, Drori et al. blocked the CB1R receptor in the liver of mice eating a high-fat diet, either by using a drug or by deleting the gene that codes for this protein. This caused mice to have higher levels of sOb-R circulating in their bloodstream. Further experiments showed that this change in sOb-R was caused by the levels of a protein called CHOP increasing in the liver when CB1R was blocked. Drori et al. found that inhibiting CB1R caused these obese mice to lose weight and have healthier, less fatty livers as a result of their livers no longer being resistant to the effects of leptin. Scientists, doctors and pharmaceutical companies are trying to develop new strategies to combat obesity. The results from these experiments suggest that blocking CB1R in the liver could allow this organ to react to leptin appropriately again. Drugs blocking CB1R, including the one used in this study, will be tested in clinical trials and could provide a new approach for treating obesity.
Assuntos
Estresse do Retículo Endoplasmático , Hepatócitos/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores para Leptina/metabolismo , Fator de Transcrição CHOP/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Endocanabinoides/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética , Receptores para Leptina/genética , Transdução de Sinais , Fator de Transcrição CHOP/genéticaRESUMO
OBJECTIVE: The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB1R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. METHODS: We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB1R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. RESULTS: Using an unbiased normalized phylogenetic profiling analysis, we found that the CB1R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPARα), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB1R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPARα-/- mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPARα as well as elevated hepatic levels of the PPARα-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPARα. Both of these signaling molecules were modulated by the CB1R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB1R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB1R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPARα. CONCLUSIONS: We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPARα signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB1R blockade.
Assuntos
Fígado Gorduroso/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Fígado Gorduroso/genética , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Obesidade/metabolismo , Oxirredução , PPAR alfa/metabolismo , Filogenia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Transdução de Sinais , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
INTRODUCTION: The Ontario High Risk Breast Screening program follows women aged 30-69 at an increased risk of breast cancer, using a yearly mammography and breast MRI. The aim of this study is to determine the clinical outcomes for the enrolled women. METHODS: Observational cohort study following 2081 participants in the high-risk screening program 2011-2017. The participants were divided into three subgroup according to their risk criteria: (a) known carriers of pathogenic variants (PV) in hereditary breast cancer genes. (b) Previous chest radiotherapy. (c) Estimated life time risk (ELR) ≥ 25%, calculated using the International Breast Cancer Intervention Study (IBIS) tool, with no known mutation or previous radiation. All Breast Cancer (BC) diagnosed during the follow-up time were recorded. RESULTS: 673 women carried PVs in hereditary breast cancer genes, 159 had a history of chest radiotherapy, and 1249 had an ELR ≥ 25%. The total cohort of screening years was 8126. Median age at BC diagnosis was 41 for the first group, 47 for the second group and 51 for the third. BC incidence rate was 18.2 for PV mutation carriers, 17.9 for the chest radiotherapy group and 6.2 for ELR ≥ 25%. Hazard ratio was similar for the first two groups, but significantly lower for the ELR ≥ 25% group. When stratifying by age, the incidence rate in the ELR ≥ 25% increased over time, until it became similar to that of the other subgroups after age 50. CONCLUSION: Our findings question the need to screen women with an elevated lifetime risk using the same screening practices used for women who are PV mutation carriers, or with a history of chest radiation, prior to the age of 50.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Detecção Precoce de Câncer , Feminino , Humanos , Mamografia , Programas de Rastreamento , Pessoa de Meia-Idade , OntárioRESUMO
OBJECTIVE: To quantify the association between physical exercise intervention (PEI) and reduction in depressive symptoms in older adults. DATA SOURCES: MEDLINE, PsycINFO, and EMBASE were searched from inception through December 2018 with no language restrictions using keywords related to exercise, depression, elderly adults, and randomized controlled trials. STUDY SELECTION: Randomized controlled trials comparing a sedentary control group, with no physically active intervention, to a supervised, moderate-to-vigorous PEI with participants aged ≥ 60 years and having a primary outcome of depressive symptoms were included. DATA EXTRACTION: Data on pre- and post-intervention scores on scales measuring depressive symptoms were extracted using a standard form. Random-effects models were used to pool standardized mean differences (Hedges g) in depressive symptoms across studies. DATA SYNTHESIS: Nine studies involving 1,308 participants were included; mean participant age was 82 years. Moderate-to-vigorous PEI was associated with a medium effect size of 0.64 (95% CI, 0.27 to 1.01; z = 3.38; P < .001) in reducing depressive symptoms. However, there was considerable heterogeneity (T² = 0.22, Q = 36.34, P < .0001; I² = 78.0%) in the effect of PEI across included studies. Age > 80 years, Mini-Mental State Examination (MMSE) score < 23, and no depressive symptoms at baseline contributed to heterogeneity. Fitness metrics and adherence to exercise were inconsistently reported, and 5 of 9 studies were deemed at high risk of bias. CONCLUSIONS: A moderate reduction in depressive symptoms was seen with PEI among older adults. Nevertheless, more work is needed to support PEI for late-life depression in adults over age 80 years or with MMSE scores < 23 suggestive of cognitive decline.
Assuntos
Depressão/terapia , Terapia por Exercício/métodos , Idoso , Idoso de 80 Anos ou mais , Exercício Físico/psicologia , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND AND PURPOSE: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB1 receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD. EXPERIMENTAL APPROACH: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB1 receptor/iNOS antagonist, MRI-1867 (3 mg·kg-1 ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB1 receptor antagonist (JD5037; 3 mg·kg-1 ), iNOS antagonist (1400W; 10 mg·kg-1 ), and pair feeding. Mice with high-fat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls. KEY RESULTS: Enhanced expression of CB1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling. CONCLUSIONS AND IMPLICATIONS: Collectively, our results highlight the therapeutic relevance of blocking CB1 receptors and iNOS in ameliorating obesity-induced CKD.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Obesidade/prevenção & controle , Receptor CB1 de Canabinoide/antagonistas & inibidores , Insuficiência Renal Crônica/prevenção & controle , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/uso terapêutico , Linhagem Celular Transformada , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismoRESUMO
INTRODUCTION: Two recent observational studies have investigated the association between androgen deprivation therapy (ADT) and rheumatoid arthritis (RA), but generated discrepant findings and had important methodological limitations. Thus, the objective of this study was to determine whether the use of ADT is associated with an increased risk of RA in men with prostate cancer. PATIENTS AND METHODS: We conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink. The cohort included all men, at least 40 years of age, newly diagnosed with prostate cancer between 1 January 1988 and 31 March 2014, with follow-up until 30 September 2014. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays and latency. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RA, comparing use of ADT with non-use. Secondary analyses were conducted to assess whether the association varied according to ADT type and cumulative duration of use. Finally, we conducted several sensitivity analyses to assess the robustness of our findings. RESULTS: The cohort included 32,302 men followed for a median of 3.3 years. During follow-up, 63 patients were newly diagnosed with RA, generating an incidence rate of 46.5/100,000 person-years. Compared with non-use, the use of ADT was not associated with an increased risk of RA (HR 0.84, 95% CI 0.49-1.45). In secondary analyses, the association did not vary according to ADT type or with cumulative duration of use (p trend = 0.53). The results remained consistent in sensitivity analyses. CONCLUSION: In this population-based study, the use of ADT was not associated with an increased risk of RA in men with prostate cancer.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Artrite Reumatoide/epidemiologia , Neoplasias da Próstata/terapia , Idoso , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Artrite Reumatoide/etiologia , Estudos de Coortes , Estrogênios/administração & dosagem , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Masculino , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/cirurgia , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: To assess the effectiveness of system-wide interventions designed to increase the implementation of thromboprophylaxis and decrease the incidence of venous thromboembolism (VTE) in hospitalised medical and surgical patients at risk of VTE. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: Medline, PubMed, Embase, BIOSIS, CINAHL, Web of Science, CENTRAL, DARE, EED, LILACS and clinicaltrials.gov without language restrictions from inception to 7 January 2017, as well as the reference lists of relevant review articles. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: RCTs that evaluated the effectiveness of system-wide interventions such as alerts, multifaceted, education, and preprinted orders when compared with no intervention, existing policy or another intervention. RESULTS: We included 13 RCTs involving 35 997 participants. Eleven RCTs had data available for meta-analysis. Compared with control, we found absolute increase in the prescription of prophylaxis associated with alerts (21% increase, 95% CI [15% to 275%]) and multifaceted interventions (4% increase, 95% CI [3% to 11%]), absolute increase in the prescription of appropriate prophylaxis associated with alerts (16% increase, 95% CI [12% to 20%]) and relative risk reductions (risk ratio 64%, 95% CI [47% to 86%]) in the incidence of symptomatic VTE associated with alerts. Computer alerts were found to be more effective than human alerts, and multifaceted interventions with an alert component appeared to be more effective than multifaceted interventions without, although comparative pooled analyses were not feasible. The quality of evidence for improvement in outcomes was judged to be low to moderate certainty. CONCLUSIONS: Alerts increased the proportion of patients who received prophylaxis and appropriate prophylaxis, and decreased the incidence of symptomatic VTE. Multifaceted interventions increased the proportion of patients who received prophylaxis but were found to be less effective than alerts interventions. TRIAL REGISTRATION NUMBER: CD008201.
Assuntos
Tromboembolia Venosa/prevenção & controle , Anticoagulantes/uso terapêutico , Hospitalização , Humanos , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Medicamentos Genéricos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Administrative health care databases are increasingly being used to study pulmonary embolism (PE), but the validity of single PE codes is variable. Using data from Quebec, Canada, we developed ASPECT (Algorithm for Suspected Pulmonary Embolism Confirmation and Treatment), combining 3 components to ascertain confirmed PE: emergency department (ED) diagnoses, imaging codes, and dispensed prescriptions or hospital diagnoses. Herein, we used unrelated administrative health care databases to externally validate ASPECT. METHODS: We used ED electronic health records (ED-EHRs) to identify all residents of Calgary (Alberta, Canada) with PE codes between January and June, 2016. We applied ASPECT by identifying imaging studies in the ED-EHR, admission diagnoses in linked discharge abstract database and filled prescriptions in linked pharmacy information. Confirmed PE in ASPECT was validated against chart review in the ED-EHR. RESULTS: The cohort included 498 patients. Overall, 258 (51.9%) were managed as outpatients and 327 were adjudicated to have confirmed PE; the positive predictive value (PV) of single PE codes was 65.6%. With ASPECT the positive PV was 96.5% [95% confidence interval (CI), 94.4-98.5%] and positive likelihood ratio was 10.9 (95% CI, 6.8-15.1). The negative PV and negative likelihood ratio were 85.1% (95% CI, 80.0-90.2%) and 0.1 (95% CI, 0.0-0.1), respectively. Overall agreement of ASPECT with confirmed PE was 92.2%. Further, ASPECT was similarly robust in inpatients and outpatients and was more precise than any 2-component combination of ASPECT. CONCLUSIONS: Our findings reiterate the limitations of using single administrative codes for PE and suggest ASPECT as an acceptable tool to study PE.
Assuntos
Embolia Pulmonar/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alberta , Algoritmos , Bases de Dados como Assunto , Registros Eletrônicos de Saúde , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/terapia , Quebeque , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2-/- mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2-/- mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss. © 2018 American Society for Bone and Mineral Research.
Assuntos
Antígenos de Neoplasias , Remodelação Óssea , Osteogênese , Síndrome de Prader-Willi , Proteínas , Serina/metabolismo , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Humanos , Camundongos , Camundongos Knockout , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo , Síndrome de Prader-Willi/patologia , Proteínas/genética , Proteínas/metabolismo , Serina/farmacologiaRESUMO
AIMS: To evaluate the specific role of the endocannabinoid/cannabinoid type-1 (CB1 R) system in modulating mitochondrial dynamics in the metabolically active renal proximal tubular cells (RPTCs). MATERIALS AND METHODS: We utilized mitochondrially-targeted GFP in live cells (wild-type and null for the CB1 R) and electron microscopy in kidney sections of RPTC-CB1 R-/- mice and their littermate controls. In both in vitro and in vivo conditions, we assessed the ability of CB1 R agonism or fatty acid flux to modulate mitochondrial architecture and function. RESULTS: Direct stimulation of CB1 R resulted in mitochondrial fragmentation in RPTCs. This process was mediated, at least in part, by modulating the phosphorylation levels of the canonical fission protein dynamin-related protein 1 on both S637 and S616 residues. CB1 R-induced mitochondrial fission was associated with mitochondrial dysfunction, as documented by reduced oxygen consumption and ATP production, increased reactive oxygen species and cellular lactate levels, as well as a decline in mitochondrial biogenesis. Likewise, we documented that exposure of RPTCs to a fatty acid flux induced CB1 R-dependent mitochondrial fission, lipotoxicity and cellular dysfunction. CONCLUSIONS: CB1 R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases.
Assuntos
Túbulos Renais Proximais , Mitocôndrias/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Linhagem Celular , Túbulos Renais Proximais/química , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Microscopia de FluorescênciaRESUMO
BACKGROUND: In the current study, the authors determined whether adhering to molecular monitoring guidelines in patients with chronic myeloid leukemia (CML) is associated with major molecular response (MMR) and assessed barriers to adherent monitoring. METHODS: Newly treated patients with CML from the Quebec province-wide CML registry from 2005 to 2016 were included. Timely polymerase chain reaction (tPCR) was defined as the molecular assessment of BCR-ABL1 at the 3-month, 12-month, and 18-month time points from the initiation of tyrosine kinase inhibitor (TKI) therapy. The cohort was analyzed as a nested case-control study. Cases with a first-ever MMR (BCR-ABL1 ≤0.1%, assessed at any time during follow-up) were matched to up to 5 controls by duration of TKI therapy, volume of patients with CML at the treatment center, year of cohort entry, and age. Odds ratios (ORs) for the performance of tPCR and MMR were adjusted for sex, comorbidities, type of TKI, and other important covariates. RESULTS: The cohort included 496 patients. Of 392 MMR events, 67.9% occurred before 18 months. The performance of tPCR was associated with a doubling of the MMR rate (OR, 2.23; 95% confidence interval [95% CI], 1.56-3.21) and was similar with 1 to 3 tPCRs performed (P = .67). Furthermore, tPCRs at 3 months (OR, 2.77; 95% CI, 1.81-4.23) and 12 months (OR, 3.00; 95% CI, 1.64-5.49) were associated with achieving early MMR, whereas tPCRs at 18 months were not (OR, 1.23; 95% CI, 0.80-1.89). Low-volume centers were found to have lower adherence to tPCR (OR, 0.60; 95% CI, 0.40-0.89). CONCLUSIONS: Timely molecular assessment at 3 months and 12 months appears to benefit patients with CML. Adherence to timely monitoring should be encouraged, especially in low-volume treatment centers.
Assuntos
Monitoramento de Medicamentos/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Conduta Expectante/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/metabolismoRESUMO
Associations of organochlorine (OC) pesticides and polychlorinated biphenyls (PCBs) with non-Hodgkin lymphoma are controversial. We compared serum levels of 6 OC pesticides and 38 PCBs in Israeli Jews (IJ) and Palestinian Arabs (PA) and assessed possible associations with B-cell non-Hodgkin lymphoma (B-NHL). Ninety B-NHL cases (50 IJ and 40â¯PA) and 120 controls (65 IJ and 55â¯PA) were included. Median concentrations of analytes in controls were compared across ethnic groups using quantile regression, adjusting for age and sex. We used logistic regression to derive odds ratios (OR) and 95% confidence intervals (CI) for detectable analytes and B-NHL, adjusting for age, ethnic group, faming and body mass index. Median values of PCBs and dichlorodiphenyldichloroethylene (DDE) were higher in IJ vs PA controls (Pâ¯=â¯0.0007), as were several PCBs (74, 99, 118, 138, 146, 153, 156, 163, 170, and 180). Overall, OC pesticide and PCB exposures were comparable with reports from high-income countries. B-NHL was associated with PCB 146 (OR 1.70, 95% CI: 1.02, 2.83), PCB 156 (OR 1.75, 95% CI: 1.06, 2.89), and high-chlorinated PCBs (OR 1.55, 95% CI: 1.00, 2.40) in all study subjects. These associations were robust in quantile as well as sensitivity analyses. An association of DDE with B-NHL was noted in PA (OR 1.72, 95% CI: 1.07, 2.77), but not in IJ (OR 0.87, 95% CI: 0.59, 1.27). Although high-chlorinated PCB concentrations did not indicate high exposure levels, our findings indicate that B-NHL may be associated with this exposure.
Assuntos
Hidrocarbonetos Clorados/sangue , Linfoma não Hodgkin/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Árabes , Estudos de Casos e Controles , Feminino , Humanos , Israel , Judeus , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. While numerous randomized controlled trials (RCTs) have shown that the appropriate use of thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective, and cost-effective, thromboprophylaxis remains underused or inappropriately used. Our previous review suggested that system-wide interventions, such as education, alerts, and multifaceted interventions were more effective at improving the prescribing of thromboprophylaxis than relying on individual providers' behaviors. However, 47 of the 55 included studies in our previous review were observational in design. Thus, an update to our systematic review, focused on the higher level of evidence of RCTs only, was warranted. OBJECTIVES: To assess the effects of system-wide interventions designed to increase the implementation of thromboprophylaxis and decrease the incidence of VTE in hospitalized adult medical and surgical patients at risk for VTE, focusing on RCTs only. SEARCH METHODS: Our research librarian conducted a systematic literature search of MEDLINE Ovid, and subsequently translated it to CENTRAL, PubMed, Embase Ovid, BIOSIS Previews Ovid, CINAHL, Web of Science, the Database of Abstracts of Reviews of Effects (DARE; in the Cochrane Library), NHS Economic Evaluation Database (EED; in the Cochrane Library), LILACS, and clinicaltrials.gov from inception to 7 January 2017. We also screened reference lists of relevant review articles. We identified 12,920 potentially relevant records. SELECTION CRITERIA: We included all types of RCTs, with random or quasi-random methods of allocation of interventions, which either randomized individuals (e.g. parallel group, cross-over, or factorial design RCTs), or groups of individuals (cluster RCTs (CRTs)), which aimed to increase the use of prophylaxis or appropriate prophylaxis, or decrease the occurrence of VTE in hospitalized adult patients. We excluded observational studies, studies in which the intervention was simply distribution of published guidelines, and studies whose interventions were not clearly described. Studies could be in any language. DATA COLLECTION AND ANALYSIS: We collected data on the following outcomes: the number of participants who received prophylaxis or appropriate prophylaxis (as defined by study authors), the occurrence of any VTE (symptomatic or asymptomatic), mortality, and safety outcomes, such as bleeding. We categorized the interventions into alerts (computer or human alerts), multifaceted interventions (combination of interventions that could include an alert component), educational interventions (e.g. grand rounds, courses), and preprinted orders (written predefined orders completed by the physician on paper or electronically). We meta-analyzed data across RCTs using a random-effects model. For CRTs, we pooled effect estimates (risk difference (RD) and risk ratio (RR), with 95% confidence interval (CI), adjusted for clustering, when possible. We pooled results if three or more trials were available for a particular intervention. We assessed the certainty of the evidence according to the GRADE approach. MAIN RESULTS: From the 12,920 records identified by our search, we included 13 RCTs (N = 35,997 participants) in our qualitative analysis and 11 RCTs (N = 33,207 participants) in our meta-analyses. PRIMARY OUTCOME: Alerts were associated with an increase in the proportion of participants who received prophylaxis (RD 21%, 95% CI 15% to 27%; three studies; 5057 participants; I² = 75%; low-certainty evidence). The substantial statistical heterogeneity may be in part explained by patient types, type of hospital, and type of alert. Subgroup analyses were not feasible due to the small number of studies included in the meta-analysis.Multifaceted interventions were associated with a small increase in the proportion of participants who received prophylaxis (cluster-adjusted RD 4%, 95% CI 2% to 6%; five studies; 9198 participants; I² = 0%; moderate-certainty evidence). Multifaceted interventions with an alert component were found to be more effective than multifaceted interventions that did not include an alert, although there were not enough studies to conduct a pooled analysis. SECONDARY OUTCOMES: Alerts were associated with an increase in the proportion of participants who received appropriate prophylaxis (RD 16%, 95% CI 12% to 20%; three studies; 1820 participants; I² = 0; moderate-certainty evidence). Alerts were also associated with a reduction in the rate of symptomatic VTE at three months (RR 64%, 95% CI 47% to 86%; three studies; 5353 participants; I² = 15%; low-certainty evidence). Computer alerts were associated with a reduction in the rate of symptomatic VTE, although there were not enough studies to pool computer alerts and human alerts results separately. AUTHORS' CONCLUSIONS: We reviewed RCTs that implemented a variety of system-wide strategies aimed at improving thromboprophylaxis in hospitalized patients. We found increased prescription of prophylaxis associated with alerts and multifaceted interventions, and increased prescription of appropriate prophylaxis associated with alerts. While multifaceted interventions were found to be less effective than alerts, a multifaceted intervention with an alert was more effective than one without an alert. Alerts, particularly computer alerts, were associated with a reduction in symptomatic VTE at three months, although there were not enough studies to pool computer alerts and human alerts results separately.Our analysis was underpowered to assess the effect on mortality and safety outcomes, such as bleeding.The incomplete reporting of relevant study design features did not allow complete assessment of the certainty of the evidence. However, the certainty of the evidence for improvement in outcomes was judged to be better than for our previous review (low- to moderate-certainty evidence, compared to very low-certainty evidence for most outcomes). The results of our updated review will help physicians, hospital administrators, and policy makers make practical decisions about adopting specific system-wide measures to improve prescription of thromboprophylaxis, and ultimately prevent VTE in hospitalized patients.
Assuntos
Hospitalização , Tromboembolia Venosa/prevenção & controle , Adulto , Anticoagulantes/uso terapêutico , Austrália , Europa (Continente) , Hospitais , Humanos , América do Norte , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Tromboembolia Venosa/epidemiologia , Trombose Venosa/epidemiologia , Trombose Venosa/prevenção & controleRESUMO
Patients with end-stage renal disease (ESRD) were excluded from pivotal clinical trials with oral anticoagulants. While such patients are at an increased risk of venous and arterial thromboembolism, their risk of bleeding is also elevated. It is thus of little surprise that stroke prevention with vitamin K antagonists (VKAs) in ESRD patients with atrial fibrillation is controversial, with observational evidence ranging from beneficial to harmful. This uncertainty extends to the less studied use of VKAs for venous thromboembolism in ESRD. The direct oral anticoagulants (DOACs) apixaban and rivaroxaban have now permissive labeling in the United States for atrial fibrillation in patients with ESRD; this expanded labeling has not yet occurred either in Europe or for venous thromboembolism. This review summarizes the current evidence for the pharmacology of DOACs in ESRD as well as their utilization and safety in patients with ESRD and atrial fibrillation.