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1.
J Clin Lipidol ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34802986

RESUMO

Lipoprotein measurements are pivotal in the management of patients at risk for atherosclerotic coronary heart disease (CHD) with myocardial infarction and coronary death as the main outcomes, and for atherosclerotic cardiovascular disease (ASCVD), which includes CHD and stroke. Recent developments and changes in guidelines affect optimization of using lipid measures as cardiovascular biomarkers. This scientific statement reviews the pre-analytical, analytical, post-analytical, and clinical aspects of lipoprotein measurements. Highlights include the following: i) It is acceptable to screen with nonfasting lipids. ii) non-high-density lipoprotein HDL-cholesterol (non-HDL-C) is measured reliably in either the fasting or the nonfasting state and can effectively guide ASCVD prevention. iii) low density lipoprotein cholesterol (LDL-C) can be estimated from total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglyceride (TG) measurements. For patients with LDL-C>100 mg/dL and TG ≤150 mg/dL it is reasonable to use the Friedewald formula. However, for those with TG 150-400 mg/dL the Friedewald formula for LDL-C estimation is less accurate. The Martin/Hopkins method is recommended for LDL-C estimation throughout the range of LDL-C levels and up to TG levels of 399 mg/dL. For TG levels ≥400 mg/dL LDL-C estimating equations are currently not recommended and newer methods are being evaluated. iv) When LDL-C or TG screening results are abnormal the clinician should consider obtaining fasting lipids. v) Advanced lipoprotein tests using apolipoprotein B (apoB), LDL Particle Number (LDL-P) or remnant cholesterol may help to guide therapeutic decisions in select patients, but data are limited for patients already on lipid lowering therapy with low LDL-C levels. Better harmonization of advanced lipid measurement methods is needed. Lipid measurements are recommended 4-12 weeks after a change in lipid treatment. Lipid laboratory reports should denote desirable values and specifically identify extremely elevated LDL-C levels (≥190 mg/dL at any age or ≥160 mg/dL in children) as severe hypercholesterolemia. Potentially actionable abnormal lipid test results, including fasting triglycerides (TG) ≥500 mg/dL, should be reported as hypertriglyceridemia. Appropriate use and reporting of lipid tests should improve their utility in the management of persons at high risk for ASCVD events.

2.
Front Med (Lausanne) ; 8: 764563, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790682

RESUMO

Pneumonitis is a well-described, potentially life-threatening adverse effect of immune checkpoint inhibitors (ICI) and thoracic radiotherapy. It can require additional investigations, treatment, and interruption of cancer therapy. It is important for clinicians to have an awareness of its incidence and severity, however real-world data are lacking and do not always correlate with findings from clinical trials. Similarly, there is a dearth of information on cost impact of symptomatic pneumonitis. Informatics approaches are increasingly being applied to healthcare data for their ability to identify specific patient cohorts efficiently, at scale. We developed a Structured Query Language (SQL)-based informatics algorithm which we applied to CT report text to identify cases of ICI and radiotherapy pneumonitis between 1/1/2015 and 31/12/2020. Further data on severity, investigations, medical management were also acquired from the electronic health record. We identified 248 cases of pneumonitis attributable to ICI and/or radiotherapy, of which 139 were symptomatic with CTCAE severity grade 2 or more. The grade ≥2 ICI pneumonitis incidence in our cohort is 5.43%, greater than the all-grade 1.3-2.7% incidence reported in the literature. Time to onset of ICI pneumonitis was also longer in our cohort (mean 4.5 months, range 4 days-21 months), compared to the median 2.7 months (range 9 days-19.2 months) described in the literature. The estimated average healthcare cost of symptomatic pneumonitis is £3932.33 per patient. In this study we use an informatics approach to present new real-world data on the incidence, severity, management, and resource burden of ICI and radiotherapy pneumonitis. To our knowledge, this is the first study to look at real-world incidence and healthcare resource utilisation at the per-patient level in a UK cancer hospital. Improved management of pneumonitis may facilitate prompt continuation of cancer therapy, and improved outcomes for this not insubstantial cohort of patients.

3.
Am J Psychiatry ; 178(10): 932-940, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256606

RESUMO

OBJECTIVE: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system. METHODS: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group. RESULTS: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine. CONCLUSIONS: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.


Assuntos
Antipsicóticos , Hospitalização/estatística & dados numéricos , Pacientes Ambulatoriais/estatística & dados numéricos , Esquizofrenia , Veteranos , Administração Oral , Antipsicóticos/classificação , Antipsicóticos/uso terapêutico , Pesquisa Comparativa da Efetividade , Preparações de Ação Retardada/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Esquizofrenia/terapia , Resultado do Tratamento , Estados Unidos/epidemiologia , United States Department of Veterans Affairs/estatística & dados numéricos , Veteranos/psicologia , Veteranos/estatística & dados numéricos , Suspensão de Tratamento/estatística & dados numéricos
5.
Med J (Ft Sam Houst Tex) ; (PB 8-21-04/05/06): 9-13, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251659

RESUMO

INTRODUCTION: The US Army's transition from counterinsurgency operations to preparation for large-scale combat operations is likely to bring unique access to care challenges on the battlefield. Ruggedized computer systems exist that allow forward medical personnel to establish telehealth connections with rear-based specialists. We describe our use of one such device during simulated force on force operations at the Joint Readiness Training Center (JRTC). METHODS: Our infantry brigade combat team brought a telehealth device to JRTC 20-02. The device comprised a mobile laptop and peripheral medical devices. We used the Warfighter Information Network-Tactical Increment 2 Tactical Communications Node (TCN) to establish communication between the device and external entities. We sought to establish connectivity in the Fort Polk, LA, cantonment area as part of reception, staging, onward movement, and integration operations. RESULTS: We successfully executed video calls from the field utilizing the telehealth device at the JRTC rear aid station and the local military treatment facility on Fort Polk, LA. We also executed calls to our home station military treatment facility on Fort Carson, CO. Each of these calls lasted approximately five minutes with sustained high-quality video and audio feeds. CONCLUSIONS: Our experience provides proof of concept that telehealth may enable rear-based medical personnel to expand the medical capabilities of medics based forward in the battlespace. Telehealth devices may prove feasible for use with strictly tactical communications architecture in the kinetic setting of large scale combat operations.


Assuntos
Telemedicina , Comunicação
6.
Lung Cancer ; 156: 147-150, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33965281

RESUMO

Durvalumab is the first approved adjuvant immunotherapy agent for patients with stage III NSCLC treated with concurrent chemoradiotherapy and is associated with improved overall survival. In order to minimise the number of hospital visits for patients receiving durvalumab during the COVID-19 pandemic we implemented 4-weekly (20 mg/kg) durvalumab in place of 2-weekly infusions at The Royal Marsden Hospital. We assessed the potential impact of the safety of a 4-weekly schedule in patients receiving adjuvant durvalumab. We carried out a retrospective study of 40 patients treated with 2-weekly and 4-weekly infusions of durvalumab prior to and during the COVID-19 pandemic. Clinical documentation was analysed from 216 consultations across 40 patients receiving 2-weekly durvalumab and 66 consultations of 14 patients who switched from 2-weekly to 4-weekly durvalumab during the COVID-19 pandemic. In patients receiving 2-weekly durvalumab, the rate of grade 3 and 4 toxicities was 15 % compared to 7% in patients receiving 4-weekly durvalumab. Pre-existing autoimmune disease was considered a risk factor for the development of grade 3 or 4 toxicities. We did not observe any difference in the rate of grade 1 and 2 toxicities between the two groups. Our findings support the use of 4-weekly durvalumab during the COVID-19 pandemic and beyond, obviating the need for 2-weekly face-to-face consultations and blood tests, relevant given the current pandemic and the need to re-structure cancer services to minimise patient hospital visits and exposure to SARS-CoV-2.


Assuntos
COVID-19 , Neoplasias Pulmonares , Anticorpos Monoclonais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Pandemias , Estudos Retrospectivos , SARS-CoV-2
7.
Eur Neuropsychopharmacol ; 51: 33-42, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34023797

RESUMO

Nicotinic agonists have been shown to improve cognition and mood, but this improvement is inconsistent and short-lived, possibly due to receptor desensitization. Positive Allosteric Modulators (PAMs) of the nicotinic alpha-7 nicotinic-acetyl-choline receptor (a7nAChR) are hypothesized to change the configuration of the nicotinic receptor and delay desensitization, potentially increasing the duration of the activation of the receptor, and improving clinical efficacy. This was a randomized controlled trial (RCT) adding JNJ-39393406 9 (a PAM of the a7nAChR) (n=35) or placebo (n=36) to treatment as usual for two weeks in 71 patients with unipolar depression. Mixed models for repeated measures analyses were performed Primary outcome measures were the Brief Assessment of Cognition in Schizophrenia (BACS) composite and the Montgomery-Asperg Depression Rating Scale (MADRS) scores. The drug was well tolerated, however mixed models for repeated measures comparing JNJ-39393406 to placebo showed no significant difference for MADRS total score (p=0.78), BACS composite score (p=0.34), or any of the secondary outcome measures. There was no significant difference in adverse events between the study groups (p=0.44). In conclusion, this study's findings do not support the hypothesis that a positive nicotinic receptor modulator can improve cognitive or depressive symptomatology in patients with unipolar depression.

8.
Lancet ; 397(10289): 2060-2069, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34015342

RESUMO

BACKGROUND: IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. METHODS: RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. FINDINGS: Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. INTERPRETATION: Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. FUNDING: Novo Nordisk.

9.
JAMA Cardiol ; 2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-33993205

RESUMO

Importance: In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes. Objective: To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo. Design, Setting, and Participants: A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020). Interventions: Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil. Main Outcomes and Measures: The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization. Results: Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 µg/mL (interquartile range [IQR], 46-131 µg/mL) for EPA and 91 µg/mL (IQR, 71-114 µg/mL) for DHA with top tertile levels of 151 µg/mL (IQR, 132-181 µg/mL) and 118 µg/mL (IQR, 102-143 µg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results. Conclusions and Relevance: Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk. Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

10.
Br J Nurs ; 30(7): 428-432, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830792

RESUMO

This article describes nurse education with the Open University in Scotland (OUiS). Although there are problems with nurse recruitment and retention across the UK, in Scotland the landscape is somewhat different, with greater support for students required in remote and rural areas. Despite these challenges, the OUiS continues to recruit to the commissioned numbers of places. OUiS nursing students are primarily health care support workers who are a key group within the health and social care workforce but historically have faced many challenges in developing clear career pathways into nursing. At the heart of the OU is the fundamental recognition of distance online pedagogy, complemented by work-based learning support by employers. Partnership working between the OU, employers and education commissioners is crucial to its success.


Assuntos
Educação em Enfermagem , Universidades , Educação em Enfermagem/tendências , Previsões , Humanos , Escócia
11.
Schizophr Bull ; 47(5): 1254-1260, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-33860793

RESUMO

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.

12.
Curr Opin Lipidol ; 32(2): 151-156, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33651748

RESUMO

PURPOSE OF REVIEW: This review examines recent contradictory large, well-controlled randomized control trials assessing the effects of omega-3 fatty acids and colchicine on cardiovascular (CV) outcomes. RECENT FINDINGS: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) and Statin Residual Risk Reduction with Epanova in high Cardiovascular Risk patients with Hypertriglyceridemia (STRENGTH) trial assessed the CV outcomes using high-dose omega-3 fatty acids in statin-treated patients with moderate hypertriglyceridemia and high-risk for CV disease with differing results. Similarly, Colchicine Cardiovascular Outcomes trial, (COLCOT) second Low Dose Colchicine (LoDoCo2), and Colchicine in patients with Acute Coronary Syndrome (COPS) assessed the CV outcomes using low-dose colchicine in patients with coronary artery disease with inconsistent results. These contradictory findings among studies assessing similar questions with the same drug or a drug within the same class challenge the scientific validity and clinical applicability of the derived conclusions. SUMMARY: A comprehensive review revealed many differences between the trials, which could have contributed to observed divergent results. Consistent findings across multiple trials help strengthen the evidence for specific endpoints or sub-populations, and these findings must be included in guidelines. Large prospective cohort studies with diligent study protocols are warranted in the future to resolve unanswered dilemmas.

13.
BMC Psychiatry ; 21(1): 146, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33691668

RESUMO

BACKGROUND: Acute Day Units (ADUs) provide intensive, non-residential, short-term treatment for adults in mental health crisis. They currently exist in approximately 30% of health localities in England, but there is little research into their functioning or effectiveness, and how this form of crisis care is experienced by service users. This qualitative study explores the views and experiences of stakeholders who use and work in ADUs. METHODS: We conducted 36 semi-structured interviews with service users, staff and carers at four ADUs in England. Data were analysed using thematic analysis. Peer researchers collected data and contributed to analysis, and a Lived Experience Advisory Panel (LEAP) provided perspectives across the whole project. RESULTS: Both service users and staff provided generally positive accounts of using or working in ADUs. Valued features were structured programmes that provide routine, meaningful group activities, and opportunities for peer contact and emotional, practical and peer support, within an environment that felt safe. Aspects of ADU care were often described as enabling personal and social connections that contribute to shifting from crisis to recovery. ADUs were compared favourably to other forms of home- and hospital-based acute care, particularly in providing more therapeutic input and social contact. Some service users and staff thought ADU lengths of stay should be extended slightly, and staff described some ADUs being under-utilised or poorly-understood by referrers in local acute care systems. CONCLUSIONS: Multi-site qualitative data suggests that ADUs provide a distinctive and valued contribution to acute care systems, and can avoid known problems associated with other forms of acute care, such as low user satisfaction, stressful ward environments, and little therapeutic input or positive peer contact. Findings suggest there may be grounds for recommending further development and more widespread implementation of ADUs to increase choice and effective support within local acute care systems.


Assuntos
Transtornos Mentais , Serviços de Saúde Mental , Adulto , Cuidadores , Inglaterra , Humanos , Transtornos Mentais/terapia , Saúde Mental , Pesquisa Qualitativa
14.
Future Cardiol ; 17(7): 1249-1260, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33464124

RESUMO

Dyslipidemia promotes atherosclerosis and causes cardiovascular diseases. Statins are potent lipid-lowering medications with a cardiovascular mortality benefit. They are generally safe and well tolerated but sometimes can be associated with side effects of variable severity. The most common side effect is statin-associated muscle symptoms. Uncommon side effects include new-onset diabetes mellitus and elevation in liver enzymes. These effects can lead to noncompliance and premature discontinuation of the medication. Hence, it is crucial to identify patients with true statin-associated side effects (SASE) to ensure optimal statin use. The appropriate evaluation of the patient before starting statins and proactive utilization of available diagnostic tests to rule out alternate etiologies mimicking adverse effects are essential for accurate diagnosis of SASE. In patients with true SASE, timely intervention with modified statin or non-statins is beneficial. Herein, we discuss key clinical trial data on statins and non-statins, and describe our center's approach toward patients with SASE.

15.
Schizophr Bull ; 47(4): 1077-1087, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-33479775

RESUMO

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was -3.9 (95% CI: -8.4 to 0.5, P = .10, effect size (ES) = -0.25) and at 8 weeks was -3.5 (95% CI: -7.5 to 0.5, P = .11, ES = -0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: -4.1 to 4.7, P = .90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: -1.0 to 2.1, P = .50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was -2.9 (95% CI: -6.6 to 0.7; P = .21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36.

16.
J Am Soc Nephrol ; 32(1): 211-222, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33272965

RESUMO

BACKGROUND: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. METHODS: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. RESULTS: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. CONCLUSIONS: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.


Assuntos
Anemia/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Inflamação/tratamento farmacológico , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Adulto , Idoso , Anemia/complicações , Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Método Duplo-Cego , Feminino , Hematínicos/uso terapêutico , Hepcidinas/metabolismo , Humanos , Inflamação/complicações , Interleucina-6/antagonistas & inibidores , Falência Renal Crônica/complicações , Ligantes , Masculino , Pessoa de Meia-Idade , Albumina Sérica/metabolismo , Resultado do Tratamento
17.
Trends Cardiovasc Med ; 31(7): 419-424, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32858149

RESUMO

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide that have been shown to have a strong association with dyslipidemia. Despite efficacious LDL-C lowering therapies, there is evidence of residual CVD risk prompting a need for a novel approach to mitigate CVD. This review aims to provide a comprehensive overview of recent and emerging therapies for various dyslipidemias.

18.
JAMA ; 324(22): 2268-2280, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33190147

RESUMO

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%). Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Óleo de Milho/uso terapêutico , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Adulto , Colesterol/sangue , Método Duplo-Cego , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangue
19.
Schizophr Res ; 223: 128-134, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32631701

RESUMO

BACKGROUND: Cognitive deficits, particularly in processing speed, are widely recognized as a critical feature of schizophrenia, and are also present across schizophrenia spectrum disorders. A number of important confounders, however, such as hospitalization effects and antipsychotic medication, have been shown to affect processing speed, causing debate as to the core cognitive deficits of schizophrenia. The study of individuals who are not clinically psychotic but have schizotypal traits allows investigation of cognitive deficits associated with both positive and negative schizotypy dimensions while excluding potential confounds. METHODS: A population-based community sample of 242 healthy adult volunteers assessed using the Structured Interview of Schizotypy - Revised (SIS-R) scale, and a neuropsychological testing battery that included measures of verbal ability, visual and verbal memory, verbal fluency, working memory, executive functions and processing speed. Participants were classified in High or Low Positive Schizotypy (H-PST or L-PST), High or Low Paranoia-like traits (H-PAR or L-PAR) and High or Low Negative Schizotypy (H-NST or L-NST) groups, respectively. RESULTS: Individuals with H-PST performed significantly (p < 0.05) worse than L-PST on measures of processing speed and executive functions. Processing speed deficits were also observed in individuals with H-PAR compared to L-PAR (p < 0.05). There were no statistically significant differences in neuropsychological performance between H-NST and L-NST on any measure. CONCLUSIONS: In a population-based community sample, individuals with high positive schizotypal traits or paranoia-like traits show impairments in processing speed. Consistent with a dimensional view of psychosis, this supports the hypothesis that processing speed represents a core deficit of schizophrenia-like mental states.


Assuntos
Transtornos Cognitivos , Transtornos Psicóticos , Transtorno da Personalidade Esquizotípica , Adulto , Cognição , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Humanos , Testes Neuropsicológicos , Transtornos Psicóticos/complicações , Transtorno da Personalidade Esquizotípica/complicações
20.
Circ Res ; 127(8): 1094-1108, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32660330

RESUMO

RATIONALE: Circumstantial evidence links the development of heart failure to posttranslational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains sparse. OBJECTIVE: This study sought to explore the premise that mitochondrial Kac contributes to heart failure by disrupting oxidative metabolism. METHODS AND RESULTS: A DKO (dual knockout) mouse line with deficiencies in CrAT (carnitine acetyltransferase) and Sirt3 (sirtuin 3)-enzymes that oppose Kac by buffering the acetyl group pool and catalyzing lysine deacetylation, respectively-was developed to model extreme mitochondrial Kac in cardiac muscle, as confirmed by quantitative acetyl-proteomics. The resulting impact on mitochondrial bioenergetics was evaluated using a respiratory diagnostics platform that permits comprehensive assessment of mitochondrial function and energy transduction. Susceptibility of DKO mice to heart failure was investigated using transaortic constriction as a model of cardiac pressure overload. The mitochondrial acetyl-lysine landscape of DKO hearts was elevated well beyond that observed in response to pressure overload or Sirt3 deficiency alone. Relative changes in the abundance of specific acetylated lysine peptides measured in DKO versus Sirt3 KO hearts were strongly correlated. A proteomics comparison across multiple settings of hyperacetylation revealed ≈86% overlap between the populations of Kac peptides affected by the DKO manipulation as compared with experimental heart failure. Despite the severity of cardiac Kac in DKO mice relative to other conditions, deep phenotyping of mitochondrial function revealed a surprisingly normal bioenergetics profile. Thus, of the >120 mitochondrial energy fluxes evaluated, including substrate-specific dehydrogenase activities, respiratory responses, redox charge, mitochondrial membrane potential, and electron leak, we found minimal evidence of oxidative insufficiencies. Similarly, DKO hearts were not more vulnerable to dysfunction caused by transaortic constriction-induced pressure overload. CONCLUSIONS: The findings challenge the premise that hyperacetylation per se threatens metabolic resilience in the myocardium by causing broad-ranging disruption to mitochondrial oxidative machinery.


Assuntos
Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/metabolismo , Proteoma , Acetilação , Animais , Carnitina O-Acetiltransferase/deficiência , Carnitina O-Acetiltransferase/genética , Modelos Animais de Doenças , Metabolismo Energético , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Lisina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Proteômica , Sirtuína 3/deficiência , Sirtuína 3/genética
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