RESUMEN
MAS825, a bispecific IL-1ß/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 ± 1.87 and 13.5 ± 1.8 in the MAS825 and placebo groups, respectively (P = 0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days), and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels, and 16% lower interferon-γ levels, indicative of IL-1ß and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID-19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Interleucina-18 , Inflamación , Hospitalización , Resultado del TratamientoRESUMEN
BACKGROUND: The impact of remdesivir (RDV) on mortality rates in coronavirus disease 2019 (COVID-19) is controversial, and the mortality effect in subgroups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality rates in patients with COVID-19. METHODS: In this retrospective cohort study we compared persons receiving RDV with those receiving best supportive care (BSC). Patients hospitalized between 28 February and 28 May 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection were included with the development of COVID-19 pneumonia on chest radiography and hypoxia requiring supplemental oxygen or oxygen saturation ≤94% with room air. The primary outcome was overall survival, assessed with time-dependent Cox proportional hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use, and random effects for hospital. RESULTS: A total of 1138 patients were enrolled, including 286 who received RDV and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). Comparing persons receiving RDV with those receiving BSC, the hazard ratio (95% confidence interval) for death was 0.46 (.31-.69) in the univariate model (P < .001) and 0.60 (.40-.90) in the risk-adjusted model (P = .01). In the subgroup of persons with baseline use of low-flow oxygen, the hazard ratio (95% confidence interval) for death in RDV compared with BSC was 0.63 (.39-1.00; P = .049). CONCLUSION: Treatment with RDV was associated with lower mortality rates than BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Humanos , Oxígeno , Estudios Retrospectivos , SARS-CoV-2RESUMEN
STUDY OBJECTIVES: To examine the association between substance use and short sleep duration in individuals with schizophrenia or schizoaffective disorder, depressive type (SADD). DESIGN: Cross-sectional, retrospective study. SETTING: Urban, suburban, and rural centers across the United States. PARTICIPANTS: 2,462 consented, adult individuals with schizophrenia or schizoaffective disorder, depressive type (SADD). Participants included inpatients in acute or chronic care settings as well as outpatients and residents in community dwellings. MEASUREMENTS: Substance use was assessed with 10 questions adopted from well-validated measures (e.g., CAGE questionnaire) for alcohol, marijuana, and illicit drugs. Short sleep duration was defined as <6 hr of self-reported sleep per night. RESULTS: Close to 100% of our sample used nicotine while 83% used substances other than nicotine. More importantly, there was a significant association between substance use and short sleep duration. Interestingly, this association was strongest among African-Americans with schizophrenia or SADD. CONCLUSIONS: Because psychiatric medications often target chemical receptors involved with both sleep and substance use, understanding the association between short sleep duration and substance use in individuals with schizophrenia and SADD is important. Given that the majority of premature deaths in individuals with psychotic illness are due to medical conditions associated with modifiable risk factors, prospective studies designed to examine the effect of short sleep duration on behaviors like substance use should be undertaken. Finally, analyzing genetic and environmental data in a future study might help illuminate the strong association found between short sleep duration and substance use in African-Americans with schizophrenia and SADD. © 2015 Wiley Periodicals, Inc.
Asunto(s)
Trastornos Psicóticos/psicología , Psicología del Esquizofrénico , Trastornos del Sueño-Vigilia/psicología , Trastornos Relacionados con Sustancias/psicología , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Esquizofrenia , Autoinforme , Sueño , Encuestas y CuestionariosRESUMEN
Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.
Asunto(s)
Células T Asesinas Naturales , Neoplasias , Síndrome de Dificultad Respiratoria , Humanos , Citocinas/metabolismo , AntiinflamatoriosRESUMEN
Persistent post-COVID syndrome, also referred to as long COVID, is a pathologic entity, which involves persistent physical, medical, and cognitive sequelae following COVID-19, including persistent immunosuppression as well as pulmonary, cardiac, and vascular fibrosis. Pathologic fibrosis of organs and vasculature leads to increased mortality and severely worsened quality of life. Inhibiting transforming growth factor beta (TGF-ß), an immuno- and a fibrosis modulator, may attenuate these post-COVID sequelae. Current preclinical and clinical efforts are centered on the mechanisms and manifestations of COVID-19 and its presymptomatic and prodromal periods; by comparison, the postdrome, which occurs in the aftermath of COVID-19, which we refer to as persistent post-COVID-syndrome, has received little attention. Potential long-term effects from post-COVID syndrome will assume increasing importance as a surge of treated patients are discharged from the hospital, placing a burden on healthcare systems, patients' families, and society in general to care for these medically devastated COVID-19 survivors. This review explores underlying mechanisms and possible manifestations of persistent post-COVID syndrome, and presents a framework of strategies for the diagnosis and management of patients with suspected or confirmed persistent post-COVID syndrome.
Asunto(s)
COVID-19 , Síndrome Post Agudo de COVID-19 , Humanos , Progresión de la Enfermedad , Terapia de Inmunosupresión , Calidad de VidaRESUMEN
BACKGROUND: The COVID-19 pandemic forced a reconsideration of surgical patient management in the setting of scarce resources and risk of viral transmission. Herein we assess the impact of implementing a protocol of more rigorous patient education, recovery room assessment for non-ICU admission, earlier mobilization and post-discharge communication for patients undergoing brain tumor surgery. METHODS: A case-control retrospective review was undertaken at a community hospital with a dedicated neurosurgery and otolaryngology team using minimally invasive surgical techniques, total intravenous anesthesia (TIVA) and early post-operative imaging protocols. All patients undergoing craniotomy or endoscopic endonasal removal of a brain, skull base or pituitary tumor were included during two non-overlapping periods: March 2019-January 2020 (pre-pandemic epoch) versus March 2020-January 2021 (pandemic epoch with streamlined care protocol implemented). Data collection included demographics, preoperative American Society of Anesthesiologists (ASA) status, tumor pathology, and tumor resection and remission rates. Primary outcomes were ICU utilization and hospital length of stay (LOS). Secondary outcomes were complications, readmissions and reoperations. FINDINGS: Of 295 patients, 163 patients were treated pre-pandemic (58% women, mean age 53.2±16 years) and 132 were treated during the pandemic (52% women, mean age 52.3±17 years). From pre-pandemic to pandemic, ICU utilization decreased from 92(54%) to 43(29%) of operations (p<0.001) and hospital LOS≤1 day increased from 21(12.2%) to 60(41.4%), p<0.001, respectively. For craniotomy cohort, median LOS was 2 days for both epochs; median ICU LOS decreased from 1 to 0 days (p<0.001), ICU use decreased from 73(80%) to 29(33%),(p<0.001). For endonasal cohort, median LOS decreased from 2 to 1 days; median ICU LOS was 0 days for both epochs; (p<0.001). There were no differences pre-pandemic versus pandemic in ASA scores, resection/remission rates, readmissions or reoperations. CONCLUSION: This experience suggests the COVID-19 pandemic provided an opportunity for implementing a brain tumor care protocol to facilitate safely decreasing ICU utilization and accelerating discharge home without an increase in complications, readmission or reoperations. More rigorous patient education, recovery room assessment for non-ICU admission, earlier mobilization and post-discharge communication, layered upon a foundation of minimally invasive surgery, TIVA anesthesia and early post-operative imaging are possible contributors to these favorable trends.
Asunto(s)
Neoplasias Encefálicas/cirugía , COVID-19/prevención & control , Pandemias/prevención & control , Estudios de Casos y Controles , Craneotomía/métodos , Recuperación Mejorada Después de la Cirugía , Femenino , Hospitalización , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Alta del Paciente , Readmisión del Paciente , Complicaciones Posoperatorias/prevención & control , Periodo Posoperatorio , Reoperación/métodos , Estudios RetrospectivosRESUMEN
[This corrects the article DOI: 10.1186/s41231-021-00095-0.].
RESUMEN
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.
Asunto(s)
COVID-19 , Senescencia Celular , Fibrinólisis , Humanos , Pulmón , SARS-CoV-2RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious zoonotic pathogen that has exacted heavy public health, social and economic tolls. In February 2020, the World Health Organization acronymed the disease caused by SARS-CoV-2 as COVID-19, for coronavirus disease 2019. The number of confirmed COVID-19 infections, which has been detected in at least 103 countries, has reached 1,970,225 worldwide as of April 14, 2020 with 124,544 deaths, according to the U.S. Centers for Disease Control and Prevention (CDC). Many cases of COVID-19 resolve quickly. However, the disease, which, like other respiratory pathogens that cause common cold symptoms is believed to be transmitted through respiratory droplets. Infection with COVID-19 can also lead to significant morbidity and death; this is particularly the case for cancer patients. Moreover, because the signs and symptoms of COVID-19 are easily misattributed to the sequelae of cancer itself, such as pulmonary embolism, or its treatment, such as nausea and diarrhea, diagnosis may be delayed or missed. Potential COVID-19 rule out criteria, based on the Wells' criteria for pulmonary embolism, another protean disease entity, are provided as a decision-making aid. This review summarizes the current understanding of the transmission, clinical presentation, diagnosis and differential diagnosis, pathogenesis, rationale to treat the cancer or not, treatment and prevention of COVID-19 with an emphasis on implications in cancer.
Asunto(s)
COVID-19/diagnóstico , COVID-19/patología , Toma de Decisiones Clínicas , Neoplasias/complicaciones , Neoplasias/terapia , Inmunidad Adaptativa , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/prevención & control , COVID-19/transmisión , Diagnóstico Diferencial , Humanos , Sistema Renina-Angiotensina , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , VacunaciónRESUMEN
Positive airway pressure (PAP) therapy has been the standard treatment of choice for sleep disordered breathing, with 29-83% of patients being noncompliant. With the advent of newly Food and Drug Adminisatration (FDA)-approved implantable stimulators for treating sleep disordered breathing in a fraction of noncompliant PAP therapy patients, the landscape of sleep medicine and sleep technology is changing to narrow the gap between compliant and non-compliant patients. The remede® System for treating central sleep apnea and the Inspire® upper airway stimulation (UAS) therapy for treating obstructive sleep apnea are providing new tools for sleep physicians, elevating sleep technologists' expertise, and paving the way for personalized medicine.
RESUMEN
Sleep-disordered breathing (SDB) has been noted commonly in hemodialysis (HD) patients, but it is not known whether this is related directly to the treatment of kidney failure with HD or to the higher prevalence of obesity and older age. Forty-six HD patients were compared with 137 participants from the Sleep Heart Health Study (SHHS) who were matched for age, gender, body mass index (BMI), and race. Home unattended polysomnography was performed and scored using similar protocols. The study sample was 62.7 +/- 10.1 yr, was predominantly male (72%) and white (63%), and had an average BMI of 28 +/- 5.3 kg/m(2). The HD sample had a higher systolic BP (137 versus 121 mmHg; P < 0.01) and a higher prevalence of diabetes (33 versus 9%; P < 0.01) and cardiovascular disease (33 versus 13%; P < 0.01) compared with the SHHS sample. The HD group had significantly less sleep time (320 versus 379 min; P < 0.0001) but similar sleep efficiency. HD patients had a higher frequency of arousals per hour (25.1 versus 17.1; P < 0.0001) and apnea-hypopneas per hour (27.2 versus 15.2; P < 0.0001) and greater percentage of the total sleep time below an oxygen saturation of 90% (7.2 versus 1.8; P < 0.0001). HD patients were more likely to have severe SDB (>30 respiratory events per hour) compared with the SHHS sample (odds ratio 4.07; 95% confidence interval 1.83 to 9.07). There was a strong association of HD with severe SDB and nocturnal hypoxemia independent of age, BMI, and the higher prevalence of chronic disease. The potential mechanisms for the higher likelihood of SDB in the HD population must be identified to provide specific prevention and therapy.