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The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity1. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic2. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identified an LNA ASO binding to the 5 leader sequence of SARS-CoV-2 ORF1a/b that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the K18-hACE2 humanized COVID-19 mouse model potently (98-99%) suppressed viral replication in the lungs of infected mice, revealing strong prophylactic and treatment effects. We found that the LNA ASO also represses viral infection in golden Syrian hamsters, and is highly efficacious in countering all SARS-CoV-2 "variants of concern" tested in vitro and in vivo, including B.1.427, B.1.1.7, and B.1.351 variants3. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce transmission of variants partially resistant to vaccines and monoclonal antibodies, and could be deployed intranasally for prophylaxis or via lung delivery by nebulizer to decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences4, and they may have particular impact in areas where vaccine distribution is a challenge, and could be stockpiled for future coronavirus pandemics.
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Alzheimer's disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aβ), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.
Assuntos
Animais , Humanos , Doença de Alzheimer , Diagnóstico , Terapêutica , Biomarcadores , Sangue , Pesquisa Biomédica , Métodos , Progressão da Doença , Imageamento por Ressonância MagnéticaRESUMO
Objective To evaluate the effect of precision anesthesia strategy on postoperative cognitive function in elderly patients undergoing hip replacement.Methods Seventy elderly patients of both sexes,aged 65-85 yr,weighing 50-75 kg,of American Society of Anesthesiologists physical status Ⅰ or Ⅱ,scheduled for elective unilateral hip replacement under general anesthesia,with years of education＞6 yr,were divided into 2 groups (n =35 each) using a random number table:precision anesthesia group (group P) and routine anesthesia group (group R).Anesthetic protocol and perioperative management were optimized using precision anesthesia strategy in group P.Routine anesthetic protocol and perioperative management were performed in group R.Peripheral venous blood samples were collected at 1 day before operation (T0) and 1,6,12 and 24 h after operation (T1-4) for determination of serum S100β protein,neuronspecific enolase (NSE),interleukin-1beta (IL-1β),IL-6,tumor necrosis factor-alpha (TNF-α) and Creactive protein (CRP) concentrations by enzyme-linked immunosorbent assay.The patient's cognitive function was assessed using Mini-Mental State Examination (MMSE) at T0 and 3 and 7 days after operation (T5,6).Results Compared with the baseline at T0,the serum S100β protein and NSE concentrations were significantly increased at T1-3,the serum IL-1β,IL-6 and TNF-α concentrations were increased at T1-4,the CRP concentrations were increased at T2,3,MMSE scores were decreased at T5 in group R,and the serum S100β protein,IL-1β and IL-6 concentrations were significantly increased at T1-3,the serum NSE and CRP concentrations were increased at T2,the serum TNF-α concentrations were increased at T1-4,and MMSE cores were decreased at T5 in group P (P＜0.05).Compared with group R,the serum S100β protein and IL-1β concentrations were significantly decreased at T1,2,the serum NSE and TNF-α concentrations were decreased at T1-3,the serum IL-6 concentrations were decreased at T2,3,and MMSE scores were increased at T5 in group P (P＜ 0.05).Conclusion Precision anesthesia strategy can improve postoperative cognitive function in elderly patients undergoing hip replacement,which is related to inhibiting inflammatory responses.
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Objective To investigate the angiographic manifestations of renal artery injury caused by percutaneous nephrolithotomy, and to evaluate the therapeutic effect of super-selective renal arterial embolization in treating renal artery injury. Methods A total of 22 patients with persistent or intermittent gross hematuria that occurred after percutaneous nephrolithotomy, who were encountered at authors’ hospital during the period from Jan. 2010 to June 2014, were included in this study. The diagnosis was confirmed by renal angiography in all patients, and super-selective renal arterial embolization with steel micro-coils was carried out in all patients. The patients were followed up for three months. The results were analyzed. Results Of the 22 patients, DSA examination showed that renal artery pseudoaneurysm (RAP) was found in 14 (63.6%), renal arteriovenous fistula (RAVF) in 5 (22.7%) and RAP associated with RAVF in 3 (13.6%). Renal angiography performed after super-selective renal arterial embolization showed that complete obstruction of the bleeding arteries was achieved in all patients, and the active bleeding stopped. Both the technical success rate and the hemostasis rate were 100%. During the follow-up period lasting for three months, no recurrence of hematuria or severe complications occurred. In 20 patients, different degree of embolism syndrome was observed after the treatment. Conclusion Renal artery pseudoaneurysm and renal arteriovenous fistula are the main types of renal artery injury after percutaneous nephrolithotomy. Super-selective renal arterial embolization with micro-coils can be used as the treatment of choice for patients who has failed to respond to conservative therapy.
