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51.
Hit, Lead & Candidate Discovery
A variety of novel 2-(methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl)phenyl) quinazolin-4(3H)-ones have been synthesized by treating 3-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)-2-(methyl/phenyl)-quinazolin-4(3H)-one with a variety of secondary amines. Graph theoretical analysis was used in identification of drug target that is, NMDAR (N-methyl-d -aspartate receptors). The observed reports of in silico modeling and ligand based toxicity, metabolism prediction studies were encouraging us to synthesize of title compounds and evaluate their antiepileptic effects. The title compounds were tested for its antiepileptic potency by MES and scPTZ model. Rotorod test is used to assess its neurotoxicity. In the preliminary test it was found that in MES test, analogs 6d , 6e , 6f, and 6l were potent; whereas in scPTZ test analogs 6d , 6e , 6f, and 6k displayed potent antiepileptic activity. Additionally these five derivatives were tested in rats orally at a dose of 30 mg/kg and found that compounds 2-methyl-3-(4-(5-morpholino-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4(3H)-one 6e and 2-methyl-3-(4-(5-(piperidin-1-yl)-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4(3H)-one 6f exhibited superior activity than reference Phenytoin. In MES test, these derivatives 6e and 6f showed activity at 30 mg/kg i.p. dose after 0.5 hr and 4.0 hr. In scPTZ test these derivatives 6e and 6f showed activity at 100 and 300 mg/kg i.p. dose after 0.5 hr and 4.0 hr, respectively.  相似文献   
52.
53.

Objective

Triage is basically a categorization process to prioritize various treatments for patients based on the types of disease, severity, prognosis and resource availability. However, the term triage is more appropriate to be used in the context of natural disaster or mass casualties. Within the context of emergency situation in emergency department, the term triage refers to a method used to assess the severity of patients’ condition, determine the level of priority, and mobilize the patients to the suitable care unit. ESI is a new concept of triage using five scales in classifying the patients in emergency department. The real implementation of this concept demands nurses have to immediately make assessment about patients’ condition right away, besides they must give their final decision, whether to move the patients to the ward or to let them leave the hospital.

Method

This research was done using Pretest–Posttest one Group Design, involving 21 nurses in the Emergency Department of RSUD Pariaman as research respondents. Before respondents were introduced to ESI method, their basic skills had been previously evaluated, which evaluation results were compared to the after-treatment results. A set of questionnaires consisting of 10 cases were used as research instrument.

Results

The result of this research showed that the value or rank difference between common triage and ESI triage categorization was positive (N). The mean rank was found at 11.00, while the sum of positive rank was 231.0 as shown in Asymp. Sig. (2-tailed) score of 0.00 lower than 0.05. Therefore, the null hypothesis was rejected.

Conclusions

There were differences in triage categorization before and after respondents were introduced to ESI method.  相似文献   
54.
小儿急性咳嗽作为儿科常见病,因小儿脏腑娇嫩、形气未充,具有发病急骤、传变迅速的病理特点,故易出现各种变证,建立完善的小儿急性咳嗽诊治体系就显得尤为重要。因咳嗽病程不同,病邪部位有异,辨证论治之法亦有不同,唐方教授通过多年临床实践归纳和总结出小儿咳嗽从"肺胃肝三脏"治疗理论。该理论以脏腑辨证为基础,具有紧抓主症、用药考究、灵活加减的特点。临床用药加减则依据肺主宣发肃降,故多予炙麻黄、桔梗开宣肺气,予桑白皮、葶苈子降气止咳,且小儿生理特点为"脾常不足",故而过量进食之后,损伤脾胃,造成肺胃热盛同病,胃多气多血之腑,故予红景天、地龙、牡丹皮活血凉血清热。通过对临床医案的分析,进一步阐释从"肺胃肝三脏"治疗理论,从而为小儿咳嗽的临床诊治工作提供有益借鉴。  相似文献   
55.

Objectives

Although valved venous homografts (VVHs) are used for establishing right ventricle-to-pulmonary artery continuity in some complex heart defects, the tissue changes that occur in situ have not been described. We review the gross and microscopic changes observed in explanted VVH conduits and their effects on functionality.

Methods

In total, 20 explanted VVH conduits were evaluated for valve integrity, presence of thrombus, and stenosis. Hematoxylin and eosin– and trichrome-stained sections were reviewed for neointima formation, wall remodeling, inflammation, and calcification. Regurgitation and narrowing were assessed on pre-explant echocardiogram, and angiographic video clips were correlated with tissue findings. The source of the proliferating cells within the conduits was investigated by fluorescent in situ hybridization.

Results

Thirteen male and 7 female infants underwent VVH implantation either as part of a composite Sano shunt (65%) or to establish right ventricle-to-pulmonary artery continuity in biventricular hearts (35%). The median duration of conduits in situ was 140 days (range: 98-340 days). Conduits were predominantly explanted for staged conversion to bidirectional Glenn (60%) and conduit upsizing (20%). The valves remained intact and functional in 75% of cases. Occlusive thrombosis was absent in all. Wall thickening due to neointima formation and wall remodeling was uniformly present and appeared to be driven by smooth muscle actin–expressing cells, which by fluorescent in situ hybridization are predominantly of recipient origin. Minimal calcification and mild adventitial chronic inflammation were present.

Conclusions

Vein wall thickening is a uniform finding and can cause stenosis. The valves remain functional in most, and vein walls undergo remodeling with only minimal inflammation and calcification.  相似文献   
56.
57.

Background

The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies.

Methods

Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomly vaccinated with RZV or placebo. Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants receiving at least one dose of RZV or placebo. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30?days after each vaccination, respectively. Serious AEs (SAEs) were collected from the first vaccination until 12?months post-last dose. Fatal AEs, vaccination-related SAEs, and potential immune-mediated diseases (pIMDs) were collected during the entire study period.

Results

Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recipients reported unsolicited AEs (50.5% versus 32.0%); the difference was driven by transient injection site and solicited systemic reactions that were generally seen in the first week post-vaccination. The occurrence of overall SAEs (RZV: 10.1%; Placebo: 10.4%), fatal AEs (RZV: 4.3%; Placebo: 4.6%), and pIMDs (RZV: 1.2%; Placebo: 1.4%) was balanced between groups. The occurrence of possible exacerbations of pIMDs was rare and similar between groups. Overall, except for the expected local and systemic symptoms, the safety results were comparable between the RZV and Placebo groups irrespective of participant age, gender, or race.

Conclusions

No safety concerns arose, supporting the favorable benefit-risk profile of RZV.  相似文献   
58.
《Vaccine》2019,37(43):6310-6316
BackgroundSerotype 3 pneumococcal disease has not substantially declined at the population level after the routine introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into pediatric immunization programs across the globe. This epidemiological finding has generated debate regarding the effectiveness of PCV13 against serotype 3 disease. Evaluating PCV13 effectiveness against serotype 3 is especially critical in adults, where serotype 3 makes up an important amount of remaining pneumococcal disease.MethodsWe performed a systematic review of the published literature to assess the direct effectiveness of PCV13 against serotype 3 community-acquired pneumonia (CAP) among adults. We then estimated overall vaccine effectiveness (VE) using a pooled analysis of the individual-level, raw data.ResultsTwo published studies met inclusion criteria. One was a randomized controlled trial conducted in the Netherlands and published in 2014. The other was a recently-published case-control study conducted in Louisville, Kentucky that used a test-negative design (TND). We also identified a third TND study conducted in Argentina that was recently presented as a conference abstract but is not yet published. All three studies were conducted in adults aged ≥65 years. PCV13 VE against serotype 3 hospitalized CAP was 52.5% (95%CI: 6.2–75.9%) from the pooled analysis of individual-level data from all three studies. Results were similar if the unpublished estimate was excluded (serotype 3 VE = 53.6% [95%CI: 6.7–76.9%]). No heterogeneity was observed.ConclusionsCurrently-available evidence, although limited to three studies, suggests that PCV13 provides direct protection against serotype 3 hospitalized CAP in adults aged ≥65 years.  相似文献   
59.
《Vaccine》2019,37(44):6696-6706
Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials.  相似文献   
60.
《Vaccine》2019,37(22):2952-2959
CD8+ T cells are known to control infections, but their role in preventing latent infection from establishing has not been thoroughly investigated.We hypothesized that a potent CD8+ T cell response patrolling the mucosal viral entry points could kill the first infected cells and thereby abrogate the infection before latency is established.To investigate this, replication deficient adenovirus serotype 5 vectors encoding murine γ-herpesvirus-68 CD8+ T cell epitopes linked to the T cell adjuvant Invariant chain, were developed. We show that intranasal vaccination of mice reduces the risk of establishment of latent infection from multiple intranasal ID50 challenges with murine γ-herpesvirus-68 by 81% per exposure at 14 days post vaccination. Protection waned over time, but immune responses were extended by heterologous prime-boost vaccination applied simultaneously intramuscularly and intranasally, and animals vaccinated 66 days prior to challenge showed a strong trend of long-term protection.Our data provides evidence that CD8+ T cells are able to protect against establishment of latent infection. Although the protective efficacy is difficult to maintain over time, this proof-of-concept study suggests a role for a CD8+ T cell arm in future vaccine strategies against latent human viral infections caused by pathogens such as HIV and multiple herpes virus.  相似文献   
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