Clinical characteristics of imported and second-generation coronavirus disease 2019 (COVID-19) cases in Shaanxi outside Wuhan, China: a multicentre retrospective study.

The mortality of coronavirus disease 2019 (COVID-19) differs between countries and regions. This study aimed to clarify the clinical characteristics of imported and second-generation cases in Shaanxi. This study included 134 COVID-19 cases in Shaanxi outside Wuhan. Clinical data were compared between severe and non-severe cases. We further profiled the dynamic laboratory findings of some patients. In total, 34.3% of the 134 patients were severe cases, 11.2% had complications. As of 7 March 2020, 91.8% patients were discharged and one patient (0.7%) died. Age, lymphocyte count, C-reactive protein, erythrocyte sedimentation rate, direct bilirubin, lactate dehydrogenase and hydroxybutyrate dehydrogenase showed difference between severe and no-severe cases (all P < 0.05). Baseline lymphocyte count was higher in survived patients than in non-survivor case, and it increased as the condition improved, but declined sharply when death occurred. The interleukin-6 (IL-6) level displayed a downtrend in survivors, but rose very high in the death case. Pulmonary fibrosis was found on later chest computed tomography images in 51.5% of the pneumonia cases. Imported and second-generation cases outside Wuhan had a better prognosis than initial cases in Wuhan. Lymphocyte count and IL-6 level could be used for evaluating prognosis. Pulmonary fibrosis as the sequelae of COVID-19 should be taken into account.

Ischemic Stroke in Young Adults of Northern China: Characteristics and Risk Factors for Recurrence.

BACKGROUND: Young adults accounted for 10-14% of ischemic stroke patients. The risk factors may differ in this population from elder patients. In addition, the factors associated with stroke recurrence in this population have not been well investigated. OBJECTIVE: The study aimed to investigate the characteristics and risk factors associated with recurrence of ischemic stroke in young adults. METHODS: Clinical data of 1,395 patients of age 18-45 years who were treated between 2008 and 2014 in 3 centers located in northern China was reviewed. The first onset of stroke was taken as the initial events and recurrent stroke as the end point events. The end point events, age, gender, duration after first onset of stroke, history of disease, National Institutes of Health Stroke Scale (NIHSS) score at admission, Trial of Org 10172 in Acute Stroke Treatment classifications of the cause of stroke and adherence to medication were recorded. These factors were analyzed and compared between recurrence and non-recurrence group. Information about recurrent stroke was collected through clinical (readmission to hospital with ischemic stroke) or telephone follow-up survey. Logistic regression was used to analyze the risk factors of recurrence. RESULTS: The most common causes of stroke were large vessel atherosclerosis and small vessel occlusion, followed by cardioembolism. NIHSS score at admission (OR 1.088; 95% CI 1.028-1.152; p = 0.004) were associated with recurrence. CONCLUSIONS: Vascular disease, especially premature atherosclerosis, is the major risk factor for ischemic stroke in the young adult population of northern China. Timely screening of the cause of stroke with severe NIHSS score needs further attention.

Thermochromic Hydrogels with Adjustable Transition Behavior for Smart Windows.

With the fast economic development and accelerating urbanization, more and more skyscrapers made entirely of concrete and glass are being constructed. To keep a comfortable indoor environment, massive energy for air conditioning or heating appliances is consumed. A huge amount of heat (>30%) is gained or released through glass windows. Using smart windows with the capability to modulate light is an effective way to reduce building energy consumption. Thermochromic hydrogel is one of the potential smart window materials due to its excellent thermal response, high radiation-blocking efficiency, cost-effectiveness, biocompatibility, and good uniformity. In this work, polyhydroxypropyl acrylate (PHPA) hydrogels with controllable lower critical solution temperature (LCST) were prepared by photopolymerization. The transition temperature and transition rate under "static transition" conditions were investigated. Unlike "static" conditions in which the transition temperature was not affected by the initial and final temperature and heating/cooling ramp, the transition temperature varied with the rate of temperature change under dynamic conditions. The "dynamic" transition temperature of the PHPA hydrogel gradually increased with the increase of the heating rate. It was the result of the movement of the molecular chains lagging behind the temperature change when the temperature change was too fast. The results of the solar irradiation experiment by filling PHPA hydrogels into double glazing windows showed that the indoor temperature was about 15 °C lower than that of ordinary glass windows, indicating that it can significantly reduce the energy consumption of air conditioning. In addition, a wide range of adjustable transition temperatures and fast optical response make PHPA hydrogels potentially applicable to smart windows.

Nocebo response intensity and influencing factors in the randomized clinical trials of irritable bowel syndrome: A systematic review and meta-analysis.

Objective: To estimate the magnitude of the nocebo response and explore its influencing factors in irritable bowel syndrome (IBS). Methods: The PubMed, Embase, and Cochrane Library databases were searched up to March 2021. We performed a random effects meta-analysis of the proportion of adverse events (AEs) in placebo-treated patients with IBS who are involved in parallel-designed, randomized, placebo-controlled trials investigating pharmacological interventions and evaluated the effect of trial characteristics on the magnitude of the nocebo response rate. Results: A total of 6,107 studies were identified from the databases. After evaluation, 53 met the eligibility criteria and were included. The overall pooled nocebo response rate was 32% (95% CI: 26-38%). The most commonly reported AEs were headache (9%), nasopharyngitis (7%), abdominal pain (4%), and nausea (4%). The nocebo response rate was low compared with that in the treatment group applying probiotics, antispasmodics, and Traditional Chinese medicine, but high compared with that in antibiotic treatment group. The nocebo rate in patients using diaries to record AEs was lower than the average, and was higher in patients recording through checkup. Discussion: Patients with IBS have significant nocebo response intensity in clinical trials. Based on findings in this study, we recommend the researchers pay attention to the common AEs and carefully analyze the relation to the intervention.

Patterned Magnetofluids via Magnetic Printing and Photopolymerization for Multifunctional Flexible Electronic Sensors.

Liquid conductor-based flexible sensors with high mechanical deformability and reliable electrical reversibility have aroused great interest in electronic skin, soft robotics, environmental monitoring, and other fields. Herein, we develop a novel strategy to fabricate liquid conductor-based flexible sensors by combining ionic liquid-based magnetofluids (IL-MFs), magnetic printing, and photopolymerization techniques. The as-prepared sensors exhibit excellent electromechanical properties, such as a wide detection range, low hysteresis, fast response time, good durability, etc. Moreover, the gauge factors (GFs) of the sensor could be easily adjusted by changing the modulators with different line widths or patterns, and the strain sensors can also be designed for anisotropic monitoring. Apart from serving as strain sensors, the magnetofluid-based flexible sensors can be used to detect external pressure, human activities, and changes in temperature, illumination, and magnetic field as well. This work provides a facile strategy to fabricate liquid conductor-based multifunctional sensors. Such a magnetofluid-based sensor has a great promising future.

Post-infection A77-1726 blocks pathophysiologic sequelae of respiratory syncytial virus infection.

Despite respiratory syncytial virus (RSV) bronchiolitis remaining the most common cause of lower respiratory tract disease in infants worldwide, treatment has progressed little in the past 30 years. The aim of our study was to determine whether post-infection administration of de novo pyrimidine synthesis inhibitors could prevent the reduction in alveolar fluid clearance (AFC) and hypoxemia that occurs at Day 2 after intranasal infection of BALB/c mice with RSV. BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice after instillation of 5% bovine serum albumin into the dependent lung. Post-infection systemic treatment with leflunomide has no effect on AFC. However, when added to the AFC instillate, leflunomide's active metabolite, A77-1726, blocks RSV-mediated inhibition of AFC at Day 2. This block is reversed by uridine (which allows pyrimidine synthesis via the scavenger pathway) and not recapitulated by genistein (which mimics the tyrosine kinase inhibitor effects of A77-1726), indicating that the effect is specific for the de novo pyrimidine synthesis pathway. More importantly, when administered intranasally at Day 1, A77-1726, but not its vehicle dimethyl sulfoxide, maintains its beneficial effect on AFC and lung water content until Day 2. Intranasal instillation of A77-1726 at Day 1 also reduces bronchoalveolar lavage nucleotide levels, lung inflammation, and hypoxemia at Day 2 without impairing viral replication at Day 2 or viral clearance at Day 8. Post-infection intranasal or aerosolized treatment with pyrimidine synthesis inhibitors may provide symptomatic relief from the pathophysiologic sequelae of impaired AFC in children with RSV bronchiolitis.

In vitro and in vivo fitness of respiratory syncytial virus monoclonal antibody escape mutants.

Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.

Leflunomide prevents alveolar fluid clearance inhibition by respiratory syncytial virus.

RATIONALE: Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors. OBJECTIVES: To confirm that RSV-induced inhibition of AFC is mediated by uridine triphosphate (UTP), and to demonstrate that inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. METHODS: BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice by instillation of 5% bovine serum albumin into the dependent lung. Some mice were pretreated with leflunomide or 6-mercaptopurine. MEASUREMENTS AND MAIN RESULTS: RSV-mediated inhibition of AFC is associated temporally with a 20-nM increase in UTP and ATP content of bronchoalveolar lavage fluid, hypoxemia, and altered nasal potential difference. RSV-mediated nucleotide release, AFC inhibition, and physiologic sequelae thereof can be prevented by pretreatment of mice with the de novo pyrimidine synthesis inhibitor leflunomide, which is not toxic to the mice, and which does not affect RSV replication in the lungs. In contrast, pretreatment of mice with 6-mercaptopurine, an inhibitor of de novo purine synthesis, has no beneficial effect on AFC or other indicators of disease progression. Finally, RSV-mediated inhibition of AFC is prevented by volume-regulated anion channel inhibitors. CONCLUSION: Pyrimidine synthesis or release pathways may provide novel therapeutic targets to counter the pathophysiologic sequelae of impaired AFC in RSV disease.

Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is characterized by excess accumulation of protoporphyrin, which is due to deficient activity of the enzyme ferrochelatase (FECH). This results in photosensitivity and in some patients liver disease which may necessitate liver transplantation. The aim of this study was to delineate the abnormalities in the FECH gene which cause phenotypic expression in EPP. We identified 43 individuals from 25 North American families with EPP who were heterozygous for various FECH mutations, but the mutations did not adequately explain the variable phenotype. We also examined the presence of an intron polymorphism (IVS3-48c) in the FECH gene which was shown to cause the formation of aberrantly spliced FECH mRNA. FECH DNA analysis demonstrated that 94% of 31 symptomatic individuals with FECH mutations were heterozygous for IVS3-48c, whereas 12 asymptomatic individuals with FECH mutations were homozygous for IVS3-48t. Haplotype analysis in four families showed that symptomatic members had the IVS3-48c polymorphism in the non-mutant FECH allele. Sequencing of the proximal FECH gene promoter showed no additional changes which might affect gene expression. The levels of normal FECH mRNA, measured by relative quantitative RT-PCR, and FECH enzyme activity were correspondingly lower in the cultured lymphoblasts of family members with the IVS3-48c polymorphism. These results indicate that symptomatic disease in most North American patients with EPP is explained by the inheritance of a mutation in one FECH allele which causes a structural alteration in the protein, together with a low expressing non-mutant FECH allele which is caused by the IVS3-48c polymorphism.

Respiratory syncytial virus escape mutant derived in vitro resists palivizumab prophylaxis in cotton rats.

Palivizumab (PZ) is the only monoclonal antibody in human use against an infectious disease. PZ is a humanized monoclonal antibody that recognizes the fusion protein of respiratory syncytial virus (RSV). PZ prophylaxis reduces the likelihood of hospitalization for young children at risk for severe RSV infections. The quasispecies nature of RNA viruses allows rapid emergence of viruses with a selective advantage. A PZ resistant virus was selected by passage of RSV in the presence of PZ in cell culture. The cell culture-derived virus was completely resistant to PZ prophylaxis in cotton rats. The increasing use of PZ, and in particular, the use of PZ in immunosuppressed patients, provide opportunities for resistant viruses to emerge. Whether such viruses will appear and be of clinical significance for humans is unknown. Preclinical studies in cotton rats predicted the efficacy of PZ in humans; these results suggest that if PZ resistant viruses arise in humans, PZ prophylaxis may be ineffective.

Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease.

A deficiency of ferrochelatase (FECH) activity underlies the excess accumulation of protoporphyrin that occurs in erythropoietic protoporphyria (EPP). In some patients, protoporphyrin accumulation causes liver damage that necessitates liver transplantation. The purpose of this study was to determine if specific mutations in the FECH gene are present in patients who develop liver disease. FECH cDNA and all 11 exons and their flanking intron regions in the FECH gene were amplified and sequenced by specific polymerase chain reactions. Gene mutations were determined in 34 individuals from 24 families: 14 had liver disease, 10 necessitating liver transplantation. All individuals were heterozygous for mutations that altered the coding region of FECH mRNA. The mutations in patients with liver disease were heterogenous, but usually caused a major structural alterations in the FECH protein, most commonly as a result of exon skipping in FECH mRNA. However, the mutations could not account for the severe phenotype by themselves, since the same mutations were found in asymptomatic family members of patients with liver disease and in patients from families in which liver disease was not present. Other genetic factors, and possibly acquired factors, also must be critical to the development of this severe phenotype in EPP.

Variable resistance to palivizumab in cotton rats by respiratory syncytial virus mutants.

BACKGROUND: Palivizumab (PZ) is the only monoclonal antibody in use against a human infectious disease. PZ is given as prophylaxis against infection with respiratory syncytial virus (RSV). An RSV escape mutant, MP4, has been shown to resist PZ prophylaxis in cotton rats. METHODS: To further define the potential of RSV to resist prophylaxis, additional PZ-resistant viruses were selected in cell culture and were tested for susceptibility to PZ in cotton rats. RESULTS: Mutant MS412 had an A-->C mutation at nucleotide position 827 in the F gene, resulting in an amino acid change from Lys to Gln at position 272. Mutant F212 had an A-->T mutation at position 816, leading to an amino acid change from Asn to Ile at position 268. In vitro, F212 had impaired growth kinetics. In cell culture, F212 was partially and MS412 was completely resistant to PZ neutralization. A single prophylactic dose of 15 mg/kg PZ protected cotton rats from infection with F212 but not with MS412. CONCLUSION: Both in vitro and in vivo, individual RSV PZ escape mutants varied in their susceptibility to PZ. Mutations associated with resistance to PZ did not always result in failure of PZ prophylaxis.