A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

Poly traditional Chinese medicine formulation prepared with skin moisturizing properties.

Many traditional Chinese medicine compositions can moisturize the skin and utilize in cosmetics. Using a combination of Chinese Medicine Materials and guided by Traditional Chinese Medicine principles, this study selected Echinacea purpurea to protect the skin barrier, Dendrobium nobile to clear heat and promote fluid production, Sophora flavescens to clear heat for diminished inflammation, and Aloe vera combined Lycium barbarum to nourish yin, to together form a "poly TCM moisturizing formulation." These poly plant extracts were investigated and optimized for the stability, safety, and moisturizing ability. The combination moisturizing effect was determined by measuring the expression of FLG mRNA, CLDN-1 mRNA, and AQP3 protein. Toxicological analysis included a red blood cell hemolysis test and a 3T3 phototoxicity test. It has been observed that by using polysaccharide yield as the evaluation criterion showed optimal extraction at a material-to-liquid ratio of 1:100, an extraction temperature of 100°C, and an extraction time of 3 hours. Moisturizing effect experiments showed that the expression of FLG mRNA, CLDN-1 mRNA, and AQP3 protein was significantly increased. Toxicological tests showed that the composition was safe and caused no irritating effects. Based on these results, this poly traditional Chinese medicine moisturizing formulation is safe within moisturizing effects and can be used as a moisturizing raw material in cosmetics.

In vivo Raman spectroscopy study on the stimulation mechanism of surfactant.

BACKGROUND: Surfactant is widely used in skin care products and cleansers, while it may cause physical discomfort. In this study, in vivo Raman spectroscopy was used to explore surfactant irritation mechanism on skin, which was not found in literature. METHODS: Sodium dodecyl sulfate (SDS) was chosen to represent surfactant. Research on the negative effect of SDS was undertaken by scanning the two states of the skin (without and with the contact of SDS), respectively, on six volunteers, by means of Raman technique and skin magnifier. RESULTS: The damage to the surface of normal skin by SDS was visible from the photographs taken by skin magnifier, and the apparent damage matched the damage that was happening underneath the skin elucidated by Raman spectra. Compared to the normal skin, the inter-cellular lipids (ICL) lateral packing order of the damaged skin was significantly reduced in 2-12 µm of skin depth (P < 0.05), deeper than 12 µm was not detected. The skin depth of 0-2 µm could not be determined due to strong interference of SDS. Significant change in the secondary and tertiary structures of keratin was not found.

Recovery of severe COVID-19 complicated with cerebral infarction: Considerations on a case report.

RATIONALE: The standardization, individualization, and rationalization of intensive care and treatment for severe patients have improved. However, the combination of corona virus disease 2019 (COVID-19) and cerebral infarction presents new challenges beyond routine nursing care. PATIENT CONCERNS AND DIAGNOSES: This paper examines the rehabilitation nursing of patients with both COVID-19 and cerebral infarction as an example. It is necessary to develop a nursing plan for COVID-19 patients and implement early rehabilitation nursing for cerebral infarction patients. INTERVENTIONS: Timely rehabilitation nursing intervention is essential to enhance treatment outcomes and promote patient rehabilitation. After 20 days of rehabilitation nursing treatment, patients showed significant improvement in visual analogue scale score, drinking test, and upper and lower limb muscle strength. OUTCOMES: Treatment outcomes for complications, motor function, and daily activities also improved significantly. LESSONS: Critical care and rehabilitation specialist care play a positive role in ensuring patient safety and improving their quality of life by adapting measures to local conditions and the timing of care.

Evaluation for causal effects of socioeconomic traits on risk of female genital prolapse (FGP): a multivariable Mendelian randomization analysis.

BACKGROUND: Although observational studies have established some socioeconomic traits to be independent risk factors for pelvic organ prolapse (POP), they can not infer causality since they are easily biased by confounding factors and reverse causality. Moreover, it remains ambiguous which one or several of socioeconomic traits play predominant roles in the associations with POP risk. Mendelian randomization (MR) overcomes these biases and can even determine one or several socioeconomic traits predominantly accounting for the associations. OBJECTIVE: We conducted a multivariable Mendelian randomization (MVMR) analysis to disentangle whether one or more of five categories of socioeconomic traits, "age at which full-time education completed (abbreviated as "EA")", "job involving heavy manual or physical work ("heavy work")", "average total household income before tax (income)", "Townsend deprivation index at recruitment (TDI)", and "leisure/social activities" exerted independent and predominant effects on POP risk. METHODS: We first screened single-nucleotide polymorphisms (SNPs) as proxies for five individual socioeconomic traits and female genital prolapse (FGP, approximate surrogate for POP due to no GWASs for POP) to conduct Univariable Mendelian randomization (UVMR) analyses to estimate causal associations of five socioeconomic traits with FGP risk using IVW method as major analysis. Additionally, we conducted heterogeneity, pleiotropy, and sensitivity analysis to assess the robustness of our results. Then, we harvested a combination of SNPs as an integrated proxy for the five socioeconomic traits to perform a MVMR analysis based on IVW MVMR model. RESULTS: UVMR analyses based on IVW method identified causal effect of EA (OR 0.759, 95%CI 0.629-0.916, p = 0.004), but denied that of the other five traits on FGP risk (all p > 0.05). Heterogeneity analyses, pleiotropy analyses, "leave-one-out" sensitivity analyses and MR-PRESSO adjustments did not detect heterogeneity, pleiotropic effects, or result fluctuation by outlying SNPs in the effect estimates of six socioeconomic traits on FGP risk (all p > 0.05). Further, MVMR analyses determined a predominant role of EA playing in the associations of socioeconomic traits with FGP risk based on both MVMR Model 1 (OR 0.842, 95%CI 0.744-0.953, p = 0.006) and Model 2 (OR 0.857, 95%CI 0.759-0.967, p = 0.012). CONCLUSION: Our UVMR and MVMR analyses provided genetic evidence that one socioeconomic trait, lower educational attainment, is associated with risk of female genital prolapse, and even independently and predominantly accounts for the associations of socioeconomic traits with risk of female genital prolapse.

Establishment of a prognostic signature for lung adenocarcinoma by integration of 7 pyroptosis-related genes and cross-validation between the TCGA and GEO cohorts: A comprehensive bioinformatics analysis.

Pyroptosis-related genes (PRGs) have been reported to be associated with prognosis of lung adenocarcinoma (LUAD). Until now, the relationship of PRGs to the prognosis of LUAD patients and its underlying mechanisms have been poorly elucidated. Using The Cancer Genome Atlas (TCGA) LUAD cohort, a prior bioinformatics analysis constructed a prognostic signature incorporating 5 PRGs (NLRP7, NLRP1, NLRP2, NOD1, and CASP6) for predicting prognosis of LUAD patients. However, it has not been validated by the Gene Expression Omnibus (GEO) LUAD cohort yet. We implemented a modified bioinformatics analysis to, respectively, construct one prognostic signature with the TCGA cohort and with the GEO cohort and attempted to perform cross-validations by the GEO cohort and the TCGA cohort alternately in turn. Univariate and multivariate Cox regression analysis screened PRGs and constructed 2 prognostic signatures with the TCGA and GEO cohorts. All LUAD samples were classified into high- and low-risk groups according to the median risk score that was generated by regression formula. Kaplan-Meier survival analysis compared the overall survival rate between the 2 risk groups, and receiver operating characteristic curve analysis evaluated predictive performance of the 2 signatures. Additionally, risk score, combined with clinicopathological features, was subjected to multivariate Cox regression analysis, to evaluate independent prognostic value of the 2 signatures. Finally, the 2 signatures received cross-validations by the GEO and TCGA cohorts, alternately. The TCGA cohort yielded a 3-gene signature (PYCARD, NLRP1, and NLRC4), whereas the GEO cohort built a 7-gene signature (SCAF11, NOD1, NLRP2, NLRP1, GPX4, CASP8, and AIM2) for predicting the prognosis of LUAD patients. Multivariate analysis proved independent prognostic value of risk score in the TCGA cohort (hazard ratio, = 1.939,; P = 8.43 × 10-4) and the GEO cohort (hazard ratio, = 2.291,; P = 4.34 × 10-9). Cross-validations confirmed prognostic value for the 7-gene signature from the GEO cohort by the TCGA cohort but not for the 3-gene signature from the TCGA cohort by the GEO cohort. We develop and validate a 7-gene prognostic signature (SCAF11, NOD1, NLRP2, NLRP1, GPX4, CASP8, and AIM2) with independent prognostic value for patients with LUAD.

Causal relationship between insomnia and tuberculosis: A bi-directional Mendelian randomization analysis.

Previous observational studies appear to have established a bi-directional association between sleep disorders and tuberculosis. However, their conclusions are prone to be biased by confounding effects and reverse causation due to the nature of observational studies. Mendelian randomization (MR) approach provides unconfounded estimates of causal effects and overcomes the limitations of observational studies. We performed a bi-directional MR analysis to clarify whether there existed a causal effect of insomnia on tuberculosis, or tuberculosis on insomnia. In forward-direction MR, we chose genome-wide significant (P < .5 × 10-8) and independent (r2 < 0.001) single-nucleotide polymorphisms (SNPs) as instrumental variants (IVs), then extracted effect estimates of these IVs in tuberculosis genome-wide association study (GWAS) dataset to explore causal effect of genetically proxied insomnia on tuberculosis using inverse variance-weighted (IVW), MR-Egger, and weighted median methods. Additionally, we examined robustness and pleiotropy of effect estimates by heterogeneity and sensitivity analysis. Similarly, we investigated causal effect of genetically proxied tuberculosis on insomnia in reverse-direction MR. We revealed no causal relationship between genetically proxied insomnia and tuberculosis using 15 SNPs in forward-direction MR (IVW OR 5.305 [0.100-281.341], P = .410) and reverse-direction MR analysis (ORs and P values were not applicable due to no eligible SNPs in GWAS), with insignificant heterogeneity (Q = 22.6, I2 < 0.001, P = .066) and pleiotropy (intercept = 0.032, SE = 0.057, P = .592) in effect estimates. Our bi-directional MR analysis affirms no causal effect of insomnia on tuberculosis, or tuberculosis on insomnia.

Coagulation dysfunction in ICU patients with coronavirus disease 2019 in Wuhan, China: a retrospective observational study of 75 fatal cases.

Coagulation dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19) has not been well described, and the efficacy of anticoagulant therapy is unclear. In this study, we retrospectively reviewed 75 fatal COVID-19 cases who were admitted to the intensive care unit at Jinyintan Hospital (Wuhan, China). The median age of the cases was 67 (62-74) years, and 47 (62.7%) were male. Fifty patients (66.7%) were diagnosed with disseminated intra-vascular coagulation. Approximately 90% of patients had elevated D-dimer and fibrinogen degradation products, which decreased continuously after anticoagulant treatment and was accompanied by elevated albumin (all P<0.05). The median survival time of patients treated with anticoagulant was 9.0 (6.0-14.0) days compared with 7.0 (3.0-10.0) days in patients without anticoagulant therapy (P=0.008). After anticoagulation treatment, C-reactive protein levels decreased (P=0.004), as did high-sensitivity troponin (P=0.018), lactate dehydrogenase (P<0.001), and hydroxybutyrate dehydrogenase (P<0.001). In conclusion, coagulation disorders were widespread among fatal COVID-19 cases. Anticoagulant treatment partially improved hypercoagulability, prolonged median survival time, and may have postponed inflammatory processes and cardiac injury.

Linear free energy correlation analysis on the electronic effects of Rh(II) carbene O-H insertion.

The relative rate constants for the Rh(II)-catalyzed insertion of diazoacetone into the O-H bond have been measured through intermolecular competitions. The kinetic data were subjected to Hammett correlation analysis, and mechanistic implication of the results with respect to a stepwise vs a concerted O-H insertion pathway is discussed.

Investigation of the transition-metal- and acid-catalyzed reactions of beta-(N-tosyl)amino diazo carbonyl compounds.

A series of beta-(N-tosyl)amino diazo carbonyl compounds have been prepared by nucleophilic condensation of N-tosylimines with acyldiazomethanes. The diazo decomposition of these diazo carbonyl compounds under various catalytic conditions, including Rh(II) carboxylates, Cu(I) and Cu(II) complexes, PhCO(2)Ag/Et(3)N, TsOH, and SnCl(2).2H(2)O, has been investigated. It was found that, in most cases, the diazo decomposition gave preferentially 1,2-aryl migration product, but 1,2-hydride migration predominated when PhCO(2)Ag/Et(3)N was the catalytic system. Hammett correlation has been applied in the analysis of the electronic effects of 1,2-aryl migration. The factors that govern the migratory preference and the mechanistic aspects of the reaction are discussed.

Catalytic asymmetric [2,3]-sigmatropic rearrangement of sulfur ylides generated from copper(I) carbenoids and allyl sulfides.

Catalytic asymmetric sulfur ylide [2,3]-sigmatropic rearrangement of carbenoids generated from aryldiazoacetates has been investigated with a number of chiral Rh(II) and Cu(I) catalysts, and moderately high enantioselectivity (52-78% ee) can be achieved with Cu(MeCN)(4)PF(6)/2,2'-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline].