Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

Novel and founder variants of SERPINA12 in Chinese patients with autosomal recessive palmoplantar keratoderma.

1. We extend the spectrum of SERPINA12 variants in palmoplantar keratodermas. 2. The recurrent variant c.970_971del, mainly prevalent in the East Asia population, was proved to be a founder variant. 3. Considerable SERPINA12-related palmoplantar keratoderma patients could be identified from autosomal recessive, non-mutilating, diffused palmoplantar keratoderma patients. 4. Other serpin family members or their co-effect may participate in the etiologies of underexplored hereditary palmoplantar keratodermas.

Linezolid-induced thrombocytopenia in a child with a liver transplant: A case report.

OBJECTIVE: Linezolid-induced thrombocytopenia is rarely reported in liver transplant patients, especially in children. CASE SUMMARY: We report a case of a 7-month-old liver-transplanted child who suffered from thrombocytopenia induced by linezolid. We simulated the pharmacokinetics of linezolid in a healthy adult using the physiologically based pharmacokinetic (PBPK) model and found that the liver is the most abundant organ for the distribution of linezolid. PRACTICE IMPLICATIONS: Linezolid has a high distribution in the liver. As a result, an increased awareness about the risk of linezolid-induced thrombocytopenia should be strengthened in patients with liver injury. Effects of ethnicity: The differences between Chinese patients and patients of other ethnicities may lead to the diverse effects of linezolid in different patients. The influence of body weight (BW) difference in pharmacokinetics (PK) of linezolid between Asian (Chinese and Japanese) and Caucasians was demonstrated in several population PK studies [1, 2, 3]. The average BW of Asians is lower than that of the Caucasian population, the clearance and apparent volume of distribution are lower than in the European population, and Cmax is higher than in the Western population. Therefore, the adverse effects of linezolid at the same dose may increase in Chinese patients.

Impact of body composition on pharmacokinetics of tacrolimus in liver transplantation recipients.

1. There are still no studies examining the relationship between body composition and tacrolimus pharmacokinetics in liver transplantation recipients. We aimed to investigate the influence of body composition on tacrolimus pharmacokinetics in liver transplantation recipients.2. Body composition was measured in 80 patients who underwent liver transplantation at Tianjin First Central Hospital, China, between 2015 and 2018. Blood concentrations of tacrolimus were collected from therapeutic drug monitoring data. Pharmacokinetic model fitting and Bayesian estimation were performed using nonlinear mixed-effects modeling (NONMEM) and SPSS was used to examine the effect of body composition on tacrolimus pharmacokinetics.3. The apparent volume of distribution (V/F) and clearance (CL/F) of tacrolimus were 179 L and 15.4 L/h, respectively. In liver transplantation recipients with percentage body fat (PBF) ≥ 30%, the apparent V/F of tacrolimus is lower than that in liver transplantation recipients with PBF < 30% at 1 week after liver transplantation.4. The new finding is important due to the severe adverse effects of tacrolimus. In clinical practice, an effective dosage adjustment of tacrolimus may need to be considered in patients with PBF ≥ 30% at 1 week after liver transplantation.

Predictive Value of Indocyanine Green Plasma Disappearance Rate on Liver Function and Complications After Liver Transplantation.

BACKGROUND The aim of this study was to investigate the correlation between indocyanine green plasma disappearance rate (ICG-PDR) and allograft function as well as postoperative complications after liver transplantation. MATERIAL AND METHODS In this prospective study, 115 cases of adult liver transplantation performed from 1 June 2016 to 1 December 2016 were enrolled. These 115 patients were divided into a group of PDR <18%/min (50 cases) and a group of PDR ≥18%/min (65 cases). The rates of liver recovery, postoperative complications, and survival were compared between these 2 groups. RESULTS Among the total of 115 patients, 111 patients recovered well and were discharged, whereas 4 patients died during the first month after the operation. Between the 2 groups, significant differences were observed in terms of the model for end-stage liver disease (MELD) score, intraoperative bleeding volume, and the level of hemoglobin (Hb), pre-albumin (PA) and total bilirubin (TB) the first week after the operation. Overall, the incidence of hepatic arterial complications and pneumonia was much higher in the PDR<18%/min group (P<0.05). CONCLUSIONS The early postoperative value of ICG-PDR was closely related to graft function and could act as a good predictor for the incidence of postoperative arterial complications.

[Preliminary Studies on the Hydrodynamic Behaviors and Mechanisms of Hepatic Vessel Perfusion Using Simple Vessel Models].

The hydrodynamic behavior of the perfusion process(cleaning)of the liver endovascular before the operation was studied to provide a theoretical guidance to the relative operations.A straight and a curved first-class vascular entity model with foreign matter and the control equations of turbulence liquid in vessel was established.With the physical parameters of a medical infusion liquid measured,an estimation method of perfusion parameters as an example,the perfusion velocity was proposed.The simulation was performed by changing technical parameters of the perfusion.Based on the control equations of turbulent liquid in vessel and the preliminarily calculated results using the vessel model,the results fitted the values of the real operation.The simulation results showed clearly the fluid dynamics behavior around the foreign matter,for example the swirling flow.The results also showed the distribution of velocity of the fluid and the wall pressure of the vessels.With the increasing velocity of the entrance perfusion,the pressure and the velocity field were increased in the two types of the vessel model.The negative wall pressure and recirculation region appeared and located in the foreign matter.Because of influence of the shape,the fluid dynamics behavior in the curved vessel model was more complicated than that in the straight vessel model.The swirling flow and the phenomenon of stagnation of the perfusion fluid were more likely to appear in the curved vessel than in the straight vessel.The most important conclusion of this paper is that the appropriate perfusion velocity can be estimated using the methods proposed in this paper.

Occult hepatitis B virus infection predicts de novo hepatitis B infection in patients with alcoholic cirrhosis after liver transplantation.

BACKGROUND & AIMS: Occult hepatitis B virus infection (OBI) in patients undergoing liver transplantation (LT) is a suspected source of de novo hepatitis B virus (HBV) infection after LT. This study aimed to investigate the prevalence of OBI in liver transplant recipients with alcoholic cirrhosis and demonstrate the association between OBI and de novo HBV infection after LT in these patients. METHODS: Forty-three patients with alcoholic cirrhosis who were negative for HBsAg before LT were recruited in this retrospective study. DNA was extracted from paraffin-embedded native liver tissues and quantified for HBV DNA by real-time PCR. Correlation between de novo HBV infection after LT (positive HBsAg and/or detectable HBV DNA in serum) and detection of intrahepatic HBV DNA before LT was analysed. RESULTS: Detectable HBV DNA in the explanted liver was found in 41.9% (18/43) of the patients and was thus defined as OBI, which was correlated with the presence of serum hepatitis B core antibody (P = 0.008). De novo HBV infection occurred in 18.6% (8/43) of the recipients at a median of 10 months after LT. The rate of de novo HBV infection was 38.9% (7/18) in patients with OBI, compared with 4% (1/25) in patients without OBI (P = 0.004). Furthermore, de novo HBV infection was inversely correlated with the presence of hepatitis B surface antibody in recipients with OBI (P = 0.026). CONCLUSION: With a prevalence of 41.9% in liver transplant recipients with alcoholic cirrhosis, OBI in the native liver can predict de novo HBV infection after LT.

Posterior reversible encephalopathy syndrome and graft-versus-host disease after liver transplantation: a case report and review of the literature.

Case (description): A 52-year-old male patient presented with seizures on the 16th day post liver transplantation suggesting tacrolimus-associated posterior reversible encephalopathy syndrome (PRES). On the 18th day, the patient was diagnosed with graft-versus-host disease (GVHD). Calcineurin inhibitor (CNI) was stopped and the patient received 1 g methylprednisolone and 25 g immunoglobulin. However, on the 21st day, the patient's clinical condition progressively worsened and he died of multi-organ failure. GVHD could have occurred with PRES because the CNI dose was reduced. The best treatment for patients with PRES and GVHD is using immunosuppressants other than CNI. Antibody preparations and steroids could be a standard treatment.

A pilot study using low-dose Spectral CT and ASIR (Adaptive Statistical Iterative Reconstruction) algorithm to diagnose solitary pulmonary nodules.

BACKGROUND: Lung cancer is the most common cancer which has the highest mortality rate. With the development of computed tomography (CT) techniques, the case detection rates of solitary pulmonary nodules (SPN) has constantly increased and the diagnosis accuracy of SPN has remained a hot topic in clinical and imaging diagnosis. The aim of this study was to evaluate the combination of low-dose spectral CT and ASIR (Adaptive Statistical Iterative Reconstruction) algorithm in the diagnosis of solitary pulmonary nodules (SPN). METHODS: 62 patients with SPN (42 cases of benign SPN and 20 cases of malignant SPN, pathology confirmed) were scanned by spectral CT with a dual-phase contrast-enhanced method. The iodine and water concentration (IC and WC) of the lesion and the artery in the image that had the same density were measured by the GSI (Gemstone Spectral Imaging) software. The normalized iodine and water concentration (NIC and NWC) of the lesion and the normalized iodine and water concentration difference (ICD and WCD) between the arterial and venous phases (AP and VP) were also calculated. The spectral HU (Hounsfield Unit ) curve was divided into 3 sections based on the energy (40-70, 70-100 and 100-140 keV) and the slopes (λHU) in both phases were calculated. The ICAP, ICVP, WCAP and WCVP, NIC and NWC, and the λHU in benign and malignant SPN were compared by independent sample t-test. RESULTS: The iodine related parameters (ICAP, ICVP, NICAP, NICVP, and the ICD) of malignant SPN were significantly higher than that of benign SPN (t = 3.310, 1.330, 2.388, 1.669 and 3.251, respectively, P <0.05). The 3 λHU values of venous phase in malignant SPN were higher than that of benign SPN (t = 3.803, 2.846 and 3.205, P <0.05). The difference of water related parameters (WCAP, WCVP, NWCAP, NWCVP and WCD) between malignant and benign SPN were not significant (t = 0.666, 0.257, 0.104, 0.550 and 0.585, P > 0.05). CONCLUSIONS: The iodine related parameters and the slope of spectral curve are useful markers to distinguish the benign from the malignant lung diseases, and its application is extremely feasible in clinical applications.

SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-type Palmoplantar Keratoderma.

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for NPPK because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. Additionally, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a three-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a 'protease-substrate' manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor, and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in NPPK. These findings may lead to the development of therapeutic strategies for NPPK.

TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.

TRPV3 promotes sebocyte inflammation via transcriptional modulating TLR2 in acne.

Acne is a common chronic inflammatory disease of the pilosebaceous unit. Transient receptor potential vanilloid 3 (TRPV3) is an ion channel that is involved in inflammatory dermatosis development. However, the involvement of TRPV3 in acne-related inflammation remains unclear. Here, we used acne-like mice and human sebocytes to examine the role of TRPV3 in the development of acne. We found that TRPV3 expression increased in the skin lesions of Propionibacterium acnes (P. acnes)-injected acne-like mice and the facial sebaceous glands (SGs) of acne patients. TRPV3 promoted inflammatory cytokines and chemokines secretion in human sebocytes and led to neutrophil infiltration surrounding the SGs in acne lesions, further exacerbating sebaceous inflammation and participating in acne development. Mechanistically, TRPV3 enhanced TLR2 level by promoting transcriptional factor phosphorylated-FOS-like antigen-1 (p-FOSL1) expression and its binding to the TLR2 promoter, leading to TLR2 upregulation and downstream NF-κB signaling activation. Genetic or pharmacological inhibition of TRPV3 both alleviated acne-like skin inflammation in mice via the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebaceous inflammation and indicated its potential as an acne therapeutic target.

Outcomes in children with biliary atresia following liver transplantation.

BACKGROUND: Congenital biliary atresia is a rare condition characterized by idiopathic dysgenesis of the bile ducts. If untreated, congenital biliary atresia leads to liver cirrhosis, liver failure and premature death. The present study aimed to evaluate the outcomes of orthotopic liver transplantation in children with biliary atresia. METHOD: We retrospectively analyzed 45 patients with biliary atresia who had undergone orthotopic liver transplantation from September 2006 to August 2012. RESULTS: The median age of the patients was 11.0 months (5-102). Of the 45 patients, 41 were younger than 3 years old. Their median weight was 9.0 kg (4.5-29.0), 34 of the 45 patients were less than 10 kg. Thirty-one patients had undergone Kasai portoenterostomy prior to orthotopic liver transplantation. We performed 30 living donor liver transplants and 15 split liver transplants. Six patients died during a follow-up. The median follow-up time of surviving patients was 11.4 months (1.4-73.7). The overall 1-, 2- and 3-year survival rates were 88.9%, 84.4% and 84.4%, respectively. CONCLUSION: With advances in surgical techniques and management, children with biliary atresia after liver transplantation can achieve satisfactory survival in China, although there remains a high risk of complications in the early postoperative period.

Isolation and Characterization of the Wastewater Micropollutant Phenacetin-Degrading Bacterium Rhodococcus sp. Strain PNT-23.

Phenacetin, an antipyretic and analgesic drug, poses a serious health risk to both humans and aquatic organisms, which is of concern since this micropollutant is frequently detected in various aquatic environments. However, rare pure bacterial cultures have been reported to degrade phenacetin. Therefore, in this study, the novel phenacetin-degrading strain PNT-23 was isolated from municipal wastewater and identified as a Rhodococcus sp. based on its morphology and 16S rRNA gene sequencing. The isolated strain could completely degrade 100 mg/L phenacetin at an inoculum concentration of OD600 1.5 within 80 h, utilizing the micropollutant as its sole carbon source for growth. Strain PNT-23 exhibited optimal growth in LB medium at 37 °C and a pH of 7.0 with 1% NaCl, while the optimal degradation conditions in minimal medium were 30 °C and a pH of 7.0 with 1% NaCl. Two key intermediates were identified during phenacetin biodegradation by the strain PNT-23: N-acetyl-4-aminophenol and 4-aminophenol. This study provides novel insights into the biodegradation of phenacetin using a pure bacterium culture, expands the known substrate spectra of Rhodococcus strains and presents a potential new candidate for the microbial removal of phenacetin in a diverse range of environments.

Bidirectional Underwater Drag Reduction on Bionic Flounder Two-Tier Structural Surfaces.

Engineering marvels found throughout the exclusive structural features of biological surfaces have given rise to the progressive development of skin friction drag reduction. However, despite many previous works reporting forward drag reduction where the bio-inspired surface features are aligned with the flow direction, it is still challenging to achieve bidirectional drag reduction for non-morphable surface structures. Inspired by the flounder ctenoid scales characterized by tilted, millimeter-sized oval fins embedded with sub-millimeter spikes, we fabricate a bionic flounder two-tier structural surface (BFTSS) that can remarkably reduce the forward skin friction drag by ηdr = 19%. Even in the backwards direction, where the flow is completely against the tilting direction of surface structures, BFTSS still exhibits a considerable drag reduction of ηdr = 4.2%. Experiments and numerical simulations reveal that this unique bidirectional drag reduction is attributed to synergistic effects of the two-tier structures of BFTSS. The array of oval fins can distort the boundary layer flow and mitigate the viscous shear, whilst the microscale spikes act to promote the flow separation to relieve the pressure gradient in the viscous sublayer. Notably, the pressure gradient relief effect of microscale spikes remains invariant to the flow direction and is responsible for the backward drag reduction as well. The bidirectional drag reduction of BFTSS can be extensively applied in minimizing the energy consumption of ships and underwater vessels, as well as in pipeline transport.

Excess KLHL24 Impairs Skin Wound Healing through the Degradation of Vimentin.

Start codon variants in ubiquitin ligase KLHL24 lead to a gain-of-function mutant KLHL24-ΔN28, which mediates the excessive degradation of keratin 15, desmin, and keratin 14, resulting in alopecia, cardiopathy, and epidermolysis bullosa syndrome. Patients with alopecia, cardiopathy, and epidermolysis bullosa syndrome normally present atrophic scars after wounds heal, which is rare in KRT14-related epidermolysis bullosa. The mechanisms underlying the formation of atrophic scars in epidermolysis bullosa of patients with alopecia, cardiopathy, and epidermolysis bullosa syndrome remain unclear. This study showed that KLHL24-ΔN28 impaired skin wound healing by excessively degrading vimentin. Heterozygous Klhl24c.3G>T knock-in mice displayed delayed wound healing and decreased wound collagen deposition. We identified vimentin as an unreported substrate of KLHL24. KLHL24-ΔN28 mediated the excessive degradation of vimentin, which failed to maintain efficient fibroblast proliferation and activation during wound healing. Furthermore, by mediating vimentin degradation, KLHL24 can hinder myofibroblast activation, which attenuated bleomycin-induced skin fibrosis. These findings showed the function of KLHL24 in regulating tissue remodeling, atrophic scarring, and fibrosis.