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Objective: To systematically evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) in the treatment of COVID-19. Methods: PubMed, Embase, Ovid, CNKI, CBM, Wanfang, and VIP databases were searched to obtain the clinical studies of LPV/r in the treatment of COVID-19 from December 2019 to July 2020. The literatures were screened according to the inclusion and exclusion criteria. Their qualities were evaluated according to the Newcastle-Ottawa Scale (NOS) and RevMan 5.3 software was used for meta-analysis. Results: A total of 688 patients were included in five studies, involving China and France. Compared with patients in the control group, who was only treated with routine treatment, there were no significant differences of the 7-day nucleic acid negative conversion rate and 14-day nucleic acid negative conversion rate in the treatment group. However, the use of LPV/r increased the incidence of adverse reactions in the treatment group compared to the control group. Conclusion: There is no available evidence to support the use of Lopinavir/ritonavir in the treatment of COVID-19.

Contrast-induced encephalopathy (CIE) is a rare complication of angiography. According to our knowledge, the majority of CIE reports is imaging observations and rarely includes results of cerebrospinal fluid (CSF) tests. Furthermore, among the cases reporting the data for CSF testing, most of the results were normal. Here, we report a case of CIE presenting with significantly elevated levels of CSF protein. We found that the course of improvement in brain imaging findings was not consistent with the severity of clinical manifestations. The diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences were normal. Considering the lack of convenient direct indicators to observe blood-brain barrier (BBB) function, changes in the levels of CSF protein may be related to BBB permeability and recovery and may serve as a potential prognostic marker.

Background The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. Methods Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. Results Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. Conclusions The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

BACKGROUND Hepatitis B surface antigen (HBsAg) loss, a functional cure in patients with chronic hepatitis B (CHB) undergoing antiviral therapy, might be an ideal endpoint of antiviral treatment in clinical practice. The factors that contribute to the functional cure remain unclear, and the predictors of functional cure are worth exploring. The concentration and kinetics of soluble programmed death-1 (sPD-1) in patients with CHB may play an important role in elucidating the immune response associated with functional cure after nucleos(t)ide analogs therapy. AIM To investigate the factors associated with HBsAg loss and explore the influence of sPD-1 Levels. METHODS This study analyzed the data and samples from patients with CHB who underwent antiviral treatment in a non-interventional observational study conducted at Peking University First Hospital in Beijing (between 2007 and 2019). All patients were followed up: Serum samples were collected every 3 mo during the first year of antiviral treatment and every 6 mo thereafter. Patients with positive hepatitis B e antigen levels at baseline and with available sequential samples who achieved HBsAg loss during antiviral treatment served as the case group. This case group (n = 11) was further matched to 44 positive hepatitis B e anti patients without HBsAg loss as controls. The Spearman’s rank correlation test and receiver operating characteristic curves analysis were performed. RESULTS The sPD-1 Levels were higher in patients with HBsAg loss than in those without HBsAg loss from baseline to month 96, and the differences were significant between the groups at baseline (P = 0.0136), months 6 (P = 0.0003), 12 (P < 0.0001), 24 (P = 0.0007), 48 (P < 0.0001), and 96 (P = 0.0142). After 6 mo of antiviral treatment, the sPD-1 levels were positively correlated with alanine transaminase (ALT) levels (r = 0.5103, P = 0.0017), and the sPD-1 levels showed apparent correlation with ALT (r = 0.6883, P = 0.0192) and HBV DNA (r = 0.5601, P = 0.0703) levels in patients with HBsAg loss. After 12 mo of antiviral treatment, the sPD-1 levels also showed apparent correlation with ALT (r = 0.8134, P = 0.0042) and HBV DNA (r = 0.6832, P = 0.0205) levels in patients with HBsAg loss. The sPD-1 levels were negatively correlated with HBsAg levels in all patients after 12 mo of antiviral treatment, especially at 24 (r = -0.356, P = 0.0497) and 48 (r = -0.4783, P = 0.0037) mo. After 6 mo of antiviral treatment, the AUC of sPD-1 for HBsAg loss was 0.898 (P = 0.000), whereas that of HBsAg was 0.617 (P = 0.419). The cut-off value of sPD-1 was set at 2.34 log pg/mL; the sensitivity and specificity were 100% and 66.7%, respectively. CONCLUSION The sPD-1 levels at 6 mo can predict HBsAg loss after 144 mo of antiviral treatment.

Limited data are currently available regarding fibrosis progression after hepatitis C virus (HCV) eradication. The goal of the present study was to evaluate the effects of HCV eradication on liver stiffness measurements (LSMs), aspartate aminotransferase/platelet ratio index (APRI) scores, fibrosis-4(FIB-4) scores, chitinase-3-like protein 1 (CHI3L1) levels and Golgi protein 73 (GP73) levels in patients with chronic hepatitis C (CHC). One hundred and two patients who received direct antiviral agents (DAAs) therapy at Peking University First Hospital participated in the present study. Clinical information and serum samples were collected at baseline, at the end of treatment (EOT), and at the weeks 12, 24 and 48 after treatment (W12, W24 and W48, respectively). Of the 102 patients, 51 had mild-to-moderate fibrosis (F1/F2), and 51 had advanced fibrosis (F3/F4). The LSMs improved for all patients at the EOT, with observed changes of 2.85 kPa, and the decrease continued to W12. However, a more pronounced improvement was noted for the advanced fibrosis (F3/F4) patients, with a change of 3.6 kPa from baseline to the EOT. Significant decreases between the baseline and EOT measurements were observed in the APRI and FIB-4 scores [0.64 (0.39-1.21) vs. 0.35 (0.26-0.52), p

Background Primary adrenal insufficiency (PAI) is life-threatening, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features. Methods Seventy children were enrolled in this cross-sectional study. Clinical information was collected, and combined genetic tests were performed according to the children’s manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants. Results Among the 70 children, 84.3% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and 21-hydroxylase deficiency (21-OHD) was genetically confirmed in 91.5% of these cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.1% (39/59), 30.5% (18/59), and 3.4% (2/59) of the cases, respectively. The 17-hydroxyprogesterone (17-OHP) and testosterone (TES) levels were significantly higher in children with SW than with SV. The 17-OHP and cortisol levels in female SW patients were significantly higher than those in males. The 17-OHP, cortisol, dehydroepiandrosterone (DHEAS) and TES levels in female SW patients were significantly higher than those in female SV patients. Additionally, 72.7% (8/11) of uncharacterized PAI patients had positive genetic findings. Among all the patients, two novel variants in the CYP21A2 gene (c.833dupT and c.651 + 2T > G) were found. A microdeletion (Xp21.2–21.3) and five novel variants, including 2 in the NR0B1 gene (c.323–324CG > GA and c.1231_1234delCTCA), 2 in the AAAS gene (c.399 + 1G > A and c.250delT) and 1 in the NNT gene (c.2274delT), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 skipping during mRNA transcription and produce a truncated ALADIN protein. Conclusions We found ethnicity-based differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and TES levels, which warrants caution in relation to the effects of virilization. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of PAI, however, further improvement of genetic testing tools beyond our protocol are still needed to uncover the complete aetiology of PAI in children.

A new type of polyvinylidene fluoride (PVDF)/polymethyl methacrylate (PMMA) hollow fiber membrane (HFM) with five bores was prepared. The effects of polyvinylpyrrolidone (PVP), β-cyclodextrine (β-CD), polyethylene glycol (PEG) and polysorbate 80 (Tween 80) and their combinations on the PVDF/PMMA five-bore HFMs were investigated. The performance and fouling characteristics of five-bore HFMs for dyeing wastewater treatment were evaluated. Results indicated that adding 5 wt.% PVP increased the porosity and water flux of the membrane but decreased the bovine serum albumin (BSA) rejection rate. Adding 5 wt.% β-CD significantly improved the tensile strength and rejection of the HFMs with no effect on the increase of water flux. The characteristic of the HFMs with different additive combinations proved that the mixture of 5 wt.% PVP and 1 wt.% β-CD gave the best membrane performance, with a pure water flux of 427.9 L/ m2·h, a contact angle of 25°, and a rejection of BSA of 89.7%. The CODcr and UV254 removal rates of dyeing wastewater treatment were 61.10% and 50.41%, respectively. No breakage or leakage points were found after 120 days of operation, showing their reliable mechanical properties. We set the operating flux to 55 L/m2·h and cross-flow rate to 10%, which can effectively control membrane fouling. HIGHLIGHTS PVDF/PMMA five-bore HFMs were prepared by dry-wet spinning.; The addition of PVP and β-CD had significant effects on HFM hydrophilicity and rejection respectively.; The best film properties were obtained by mixing 5 wt% PVP and 1 wt% β-CD.; The laboratory-made membrane module could effectively remove chemical oxygen demand and the turbidity of the dyeing wastewater.; No breakage or leakage points were found after 120 days of operation, showing their reliable mechanical properties.

Background The gold standard for the diagnosis of central precocious puberty (CPP) is gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation test. But the stimulation test is time-consuming and costly. Our objective was to develop a risk score model readily adoptable by clinicians and patients. Methods A cross-sectional study based on the electronic medical record system was conducted in the Children’s Hospital, Fudan University, Shanghai, China from January 2010 to August 2016. Patients with precocious puberty were randomly split into the training (n = 314) and validation (n = 313) sample. In the training sample, variables associated with CPP (P Results CPP was diagnosed in 54.8% (172/314) and 55.0% (172/313) of patients in the training and validation sample, respectively. The CPP risk score model included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume. The C-index was 0.85 (95% CI: 0.81–0.89) and 0.86 (95% CI: 0.82–0.90) in the training and the validation sample, respectively. Two cut-off points were selected to delimitate a low- ( Conclusions A risk score model for the risk of CPP had a moderate predictive performance, which offers the advantage of helping evaluate the requirement for further diagnostic tests (GnRH or GnRHa stimulation test).

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype–phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO.

Summary Background Blockade of tyrosine kinase 2 (TYK2) signalling has previously shown therapeutic potential in the treatment of psoriasis. The primary objective of this study was to assess the safety and tolerability of the TYK2 inhibitor PF-06826647. Methods This phase 1, randomised, double-blind, placebo-controlled, parallel-group study assessed once daily oral dosing of PF-06826647 in participants with plaque psoriasis, at a single clinical research site in the USA. Eligible participants (aged 18–65 years) had plaque psoriasis covering at least 15% of total body surface area and a psoriasis area and severity index (PASI) score of at least 12 at baseline. Participants received PF-06826647 (100 mg or 400 mg), or placebo once daily for 28 days. Using a computer-generated randomisation schedule with a block size of 3, participants were sequentially randomly assigned into two cohorts by the investigator; in the first cohort, participants were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 400 mg or placebo once daily, whereas participants in the second cohort were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 100 mg or placebo once daily. Site, investigator, Pfizer personnel, and participants, were masked to treatment. The primary endpoint was the safety of multiple-dose PF-06826647 in participants with plaque psoriasis. Secondary endpoints were the characterisation of the pharmacokinetics of multiple-dose PF-06826647 in plasma and the change in PASI score at day 28. Safety analysis was done in all participants who received at least one dose of study drug. Efficacy analysis was done in all participants who received at least one dose of randomised study drug, and had a baseline and at least one post-baseline measurement. This study is registered as a randomised, controlled trial with ClinicalTrials.gov , NCT03210961 and is completed. Findings The trial was done between July 14, 2017, and Jan 25, 2019. Overall from 91 participants assessed, 40 participants with moderate-to-severe psoriasis were randomly assigned to treatment (placebo 14 [35%] of 40; PF-06826647 100 mg, 11 [28%] of 40; PF-06826647 400 mg, 15 [38%] of 40). Treatment-emergent adverse events (TEAEs) were reported in 12 (80%) of 15 participants in the PF-06826647 400 mg group, seven (50%) of 14 in the placebo group and five (45%) of 11 in the 100 mg group. All TEAEs were mild in severity, except one moderate TEAE of vomiting reported in the placebo group. There were no deaths, serious TEAEs, severe TEAEs, dose reductions, or temporary discontinuations. Compared with placebo, the change from baseline in PASI score at day 28 showed a significant reduction in least squares mean difference for the PF-06826647 400 mg group (−13·05; 90% CI −18·76 to −7·35; p=0·00077) but not for the PF-06826647 100 mg group (−3·49; −9·48 to 2·50; p=0·33). Both the area under the concentration–time curve over the dosing interval and the maximum concentration increased in a less than dose proportional manner with increasing dose from 100 mg to 400 mg PF-06826647. Interpretation PF-06826647 showed significant improvement in disease activity within 4 weeks of dosing with an acceptable safety profile. PF-06826647 holds promise over conventional oral treatments for psoriasis that have shown limited efficacy or unfavourable safety profiles. Funding Pfizer.

Aims/Introduction Chronic inflammation is an underlying feature of type 2 diabetes mellitus. Hypovitaminosis D is associated with type 2 diabetes mellitus, but whether it contributes to chronic inflammation is unclear. We examined the effects of vitamin D on various immune markers to evaluate its contribution to systemic inflammation in type 2 diabetes mellitus. Materials and Methods We retrospectively analyzed data from type 2 diabetes mellitus patients, people with prediabetes and control patients without diabetes (n = 9,746). Demographic and clinical variables were evaluated using descriptive statistics and generalized linear regression. A stratified analysis based on total serum vitamin D was also carried out. Results Neutrophil count was a significant predictor of 1,5‐anhydroglucitol and glycated hemoglobin (HbA1c) in patients with prediabetes (1,5‐anhydroglucitol: β = −0.719, P 0.05 for all). Among patients with prediabetes, those who were vitamin D‐deficient had the highest NLR (P = 0.040). Among patients with diabetes, those who were vitamin D‐deficient had the highest neutrophil count (P = 0.001), lowest lymphocyte count (P = 0.016) and highest NLR (P, The neutrophil‐to‐lymphocyte ratio was a predictor of glycated hemoglobin in people without diabetes. Among people with prediabetes, vitamin D deficiency led to the highest neutrophil‐to‐lymphocyte ratio. Among people with diabetes, vitamin D deficiency led to the highest neutrophil and lowest lymphocyte counts.

Brucellosis, which is caused by Brucella spp., is an important zoonotic infectious disease that can cause great hazard to public health and safety. However, the current vaccines have several drawbacks, including residual virulence for animals and humans. Bacterial ghost is the empty envelopes of bacteria, which emerge as a proper vaccine candidate. With the purpose of generating B. abortus ghosts and investigating the immunogenicity of bacterial ghosts as vaccine candidate, we used homologous recombination and bacterial ghost technologies to construct 2308ΔgntR ghost strain. Mice were injected with 2308ΔgntR ghost and the safety and immunogenicity of ghost were further evaluated. The mice inoculated with ghost showed no splenomegaly. The 2308ΔgntR ghost induced high protective immunity in BALB/c mice against challenge with S2308, and elicited an anti-Brucella-specific immunoglobulin G (IgG) response and induced the secretion of interferon gamma (IFN-γ) and interleukin-4 (IL-4). Additionally, 2308ΔgntR ghost demonstrated strong spleen CD4+ and CD8+ T cell responses. These results suggest that 2308ΔgntR ghost is a potential vaccine candidate and may represent a promising new approach for vaccination against Brucella infection.

The risk of opportunistic fungal infections is high in immunocompromised patients. The Penicillium genus is common and diverse in nature. However, it rarely causes infection in humans. Here, we reported a case of Penicillium janthinellum pneumonia in a systemic lupus erythematosus (SLE) patient, and the morphological characteristics of P. janthinellum were also described. The patient was a 64-year-old female. She had been diagnosed with SLE and membranous lupus nephritis 10 months previously. Her medications included methylprednisolone, cyclosporine, and hydroxychloroquine. She was admitted because of fever and diagnosed with pneumonia. P. janthinellum was isolated from sputum and bronchoalveolar lavage (BAL) samples. BAL fluid stained with multiple stains showed the presence of somewhat dichotomously branching septate fungal hyphae. P. janthinellum was identified, and its morphological features were described. Antibiotic susceptibility profiles showed that this strain had higher minimum inhibitory concentration (MIC) values in response to multiple antifungal drugs. The patient died 10 days after diagnosis. To the best of our knowledge, this report is the second to demonstrate that P. janthinellum causes infection and is the first to present an infection (pneumonia) caused by P. janthinellumi in an SLE patient. Clinical and laboratory personnel should be aware that the Penicillium genus also contains pathogenic bacteria that cannot simply be treated as contaminants, especially in immunosuppressed patients.

ContextLong-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.ObjectiveWe studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.Design, Setting, and PatientsThis multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.InterventionSubjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks.Main Outcome MeasureThe primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes.ResultsAt week 26, the median HtSDSCA changed from −2.75, −2.82, and −2.78 to −2.31, −2.43, and −2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%–90.34% and 76.08%–90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups.ConclusionsAlthough notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions.Clinical Trial Registrationclinicaltrials.gov, identifier NCT02976675.

Previous studies have shown that cold exposure can cause disturbance of estrus cycle in female rats. However, whether cold exposure can cause organic pathological damage to the reproductive system of female rats was undefined. Meanwhile there are few reports on the mechanism of decompensation in rat reproductive function after cold exposure. This study aims to further discuss how cold exposure impact female ovarian reserve function in rats. Female rats were randomly divided into control group and cold exposure group. Ovarian reserve function, differential genes in hypothalamus reproductive regulation center or peripheral were evaluated. After cold exposure, ovarian reserve function was impaired, follicle development was abnormal, the number of mature follicles decreased significantly, the key hypothalamic reproductive regulation molecule GnRH decreased significantly, the response of its regulatory receptor NPY-5R was down-regulated, and the peripheral hormone serum leptin, which is closely related to it, decreased significantly. Our results indicate that cold exposure can lead to impaired ovarian function in female rats, resulting from decrease in serum leptin cause by WAT leptin depletion, which can release the inhibitory of NPY in the hypothalamus, and further lead to the down-regulation of GnRH expression, resulting in the whole HPO axis.

The structure and composition of gut microbiota correlate with the occurrence and development of host health and disease. Diarrhea can cause alterations in gut microbiota in animals, and the changes in the gut microbial structure and composition may affect the development of diarrhea. However, there is a scarcity of information on the effects of diarrhea on gut fungal composition and structure, particularly in Baer's pochard (Aythya baeri). The current study was performed for high-throughput sequencing of the fungal-specific internal transcribed spacer 1 (ITS-1) to detect the differences of gut mycobiota in healthy and diarrheal Baer's pochard. Results showed that the gut mycobiota not only decreased significantly in diversity but also in structure and composition. Statistical analysis between two groups revealed a significant decrease in the abundance of phylum Rozellomycota, Zoopagomycota, Mortierellomycota, and Kickxellomycota in diarrheal Baer's pochard. At the genus levels, fungal relative abundance changed significantly in 95 genera, with 56 fungal genera, such as Wickerhamomyces, Alternaria, Penicillium, Cystofilobasidium, and Filobasidium, increasing significantly in the gut of the diarrheal Baer's pochard. In conclusion, the current study revealed the discrepancy in the gut fungal diversity and community composition between the healthy and diarrheal Baer's pochard, laying the basis for elucidating the relationship between diarrhea and the gut mycobiota in Baer's pochard.

Mutations in VPS16 have been identified to be responsible for generalized dystonia. We screened VPS16 variants in 53 unrelated subjects with isolated dystonia via whole-exome sequencing. A novel pathogenic frameshift mutation p.R643fs* was found in a patient with early-onset multifocal dystonia with prominent oromandibular and bulbar involvement. Our findings expanded the spectrum of VPS16-related dystonia and suggested that mutations in VPS16 should be considered in patients with progressive early-onset dystonia.

Microplastics (MPs) released into aquatic environment interact with other pollutants that already exist in water, potentially altering their toxicity, which poses a new problem for aquatic ecosystems. In the present study, we first evaluated the effects of polystyrene MPs (mPS) on copper (Cu) toxicity to the protozoan Euglena gracilis using three methods based on 96-h acute toxicity, orthogonal test and 12-d sub-acute toxicity data. Thereafter, the 12-d sub-acute exposure was employed to investigate protozoan growth, photosynthetic parameters and pigments, soluble protein, total antioxidant capacity and trace metal accumulation in E. gracilis after exposure to either 1.5 mg/L of Cu, 75-nm mPS (1 and 5 mg/L) or a combination therein, with the objective to understand the underlined mechanisms. The results show that the concentration and exposure time are key factors influencing the effects of the mPS on Cu toxicity. A mPS concentration of 5 mg/L caused significantly more dissipation energy, which is used for photosynthesis and thus decreased photosynthetic efficiency, but this effect weakened after 12 d of exposure. Exposure to Cu alone resulted in significantly high Cu accumulation in the cells and inhibited uptake of manganese and zinc. The presence of mPS did not influence the effects of Cu on trace metal accumulation. Our result suggests that application of multiple methods and indices could provide more information for a comprehensive understanding of the effects of mPS on toxicity of other pollutants. In addition, long-term exposure seems necessary for evaluating mPS toxicity.

Objective: To analyze the correlation between the vascular endothelial function (characterized by endothelin-1 and nitric oxide) and the renal hemodynamics in patients with hypertensive disorders in pregnancy (HDP) by color Doppler ultrasound. Method: Depending on the severity of the disease, 76 HDP patients were divided into three groups, namely, pregnancy-induced hypertension (PIH) group ([Formula: see text]), mild preeclampsia (PE) group ([Formula: see text]), and severe PE group ([Formula: see text]). In the meantime, 28 healthy pregnant women were selected as controls. Color Doppler ultrasound was performed to determine the following parameters in the interlobar arteries of the kidney: Resistance index (RI), peak end-diastolic velocity (EDV), pulsatility index (PI), peak systolic velocity (PSV), and S/D ratio. The correlations of these parameters with the serum levels of ET-1 and NO were then analyzed. Result: (1) In the interlobar arteries of the kidney, RI, S/D, PI were positively significantly correlated to the serum level of ET-1 in HDP patients (All [Formula: see text]) and negatively to the serum level of NO (All [Formula: see text]). (2) RI, S/D, PI of the mild and severe PE groups were significantly higher than those of the control group (All [Formula: see text]). However, EDV of the mild and severe PE groups was significantly lower than that of the control group (All [Formula: see text]). (3) The serum level of ET-1 was significantly higher in the HDP patients than in the control group ([Formula: see text]). However, the serum level of NO was significantly lower in the former than in the latter ([Formula: see text]). As HDP became more severe, there was an elevation in the serum level of ET-1 and a decrease in NO. Conclusion: Indicators of renal hemodynamics measured by color Doppler ultrasound were correlated to the serum levels of ET-1 and NO characterizing the vascular endothelial function. They were sensitive indicators reflecting hemodynamic changes and renal impairment in HDP patients.

Background Widespread disruption of the mucosal immune system is central to the pathogenesis of ulcerative colitis (UC). One component, tumour necrosis factor (TNF) α-like ligand 1A (TL1A), is upregulated at the site of active disease in UC. Treatment of preclinical rodent models with anti-TL1A antibodies decreases disease activity, highlighting their therapeutic potential for UC. PF-06480605 is a first-in-class fully human immunoglobulin G1 monoclonal antibody targeting TL1A. Methods The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in treatment of moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. Primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and endoscopic improvement (EI) (Mayo endoscopic subscore [centrally read] of ≤1 without friability) at Week 14, respectively. Secondary efficacy endpoints included remission (total Mayo score ≤2, with no individual subscore >1) and endoscopic remission (Mayo endoscopic subscore = 0) at Week 14. Transcriptomic profiling on intestinal biopsies was performed. Results Of the 50 participants who received PF-06480605, 42 completed the study. The majority were male (56.0%) and white (96.0%), with a mean age of 40.0 years and prior experience of anti-TNF inhibitors (72.0%). Pancolitis (48.0%) and left-sided colitis (32.0%) were the most common forms of UC at baseline. There were 109 TEAEs, of which 18 were treatment-related. Aside from worsening UC, the most common TEAE by system organ class was arthralgia, which occurred in 6 participants, and 1 was treatment-related. Treatment-emergent serious adverse events were reported in 3 participants, and considered treatment-related in 1 participant (Table 1). No malignancies or deaths were reported. At Week 14, statistically significant EI was observed in 38.2% of participants (Table 2). The proportions of participants achieving remission and endoscopic remission at Week 14 were 24.0% and 10.0%, respectively. Transcriptomic analyses demonstrated normalisation towards a non-inflamed transcriptome in participants with EI. Conclusion PF-06480605 exhibited an acceptable safety and tolerability profile and statistically significant EI in participants with moderate to severe UC. These results warrant further evaluation in subsequent studies.

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long-time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment-naive and had begun a 7-year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real-time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg-negative rates also increased. After 48 weeks' NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA-positive. After 7 years of treatment, more HBV pgRNA-negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA-positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA-positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75-31.08). The median time to HBeAg clearance in the HBV pgRNA-positive patients was longer than that of the HBV pgRNA-negative patients (152 weeks vs 72 weeks). The HBV pgRNA-positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33-144.67 vs 48 weeks, 95% CI: 34.80-61.20). The HBV pgRNA status after NA treatment can predict the long-term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA-positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.

Background High demand on anti-aging skin care encourage the improvement and development of more personalized formulations with additional benefits for general skin health and age associated skin signs. The skin aging physical and biological phenotypes manifest differently between diverse ethnic populations. A highly polluted environment can be viewed as an extrinsic factor accelerating the skin aging process. Aim To develop a unique formula with active complexes, having multifunctional effects for anti-pollution, brightening and anti-aging/barrier strengthening purposes with confirmed activities in vitro and ex vivo skin models, suitable for polluted skin. Methods In vitro culture model with primary human skin cells, ex vivo studies with full-thickness human skin, melanocyte 3D coculture model, gene expression of epidermal and dermal genes, anti-glycation, proteasomal activity, melanin, and cytokine assays. Results In vitro and ex vivo studies clearly demonstrated that diglucosyl gallic acid (active A) and the formulation complex inhibited pollution mediated MMP1 protein, CYP1A1 gene expression, and IL-6 protein secretion, while caprylic/capric triglyceride, diacetyl boldine (active B) had anti-melanogenic effect in in vitro primary melanocyte monoculture and 3D spheroid model. Another active compound, acetyl dipeptide 1 cetyl ester (active D), significantly upregulated epidermal barrier genes (Aquaporin 3 [AQP3], Filaggrin [FLG], caspase 14, and keratin 10) in human primary keratinocytes. Interestingly, both acetyl dipeptide 1 cetyl ester (active D) and niacinamide (active C) improved dermal gene expression (fibrillin-1, Collagen type 1 alpha 1, Decorin, Lysyl oxidase-like 1) and, moreover, had significant anti-glycant and proteasomal promoter activity in human primary fibroblasts. Conclusion Considering consumers need in heavily polluted areas, we developed a multipurpose formulation comprised of unique active complexes toward pollution, pollution induced inflammation, skin brightening, and antiaging concerns with beneficial results demonstrated by in vitro and ex vivo studies.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation-dependent probe amplification (MLPA) testing in all patients and next-generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.

The study evaluated the relationship between the histological grade of hepatocellular carcinoma (HCC) and the histogram-derived parameters of apparent diffusion coefficient (ADC) obtained from the whole-lesion assessment of diffusion-weighted magnetic resonance (MR) imaging in the liver. A total of 51 patients were included. The parameters were correlated with the Edmondson-Steiner grades by using the Spearman correlation coefficient (ρ). The differences of ADC parameters between different tumor histological grades were compared using the Mann–Whitney U test. The extent to which each parameter aided in differentiating tumors with poor performance (III, IV) and fair performance (I, II) was assessed by using the area under the receiver operating characteristic curve (Az). The 25th percentile ADC exhibits the most negative correlation with histological grade (ρ = − 0.397), followed by the 30th percentile ADC (ρ = − 0.395), the minimum ADC value (ρ = − 0.390) and the 20th percentile ADC (ρ = − 0.385), whereas the minimum ADC value yielded the highest Az (0.763) in the discrimination of tumor foci with poor differentiation from fairly differentiated HCCs. The minimum ADC of 4.15 × 10−3 mm2/s or lower was considered to indicate poorly differentiated performance, and the corresponding sensitivity and specificity were 66.7 and 90.9%, respectively. The 25th percentile ADC showed a stronger correlation with the histological grade of HCC than other ADC parameters, and the minimum ADC value might be an optimal metric for determining poor and fair differentiations of HCC in DWI.

Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18F DOPA-PET CT scanning–based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 μIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation. Conclusion: Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients. What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations.• Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients.

In recent years, a growing body of evidence has provided support for the important role of microRNAs (miRNAs) in the progression of human cancers. A recent study showed that a novel miRNA miR-3650 expression was significantly decreased in hepatocellular carcinoma (HCC). However, the precise role of miR-3650 in HCC have remained poorly understood. In this study, we found that miR-3650 expression was frequently decreased in HCC tissues. Low expression of miR-3650 is positively associated with tumor metastasis and poor survival of HCC patients. Forced expression of miR-3650 significantly inhibited the migration and epithelial-mesenchymal transition (EMT) of HCC cells. Through bioinformatic analysis and luciferase assays, we confirmed that neurofascin (NFASC) is a directly target mRNA of miR-3650. Rescue experiment demonstrated that NAFSC overexpression could partially counteracted the inhibitory effect of miR-3650 in HCC metastasis and EMT. In conclusion, our findings are the first time to demonstrate that reduced expression of miR-3650 in HCC was correlated with tumor metastasis and poor survival. MiR-3650 repressed HCC migration and EMT by directly targeting NFASC. Our findings suggested that miR-3650 may serve as a potential prognostic marker and promising application in HCC therapy.

Aims PRRT2 variants are associated with various paroxysmal disorders. To date, more than 90 PRRT2 variants have been reported in PRRT2‐related disorders. Lack of functional study in majority of missense variants makes their pathogenicity uncertain. We aim to evaluate the clinical significance of PRRT2 missense variants by performing in vitro experiments. Methods We systematically reviewed PRRT2‐related disorders and summarized reported PRRT2 missense variants. Protein expression and subcellular localization of mutant PRRT2 were investigated in mammal cells. American College of Medical Genetics and Genomics (ACMG) guidelines were used to analyze the pathogenicity of PRRT2 missense variants. Results A total of 29 PRRT2 missense variants were identified in PRRT2‐related disorders. Ten variants were observed to affect both subcellular localization and protein level, three variants only affect membrane localization, and two variants only affect protein level. According to ACMG guidelines, 15 variants were finally classified as “likely pathogenic”, three as “benign”, three as “likely benign”, and eight as “uncertain significance” variants. The likely pathogenic variants were concentrated in the C‐terminal of PRRT2. Conclusions The pathogenicity of eight uncertain significance variants needs further investigation. C‐terminal of PRRT2 is crucial for its physiological function.

The limited available studies have unveiled different natural histories and prognosis associated with pediatric type 2 diabetes (T2D) and adult T2D. To date, data on the clinical features, metabolic profiles and beta-cell function characteristics are still limited in the Chinese pediatric T2D population. A total of 56 children with T2D, 31 with prediabetes and 159 with obesity were recruited. Clinical characteristics, metabolic profiles, beta-cell function and insulin resistance were analyzed. The mean onset age of T2D was 12.35 ± 1.99 (7.9–17.8) years, and 7% of children were younger than 10 years; 55% of them were male, 57% had a family history of diabetes and 64% had classic symptoms, and 25% had a low or high birth weight. 89% of T2D patients were obese or overweight. A total of 58% of the patients with prediabetes were male. The fast serum C-peptide level was highest in the obesity group (P

Background and Aims To define pharmacodynamic and efficacy biomarkers in ulcerative colitis [UC] patients treated with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody, in the TURANDOT study. Methods Transcriptome, proteome and immunohistochemistry data were generated in peripheral blood and intestinal biopsies from 357 subjects in the TURANDOT study. Results In peripheral blood, C-C motif chemokine receptor 9 [CCR9] gene expression demonstrated a dose-dependent increase relative to placebo, but in inflamed intestinal biopsies CCR9 gene expression decreased with increasing PF-00547659 dose. Statistical models incorporating the full RNA transcriptome in inflamed intestinal biopsies showed significant ability to assess response and remission status. Oncostatin M [OSM] gene expression in inflamed intestinal biopsies demonstrated significant associations with, and good accuracy for, efficacy, and this observation was confirmed in independent published studies in which UC patients were treated with infliximab or vedolizumab. Compared with the placebo group, intestinal T-regulatory cells demonstrated a significant increase in the intermediate 22.5-mg dose cohort, but not in the 225-mg cohort. Conclusions CCR9 and OSM are implicated as novel pharmacodynamic and efficacy biomarkers. These findings occur amid coordinated transcriptional changes that enable the definition of surrogate efficacy biomarkers based on inflamed biopsy or blood transcriptomics data. ClinicalTrials.gov identifier NCT01620255

BACKGROUND Characteristics of alterations of serum hepatitis B virus (HBV) RNA in different chronic hepatitis B (CHB) patients still cannot be fully explained. Whether HBV RNA can predict HBeAg seroconversion is still controversial. AIM To investigate whether HBV RNA can predict virological response or HBeAg seroconversion during entecavir (ETV) treatment when HBV DNA is undetectable. METHODS The present study evaluated 61 individuals who were diagnosed and treated with long-term ETV monotherapy at the Department of Infectious Diseases of Peking University First Hospital (China) from September 2006 to December 2007. Finally, 30 treatment-naive individuals were included. Serum HBV RNA were extracted from 140 μL serum samples at two time points. Then they were reverse transcribed to cDNA with the HBV-specific primer. The product was quantified by real-time quantitative PCR (RT-PCR) using TAMARA probes. Statistical analyses were performed with IBM SPSS 20.0. RESULTS Level of serum HBV RNA at baseline was 4.15 ± 0.90 log10 copies/mL. HBV RNA levels showed no significant difference between the virological response (VR) and partial VR (PVR) groups at baseline (P = 0.940). Serum HBV RNA significantly decreased among patients who achieved a VR during ETV therapy (P < 0.001). The levels of HBV RNA in both HBeAg-positive patients with seroconversion group and those with no seroconversion increased after 24 wk of treatment. Overall, HBV RNA significantly but mildly correlated to HBsAg (r = 0.265, P = 0.041), and HBV RNA was not correlated to HBV DNA (r = 0.242, P = 0.062). Furthermore, serum HBV RNA was an independent indicator for predicting HBeAg seroconversion and virological response. HBeAg seroconversion was more likely in CHB patients with HBV RNA levels below 4.12 log10 copies/mL before treatment. CONLUSION The level of serum HBV RNA could predict HBeAg seroconversion and PVR during treatment. In the PVR group, the level of serum HBV RNA tends to be increasing.

Background: This study aimed to investigate the effects of cold exposure on peri-ovarian adipose tissue (POAT) and the relationship between POAT changes and ovarian function, to gain a deeper understanding of the mechanisms associated with cold exposure-induced changes in female reproductive health. Methods: Twenty female rats with regular estrus cycles were randomly divided into two groups: (1) the cold exposure group, which was exposed to –10°C, for 4 hours/day, for two weeks, and (2) the control group, which was maintained at 23 ± 1°C. Results: Cold exposure can increase serum E2 and FSH levels, and reduce AMH hormone levels, and cause the numbers of primary and secondary follicles in the cold-exposed group were significantly higher than those in the control group. Meanwhile, cold-stress-induced browning-related genes, including UCP1, PGC -1a, PRDM16, Fndc5 were upregulated in POAT, and the number of mitochondria in the cold-exposed group was significantly increased. Under cold exposure, the level of adipokines, including APDN, Lep, AMPK were significantly upregulated in POAT. FST was also upregulated in POAT, whereas MST, an AMPK inhibitor, was downregulated. The E2 synthesis rate-limiting-enzymes Cyplla1 and Cyp19 were upregulated in POAT. Conclusion: Cold exposure caused abnormal follicle development and promoted the browning of POAT. POAT browning was accompanied by the activation of the AMPK-PGC1α-Fndc5 pathway.