Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Magnetic resonance imaging-based deep learning imaging biomarker for predicting functional outcomes after acute ischemic stroke.

PURPOSE: Clinical risk scores are essential for predicting outcomes in stroke patients. The advancements in deep learning (DL) techniques provide opportunities to develop prediction applications using magnetic resonance (MR) images. We aimed to develop an MR-based DL imaging biomarker for predicting outcomes in acute ischemic stroke (AIS) and evaluate its additional benefit to current risk scores. METHOD: This study included 3338 AIS patients. We trained a DL model using deep neural network architectures on MR images and radiomics to predict poor functional outcomes at three months post-stroke. The DL model generated a DL score, which served as the DL imaging biomarker. We compared the predictive performance of this biomarker to five risk scores on a holdout test set. Additionally, we assessed whether incorporating the imaging biomarker into the risk scores improved the predictive performance. RESULTS: The DL imaging biomarker achieved an area under the receiver operating characteristic curve (AUC) of 0.788. The AUCs of the five studied risk scores were 0.789, 0.793, 0.804, 0.810, and 0.826, respectively. The imaging biomarker's predictive performance was comparable to four of the risk scores but inferior to one (p = 0.038). Adding the imaging biomarker to the risk scores improved the AUCs (p-values) to 0.831 (0.003), 0.825 (0.001), 0.834 (0.003), 0.836 (0.003), and 0.839 (0.177), respectively. The net reclassification improvement and integrated discrimination improvement indices also showed significant improvements (all p < 0.001). CONCLUSIONS: Using DL techniques to create an MR-based imaging biomarker is feasible and enhances the predictive ability of current risk scores.

A Review on Traditional Uses, Phytochemistry, Pharmacology and Clinical Application of Tinospora sinensis (Lour.) Merr.

Tinospora sinensis (T. sinensis), whose Tibetan name is "Lezhe", as a traditional medicine, is widely distributed in China, India and Sri Lanka. It is used for the treatment of rheumatic arthralgia, sciatica, lumbar muscle strain and bruises. Research over the previous decades indicated that T. sinensis mainly contains terpenes, lignans, alkaloids, phenol glycosides and other chemical components. A wide range of pharmacologic activities such as anti-inflammatory, analgesic, immunosuppressive, anti-aging, anti-radiation, anti-leishmania and liver protection have been reported. However, the scholar's research on the pharmacodynamic material basis of T. sinensis is relatively weak. Data regarding many aspects such as links between the traditional uses and bioactivities, pharmacokinetics, and quality control standard of active compositions is still limited and need more attention. This review reports a total of 241 compounds, the ethnopharmacology and clinical application of T. sinensis, covering the literature which were searched by multiple databases including Web of Science, PubMed, Google Scholar, Science Direct, CNKI and other literature sources from 1996 to date, with a view to provide a systematic and insightful reference and lays a foundation and inspiration for the application and further in-depth research of T. sinensis resources.

Immunogenicity and safety of an Escherichia coli-produced human papillomavirus (types 6/11/16/18/31/33/45/52/58) L1 virus-like-particle vaccine: a phase 2 double-blind, randomized, controlled trial.

The Escherichia coli-produced human papillomavirus (HPV) 16/18 bivalent vaccine (Cecolin) has received prequalification by the World Health Organization based on its high efficacy and good safety profile. We aimed to evaluate the immunogenicity and safety of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine (Cecolin 9) through the randomized, blinded phase 2 clinical trial. Eligible healthy women aged 18-45 years were randomly (1:1) allocated to receive three doses of 1.0 mL (270 µg) of Cecolin 9 or placebo with a 0-1-6-month schedule. The primary endpoint was the seroconversion rate and geometric mean titer of neutralizing antibodies (nAbs) one month after the full vaccination course (month 7). The secondary endpoint was the safety profile including solicited adverse reactions occurring within 7 d, adverse events (AEs) occurring within 30 d after each dose, and serious adverse events (SAEs) occurring during the 7-month follow-up period. In total, 627 volunteers were enrolled and randomly assigned to Cecolin 9 (n = 313) or placebo (n = 314) group in Jiangsu Province, China. Almost all participants in the per-protocol set for immunogenicity (PPS-I) seroconverted for nAbs against all the nine HPV types at month 7, while two failed to seroconvert for HPV 11 and one did not seroconvert for HPV 52. The incidence rates of total AEs in the Cecolin 9 and placebo groups were 80.8% and 72.9%, respectively, with the majority of them being mild and recovering shortly. None of the SAEs were considered related to vaccination. In conclusion, the E. coli-produced 9-valent HPV (9vHPV) vaccine candidate was well tolerated and immunogenic, which warrants further efficacy studies in larger populations.

Clinical narratives as a predictor for prognosticating functional outcomes after intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke type that causes high mortality rates and severe disability among survivors. Many prognostic models are available for prognosticating patients with ICH. This study aimed to investigate whether clinical narratives can improve the performance for predicting functional outcomes after ICH. METHODS: This study used data from the hospital stroke registry and electronic health records. The study population (n = 1363) was randomly divided into a training set (75%, n = 1023) and a holdout test set (25%, n = 340). Five risk scores for ICH were used as baseline prognostic models. Using natural language processing (NLP), text-based markers were generated from the clinical narratives of the training set through machine learning (ML) and deep learning (DL) approaches. The primary outcome was a poor functional outcome (modified Rankin Scale score of 3 to 6) at hospital discharge. The predictive performance was compared between the baseline models and models enhanced by incorporating the text-based markers using the holdout test set. RESULTS: The enhanced prognostic models outperformed the baseline models, regardless of whether ML or DL approaches were used. The areas under the receiver operating characteristic curve (AUCs) of the baseline models were between 0.760 and 0.892. Adding the text-based marker to the baseline models significantly increased the model discrimination, with AUCs ranging from 0.861 to 0.914. The net reclassification improvement and integrated discrimination improvement indices also showed significant improvements. CONCLUSIONS: Using NLP to extract textual information from clinical narratives could improve the predictive performance of all baseline prognostic models for ICH.

Head-to-head immunogenicity comparison of an Escherichia coli-produced 9-valent human papillomavirus vaccine and Gardasil 9 in women aged 18-26 years in China: a randomised blinded clinical trial.

BACKGROUND: An Escherichia coli-produced human papillomavirus (HPV) 16 and 18 bivalent vaccine (Cecolin) was prequalified by WHO in 2021. This study aimed to compare the immunogenicity of the E coli-produced HPV 9-valent vaccine Cecolin 9 (against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) with Gardasil 9. METHODS: This was a randomised, single-blind trial conducted in China. Healthy non-pregnant women aged 18-26 years, who were not breastfeeding and with no HPV vaccination history, were enrolled in the Ganyu Centre for Disease Control and Prevention (Lianyungang City, Jiangsu Province, China). Women were stratified by age (18-22 years and 23-26 years) and randomly assigned (1:1) using a permutated block size of eight to receive three doses of Cecolin 9 or Gardasil 9 at day 0, day 45, and month 6. All participants, as well as study personnel without access to the vaccines, were masked. Neutralising antibodies were measured by a triple-colour pseudovirion-based neutralisation assay. The primary outcomes, seroconversion rates and geometric mean concentrations (GMCs) at month 7, were analysed in the per-protocol set for immunogenicity (PPS-I). Non-inferiority was identified for the lower limit of the 95% CI of the GMC ratio (Cecolin 9 vs Gardasil 9) at a margin of 0·5 and a seroconversion rate difference (Cecolin 9-Gardasil 9) at a margin of -5%. This study was registered at ClinicalTrials.gov (NCT04782895) and is completed. FINDINGS: From March 14 to 18, 2021, a total of 553 potential participants were screened, of which 244 received at least one dose of Cecolin 9 and 243 received at least one dose of Gardasil 9. The seroconversion rates for all HPV types in both groups were 100% in the PPS-I, with the values of the lower limits of 95% CIs for seroconversion rate differences ranging between -1·8% and -1·7%. The GMC ratios of five types were higher than 1·0, with the highest ratio, for HPV 58, at 1·65 (95% CI 1·38-1·97), and those of four types were lower than 1·0, with the lowest ratio, for HPV 11, at 0·79 (0·68-0·93). The incidence of adverse reactions in both groups was similar (43% [104/244] vs 47% [115/243]). INTERPRETATION: Cecolin 9 induced non-inferior HPV type-specific immune responses compared with Gardasil 9 and is a potential candidate to accelerate the elimination of cervical cancer by allowing for global accessibility to 9-valent HPV vaccinations, especially in low-income and middle-income countries. FUNDING: National Natural Science Foundation, Fujian Provincial Natural Science Foundation, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax.

Safety and immunogenicity of a skin- and neuro-attenuated live vaccine for varicella: a randomized, double-blind, controlled, dose-escalation and age de-escalation phase 1 clinical trial.

Background: Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin- and neuro-attenuated varicella vaccine candidate (v7D). Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay. Findings: Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3). Interpretation: The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine. Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai CO., LTD.

Safety and immunogenicity of an Escherichia coli-produced 9-valent human papillomavirus L1 virus-like particle vaccine (types 6/11/16/18/31/33/45/52/58) in healthy adults: an open-label, dose-escalation phase 1 clinical trial.

Background: A safe and highly efficacious Escherichia coli (E. coli)-produced HPV 16/18 bivalent vaccine has been prequalified by the World Health Organization. Here, we conducted a single-center, open-label, dose-escalation phase 1 clinical trial to evaluate the safety and immunogenicity of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine. Method: Twenty-four eligible volunteers aged 18-45 years were enrolled in January 2019 in Dongtai, China and received 0.5 mL (135 µg) or 1.0 mL (270 µg) of the candidate vaccine with a 0/1/6-month dose-escalation schedule. Local and systemic adverse events (AEs) occurring within 30 days after each vaccination and serious adverse events (SAEs) occurring within 7 months were recorded. Blood samples from each participant were collected before and 2 days after the first and third vaccinations to determine changes in laboratory parameters. Serum IgG and neutralizing antibody (nAb) levels against each HPV type at month 7 were analyzed (ClinicalTrials.gov: NCT03813940). Findings: The incidences of total AEs in the 135 µg and 270 µg groups were 66.7% and 83.3%, respectively. All AEs were mild or moderate, and no SAEs were reported. No clinically significant changes were found in paired blood indices before or after any of the vaccinations. All the participants in the per-protocol set except for two who failed to seroconvert for HPV 11 or 58 in the 135 µg group seroconverted at month 7 for both IgG and nAbs. Interpretation: The candidate E. coli-produced 9vHPV vaccine has been preliminarily proven to be well tolerated and immunogenic, which encourages further studies in large cohorts with a wider age range. Funding: This study was supported by the National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Fujian Province Health and Education Joint Research Program, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax Biotechnology Co., Ltd.

Four new diastereoisomeric neolignan glycosides from the root bark of Lycium chinense Miller. and their α-glucosidase inhibitory activity.

Four new diastereoisomeric neolignan glycosides (1-4) along with nine known lignan glycosides (5-13) were isolated from the root bark of Lycium chinense Mill. Their structures with absolute configurations were elucidated on the basis of NMR spectroscopy, ECD, Mo2(OAc)4-induced ECD spectra, enzymatic hydrolysis and acid hydrolysis. The isolated compounds were evaluated for their α-glucosidase inhibitory activity. Compounds 8 and 13 exhibited moderate inhibitory activities against α-glucosidase with IC50 values of 26.82 ± 2.71 and 43.14 ± 2.81 µg/mL.

Clinical characteristics and prognosis of paroxysmal sympathetic hyperactivity in patients with severe nontraumatic brain injury.

OBJECTIVE: This prospective study investigated and analyzed the clinical characteristics and prognosis of paroxysmal sympathetic hyperactivity (PSH) in patients with severe nontraumatic brain injury. METHODS: Patients presenting with severe nontraumatic brain injury with PSH from July 2018 to June 2019 were enrolled. A PSH assessment measure ≥ 8 points was used as the criterion for PSH. Clinical data, indicators related to PSH, treatment effects and the prognosis were prospectively collected and analyzed. RESULTS: A total of 220 patients with severe nontraumatic brain injury were analyzed, and PSH occurred in 8 patients (3.6%).     The primary neurological diseases included acute cerebral infarction, anti-N-methyl-D-aspartate receptor encephalitis, hypoxic encephalopathy and acute disseminated encephalitis. The Glasgow Coma Scale score was lower than 8 in the 8 patients with PSH. Seven of these eight patients had a Glasgow outcome scale (GOS) score of 3 or less than 3, and one patient had a GOS of 5 after 6 months. The medicines that effectively controlled PSH included dexmedetomidine, clonazepam, midazolam and diazepam. CONCLUSIONS: Although the incidence was lower for nontraumatic brain injury complicated with PSH than for traumatic brain injury, patients with PSH had a more severe disease state and poorer prognoses. Dexmedetomidine might effectively control PSH.

Prognosis of hepatitis E infection in patients with chronic liver disease: A meta-analysis.

In individuals with underlying chronic liver disease (CLD), hepatitis E virus (HEV) infection is a potential trigger of acute-on-chronic liver failure. In this systematic review, seven electronic databases were searched. Pooled incidence rates with 95% confidence intervals (95% CIs) were calculated by the Freeman-Tukey double arcsine transformation method. The association between death or liver failure and HEV superinfection in CLD patients was estimated by the odds ratios (OR) with a 95% CI. A total of 18 studies from 5 countries were eligible for systematic review. The prevalence of acute HEV infection in hospitalized CLD patients with clinical manifestations of hepatitis was 13.6%, which was significantly higher than that in CLD patients from the community (pooled prevalence 1.1%). The overall rates of liver failure and mortality in CLD patients with HEV superinfection were 35.8% (95% CI: 26.7%-45.6%) and 14.3% (95% CI: 10.6%-18.5%), respectively, with the rates in cirrhotic patients being approximately 2-fold and 4-fold higher than those in noncirrhotic patients, respectively. The risks of liver failure (OR = 5.5, 95% CI: 1.5-20.1) and mortality (OR = 5.0, 95% CI: 1.9-13.3) were significantly higher in CLD patients with HEV superinfection than in those without HEV superinfection. HEV testing in hospitalized CLD patients is necessary due to the high prevalence of HEV infection observed in hospitalized CLD patients. HEV superinfection could accelerate disease progression in patients with underlying CLD and increase mortality in these patients. HEV vaccination is appropriate for patients with pre-existing CLD.

Efficacy, safety, and immunogenicity of an Escherichia coli-produced Human Papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial.

BACKGROUND: This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. METHODS: This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18-45 years, with intact cervix and 1-4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18-26 and 27-45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. FINDINGS: Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2-100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9-99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. INTERPRETATION: The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Safety and immunogenicity of an Escherichia coli-produced bivalent human papillomavirus type 6/11 vaccine: A dose-escalation, randomized, double-blind, placebo-controlled phase 1 trial.

A dose-escalation, randomized, double-blind, placebo-controlled phase 1 clinical trial enrolled 145 eligible participants aged 18-55 years in March 2015 in Liuzhou, China. Stratified by age and sex, the participants were randomly assigned to receive either 30, 60, or 90 µg of the HPV-6/11 vaccine (n = 41/40/40) or the parallel placebo vaccine (n = 8/8/8) with a 0/1/6-month dose-escalation schedule. Participants were actively followed-up to record local and systemic AEs occurring within 30 days after each vaccination, and SAEs occurred in 7 months. Blood and urine samples of each participant were collected before and 2 days after the first and third vaccination to determine changes in routine blood, serum biochemical, and urine indexes. Serum HPV-6/11-specific IgG and neutralizing antibody levels at month 7 were analyzed. A total of 79 adverse events were reported, and no SAEs occurred. The incidences of total adverse reactions in the 30 µg, 60 µg, and 90 µg HPV vaccine groups and the control group were 31.7%, 50.0%, 42.5%, and 62.5%, respectively. All but one of the adverse reactions was mild or moderate with grade 1 or 2. No vaccine-related changes with clinical significance were found in paired blood and urine indexes before and after vaccinations. All the participants in the per-protocol set seroconverted at month 7 for both IgG and neutralizing antibodies. The candidate novel Escherichia-coli-produced bivalent HPV-6/11 vaccine has been preliminarily proven to be well tolerated and with robust immunogenicity in a phase 1 clinical study, supporting further trials with larger sample size. The study has been registered at ClinicalTrials.gov (NCT02405520).

Distribution and changes in hepatitis C virus genotype in China from 2010 to 2020.

BACKGROUND: Hepatitis C virus (HCV) causes a large number of infections worldwide. New infections seem to be increasing according to a report of the World Health Organization in 2015. Although direct-acting antivirals are quite effective for most genotypes of the HCV, some genotypes fail to respond. Therefore, the trend of genotype distribution is vital to better control the development of this infection. AIM: To analyze the distribution and trends of the HCV genotype before and after the emergence of direct-acting antivirals in China. METHODS: We searched all literature published in five electronic databases-China National Knowledge Infrastructure, Wan Fang Data, VIP Chinese Journal Database, Chinese Biomedical Literature Service System, and PubMed-from January 1, 2010 to December 31, 2020. The search strategy combined medical subject headings and free-text terms, including "hepatitis C virus" or "HCV" and "genotype" or "subtype" and "China" or "Chinese". Additional relevant articles were searched by manual selection. Data were extracted to build a database. All of the data were totaled according to regions, periods, routes of transmission, and sexes. The percentages in various stratifications were calculated. RESULTS: There were 76110 samples from 30 provinces included in the study. Genotype 1 (G1) accounted for 58.2% of cases nationwide, followed by G2, G6, G3b, G3a, unclassified and mixed infections (17.5%, 7.8%, 6.4%, 4.9%, 1.8%, and 1.2%, respectively). The constitution of genotype varied among different regions, with G6 and G3b being more common in the south and southwest, respectively (28.1%, 15.4%). The past ten years have witnessed a decrease in G1 and G2 and an increase in G3 and G6 in almost all regions. The drug-use population had the most abundant genotypes, with G6 ranking first (33.3%), followed by G1 and G3b (23.4%, 18.5%). CONCLUSION: G3 and G6 pose a new challenge for HCV infection. This study revealed the distribution of HCV genotypes in China over the past 10 years, providing information for HCV management strategies.

Epidemiological Features, Risk Factors, and Disease Burden of Respiratory Viruses among Hospitalized Children with Acute Respiratory Tract Infections in Xiamen, China.

Well-established surveillance and monitoring systems for respiratory viruses need to be improved, and epidemiological data on respiratory viruses in China are scarce. This study aimed to investigate the epidemiological characteristics of respiratory viruses among hospitalized children aged ≤2 years with acute respiratory tract infections (ARTIs) in Xiamen, China, from October 2014 to September 2017. The clinical records of 7,248 children hospitalized for ARTIs were retrospectively analyzed. Respiratory syncytial virus (RSV) (22.3%) was the most common virus among hospitalized children aged ≤2 years, followed by parainfluenza (5.0%), adenovirus (3.5%), and influenza (1.7%). RSV-infected children had a higher disease burden, including a higher intensive care unit (ICU) admission rate (12.7%) and higher hospital charges ($635.36). Particularly, infants aged <6 months had the highest risk of RSV infection (odds ratio = 2.4; 95% CI, 1.9-2.9) and a higher ICU admission rate (12.1% vs. 4.5%, 4.6%) and hospital cost ($923.3 vs. $785.5, $811.7) than the other age groups. Therefore, infants aged 0-6 months, particularly premature infants and children with congenital diseases, should receive more attention. There is an urgent need to develop effective immunization strategies to protect these infants during the first 6 months of life and in the RSV season.

Risk of hepatocellular carcinoma in antiviral treatment-naïve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis.

BACKGROUND: Long-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction. METHODS: The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis. RESULTS: A total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis. CONCLUSION: ETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.

Epidemiology of Respiratory Pathogens Among Children Hospitalized for Pneumonia in Xiamen: A Retrospective Study.

OBJECTIVES: To investigate the etiology of common respiratory pathogens in children < 2 years of age hospitalized with pneumonia in Xiamen from 2014 to 2017. METHODS: The medical records of 5581 children with pneumonia were retrospectively reviewed. Direct immunofluorescent test was used for respiratory virus testing. Bacteria were detected by conventional culture method. The results of pathogen detection at admission were analyzed as well as the clinical outcomes of children. RESULTS: The burden of hospitalized children with pneumonia was highest among infants < 6 months old (58.2%). Respiratory syncytial virus (RSV) was the most common respiratory virus (26.0%) followed by parainfluenza (4.8%) and adenovirus (3.2%). Haemophilus influenzae was the most common bacteria detected (16.6%) followed by Moraxella catarrhalis (13.4%), Staphylococcus aureus (13.0%), Streptococcus pneumoniae (12.3%), Escherichia coli (5.1%) and Klebsiella pneumoniae (4.8%). Notably, RSV and K. pneumoniae were detected more frequently in severe pneumonia (35.0% and 10.9%) versus mild pneumonia (25.6% and 4.6%), with higher rates of ICU admissions, longer hospital stays and higher hospital costs compared to those infected with other respiratory pathogens. CONCLUSIONS: Among children < 2 years of age hospitalized with pneumonia in Xiamen, RSV was the most common respiratory virus, while H. influenzae and S. pneumoniae remained the predominant bacterial pathogens detected. Considering the low implementation rate of vaccines against pneumococcal and Hib pneumonia in China, there is an urgent need to increase both vaccination rates to reduce pneumococcal and Hib disease burden.

Antibody response in COVID-19 patients with and without re-positive RT-PCR results during the convalescent phase.

Nucleic acid testing and antibody testing data from 143 recovered COVID-19 patients during the convalescent phase were retrospectively analyzed. A total of 23 (16.1%) recovered patients re-tested positive for SARS-CoV-2 RNA by RT-PCR. Three months after symptom onset, 100% and 99.3% of the patients remained positive for total and IgG antibodies, and the antibody levels remained high. IgM antibodies declined rapidly, with a median time to seroconversion of 67 (95% CI: 59, 75) days after onset. Approximately 25% of patients were seronegative for IgA antibodies at three months after onset. There was no statistically significant difference in antibody kinetics between patients with and without re-positive RT-PCR results during the convalescent phase.

Inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Clinical efficacy of plasma exchange in patients with autoimmune encephalitis.

OBJECTIVE: To determine the clinical and antibody response after therapeutic plasma exchange (TPE) in patients with severe refractory antibody-associated autoimmune encephalitis (AE). METHODS: This single-center prospective cohort included all patients consecutively admitted to our hospital because of severe refractory AE over the period from July 2014 to June 2019. All patients received immunotherapy (steroids, intravenous immunoglobulin (IVIG), and/or TPE). The primary outcome was evaluated at 1- and 2-month postenrollment, and the long-term outcome was followed up at 6 and 12 months. AE antibody titers in the cerebrospinal fluid and plasma were evaluated before and after TPE/IVIG. RESULTS: This study enrolled 57 patients with severe refractory AE, including anti-NMDA receptor encephalitis (n = 51), anti-GABAb receptor encephalitis (n = 3), anti-LGI 1 encephalitis (n = 2), and anti-AMPA receptor encephalitis (n = 1). Of all 57 patients, 33 patients received TPE for a total of 193 procedures, and 24 patients with contraindications or refusal of TPE were in the non-TPE group. Compared with the non-TPE group, the TPE group exhibited greater clinical improvement: 21 (37%) versus 8 (14%) after 1 month (P = 0.03) and 31 (54%) versus 16 (28%) after 2 months (P = 0.01), respectively. Complications and adverse events associated with TPE occurred in 91 procedures (47%) without serious adverse events associated with the use of TPE. INTERPRETATION: TPE might be an effective rescue therapy associated with rapid functional improvement in patients with severe steroid/IVIG refractory antibody-associated AE from this nonrandomized control trial.