Summary Avian influenza A H5N1 viruses have caused many, typically severe, human infections since the first human case was reported in 1997. However, no comprehensive epidemiological analysis of ...global human cases of H5N1 from 1997 to 2015 exists. Moreover, few studies have examined in detail the changing epidemiology of human H5N1 cases in Egypt, especially given the outbreaks since November, 2014, which have the highest number of cases ever reported worldwide in a similar period. Data on individual patients were collated from different sources using a systematic approach to describe the global epidemiology of 907 human H5N1 cases between May, 1997, and April, 2015. The number of affected countries rose between 2003 and 2008, with expansion from east and southeast Asia, then to west Asia and Africa. Most cases (67·2%) occurred from December to March, and the overall case-fatality risk was 483 (53·5%) of 903 cases which varied across geographical regions. Although the incidence in Egypt has increased dramatically since November, 2014, compared with the cases beforehand, there were no significant differences in the fatality risk, history of exposure to poultry, history of patient contact, and time from onset to hospital admission in the recent cases.
Summary Background The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016–17 prompted concerns that the epidemiology of the virus might ...have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016–17 epidemic compared with previous epidemics. Methods In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques. Findings Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory-confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013–14, 219 in 2014–15, 114 in 2015–16, and 447 in 2016–17. The 2016–17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016–17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015–16 and 2016–17 epidemics (63% 72 of 114 and 61% 274 of 447, respectively) were higher than those in the first three epidemics (39% 52 of 134, 55% 169 of 306, and 56% 122 of 219, respectively). The clinical severity of individuals admitted to hospital in the 2016–17 epidemic was similar to that in the previous epidemics. Interpretation Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus. Funding The National Science Fund for Distinguished Young Scholars.
Summary Background Enterovirus 71 (EV71) outbreaks are a socioeconomic burden, especially in the western Pacific region. Results of phase 1 clinical trials suggest an EV71 vaccine has a clinically ...acceptable safety profile and immunogenicity. We aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this EV71 vaccine in healthy Chinese children. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was undertaken at one site in Donghai County, Jiangsu Province, China. Eligible participants were healthy boys or girls aged 6–36 months. Participants were randomly assigned (1:1:1:1:1) to receive either 160 U, 320 U, or 640 U alum-adjuvant EV71 vaccine, 640 U adjuvant-free EV71 vaccine, or a placebo (containing alum adjuvant only), according to a blocked randomisation list generated by SAS 9.1. Participants and investigators were masked to the assignment. The primary endpoint was anti-EV71 neutralising antibody geometric mean titres (GMTs) at day 56, analysed according to protocol. The study is registered with ClinicalTrials.gov , number NCT01399853. Findings We randomly assigned 1200 participants, 240 (120 aged 6–11 months infants and 120 aged 12–36 months children) of whom were assigned to each dose. 1106 participants completed the study and were included in the according-to-protocol analysis. The main reasons for dropout were withdrawal of consent and refusal to donate a blood sample. Infants who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (742·2 95% CI 577·3–954·3), followed by those who received the 320 U formulation (497·9 383·1–647·0). For children, those who received the 320 U formulation had the highest GMTs on day 56 (1383·2 1037·3–1844·5). Participants who received the vaccine had significantly higher GMTs than did who received placebo (p<0·0001). For the subgroup of participants who were seronegative at baseline, both infants and children who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (522·8 403·9–676·6 in infants and 708·4 524·1–957·6 in children), followed by those who received the 320 U adjuvant vaccine (358·2 280·5–457·5 in infants and 498·0 383·4–646·9 in children). 549 (45·8%) of 1200 participants (95 CI 42·9–48·6%) reported at least one injection-site or systemic adverse reaction, but the incidence of adverse reactions did not differ significantly between groups (p=0·36). The 640 U alum-adjuvant vaccine group had a significantly higher incidence of induration than did the 640 U adjuvant-free group (p=0·001). Interpretation Taking immunogenicity, safety, and production capacity into account, the 320 U alum-adjuvant formulation of the EV71 vaccine is probably the best possible formulation for phase 3 trials. Funding The National Science and Technology Major Project (2011ZX10004-902) of the Chinese Ministry of Science and Technology, China's 12–5 National Major Infectious Disease Program (2012ZX10002-001), and Beijing Vigoo Biological.
Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA ...vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD).
This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18–59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212).
Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one 5% of 20 in the 5 μg group, 13 65% of 20 in the 10 μg group, 17 85% of 20 in the 15 μg group, 19 95% of 20 in the 20 μg group, 16 100% of 16 in the 25 μg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 μg group, three (15%) of 20 in the 10 μg group, six (30%) of 20 in the 15 μg group, seven (35%) of 20 in the 20 μg group, five (31%) of 16 in the 25 μg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 μg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19.
ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.
National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.
Summary As a member of the catenin family, expression of δ -catenin and its clinical implication in numerous tumors remain unclear. In the present study, expression of δ -catenin in esophageal ...squamous cell carcinoma (ESCC) and its correlations with patient prognosis were explored. We detected the expression of δ -catenin, by immunohistochemistry, in ESCC tissues from 299 cases and analyzed the correlation between δ -catenin expression and patient clinicopathological features. Compared with a lack of expression in adjacent normal esophageal epithelium (0%, 0/47), the frequency of δ -catenin protein was increased in ESCC tissues to 41.5% (124/299, P < .001) and expression correlated with TNM stage and lymph node metastasis ( P = .025 and .019, respectively). Furthermore, Kaplan-Meier survival analysis revealed that patients with high δ -catenin expression had shorter survival than patients with low expression ( P = .010), and multivariate Cox analysis revealed that high δ -catenin expression was also an independent prognostic factor ( P = .001). In transwell assays, migration of ESCC cells was enhanced by δ -catenin overexpression, whereas proliferation of ESCC cells was unchanged. Together, our results suggest that δ -catenin acts as an oncoprotein when overexpressed in ESCC, and its expression is associated with poor prognosis and malignant cell behavior.
Background Isolated dissecting aneurysms of the posterior inferior cerebellar artery (PICA) are rare lesions, which carry high risk of rebleeding and mortality. However, the existing literature ...concerning predictors of outcome after endovascular treatment is limited and controversial. Our present study retrospectively reviewed and analyzed the clinical outcome of endovascular treatment–ruptured PICA-dissecting aneurysms and explored the predictors of outcome. Methods We retrospectively reviewed 17 consecutive patients with ruptured PICA dissecting aneurysms that underwent endovascular treatment from January 2003 to January 2014. Nine patients underwent selective coiling, whereas 7 patients underwent parent artery occlusion and 1 patient underwent stent-assisted coiling. Follow-up outcomes were evaluated using the modified Rankin Scale. The clinical outcomes of patients were categorized as favorable (modified Rankin Scale mRS score 0-1) or unfavorable (mRS score 2-6). Results Favorable outcomes (mRS score 0-1) were obtained in 13 of 17 patients. Post-treatment recurrence occurred in 1 patient with selective coiling in the 15-month follow-up, and the patient received stent-assisted coiling. The only patients with stent-assisted coiling developed PICA occlusion during follow-up. Aneurysm located in distal segment usually presented with intraventricular hemorrhage ( P = .015). Hypertension, coexisting hydrocephalus, and time to operation (latter than 2 weeks) were associated with unfavorable outcome. Conclusions Endovascular treatment of isolated dissecting aneurysm of PICA had excellent clinical outcomes, hypertension, coexisting hydrocephalus, and time to operation (latter than 2 weeks), which were associated with unfavorable outcome. Long-term follow-ups are necessary to provide stronger conclusions.
The procoagulant effect of microparticles (MPs) contributes to hypercoagulability-induced thrombosis. We provide preliminary findings of the MPs-Activated Clotting Time (MPs-ACT) assay to determine ...the procoagulant activity of MPs. MPs-rich plasma was obtained and recalcified. Changes in plasma viscoelasticity were evaluated and the time to the peak viscoelastic changes was defined as the MPs-ACT. MPs concentration was measured by flow cytometry. Coagulation products produced during plasma clotting were identified by fibrin and fibrinopeptide A. MPs were prepared in vitro and added to standard plasma to simulate pathological samples. In addition, reproducibility and sensitivity were evaluated. We confirmed the linear relationship between MPs-ACT and MP concentrations. Dynamic changes in fibrin production were depicted. We simulated the correlation between MPs-ACT and standard plasma containing MPs prepared in vitro. The reproducibility of high-value and low-value samples was 6.0% and 10.8%, respectively. MPs-ACT sensitively detected hypercoagulable samples from patients with pre-eclampsia, hip fractures, and lung tumors. MPs-ACT largely reflects the procoagulant effect of MPs. MPs-ACT sensitively and rapidly detects hypercoagulability with MPs-rich plasma. It may be promising for the diagnosis of hypercoagulable states induced by MPs.
Background Abelmoschus manihot , a single medicament of traditional Chinese medicine, has been widely used to treat kidney disease. This is the first randomized controlled clinical trial to assess ...its efficacy and safety in patients with primary glomerular disease. Study Design Prospective, open-label, multicenter, randomized, controlled, clinical trial. Setting & Participants From May 2010 to October 2011, a total of 417 patients with biopsy-proven primary glomerular disease from 26 hospitals participated in the study. Interventions A manihot in the form of a huangkui capsule, 2.5 g, 3 times per day; losartan potassium, 50 mg/d; or combined treatment, a huangkui capsule at 2.5 g 3 times per day, was combined with losartan potassium, 50 mg/d. The duration of intervention was 24 weeks. Outcomes & Measurements The primary outcome was change in 24-hour proteinuria from baseline after treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after treatment was a secondary outcome. The 24-hour proteinuria was measured every 4 weeks and eGFR was measured at 0, 4, 12, and 24 weeks. Results Mean baseline urine protein excretion was 1,045, 1,084, and 1,073 mg/d in the A manihot , losartan, and combined groups, respectively, and mean eGFR was 108, 106, and 106 mL/min/1.73 m2 , respectively. After 24 weeks of treatment, mean changes in proteinuria were protein excretion of −508, −376, and −545 mg/d, respectively ( P = 0.003 for A manihot vs losartan and P < 0.001 for the combined treatment vs losartan). Mean eGFR did not change significantly. The incidence of adverse reactions was not different among the 3 groups ( P > 0.05), and there were no severe adverse events in any group. Limitations Results cannot be generalized to those with nephrotic syndrome or reduced eGFR. Conclusions A manihot is a promising therapy for patients with primary kidney disease (chronic kidney disease stages 1-2) with moderate proteinuria.
The effect of exercise intervention on balance capacity among type 2 diabetes mellitus (T2DM) patients has not been evaluated. The objective of this systematic review and meta-analysis is to ...investigate the effect of exercise intervention on balance capacity among T2DM patients compared to the control group (usual care, waitlist, no-treatment, education). We conducted a comprehensive literature search through PubMed, EMBASE, Physiotherapy Evidence Database (PEDro), Cochrane library, Web of Science (WOS) from inception to August 2020. The literature language was limited to English. Randomized controlled trials (RCTs) or quasi-experimental (Q-E) trials that examined the effect of exercise intervention on balance capacity among T2DM patients were included. We used the standard methods of meta-analysis to evaluate the outcomes of exercise intervention for balance capacity of T2DM patients. A total of 14 trials (11 RCTs and 3 Q-E trials) involving 883 participants were eligible. The meta-analysis of some studies demonstrated that exercise intervention could significantly improve Berg Balance Scale (BBS) (MD = 2.56; 95%CI 0.35, 4.77; P = .02), SLST (Single Leg Stance Test) under the eyes-open (EO) condition (MD = 3.63; 95%CI 1.79, 5.47; P = .0001) and eyes-close (EC) condition (MD = 0.41; 95%CI 0.10, 0.72; P = .01) compared to control group. There was no significant difference in Time Up and Go Test (TUGT) (MD = −0.75; 95%CI −1.69, 0.19; P = .12) and fall efficacy (SMD = −0.44; 95%CI −0.86, −0.01; P = .05). Narrative review of some studies indicated that exercise intervention could improve postural stability measured by Sensory Organization Test (SOT) and Center of Pressure (COP) variables, etc. This systematic review and meta-analysis summarized that exercise intervention could improve balance capacity in T2DM patients. However, further studies with high quality are required to evaluate its effect.
Background Management of intracranial basilar dissecting aneurysms has been controversial and challenging, and surgical and conservative treatments usually have a bad prognosis. Our study aimed at ...evaluating the outcomes of endovascular treatment for these lesions and exploring the predictors of favorable outcome. Methods We retrospectively reviewed 50 consecutive patients with basilar dissecting aneurysms from January 2006 to January 2013. Twenty-four patients underwent stent-assisted coiling whereas 26 patients underwent conservative treatment. Follow-up outcomes were evaluated using modified Rankin Scale (mRS) score. Results Of the patients treated with stent-assisted coiling, 20 patients had a favorable outcome (mRS score, 0-1), post-treatment recurrence occurred in 3 patients, 1 had rebleeding, and 2 had no rebleeding. Of the patients treated with conservative therapy (observation or anticoagulation), 10 patients had an unfavorable outcome, 2 patients with ruptured aneurysms developed rebleeding, and 8 patients had poor outcome because of infarct progression. Stent-assisted coiling group had a more favorable outcome than the conservatively treated group (83.3% versus 55.2%, P = .019). Initial complete obliteration was related to the favorable outcome in endovascular-treated group ( P = .042). Stent placement was the only independent predictor of favorable outcome in the logistic regression analysis ( P = .030; odds ratio = 5.828; 95% confidence interval, 1.192-28.503). Conclusions Patients with basilar artery dissecting aneurysms treated with stent-assisted coiling had a more favorable outcome than the conservatively treated patients. Stent placement and initial complete occlusion were the favorable factors in patients with basilar dissecting aneurysm.
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