Summary Background A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with infection. We assessed the efficacy, safety, immunogenicity, antibody ...persistence, and immunological correlates of an inactivated alum-adjuvant EV71 vaccine. Methods We did a randomised, double-blind, placebo-controlled, phase 3 trial. Healthy children aged 6–35 months from four centres in China were randomly assigned (1:1) to receive vaccine or alum-adjuvant placebo at day 0 and 28, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and participants and their guardians were masked to the assignment. Primary endpoints were EV71-associated hand, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov , number NCT01508247. Findings 10 245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71-associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90·0% (95% CI 67·1–96·9) against EV71-associated HFMD (p=0·0001) and 80·4% (95% CI 58·2–90·8) against EV71-associated disease (p<0·0001). Serious adverse events were reported by 62 of 5117 (1·2%) participants in the vaccine group versus 75 of 5123 (1·5%) in the placebo group (p=0·27). Adverse events occurred in 3644 (71·2%) versus 3603 (70·3%; p=0·33). Interpretation EV71 vaccine provides high efficacy, satisfactory safety, and sustained immunogenicity. Funding China's 12–5 National Major Infectious Disease Program, Beijing Vigoo Biological.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary
The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms ...following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self‐limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In a national survey of 7409 surgical residents, 32% reported discrimination based on their self-identified gender, 32% verbal or physical abuse, 10% sexual harassment, and 38% burnout symptoms. ...Mistreatment was more frequently reported by female residents, and burnout symptoms were more common among residents who reported mistreatment.
Comprehensive Summary
Chemical investigation of Hedyosmum orientale led to the identification of two terpenoid derivatives, dyosmunoids A and B (1 and 2) featuring two different 3/5/6/6/5‐fused ...pentacyclic ring systems, respectively. Compound 1 is the second natural product of this C25 terpenoid compound class, and compound 2 is a rare dinor‐C25 terpenoid with a peroxide bridge. Their structural elucidation was achieved by the comprehensive analysis of spectroscopic data, single‐crystal X‐ray diffraction, and ECD calculation. Putative biosynthetic pathways for compounds 1 and 2 are proposed. Compound 2 exhibited strong antimalarial activity with an IC50 value of 0.42 μmol·L–1.
Dyosmunoids A and B (1 and 2), two terpenoid derivatives with different 3/5/6/6/5‐fused pentacyclic ring systems, respectively, were isolated from Hedyosmum orientale. Compound 1 is the second natural product of this C25 terpenoid compound class, and compound 2 was a new dinor‐C25 terpenoid containing a peroxide linkage. Their structures were fully elucidated by spectroscopic data analysis, single‐crystal X‐ray diffraction, and ECD calculation. Their plausible biosynthetic routes involving Diels‐Alder or tandem free radical reactions were also proposed. Compound 2 exhibited potent antimalarial activity against P. falciparum strain Dd2 (chloroquine‐resistant) with an IC50 value of 0.41 μmol·L–1.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The ongoing outbreak of the novel coronavirus disease (COVID-19) that occurred in China is rapidly spreading globally. China's bond and strict containment measures have been proved (in practice) to ...significantly reduce the spread of the epidemic. This was obtained through the use of emergency control measures in the epidemic areas and the integration of resources from multiple systems, including business, community, technology, education, and transportation, across the country. In order to better understand how China has managed to reduce the public health and economic impacts of the COVID-19 epidemic, this editorial systematically reviews the specific measures for infection prevention and control of the disease. The best practices for COVID-19 eradication in China provide evidence-based strategies that could be replicated in other countries.
We theoretically investigate high-harmonic generation in hexagonal boron nitride with linearly polarized laser pulses. We show that imperfect recollisions between electron-hole pairs in the crystal ...give rise to an electron-hole-pair polarization energy that leads to a double-peak structure in the subcycle emission profiles. An extended recollision model (ERM) is developed that allows for such imperfect recollisions, as well as effects related to Berry connections, Berry curvatures, and transition-dipole phases. The ERM illuminates the distinct spectrotemporal characteristics of harmonics emitted parallel and perpendicularly to the laser polarization direction. Imperfect recollisions are a general phenomenon and a manifestation of the spatially delocalized nature of the real-space wave packet; they arise naturally in systems with large Berry curvatures, or in any system driven by elliptically polarized light.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Spatial patterns of functional organization, resolved by microelectrode mapping, comprise a core principle of sensory cortices. In auditory cortex, however, recent two-photon Ca2+ imaging challenges ...this precept, as the traditional tonotopic arrangement appears weakly organized at the level of individual neurons. To resolve this fundamental ambiguity about the organization of auditory cortex, we developed multiscale optical Ca2+ imaging of unanesthetized GCaMP transgenic mice. Single-neuron activity monitored by two-photon imaging was precisely registered to large-scale cortical maps provided by transcranial widefield imaging. Neurons in the primary field responded well to tones; neighboring neurons were appreciably cotuned, and preferred frequencies adhered tightly to a tonotopic axis. By contrast, nearby secondary-field neurons exhibited heterogeneous tuning. The multiscale imaging approach also readily localized vocalization regions and neurons. Altogether, these findings cohere electrode and two-photon perspectives, resolve new features of auditory cortex, and offer a promising approach generalizable to any cortical area.
•High-sensitivity mode of transcranial imaging of cortex in unanesthetized mice•Spectral organization of auditory cortex under widefield imaging is highly regular•Neighboring neurons in AI are appreciably cotuned•Increased spectral integration is observed in neurons of AII
Understanding cortical organization across large-to-small spatial scales is critical to brain mapping. Issa et al. develop an imaging approach in GCaMP-expressing mice to characterize sound responses of auditory cortex from the level of individual neurons up to large-scale cortical maps.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neutralizing-antibody (nAb) is the major focus of most ongoing COVID-19 vaccine trials. However, nAb response against SARS-CoV-2, when present, decays rapidly. Given the myriad roles of antibodies in ...immune responses, it is possible that antibodies could also mediate protection against SARS-CoV-2 via effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), which we sought to explore here.
Plasma of 3 uninfected controls and 20 subjects exposed to, or recovering from, SARS-CoV-2 infection were collected from U.S. and sub-Saharan Africa. Immunofluorescence assay was used to detect the presence of SARS-CoV-2 specific IgG antibodies in the plasma samples. SARS-CoV-2 specific neutralizing capability of these plasmas was assessed with SARS-CoV-2 spike pseudotyped virus. ADCC activity was assessed with a calcein release assay.
SARS-CoV-2 specific IgG antibodies were detected in all COVID-19 subjects studied. All but three COVID-19 subjects contained nAb at high potency (>80% neutralization). Plasma from 19/20 of COVID-19 subjects also demonstrated strong ADCC activity against SARS-CoV-2 spike glycoprotein, including two individuals without nAb against SARS-CoV-2.
Both neutralizing and non-neutralizing COVID-19 plasmas can mediate ADCC. Our findings argue that evaluation of potential vaccines against SARS-CoV-2 should include investigation of the magnitude and durability of ADCC, in addition to nAb.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background The 2013–15 Ebola virus disease epidemic in west Africa greatly accelerated the development of Ebola vaccine. We aimed to analyse the immune persistence induced by one shot of an ...adenovirus type-5 vector-based Ebola virus vaccine up to 6 months and the effect of boosting with a homologous vector in healthy adults in China. Methods In a randomised, double-blind, placebo-controlled, phase 1 clinical trial in one site in Jiangsu Province, China, 120 healthy adults aged 18–60 years received an initial dose of intramuscular adenovirus type-5 Ebola virus vaccine of 4·0 × 1010 viral particles, 1·6 × 1011 viral particles, or placebo, and were followed up to day 168. Participants were subsequently re-recruited to receive a booster dose of the same vaccine or placebo, in the same dose, at month 6. Women who were pregnant, breastfeeding, or planned to become pregnant during the next month were excluded. Randomisation was conducted by computer-generated block randomisation. Randomisation data were unmasked for interim analysis of the data obtained between days 0–28 but not disclosed to participants or site staff. Safety and immunogenicity analysis were done on the intention-to-treat population. We aimed to assess the safety profile of the experimental vaccine and the immunity responses to a single-dose immunisation or a homologous prime-boost regimen. Primary outcomes were Ebola glycoprotein-specific ELISA antibody responses 28 days post-boost and the occurrences of adverse reactions post-boost. The original trial and the extended booster study were registered with ClinicalTrials.gov , numbers NCT02326194 and NCT02533791 , respectively. Findings Between Dec 28, 2014, and Jan 9, 2015, we enrolled 210 volunteers. 90 participants were not randomised due to not meeting inclusion criteria (61), meeting exclusion criteria (4), or withdrawal of consent (25). 120 people were randomly assigned to receive intramuscular Ebola vaccine at 4·0 × 1010 viral particles (low dose, n=40), Ebola vaccine at 1·6 × 1011 viral particles (high dose, n=40), or placebo (n=40, in two groups of 20). After prime vaccination, the geometric mean titer (GMT) of ELISA EC90 peaked at 682·7 (95% CI 424·3–1098·5) in the low-dose vaccine group and 1305·7 (970·1–1757·2) in the high-dose vaccine group at day 28, and then fell gradually through the next a few months to 575·5 (394·8–838·8) in the high-dose vaccine group and 197·9 (107·9–362·7) in the low-dose vaccine group at day 168. No specific response was recorded in the placebo group with a GMT of 5·0. Of the 120 participants involved in the initial trial, ten participants declined to participate, and 110 were included in the boost immunisation: 38 received the low dose, 35 received the high dose, and 37 received the placebo. At day 28 after boost vaccination, the ELISA EC90 titres rapidly rose to 6110 (95% CI 4705–7935) in the low-dose group and to 11825 (8904–15705) in the high dose group. 78 of 110 participants reported at least one solicited adverse reaction within the first 7 days after booster administration. Both of the groups who received vaccine showed significantly higher incidence of mild or moderate solicited adverse reactions than did the placebo group. Interpretation The adenovirus 5-vectored Ebola vaccine of 1·6 × 1011 viral particles was highly immunogenic and safe. The lower dose of 4·0 × 1010 viral particles was also safe, but immunogenicity seemed to be more vulnerable to the pre-existing immunity of adenovirus 5. A homologous priming-boosting regimen with adenovirus type-5 Ebola vaccine at 6 months interval was able to elicit greater antibody responses with longer duration. These results support an immunisation strategy to implement a booster injection for a more durable protection against Ebola virus disease. Funding Chinese Ministry of Science and Technology and The National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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