Immunogenicity, efficacy and safety of COVID-19 vaccines: an update of data published by 31 December 2021.

The unprecedented coronavirus disease 2019 (COVID-19) pandemic has caused a disaster for public health in the last 2 years, without any sign of an ending. Various vaccines were developed rapidly as soon as the outbreak occurred. Clinical trials demonstrated the reactogenicity, immunogenicity and protection efficacy in humans, and some of the vaccines have been approved for clinical use. However, waves of infections such as the recently circulating Omicron variant still occur. Newly emerging variants, especially the variants of concern, and waning humoral responses pose serious challenges to the control of the COVID-19 pandemic. Previously, we summarized the humoral and cellular immunity, safety profiles and protection efficacy of COVID-19 vaccines with clinical data published by 21 May 2021. In this review, we summarize and update the published clinical data of COVID-19 vaccines and candidates up to 31 December 2021.

Cannabidiol ameliorates inflammatory response partly by AGE-RAGE pathway in diabetic mice.

Cannabidiol (CBD), the most abundant nonpsychoactive constituent of Cannabis sativa plant, is a promising potential pharmacotherapy for the treatment of diabetes and associated comorbidities. Previous studies have shown the potential of CBD to prevent diabetes in mice, the precise mechanisms of action remain unclear. The purpose of this study was to explore the mechanism of CBD alleviating hyperglycemia. The results demonstrated that CBD reduced blood glucose of STZ-induced diabetic mice without causing hypoglycemia. To elucidate the possible mechanisms of CBD effect, RNA-seq analysis was performed on high glucose-induced human mesangial cells (HMCs). By cluster analysis of differential genes, the results showed that advanced glycation end products-receptor of advanced glycation endproducts (AGE-RAGE) pathway-related genes CCL2 and interleukin-1ß (IL-1ß) play an important role in the biological of CBD. The expression of CCL2 and IL-1ß were significantly increased in HMCs. Whereas, treatment with CBD decreased the expression of CCL2 and IL-1ß. In addition, CBD significantly reduced AGE-RAGE levels in high glucose-induced HMCs. Similar results were confirmed in diabetic mice. In conclusion, we discovered for the first time that CBD ameliorates hyperglycemia partly through AGE-RAGE mediated CCL2/IL-1ß pathway.

Progress Toward Measles Elimination - China, January 2013-June 2019.

In 2005, the World Health Organization (WHO) Western Pacific Region countries, including China, resolved to eliminate measles by 2012 or as soon as feasible thereafter (1). As of 2018, nine* of the 37 Western Pacific Region countries or areas† had eliminated§ measles. China's Measles Elimination Action Plan 2006-2012 included strengthening routine immunization; conducting measles risk assessments, followed by supplementary immunization activities (SIAs) with measles-containing vaccine (MCV) at national and subnational levels; strengthening surveillance and laboratory capacity; and investigating and responding to measles outbreaks. Most recently, progress toward measles elimination in China was described in a 2014 report documenting measles elimination efforts in China during 2008-2012 and a resurgence in 2013 (2). This report describes progress toward measles elimination in China during January 2013-June 2019.¶ Measles incidence per million persons decreased from 20.4 in 2013 to 2.8 in 2018; reported measles-related deaths decreased from 32 in 2015 to one in 2018 and no deaths in 2019 through June. Measles elimination in China can be achieved through strengthening the immunization program's existing strategy by ensuring sufficient vaccine supply; continuing to improve laboratory-supported surveillance, outbreak investigation and response; strengthening school entry vaccination record checks; vaccinating students who do not have documentation of receipt of 2 doses of measles-rubella vaccine; and vaccinating health care professionals and other adults at risk for measles.

Vaccine-derived poliovirus surveillance in China during 2001-2013: the potential challenge for maintaining polio free status.

BACKGROUND: The goal of polio eradication is to complete elimination and containment of all wild, vaccine-related and Sabin polioviruses. Vaccine-derived poliovirus (VDPV) surveillance in China from 2001-2013 is summarized in this report, which has important implications for the global polio eradication initiative. METHODS: Acute flaccid paralysis (AFP) cases and their contacts with VDPVs isolated from fecal specimens were identified in our AFP surveillance system or by field investigation. Epidemiological and laboratory information for these children were analyzed and the reasons for the VDPV outbreak was explored. RESULTS: VDPVs were isolated from a total of 49 children in more than two-thirds of Chinese provinces from 2001-2013, including 15 VDPV cases, 15 non-polio AFP cases and 19 contacts of AFP cases or healthy subjects. A total of 3 circulating VDPVs (cVDPVs) outbreaks were reported in China, resulting in 6 cVDPVs cases who had not been vaccinated with oral attenuated poliomyelitis vaccine. Among the 4 immunodeficiency-associated VDPVs (iVDPVs) cases, the longest duration of virus excretion was about 20 months. In addition, one imported VDPV case from Myanmar was detected in Yunnan Province. CONCLUSIONS: Until all wild, vaccine-related and Sabin polioviruses are eradicated in the world, high quality routine immunization and sensitive AFP surveillance should be maintained, focusing efforts on underserved populations in high risk areas.

Identification and control of a poliomyelitis outbreak in Xinjiang, China.

BACKGROUND: The last case of infection with wild-type poliovirus indigenous to China was reported in 1994, and China was certified as a poliomyelitis-free region in 2000. In 2011, an outbreak of infection with imported wild-type poliovirus occurred in the province of Xinjiang. METHODS: We conducted an investigation to guide the response to the outbreak, performed sequence analysis of the poliovirus type 1 capsid protein VP1 to determine the source, and carried out serologic and coverage surveys to assess the risk of viral propagation. Surveillance for acute flaccid paralysis was intensified to enhance case ascertainment. RESULTS: Between July 3 and October 9, 2011, investigators identified 21 cases of infection with wild-type poliovirus and 23 clinically compatible cases in southern Xinjiang. Wild-type poliovirus type 1 was isolated from 14 of 673 contacts of patients with acute flaccid paralysis (2.1%) and from 13 of 491 healthy persons who were not in contact with affected persons (2.6%). Sequence analysis implicated an imported wild-type poliovirus that originated in Pakistan as the cause of the outbreak. A public health emergency was declared in Xinjiang after the outbreak was confirmed. Surveillance for acute flaccid paralysis was enhanced, with daily reporting from all public and private hospitals. Five rounds of vaccination with live, attenuated oral poliovirus vaccine (OPV) were conducted among children and adults, and 43 million doses of OPV were administered. Trivalent OPV was used in three rounds, and monovalent OPV type 1 was used in two rounds. The outbreak was stopped 1.5 months after laboratory confirmation of the index case. CONCLUSIONS: The 2011 outbreak in China showed that poliomyelitis-free countries remain at risk for outbreaks while the poliovirus circulates anywhere in the world. Global eradication of poliomyelitis will benefit all countries, even those that are currently free of poliomyelitis.

Early-onset familial hemiplegic migraine due to a novel SCN1A mutation.

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with ß1 and ß2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.

Cross-border collaboration between China and Myanmar for emergency response to imported vaccine derived poliovirus case.

BACKGROUND: This report describes emergency response following an imported vaccine derived poliovirus (VDPV) case from Myanmar to Yunnan Province, China and the cross-border collaboration between China and Myanmar. Immediately after confirmation of the VDPV case, China disseminated related information to Myanmar with the assistance of the World Health Organization. METHODS: A series of epidemiological investigations were conducted, both in China and Myanmar, including retrospective searches of acute flaccid paralysis (AFP) cases, oral poliovirus vaccine (OPV) coverage assessment, and investigation of contacts and healthy children. RESULTS: All children <2 years of age had not been vaccinated in the village where the VDPV case had lived in the past 2 years. Moreover, most areas were not covered for routine immunization in this township due to vaccine shortages and lack of operational funds for the past 2 years. CONCLUSIONS: Cross-border collaboration may have prevented a potential outbreak of VDPV in Myanmar. It is necessary to reinforce cross-border collaboration with neighboring countries in order to maximize the leverage of limited resources.

An outbreak following importation of wild poliovirus in Xinjiang Uyghur Autonomous Region, China, 2011.

BACKGROUND: After more than 10 years without a case of wild poliovirus (WPV) in China, an outbreak occurred in 2011 in Xinjiang Uyghur Autonomous Region. METHODS: Acute flaccid paralysis (AFP) case surveillance was strengthened with epidemiological investigations and specimen collection and serological surveys were conducted among hospitalized patients. RESULTS: There were 21 WPV cases and 23 clinical compatible polio cases reported. WPV was isolated from 14 contacts of AFP cases and 13 in the healthy population. Incidence of WPV and clinical compatible polio cases were both highest among children <1 years, however, 24/44 (54.5%) polio cases were reported among adults aged 15-39 years. CONCLUSIONS: High coverage of routine immunization should be maintained among children until WPV transmission is globally eradicated. Expansion of AFP case surveillance and use of serologic surveys to estimate population immunity should be conducted rapidly to guide preparedness and response planning for future WPV outbreaks.

NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery.

Hypokalaemic periodic paralysis is typically associated with mutations of voltage sensor residues in calcium or sodium channels of skeletal muscle. To date, causative sodium channel mutations have been studied only for the two outermost arginine residues in S4 voltage sensor segments of domains I to III. These mutations produce depolarization of skeletal muscle fibres in response to reduced extracellular potassium, owing to an inward cation-selective gating pore current activated by hyperpolarization. Here, we describe mutations of the third arginine, R3, in the domain III voltage sensor i.e. an R1135H mutation which was found in two patients in separate families and a novel R1135C mutation identified in a third patient in another family. Muscle fibres from a patient harbouring the R1135H mutation showed increased depolarization tendency at normal and reduced extracellular potassium compatible with the diagnosis. Additionally, amplitude and rise time of action potentials were reduced compared with controls, even for holding potentials at which all NaV1.4 are fully recovered from inactivation. These findings may be because of an outward omega current activated at positive potentials. Expression of R1135H/C in mammalian cells indicates further gating defects that include significantly enhanced entry into inactivation and prolonged recovery that may additionally contribute to action potential inhibition at the physiological resting potential. After S4 immobilization in the outward position, mutant channels produce an inward omega current that most likely depolarizes the resting potential and produces the hypokalaemia-induced weakness. Gating current recordings reveal that mutations at R3 inhibit S4 deactivation before recovery, and molecular dynamics simulations suggest that this defect is caused by disrupted interactions of domain III S2 countercharges with S4 arginines R2 to R4 during repolarization of the membrane. This work reveals a novel mechanism of disrupted S4 translocation for hypokalaemic periodic paralysis mutations at arginine residues located below the gating pore constriction of the voltage sensor module.

Poliomyelitis eradication in China: 1953-2012.

BACKGROUND: Poliomyelitis has historically been endemic in China and has been considered an important cause of disability and death. METHODS: We reviewed strategies and measures of poliomyelitis control and eradication from 1953 to 2012. Data from notifiable disease and routine immunization reporting systems and acute flaccid paralysis (AFP) surveillance were analyzed. RESULTS: About 20 000 poliomyelitis cases were reported annually in the prevaccine era. During 1965-1977, live, attenuated oral poliomyelitis vaccine (OPV) was administered to children through annual mass campaigns in the winter, and the number of poliomyelitis cases started to decline. A cold chain system was established during 1982, and OPV coverage increased during the early stage of the Expanded Programme on Immunization, from 1978 to 1988. Between 1989 and 1999, routine immunization was strengthened, supplementary immunization activities (SIAs) were conducted, and the AFP surveillance system was established. China reported a last indigenous poliomyelitis case in 1994 and was certified as free of polio in 2000. To maintain its polio-free status, China kept >90% coverage of 3 doses of OPV, conducted SIAs in high-risk areas, and maintained high-quality of AFP surveillance. China succeeded in stopping the outbreak in Xinjiang in 2011. CONCLUSIONS: China's polio-free status was achieved and maintained through strengthening routine immunization and implementing SIAs and AFP surveillance.

Enhanced surveillance of acute flaccid paralysis following importation of wild poliovirus in Xinjiang Uygur Autonomous Region, China.

BACKGROUND: After being polio free for more than 10 years, an outbreak occurred in China in 2011 in Xinjiang Uygur Autonomous Region (Xinjiang) following the importation of wild poliovirus (WPV) originating from neighboring Pakistan. METHODS: To strengthen acute flaccid paralysis (AFP) surveillance in Xinjiang, "zero case daily reporting" and retrospective searching of AFP cases were initiated after the confirmation of the WPV outbreak. To pinpoint all the polio cases in time, AFP surveillance system was expanded to include persons of all ages in the entire population in Xinjiang. RESULTS: Totally, 578 AFP cases were reported in 2011 in Xinjiang, including 21 WPV cases, 23 clinical compatible polio cases and 534 non-polio AFP cases. Of the 44 polio cases, 27 (61.4%) cases were reported among adults aged 15-53 years. Strengthening AFP surveillance resulted in an increase in the number of non-polio AFP cases in 2011 (148 children < 15 years) compared with 76 cases < 15 years in 2010. The AFP surveillance system in Xinjiang was sensitive enough to detect polio cases, with the AFP incidence of 3.28/100,000 among children < 15 years of age. CONCLUSIONS: Incorporating adult cases into the AFP surveillance system is of potential value to understand the overall characteristics of the epidemic and to guide emergency responses, especially in countries facing WPV outbreak following long-term polio free status. The AFP surveillance system in Xinjiang was satisfactory despite limitations in biological sample collection.

Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Ca(v)1.1 mutation.

We studied a two-generation family presenting with conditions that included progressive permanent weakness, myopathic myopathy, exercise-induced contracture before normokalaemic periodic paralysis or, if localized to the tibial anterior muscle group, transient compartment-like syndrome (painful acute oedema with neuronal compression and drop foot). 23Na and 1H magnetic resonance imaging displayed myoplasmic sodium overload, and oedema. We identified a novel familial Ca(v)1.1 calcium channel mutation, R1242G, localized to the third positive charge of the domain IV voltage sensor. Functional expression of R1242G in the muscular dysgenesis mouse cell line GLT revealed a 28% reduced central pore inward current and a -20 mV shift of the steady-state inactivation curve. Both changes may be at least partially explained by an outward omega (gating pore) current at positive potentials. Moreover, this outward omega current of 27.5 nS/nF may cause the reduction of the overshoot by 13 mV and slowing of the upstroke of action potentials by 36% that are associated with muscle hypoexcitability (permanent weakness and myopathic myopathy). In addition to the outward omega current, we identified an inward omega pore current of 95 nS/nF at negative membrane potentials after long depolarizing pulses that shifts the R1242G residue above the omega pore constriction. A simulation reveals that the inward current might depolarize the fibre sufficiently to trigger calcium release in the absence of an action potential and therefore cause an electrically silent depolarization-induced muscle contracture. Additionally, evidence of the inward current can be found in 23Na magnetic resonance imaging-detected sodium accumulation and 1H magnetic resonance imaging-detected oedema. We hypothesize that the episodes are normokalaemic because of depolarization-induced compensatory outward potassium flux through both delayed rectifiers and omega pore. We conclude that the position of the R1242G residue before elicitation of the omega current is decisive for its conductance: if the residue is located below the gating pore as in the resting state then outward currents are observed; if the residue is above the gating pore because of depolarization, as in the inactivated state, then inward currents are observed. This study shows for the first time that functional characterization of omega pore currents is possible using a cultured cell line expressing mutant Ca(v)1.1 channels. Likewise, it is the first calcium channel mutation for complicated normokalaemic periodic paralysis.

A gating model for wildtype and R1448H Nav1.4 channels in paramyotonia.

We studied the consequences of the Nav1.4 mutation R1448H that is situated in the fourth voltage sensor of the channel and causes paramyotonia, a cold-induced myotonia followed by weakness. Previous work showed that the mutation uncouples inactivation from activation. We measured whole-cell Na(+) currents at 10, 15, 20, and 25°C using HEK293 cells stably transfected with wildtype (WT) and R1448H Na(+) channels. A Markov model was developed the parameters of which reproduced the data measured on WT and R1448H channels in the whole voltage and temperature range. It required an additional transient inactivated state and an additional closed-state inactivation transition not previously described. The model was used to predict single-channel properties, free energy barriers and temperature dependence of rates. It allowed us to draw the following conclusions: i) open-state inactivation results from a two-step process; ii) the channel re-openings that cause paramyotonia originate from enhanced deactivation/reactivation and not from destabilized inactivation; iii) the closed-state inactivation of R1448H is strikingly enhanced. We assume that latter explains the episodic weakness following cold-induced myotonia.

Potential of FGF21 in type 2 diabetes mellitus treatment based on untargeted metabolomics.

Fibroblast growth factor 21 (FGF21) has promise for treating diabetes and its associated comorbidities. It has been found to reduce blood glucose in mice and humans; however, its underlying mechanism is not known. Here, the metabolic function of FGF21 in diabetes was investigated. Diabetic db/db mice received intraperitoneal injections of FGF21 for 28 days, the serum of each mouse was collected, and their metabolites were analyzed by untargeted metabolomics using UHPLC-MS/MS. It was found that FGF21 reduced blood glucose and oral glucose tolerance without causing hypoglycemia. Moreover, administration of FGF21 reduced the levels of TG and LDL levels while increasing those of HDL and adiponectin. Importantly, the levels of 45 metabolites, including amino acids and lipids, were significantly altered, suggesting their potential as biomarkers. We speculated that FGF21 may treat T2DM through the regulation of fatty acid biosynthesis, the TCA cycle, and vitamin digestion and absorption. These findings provide insight into the mechanism of FGF21 in diabetes and suggest its potential for treating diabetes.

Thirty Years of Experience of Acute Flaccid Paralysis Surveillance for Polio - China, 1993-2022.

Introduction: Detecting poliovirus infections proves to be highly challenging due to their asymptomatic nature and infectious potential, highlighting the crucial importance of effective detection methods in the context of polio eradication efforts. In many countries, including China, the primary approach for identifying polio outbreaks has been through acute flaccid paralysis (AFP) surveillance. In this study, we conducted an evaluation spanning three decades (1993-2022) to assess the effectiveness of AFP surveillance in China. Methods: Data on all AFP cases identified since 1993 and national-level AFP surveillance system quality indicators aligned with the World Health Organization (WHO) standards were collected for analysis. The quality indicators assess surveillance sensitivity, completeness, timeliness of detection notification, case investigation, and laboratory workup. Surveillance sensitivity is determined by the non-polio AFP (NPAFP) detection rate among children under 15 years of age. Results: Between 1993 and 2022, a total of 150,779 AFP cases were identified and reported. Within this pool, surveillance identified 95 cases of wild poliovirus (WPV) and 24 cases due to vaccine-derived poliovirus. From 1995 onwards, the detection rate of NPAFP cases consistently adhered to the WHO and national standards of ≥1 case per 100,000, falling between 1.38 and 2.76. Starting in 1997, all timeliness indicators consistently achieved the criteria of 80%, apart from the consistency in meeting standards set for the rate of positive specimens sent to the national laboratory. Conclusions: AFP surveillance has been instrumental in China's accomplishment of maintaining a polio-free status. The ongoing adherence to key performance indicators, ensuring sensitivity and prompt specimen collection, demonstrates that AFP surveillance is proficient in detecting poliovirus in China. As we move into the post-eradication phase, AFP surveillance remains crucial for the sustained absence of polioviruses in the long term.

Analysis of a Sabin-Strain Inactivated Poliovirus Vaccine Response to a Circulating Type 2 Vaccine-Derived Poliovirus Event in Sichuan Province, China 2019-2021.

Importance: The Sabin-strain inactivated poliovirus vaccine (IPV) may be a tool for polio outbreak response in certain situations. Objective: To investigate the response to a type 2 vaccine-derived poliovirus (VDPV2) outbreak. Design, Setting, and Participants: This case series was conducted in China after a VDPV2 was detected in stool specimens from a child with acute flaccid paralysis (AFP) in Sichuan Province in 2019, 3 years after the global withdrawal of live, attenuated type 2 oral poliovirus vaccine (OPV). Investigation followed National Health Commission and World Health Organization guidance and included searching hospitals for unreported AFP cases; testing stool specimens from the child, his contacts, and local children; enhanced environmental surveillance for VDPV2s in wastewater; and measuring vaccination coverage. Sabin-strain IPV campaigns were conducted in a wide geographic area. Main Outcomes and Measures: Any VDPV2 detection after completion of the supplementary immunization activities. Results: A 28-nucleotide-change VDPV2 was isolated from a young boy. Three VDPV2s were detected in healthy children; 2 were contacts of the original child, and none had paralysis. A search of 31 million hospital records found 10 unreported AFP cases; none were polio. No type 2 polioviruses were found in wastewater. Prior to the event, polio vaccine coverage was 65% among children younger than 5 years. Sabin-strain IPV campaigns reached more than 97% of targeted children, administering 1.4 million doses. No transmission source was identified. More than 1 year of enhanced poliovirus environmental and AFP surveillance detected no additional VDPVs. Conclusions and Relevance: These findings suggest that the circulating VPDV2 outbreak in 2019 was associated with low vaccine coverage. An investigation discovered 3 infected but otherwise healthy children and no evidence of the virus in wastewater. Following Sabin-strain IPV-only campaigns expanding from county to prefecture, the poliovirus was not detected, and the outbreak response was considered by an expert panel and the World Health Organization to have been successful. This success suggests that the Sabin-strain IPV may be a useful tool for responding to circulating VDPV2 outbreaks when high-quality supplementary immunization activities can be conducted and carefully monitored in settings with good sanitation.

Red Yeast Rice for Hyperlipidemia: A Meta-Analysis of 15 High-Quality Randomized Controlled Trials.

Background: RYR is a commonly used lipid-lowering dietary supplements in Asian and European countries, showing considerable benefits and low toxicity. This quantitative study aims to present high-quality evidence regarding the efficacy and safety of RYR in treating hyperlipidemia, in order to promote its clinical application. Methods: PubMed, embase, and Cochrane Central Register of Controlled Trials databases were systematically searched, and high-quality randomized controlled trials comparing RYR with non-RYR interventions were included. RevMan5.3 software was used to conduct the meta-analysis. Results: A total of 1,012 individuals participated in this study (481 in the experimental and 531 in the control group). In comparison to statins, RYR was more effective in lowering TG (MD, -19.90; 95% CI, -32.22 to -7.58; p = 0.002), comparable in lowering LDL-C and elevating HDL-C, and less effective in lowering TC (MD, 12.24; 95% CI, 2.19 to 22.29; p = 0.02). Compared with nutraceutical, RYR significantly reduced TC (MD, -17.80; 95% CI, -27.12 to -8.48; p = 0.0002) and LDL-C (MD, -14.40; 95% CI, -22.71 to -6.09; p = 0.0007), and elevated HDL-C (MD, 7.60; 95% CI, 4.33 to 10.87; p < 0.00001). Moreover, RYR effectively synergized nutraceutical to further reduce TC (MD, -31.10; 95% CI, -38.83 to -23.36; p < 0.00001), LDL-C (MD, -27.91; 95% CI, -36.58 to -19.24; p < 0.00001), and TG (MD, -26.32; 95% CI, -34.05 to -18.59; p < 0.00001). Additionally, RYR significantly reduced apoB (MD, -27.98; 95% CI, -35.51 to -20.45; p < 0.00001) and, whether alone or in combination, did not increase the risk of adverse events in patients with hyperlipidemia. Conclusion: RYR at 200-4800 mg daily appears to be a safe and effective treatment for hyperlipidemia, effectively regulating blood lipid levels with an exceptional impact on TG. Looking forward, high-quality clinical trials with longer observation periods are required to evaluate the efficacy and safety of RYR as a long-term medication. Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/), identifier (CRD4202128450).

A PIK3R2 Mutation in Familial Temporal Lobe Epilepsy as a Possible Pathogenic Variant.

Temporal lobe epilepsy (TLE), the most common form of medically refractory focal epilepsy in adults, often requires surgery to alleviate seizures. By using next-generation sequencing, we identified a PIK3R2 mutation (NM_005027.4: c.265C > T; NP_005018.2: p.Arg89Cys) in a family with mesial temporal lobe epilepsy. PIK3R2 encodes p85ß, the regulatory subunit of Class IA phosphoinositide 3-kinase (PI3K) and the mutation we identified in PIK3R2 seems to function unexpectedly as a possible pathogenic variant. The mutation is predicted to be potentially pathogenic by multiple bioinformatics tools. Through a functional assay, we verified that the mutation enhances the function of PI3K in induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) of the proband. Finally, pathological testing of the resected temporal lobe cortex showed that the expression of PIK3R2 was significantly higher in patients with refractory temporal lobe epilepsy than in those of non-epileptic diseases as a control group. It can be inferred that PIK3R2 might play an important role in the development of TLE.

Lathyrane diterpenoids from Jatropha podagrica and their antitumor activities in human osteosarcoma cells.

Two new lathyrane-type diterpenoids, jatropodagins A and B (1 and 2), and five known analogues (3-7), were isolated from the stems of Jatropha podagrica. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all the lathyrane-type diterpenoids (1-7) were evaluated against two human osteosarcoma cell lines (Saos-2 and MG-63). Compound 1 exhibited significant cytotoxic effects against Saos-2 and MG-63 with IC50 values of 8.08 and 14.64 µM, respectively. The IC50 values for the positive control 5-FU against the Saos-2 and MG-63 cell lines were 19.01 and 25.00 µM, respectively. Morphological features of apoptosis activities were evaluated in 1-treated Saos-2 cells and the results confirmed apoptosis in a dose-dependent manner.

Assessing the burden of congenital rubella syndrome in China and evaluating mitigation strategies: a metapopulation modelling study.

BACKGROUND: A rubella vaccine was licensed in China in 1993 and added to the Expanded Programme on Immunization in 2008, but a national cross-sectional serological survey during 2014 indicates that many adolescents remain susceptible. Maternal infections during the first trimester often cause miscarriages, stillbirths, and, among livebirths, congenital rubella syndrome. We aimed to evaluate possible supplemental immunisation activities (SIAs) to accelerate elimination of rubella and congenital rubella syndrome. METHODS: We analysed residual samples from the national serological survey done in 2014, data from monthly rubella surveillance reports from 2005 and 2016, and additional publications through a systematic review. Using an age-structured population model with provincial strata, we calculated the reproduction numbers and evaluated the gradient of the metapopulation effective reproduction number with respect to potential supplemental immunisation rates. We corroborated these analytical results and estimated times-to-elimination by simulating SIAs among adolescents (ages 10-19 years) and young adults (ages 20-29 years) using a model with regional strata. We estimated the incidence of rubella and burden of congenital rubella syndrome by simulating transmission in a relatively small population lacking only spatial structure. FINDINGS: By 2014, childhood immunisation had reduced rubella's reproduction number from 7·6 to 1·2 and SIAs among adolescents were the optimal elimination strategy. We found that less than 10% of rubella infections were reported; that although some women with symptomatic first-trimester infections might have elected to terminate their pregnancies, 700 children could have been born with congenital rubella syndrome during 2014; and that timely SIAs would avert outbreaks that, as susceptible adolescents reached reproductive age, could greatly increase the burden of this syndrome. INTERPRETATION: Our findings suggest that SIAs among adolescents would most effectively reduce congenital rubella syndrome as well as eliminate rubella, owing both to fewer infections in the immunised population and absence of infections that those immunised would otherwise have caused. Metapopulation models with realistic mixing are uniquely capable of assessing such indirect effects. FUNDING: WHO and National Science Foundation.