De novo variants of IRF2BPL result in developmental epileptic disorder.

BACKGROUND: Pathogenic variants of the IRF2BPL gene have been reported to cause neurodevelopmental disorders; however, studies focused on IRF2BPL in zebrafish are limited. RESULTS: We reported three probands diagnosed with developmental delay and epilepsy and investigated the role of IRF2BPL in neurodevelopmental disorders in zebrafish. The clinical and genetic characteristics of three patients with neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures (NEDAMSS) were collected. Three de novo variants (NM_024496.4: c.1171 C > T, p.Arg391Cys; c.1157 C > T, p.Thr386Met; and c.273_307del, p.Ala92Thrfs*29) were detected and classified as pathogenic or likely pathogenic according to ACMG guidelines. Zebrafish crispants with disruption of the ortholog gene irf2bpl demonstrated a reduced body length and spontaneous ictal-like and interictal-like discharges in an electrophysiology study. After their spasms were controlled, they gain some development improvements. CONCLUSION: We contribute two new pathogenic variants for IRF2BPL related developmental epileptic disorder which provided evidences for genetic counseling. In zebrafish model, we for the first time confirm that disruption of irf2bpl could introduce spontaneous electrographic seizures which mimics key phenotypes in human patients. Our follow-up results suggest that timely cessation of spasmodic seizures can improve the patient's neurodevelopment.

[Clinical features and genetic analysis of five children with epilepsies due to variants of SCN8A gene].

OBJECTIVE: To explore the clinical and genetic characteristics of five children with epilepsies due to variants of SCN8A gene. METHODS: Clinical data of five children (four males and one female) admitted to Linyi People's Hospital due to hereditary epilepsies between August 2015 and August 2022 were collected. Whole exome sequencing was carried out for these children, and candidate variants were verified by Sanger sequencing. RESULTS: All of the five children were found to harbor variants of the SCN8A gene. Case 1, who had benign familial infantile epilepsy, inherited a known pathogenic c.4840A>G variant from his father with similar symptoms. Cases 2 to 4 had presented with intermediate epilepsy. Among these, case 2 has harbored a de novo c.3967G>A variant which was rated as pathogenic (PS1+PS2+PM1+PM2_Supporting+PP3) based on the guidelines from the American College of Medical Genetics and Genomics. Cases 3 and 4 were found to respectively harbor a de novo c.415A>T and a c.4697C>T variant, which were both rated as likely pathogenic (PS2+PM1+PM2_Supporting+PP3). Case 5, who had early-onset infantile epileptic encephalopathy transformed into Lennox Gastaut-like syndrome, has harbored a de novo c.5615G>A variant, which was known to be pathogenic. The children had their age of onset ranging from 2 to 14 months, and all had focal seizures and generalized tonic clonic seizures. Four children (cases 1, 2, 3 and 5) had cluster seizures, four (cases 1 to 4) had become seizure-free after single or dual treatment and showed normal growth and development, whilst case 5 was drug-resistant and showed severe developmental retardation. CONCLUSION: The five children had new features such as cluster seizures, occasional benign seizures in adulthood, and intermediate epilepsy which are prone to relapse after discontinuation of medication, which may be attributed to the pathogenic variants of the SCN8A gene.

[Genetic analysis of a family with epilepsy accompanied by developmental delay and brain deformity due to a de novo variant of TUBB2A gene].

OBJECTIVE: To explore the clinical manifestations and pathogenic variant in a family with epilepsy, developmental delay and brain deformity. METHODS: Clinical data of the child and his family members who had visited the Department of Pediatrics, Linyi People's Hospital on July 2, 2022 were collected. The child, his sister and parents were subjected to high-throughput sequencing, and the result was verified by Sanger sequencing. RESULTS: The child was a 6-year-old boy with developmentally delay and had epileptic seizures with fever sensitivity for four years. Cranial imaging showed brain dysplasia, while the video electroencephalogram showed abnormal discharge. High-throughput sequencing showed the child has harbored a heterozygous c.5G>T (p.Arg2Leu) variant of TUBB2A gene, which was unreported previously. His sister also carried the variant and had similar clinical manifestations, whilst his parents were of the wild-type and had normal clinical phenotypes. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PM2_Supporting+PM5+PP1+PP2+PP3). CONCLUSION: The heterozygous c.5G>T (p.Arg2Leu) variant of the TUBB2A gene, in the form of gonadal mosaicism, probably underlay the disorders in this family.

Differentiation and risk stratification of basal cell carcinoma with deep learning on histopathologic images and measuring nuclei and tumor microenvironment features.

BACKGROUND: Nuclear pleomorphism and tumor microenvironment (TME) play a critical role in cancer development and progression. Identifying most predictive nuclei and TME features of basal cell carcinoma (BCC) may provide insights into which characteristics pathologists can use to distinguish and stratify this entity. OBJECTIVES: To develop an automated workflow based on nuclei and TME features from basaloid cell tumor regions to differentiate BCC from trichoepithelioma (TE) and stratify BCC into high-risk (HR) and low-risk (LR) subtypes, and to identify the nuclear and TME characteristics profile of different basaloid cell tumors. METHODS: The deep learning systems were trained on 161 H&E -stained sections which contained 51 sections of HR-BCC, 50 sections of LR-BCC and 60 sections of TE from one institution (D1), and externally and independently validated on D2 (46 sections) and D3 (76 sections), from 2015 to 2022. 60%, 20% and 20% of D1 data were randomly splitted for training, validation and testing, respectively. The framework comprised four stages: tumor regions identification by multi-head self-attention (MSA) U-Net, nuclei segmentation by HoVer-Net, quantitative feature by handcrafted extraction, and differentiation and risk stratification classifier construction. Pixel accuracy, precision, recall, dice score, intersection over union (IoU) and area under the curve (AUC) were used to evaluate the performance of tumor segmentation model and classifiers. RESULTS: MSA-U-Net model detected tumor regions with 0.910 precision, 0.869 recall, 0.889 dice score and 0.800 IoU. The differentiation classifier achieved 0.977 ± 0.0159, 0.955 ± 0.0181, 0.885 ± 0.0237 AUC in D1, D2 and D3, respectively. The most discriminative features between BCC and TE contained Homogeneity, Elongation, T-T_meanEdgeLength, T-T_Nsubgraph, S-T_HarmonicCentrality, S-S_Degrees. The risk stratification model can well predict HR-BCC and LR-BCC with 0.920 ± 0.0579, 0.839 ± 0.0176, 0.825 ± 0.0153 AUC in D1, D2 and D3, respectively. The most discriminative features between HR-BCC and LR-BCC comprised IntensityMin, Solidity, T-T_minEdgeLength, T-T_Coreness, T-T_Degrees, T-T_Betweenness, S-T_Degrees. CONCLUSIONS: This framework hold potential for future use as a second opinion helping inform diagnosis of BCC, and identify nuclei and TME features related with malignancy and tumor risk stratification.

Comparative efficacy of 2% minoxidil alone against combination of 2% minoxidil and low-level laser therapy in female pattern hair loss-A randomized controlled trial in Chinese females.

OBJECTIVES: To investigate the effectiveness and safety of combination of 655 nm low level laser helmet device with topical 2 % minoxidil solution at FPHL in Chinese population. MATERIALS AND METHODS: Randomized, parallel, controlled, single-blind clinical trial was conducted. FPHL subjects were randomly allocated into 2 % minoxidil group and combination group. The 2 % minoxidil group received 1 ml topical 2 % minoxidil solution twice daily for 24 weeks. The combination group received 1 ml topical 2 % minoxidil solution twice daily together with 20 min 655 nm low-level laser helmet once every other day for 24 weeks. Hair parameters in two scalp areas including midscalp and vertex were evaluated at baseline, 12th week and 24th week. RESULTS: In midscalp area, the combination group showed a lower increase in intermediate hair percentage than 2 % minoxidil group, which was statistically significant. Besides, the combination group had statistically significant increase than 2 % minoxidil group in mean hair diameter. Reported relative adverse events included slightly hair loss (27.8 %), desquamation (19.0 %), pruritus (15.2 %), seborrhea (2.5 %) and hypertrichosis (2.5 %). CONCLUSION: In our trial, LLLT was demonstrated as a useful supplementary treatment for FPHL and the combination with 2 % minoxidil accomplished better improvement in intermediate hair enlargement and hair diameter of midscalp for FPHL.

Methane-dependent complete denitrification by a single Methylomirabilis bacterium.

Methane-dependent nitrate and nitrite removal in anoxic environments is thought to rely on syntrophy between ANME-2d archaea and bacteria in the genus 'Candidatus Methylomirabilis'. Here we enriched and purified a single Methylomirabilis from paddy soil fed with nitrate and methane, which is capable of coupling methane oxidation to nitrate reduction via nitrite to dinitrogen independently. Isotope labelling showed that this bacterium we name 'Ca. Methylomirabilis sinica' stoichiometrically performed methane-dependent complete nitrate reduction to dinitrogen gas. Multi-omics analyses collectively demonstrated that 'M. sinica' actively expressed a well-established pathway for this process, especially including nitrate reductase Nap. Furthermore, 'M. sinica' exhibited a higher nitrate affinity than most denitrifiers, implying its competitive fitness under oligotrophic nitrogen-limited conditions. Our findings revise the paradigm of methane-dependent denitrification performed by two organisms, and the widespread presence of 'M. sinica' in public databases suggests that the coupling of methane oxidation and complete denitrification in single cells substantially contributes to global methane and nitrogen budgets.

Source-specific ecological and health risks of polycyclic aromatic hydrocarbons in the adjacent coastal area of the Yellow River Estuary, China.

Industrialization and urbanization have led to increasing levels of PAH pollution in highly urbanized estuaries and their adjacent coastal areas globally. This study focused on the adjacent coastal area of the Yellow River Estuary (YRE) and collected surface seawater, surface sediment, and clams Ruditapes philippinarum and Mactra veneriformis at four sites (S1 to S4) in May, August, and October 2021 to analyze the source-specific ecological and health risks and bioeffects. The findings revealed that the main sources of PAHs were traffic emission (25.2% to 28.5%), petroleum sources (23.3% to 29.5%), coal combustion (24.7% to 27.5%), and biomass combustion (19.8% to 20.7%). Further, the PMF-RQ and PMF-ILCR analyses indicated that traffic emission was the primary contributor to ecological risks in seawater and health risks in both clam species, while coal combustion was the major contributor in sediment. Taken together, it is recommended to implement control strategies for PAH pollution following the priority order: traffic > coal > petroleum > biomass, to reduce the content and risk of PAHs in the YRE.

The assessment of bioavailability and environmental risk of dissolved and particulate polycyclic aromatic hydrocarbons in the seawater of typical bays.

The pollution of dissolved and particulate polycyclic aromatic hydrocarbons (PAHs) in coastal waters has been increasing in recent decades. However, limited research has been conducted on the characteristics of dissolved and particulate PAHs in seawater and their associated risk assessment. Here, we focused on the bioavailability and environmental risk of PAHs in four typical bays of Shandong Province, China, and used scallop Chlamys farreri and clam Mactra veneriformis as sentinel species. The results revealed that dissolved PAHs tended to bioaccumulate in scallop C. farreri, and their ecological risk exhibited a significant correlation with the health risk of bioaccumulated PAHs and the bioeffect of screened biomarkers in scallop. Conversely, particulate PAHs demonstrated a higher bioaccumulation potential in the clam M. veneriformis, showing a stronger correlation between their ecological risk, health risk, and bioeffect in clams. This study provides the first elucidation of the connection between the ecological risk, health risk, and bioeffect of PAHs. Furthermore, based on the better correlation of health risk and bioeffect caused by PAHs with total PAHs in seawater, we propose that the clam M. veneriformis is a more suitable sentinel species for assessing environmental risk in typical bays of Shandong Province.

Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review.

PURPOSE: Seizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. METHOD: We analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. RESULT: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00 %), seizures (36/40, 90.00 %), cranial deformity (27/40, 67.50 %), facial deformity (22/40, 55.00 %), hypotonia (22/40, 55.00 %), abnormal interseizure EEG discharge (26/40, 65.00 %), slow background activity (20/40, 50.00 %), corpus callosum deformity (18/40, 45.00 %). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. CONCLUSION: The compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

Refractory alopecia areata with single hairs imitating frontal fibrosing alopecia: a prospective observational study.

BACKGROUND: Lonely hair sign is considered as a clue to the diagnosis of frontal fibrosing alopecia (FFA). OBJECTIVE: To report an undescribed variant of alopecia areata (AA) with which the patient developed single hairs and other features similar to FFA and to determine the underlying mechanism. METHODS: We conducted a prospective observational study in patients who presented with receding hairline and single hairs, evaluating the clinical, trichoscopic, and histological features and their correlation. Immunochemistry studies were performed to describe the microenvironment. RESULTS: Eighteen patients were enrolled in the study. Despite the similarity to FFA clinically, these patients showed different histopathology which revealed a normal number of pilosebaceous units, one anagen hair in one or more pilosebaceous units, and others in telogen stage, consistent with single hairs under the naked eye or under trichoscopy. The severity of the hair loss assessed by SALT was no more than 50, but the response to conventional therapy was poor. CONCLUSIONS: This study reports a unique variant of AA. The pathological basis is an increase in the telogen hair follicles, with one anagen hair in one or more pilosebaceous units. Minimal inflammation consisting of CD3+ T lymphocytes and mast cells was demonstrated in the microenvironment.

Triple-Bioinspired Shape Memory Microcavities with Strong and Switchable Adhesion.

Smart adhesives with switchable adhesion have attracted considerable attention for their potential applications in sensors, soft grippers, and robots. In particular, surfaces with controlled adhesion to both solids and liquids have received more attention, because of their wider range of applications. However, surfaces that exhibit controllable adhesion to both solids and liquids often cannot provide sufficient adhesion strength for strong solid adhesion. To overcome this limitation, this study developed a triple-bioinspired shape memory smart adhesive, drawing inspiration from the adhesion structures found in octopus suckers, lotus leaves, and creepers. Our adhesive design incorporates microcavities formed by a shape memory polymer (SMP), which can transition between rubbery and glassy states in response to temperature changes. By leveraging the shape memory effect and the rubber-glass (R-G) phase transition of the SMP, the adhesion of the surface to smooth solids, rough solids, and water droplets could be switched by adjusting the temperature and applied force. Notably, the adhesives designed herein exhibited high adhesion strength (up to 420 kPa) on solids, facilitated by the shape interlocking effect and the negative pressure generated within the microcavities. Furthermore, the programmable transport of solids and liquids can be achieved by utilizing this switchable adhesion. This approach expands the possibilities for designing smart adhesives and holds potential for various applications in different fields.

Echocardiographic characteristics and clinical outcomes in fetuses with pulmonary stenosis or pulmonary atresia with intact ventricular septum.

OBJECTIVE: To summarize echocardiographic characteristics of the anatomy and hemodynamic and clinical outcomes in fetuses with isolated pulmonary stenosis (PS) or pulmonary atresia with intact ventricular septum (PA/IVS). METHODS: This was a single-center retrospective study of fetuses with isolated PS or PA/IVS. Echocardiographic variables and clinical outcomes after delivery were evaluated and compared. RESULTS: Between 2016 and 2021, 115 livebirths with isolated PS or PA/IVS were included. Proportion of fetuses with mild, moderate and critical PS and PA/IVS was 41.7 %, 18.3 %, 26.1 % and 13.9 %. Fetuses with more severe PS had worse anatomic and hemodynamic profiles. Specifically, the cardiothoracic ratio, pulmonary valve (PV) velocity, degree and velocity of tricuspid regurgitation increased as PS severity increased; and the pulmonary artery/aorta ratio, right ventricle/left ventricle long-axis (TV/MV) ratio, tricuspid valve/mitral valve annulus (TV/MV) ratio, and tricuspid valve inflow duration/cardiac cycle ratio decreased as PS severity increased (P <0.001 for all). PV velocity ≥2 m/s predicted PV pressure ≥40 mm Hg after delivery, with an AUC of 0.81; TV/MV ratio combined with RV/LV ratio predicted clinical outcomes, with an AUC of 0.88. Live births with more severe PS had higher mortality rate (mild 0 vs. moderate 0 vs. critical 11 % vs. PA-IVS 36 %) and lower rate of developing bi-ventricles (mild 100 % vs. moderate 95 % vs. critical 89 % vs. PA-IVS 36 %). CONCLUSION: Findings of this study help better understand the anatomy and hemodynamic and clinical outcomes in fetuses with isolated PS or PA/IVS, which could have implications for prenatal counseling and prediction of fetal outcome.

The ban on the sale of new petrol and diesel cars: Can it help control prospective marine pollution of polycyclic aromatic hydrocarbons (PAHs) in Shandong Province, China?

The constantly increasing amount of road vehicles causes massive exhaust emissions of pollutants, including polycyclic aromatic hydrocarbons (PAHs), necessitating a global responsibility to implement the policy of the ban on the sale of new petrol and diesel cars. Here, we assessed the policy control efficiency on marine pollution of PAHs in China through scenario modeling and prediction models, based on pollution monitoring, risk assessment, and source apportionment of PAHs in typical bays of Shandong Province. The results showed that in 2021, the pollution risk levels were relatively low (HI: 0.008-0.068, M-ERM-Q: 0.001-0.016, IBR: 1.23-2.69, ILCR: 8.11 ×10-6-1.99 ×10-5), and PAHs were mainly derived from traffic emissions (24.9%-35.2%), coal combustion (25.2%-32.9%), petroleum (17.2%-28.9%), and biomass combustion (17.6%-22.8%). In 2050, the predicted decrease of pollution risk values after the implementation of the policy was significant (12%-26%), and the gap between 2021 and 2050 was also significantly huge (18%-85%) without considering possible substitution of conventional energy. Collectively, this study built systematic approaches for assessing prospective marine pollution of PAHs. However, due to the particularity of Shandong Province, i.e., its national predominance of conventional energy consumption, the policy may be more effective when it comes to other coastal areas worldwide, calling for a larger scale research.

Ayanin, a natural flavonoid inhibitor of Caseinolytic protease, is a promising therapeutic agent to combat methicillin-resistant Staphylococcus aureus infections.

Antimicrobial resistance (AMR) is a global health threat. The dramatic increase of Methicillin-resistant Staphylococcus aureus (MRSA) infections emphasizes the need to find new anti-infective agents with a novel mode of action. The Caseinolytic protease (ClpP) is a central virulence factor in stress survival, virulence, and antibiotic resistance of MRSA. Here, we found ayanin, a flavonoid isolated from Callicarpa nudiflora, was an inhibitor of MRSA ClpP with an IC50 of 19.63 µM. Using quantitative real-time PCR, ayanin reduced the virulence of Staphylococcus aureus (S. aureus) by down-regulating the level of some important virulence factors, including agrA, RNAⅢ, hla, pvl, psmα and spa. The results of cellular thermal shift assay and thermal shift assay revealed a binding between ayanin and ClpP. Molecular docking showed that ASP-168, ASN-173 and ARG-171 were the potential binding sites for ClpP binding to ayanin. ClpP mutagenesis study further indicated that ARG-171 and ASN-173 were the main active sites of ClpP. The affinity constant (KD) value of ayanin with ClpP was 3.15 × 10-5 M measured by surface plasmon resonance. In addition, ayanin exhibited a significant therapeutic effect on pneumonia infection induced by S. aureus in mice in vivo, especially in combination with vancomycin. This is the first report of ayanin with in vivo and in vitro efficacy against S. aureus infection. In conclusion, ayanin is a promising therapeutic agent to combat MRSA infections by targeting ClpP.

[Genetic analysis and prenatal diagnosis of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 due to variants of PIGT gene].

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents. METHODS: A female child who had presented at Linyi People's Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks' gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci. RESULTS: The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+PM2_Supporting+PM4), and c.1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2_Supporting+PM3+PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor. CONCLUSION: The c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q) compound heterozygous variants of the PIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.

On summary ROC curve for dichotomous diagnostic studies: an application to meta-analysis of COVID-19.

In a systematic review of a diagnostic performance, summarizing performance metrics is crucial. There are various summary models in the literature, and hence model selection becomes inevitable. However, most existing large-sample-based model selection approaches may not fit in a meta-analysis of diagnostic studies, typically having a rather small sample size. Researchers need to effectively determine the final model for further inference, which motivates this article to investigate existing methods and to suggest a more robust method for this need. We considered models covering several widely-used methods for bivariate summary of sensitivity and specificity. Simulation studies were conducted based on different number of studies and different population sensitivity and specificity. Then final models were selected using several existing criteria, and we compared the summary receiver operating characteristic (sROC) curves to the theoretical ROC curve given the generating model. Even though parametric likelihood-based criteria are often applied in practice for their asymptotic property, they fail to consistently choose appropriate models under the limited number of studies. When the number of studies is as small as 10 or 5, our suggestion is best in different scenarios. An example for summary ROC curves for chemiluminescence immunoassay (CLIA) used in COVID-19 diagnosis is also illustrated.

Protective Effect of Inactivated COVID-19 Vaccines against Omicron BA.2 Infection in Guangzhou: A Test-Negative Case-Control Real-World Study.

This study aims to explore the relationship between the doses of inactivated COVID-19 vaccines received and SARS-CoV-2 Omicron infection in the real-world setting, so as to preliminarily evaluate the protective effect induced by COVID-19 vaccination. We conducted a test-negative case-control study and recruited the test-positive cases and test-negative controls in the outbreak caused by Omicron BA.2 in April 2022 in Guangzhou, China. All the participants were 3 years and older. The vaccination status between the case group and the control group was compared in the vaccinated and all participants, respectively, to estimate the immune protection of inactivated COVID-19 vaccines. After adjusting for sex and age, compared with a mere single dose, full vaccination of inactivated COVID-19 vaccines (OR = 0.191, 95% CI: 0.050 to 0.727) and booster vaccination (OR = 0.091, 95% CI: 0.011 to 0.727) had a more superior protective effect. Compared with one dose, the second dose was more effective in males (OR = 0.090), as well as two doses (OR = 0.089) and three doses (OR = 0.090) among individuals aged 18-59. Whereas, when compared with the unvaccinated, one dose (OR = 7.715, 95% CI: 1.904 to 31.254) and three doses (OR = 2.055, 95% CI: 1.162 to 3.635) could contribute to the increased risk of Omicron infection after adjusting for sex and age. Meanwhile, by contrast with unvaccinated individuals, the result of increased risk was also manifested in the first dose in males (OR = 12.400) and one dose (OR = 21.500), two doses (OR = 1.890), and a booster dose (OR = 1.945) in people aged 18-59. In conclusion, the protective effect of full and booster vaccination with inactivated COVID-19 vaccines exceeded the incomplete vaccination, of which three doses were more effective. Nevertheless, vaccination may increase the risk of Omicron infection compared with unvaccinated people. This may result from the transmission traits of BA.2, the particularity and stronger protection awareness of the unvaccinated population, as well as the ADE effect induced by the decrease of antibody titers after a long time of vaccination. It is crucial to explore this issue in depth for the formulation of future COVID-19 vaccination strategies.

Toxicological mechanism of ammonia-N on haematopoiesis and apoptosis of haemocytes in Litopenaeus vannamei.

Ammonia, as an important pollutant, contributed to the reduction of immunity, disruption of physiology in animals. RNA interference (RNAi) was performed to understand the function of astakine (AST) in haematopoiesis and apoptosis in Litopenaeus vannamei under ammonia-N exposure. Shrimps were exposed to 20 mg/L ammonia-N from 0 to 48 h with injection of 20 µg AST dsRNA. Further, shrimps were exposed to 0, 2, 10 and 20 mg/L ammonia-N also from 0 to 48 h. The results showed that the total haemocytes count (THC) decreased under ammonia-N stress and the knockdown of AST resulted in a further decrease of THC, suggesting that 1) the proliferation was decreased through the reduction of AST and Hedgehog, the differentiation was interfered by Wnt4, Wnt5 and Notch, and the migration was inhibited by the decrease of VEGF; 2) oxidative stress was induced under ammonia-N stress, leading to the increase of DNA damage with the up-regulated gene expression of death receptor, mitochondrial and endoplasmic reticulum stress pathways; 3) the changes of THC resulted from the decrease of proliferation, differentiation and migration of haematopoiesis cells and the increase of apoptosis of haemocytes. This study helps to deepen our understanding of risk management in shrimp aquaculture.

A novel heterozygous ATP1A2 pathogenic variant in a Chinese child with MELAS-like alternating hemiplegia.

BACKGROUND: Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS-like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura. METHODS: The patient was an 8-year-old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS-like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole-exome sequencing (WES). RESULTS: WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic. CONCLUSION: At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS-like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.