[Newborn screening, clinical features and genetic analysis for Citrin deficiency in Henan province].

OBJECTIVE: To explore the prevalence, clinical features, genetic characteristics and prognosis of Citrin deficiency in Henan province of China. METHODS: A total of 986 565 neonates screened by tandem mass spectrometry at the Third Affiliated Hospital of Zhengzhou University from January 2013 to December 2021 were retrospectively analyzed. Analysis of SLC25A13 gene variants and parental verification were carried out for neonates suspected for Citrin deficiency by next-generation sequencing. The clinical, biochemical and genetic characteristics of Citrin deficiency patients were integrated to guide the diet treatment and follow up the growth and development. Paired-t test was used to compare the amino acid levels in the peripheral blood samples before and after the treatment. RESULTS: Nine cases of Citrin deficiency were diagnosed among the 986 565 neonates. Specific elevation of citrulline was observed in all of the 9 cases. Six variants were detected by genetic sequencing, among which c.852_855delTATG, c.615+5G>A, c.550C>T and IVS16ins3kb were known pathogenic variants, whilst c.1111_1112delAT and c.837T>A were unreported previously. The detection rate for c. 852_855delTATG was the highest (61.6%, 11/18), followed by IVS16ins3kb (16.7%, 3/18). The clinical symptoms of all patients were relieved after the treatment, and the blood amino acid profile and biochemical parameters were significantly improved by gradually falling within the normal range. By June 2022, all patients had shown a good prognosis. CONCLUSION: The prevalence of Citrin deficiency among neonates from Henan Province by tandem mass spectrometry is 1/109 618, and the carrier rate for the pathogenic variants of the SLC25A13 gene was 1/166. The c.852_855delTATG may be a hot spot variant among the patients. Discovery of the novel variants has enriched the mutational spectrum of the SLC25A13 gene. Above results have provided a basis for the early diagnosis, treatment, prognosis and genetic counseling for the affected families.

Knowledge, attitude, and practice of patients with major depressive disorder on exercise therapy.

BACKGROUND: This study aimed to explore the knowledge, attitude, and practice (KAP) toward exercise therapy of patients with major depressive disorder (MDD). METHODS: This cross-sectional study was conducted at the First Hospital of Shanxi Medical University between April and October 2023 in patients with MDD. A self-designed questionnaire was used to evaluate the KAP (Cronbach's α = 0.787). The minimum-maximum scores were 2-23 for knowledge, 11-55 for attitude, and 7-35 for practice. RESULTS: A total of 494 valid questionnaires were analyzed. The mean KAP dimension scores were 15.39 ± 3.34/23 (66.91%), 36.54 ± 19.33/55 (66.44%), and 19.33 ± 5.22/35 (55.23%), indicating poor knowledge, negative attitude, and weak practice. Multivariable logistic regression analysis showed that female (OR = 0.613, 95%CI: 0.376-1.000, P = 0.050), urban residence (OR = 0.443, 95%CI: 0.259-0.758, P = 0.003), suburban residence (OR = 0.047, 95%CI: 0.016-0.138, P < 0.001), higher income (OR = 3.889-7.928, all P < 0.001), and unclear self-reported depression level (OR = 0.078, 95%CI: 0.027-0.221, P < 0.001) were independently associated with the knowledge scores. Knowledge scores (OR = 1.102, 95%CI: 1.022-1.188, P = 0.011), female gender (OR = 0.437, 95%CI: 0.246-0.776, P = 0.005), city (OR = 0.410, 95%CI: 0.226-0.744, P = 0.003), married (OR = 3.577, 95%CI: 1.751-7.650, P < 0.001), higher income (OR = 0.065-0.392, both P < 0.050), depressive trend (OR = 2.640, 95%CI: 1.110-6.278, P = 0.028), high depression score level (OR = 0.176, 95%CI: 0.104-0.300, P < 0.001), and unclear self-reported depression score (OR = 0.023, 95%CI: 0.007-0.076, P < 0.001) were independently associated with the attitude scores. Finally, knowledge scores (OR = 1.130, 95%CI: 1.051-1.215, P = 0.001), attitude scores (OR = 1.199, 95%CI: 1.124-1.280, P < 0.001), and city (OR = 0.583, 95%CI: 0.352-0.965, P = 0.036) were independently associated with the practice scores. The structural equation modeling analysis showed that knowledge, but not attitude (ß = 0.103, P = 0.092) or practice (ß = 0.034, P = 0.603), influenced the depression level (ß=-0.074, P < 0.001); attitude influenced practice (ß = 0.369, P < 0.001). CONCLUSION: The KAP toward exercise among MDD patients is poor in Shanxi. Females, people living in urban or suburban areas, with lower income, and self-reported unclear depression levels should be targeted by education interventions.

MD-UNet: a medical image segmentation network based on mixed depthwise convolution.

In the process of cancer diagnosis and treatment, accurate extraction of the lesion area helps the doctor to judge the condition. Currently, medical image segmentation algorithms based on UNet have been verified to be able to play an important role in clinical diagnosis. However, these methods still have the following drawbacks in extracting the region of interest (ROI): (1) ignoring the intra-class variability of medical images. (2) Failure to obtain effective feature redundancy. To address these problems, a U-shaped medical image segmentation network based on a Mixed depthwise convolution residual module (MDRM), called MD-UNet, is proposed in this paper. In MD-UNet, the MDRM built with a Mixed depthwise convolution attention block (MDAB) captures both local and global dependencies in the image to mitigate the effects of intra-class differences. MDAB captures valid redundant features and further captures global features of the input data. At the same time, the lightweight MDAB senses changes in the receptive field and generates multiple feature mappings. Compared with UNeXt on the ISIC2018 dataset, the MD-UNet segmentation accuracy Dice and IoU are improved by 1.33% and 1.91%, respectively. The code is available at https://github.com/Cloud-Liu/MD-UNet .

Atmospheric-moisture-induced polyacrylate hydrogels for hybrid passive cooling.

Heat stress is being exacerbated by global warming, jeopardizing human and social sustainability. As a result, reliable and energy-efficient cooling methods are highly sought-after. Here, we report a polyacrylate film fabricated by self-moisture-absorbing hygroscopic hydrogel for efficient hybrid passive cooling. Using one of the lowest-cost industrial materials (e.g., sodium polyacrylate), we demonstrate radiative cooling by reducing solar heating with high solar reflectance (0.93) while maximizing thermal emission with high mid-infrared emittance (0.99). Importantly, the manufacturing process utilizes only atmospheric moisture and requires no additional chemicals or energy consumption, making it a completely green process. Under sunlight illumination of 800 W m-2, the surface temperature of the film was reduced by 5 °C under a partly cloudy sky observed at Buffalo, NY. Combined with its hygroscopic feature, this film can simultaneously introduce evaporative cooling that is independent of access to the clear sky. The hybrid passive cooling approach is projected to decrease global carbon emissions by 118.4 billion kg/year compared to current air-conditioning facilities powered by electricity. Given its low-cost raw materials and excellent molding feature, the film can be manufactured through simple and cost-effective roll-to-roll processes, making it suitable for future building construction and personal thermal management needs.

Acute aerobic exercise regulation of myocardial calcium homeostasis involves CASQ1, CASQ2, and TRDN.

Exercise maintains cardiac calcium homeostasis and promotes cardiovascular health. This study explored temporal changes of calcium-related myocardial transcriptome changes during the recovery phase following a single bout of moderate-intensity aerobic exercise. Healthy male Sprague-Dawley rats were anesthetized with sodium pentobarbital after moderate-intensity aerobic exercise at four time points (0, 12, 24, and 72 h postexercise). The hearts were removed and RNA-seq and bioinformatics analyses were used to examine temporal transcriptional changes in the myocardium. Casq1, Casq2, and Trdn were identified as key genes in the regulation of calcium homeostasis during myocardial recovery. The highest expression of Casq1, Casq2, and Trdn genes and the proteins they encode occurred 24 h after exercise. An in vitro calcium overload heart model using the Langendorff heart perfusion method was used to examine myocardial calcium buffering capacity. Calcium overload caused the least changes in left ventricular developed pressure, infarct area, Lactate dehydrogenase release, and extent of morphological damage to myocardial cells, with the highest protein expressions of CASQ1, CASQ2, and TRDN at 24 h after acute exercise. This study indicates that maximal myocardial Ca2+ buffering capacity occurs 24 h postexercise in rats. Our study provides insights into exercise-mediated improvements in cardiovascular function and exercise preconditioning.NEW & NOTEWORTHY Acute aerobic exercise upregulates myocardial Casq1, Casq2, and Trdn genes and the proteins they encode in rats. Higher protein levels of CASQ1, CASQ2, and TRDN conferred an improved ability of the myocardium to resist calcium overload. Furthermore, 24 h postexercise is the time point with optimal myocardial calcium buffer capacity.

Inherited disease-linked arginine76/75 mutants in Cx50 and Cx45 showed impaired homotypic and heterotypic gap junction function, but not Cx43.

Connexins form intercellular communication channels, known as gap junctions (GJs), in many tissues/organs. Mutations in connexin genes are found to be linked to various inherited diseases, but the mechanisms are not fully clear. The Arg76 (R76) in Cx50 is fully conserved across the entire connexin family and is a hotspot for five connexin-linked inherited diseases, including Cx50 and Cx46-linked congenital cataract, Cx43-linked oculodentodigital dysplasia, and Cx45-linked cardiac arrhythmias. To better understand the molecular and cellular mechanism of dysfunction caused by R76/75 mutations, we examined the functional status and properties of GJs containing R76 mutations in Cx50 (R76H/C), Cx43 (R76H/S/C), and Cx45 (R75H) with an emphasis on heterotypic GJs in connexin-deficient model cells. All tested mutants showed an impairment of homotypic GJ function reflected by a decreased coupling% and conductance, except for Cx43 R76H/S. These connexin mutants also showed impaired GJ function when paired with a docking-compatible connexin, such as Cx50/Cx46 or Cx45/Cx43, except for all mutants on Cx43 which formed functional heterotypic GJs with Cx45. Localization studies on fluorescent protein tagged connexin mutants revealed that Cx45 R75H and Cx43 R76C showed impaired localization. Our homology structure models indicated that mutations of R76/75 in these GJs led to a loss of intra- and/or inter-connexin non-covalent interactions (salt bridges) at the sidechain of this residue, which could contribute to the observed GJ impairments underlying diseases. It is interesting that unlike those disease-linked variants in Cx50 and Cx45, Cx43 can tolerate some variations at R76.

Antiviral and Anti-Inflammatory Therapeutic Interventions for Treating Herpes Stromal Keratitis: A Systematic Review.

PURPOSE: Herpes stromal keratitis (HSK) is an immune-mediated corneal inflammation that occurs after a herpes simplex virus infection. This paper aims to systematically identify and compare interventions for treating HSK and their patient outcomes. METHODS: This systematic review followed the PRISMA methodology. Online databases were searched to obtain all relevant papers. Two independent reviewers screened through 168 records. Seven papers were included and used for data extraction. A qualitative analysis was conducted. RESULTS: HSK patients receiving prednisolone phosphate and acyclovir showed a higher treatment success rate and significantly longer time to failure compared to patients receiving only acyclovir (P < .001). No difference in resolution time was found between oral and topical acyclovir. Between groups receiving dexamethasone and flurbiprofen, resolution occurred in 93% and 67% of patients, and BCVA (LogMAR) improved from 1.0 to 0.30 and 0.48, respectively. BCVA improved in both cyclosporine-A (P < .001) and its control (prednisolone) groups (P = .002). A tacrolimus treatment group showed greater improvement in BCVA compared to its control (prednisolone) group (P < .001). CONCLUSION: Corticosteroids and antivirals managed HSK most effectively only when used concurrently. Oral acyclovir showed similar effectiveness to its ointment counterpart, a preferable alternative for easier administration. Corticosteroid use could induce greater therapeutic benefits when tapered in concentration and frequency and administrated for at least 10 weeks. Anti-inflammatory drugs including flurbiprofen, cyclosporine-A, and tacrolimus could be safe and effective for treating HSK. Future long-term follow-up and RCTs could provide insights on the therapeutic benefits of these potential alternatives.

Allelic phenotype prediction of phenylketonuria based on the machine learning method.

BACKGROUND: Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Our study aimed to predict the phenotype using the allelic genotype. METHODS: A total of 1291 PKU patients with 623 various variants were used as the training dataset for predicting allelic phenotypes. We designed a common machine learning framework to predict allelic genotypes associated with the phenotype. RESULTS: We identified 235 different mutations and 623 various allelic genotypes. The features extracted from the structure of mutations and graph properties of the PKU network to predict the phenotype of PKU were named PPML (PKU phenotype predicted by machine learning). The phenotype of PKU was classified into three different categories: classical PKU (cPKU), mild PKU (mPKU) and mild hyperphenylalaninemia (MHP). Three hub nodes (c.728G>A for cPKU, c.721 for mPKU and c.158G>A for HPA) were used as each classification center, and 5 node attributes were extracted from the network graph for machine learning training features. The area under the ROC curve was AUC = 0.832 for cPKU, AUC = 0.678 for mPKU and AUC = 0.874 for MHP. This suggests that PPML is a powerful method to predict allelic phenotypes in PKU and can be used for genetic counseling of PKU families. CONCLUSIONS: The web version of PPML predicts PKU allele classification supported by applicable real cases and prediction results. It is an online database that can be used for PKU phenotype prediction http://www.bioinfogenetics.info/PPML/ .

Access to Pediatric Eye Care During a Pandemic: Systematic Review and Meta-Analysis.

Visual impairment affects many children and can lead to blindness if untreated. The coronavirus disease 2019 (COVID-19) pandemic has led to various restrictions and other challenges accessing in-person medical care, including essential pediatric eye care. The aim of this article was to determine and quantify the effect that pandemics have on access to pediatric eye care. A systematic literature search was conducted using various databases, which yielded 257 articles; nine were included in the final review. All included studies reported a decrease in the number of children accessing eye care during COVID-19. Most studies described virtual triage systems, which restricted in-person care to emergent cases. The average decrease in daily pediatric visits was 67.32% and reached statistical significance in the meta-analysis (P < .01). However, out of all patients with ocular complaints, the proportion of pediatric visits was unchanged, suggesting that the decrease in access to eye care was not specific to pediatric patients. [Pediatr Ann. 2023;52(2):e68-e75.].

Mutation screening of eight genes and comparison of the clinical data in a Chinese cohort with congenital hypothyroidism.

BACKGROUND: Congenital hypothyroidism (CH) is a common neonatal endocrine disorder, characterized by irreversible intellectual disability and short stature if left untreated. It can be divided into thyroid dysgenesis (TD), including athyreosis, ectopy and hypoplasia, and dyshormonogenesis (DH), also referring to gland in situ (GIS), in which patients have eutopic thyroids with normal size or goiter. This study aims to analyze the clinical and genetic data of 375 Chinese CH patients without DUOX2 and thyroid transcription factor (TTF) variants, and to explore the mutation frequencies of the eight genes and the inheritance pattern of CH. METHODS: Targeted next generation sequencing (NGS) and statistical analysis were performed for mutation screening on eight CH-related genes and the comparison of clinical data in a cohort of 606 Chinese CH patients from Henan Province. RESULTS: A total of 104 variants were detected in genes required for thyroid formation (TSHR, GLIS3, BOREALIN, NTN1, JAG1 and TUBB1) and thyroid hormone synthesis (TG and TPO) in 83 subjects. Monogenic variants were the most prevalent with a percentage of 75.00% (78/104) followed by oligogenic variants (25.00%, 26/104). No differences were found in various clinical data between patients with and without variants. However, it should be noted that only initial L-T4 dose was statistically different between patients with monogenic variants and oligogenic variants. CONCLUSIONS: Our results suggested that apart from Mendelian monogenic inheritance, oligogenic inheritance of CH could not be excluded and also involves other factors, such as penetrance, epigenetic mechanisms and environmental factors.

Newborn screening and genomic analysis of duchenne muscular dystrophy in Henan, China.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a rare disorder caused by mutations in the dystrophin gene. Recent availability in treatment for DMD raised the need of early screening in our center, but newborn screening (NBS) for DMD has not been carried out in Henan Province. OBJECTIVES: To determine an optimal cutoff value through the quantitative determination of the creatine kinase isoform MM (CK-MM) concentration dried blood spot (DBS) to identify male DMD, and to evaluate assess the detection rate and mutation spectrum of DMD in Henan, China. METHODS: The CK-MM level in DBS was measured using with a GSP® neonatal creatine kinase -MM kit from 13,110 male newborns to establish the cut-off value for CK-MM. Multiplex ligation-dependent probe amplification (MLPA) were carried out for infants with elevated CK levels to detect DMD gene deletions/ duplications, NGS and sanger sequencing were then applied to exclude MLPA-negative samples to single-nucleotide variants. Phenotype-genotype correlations were analyzed using REVEL For novel missense mutations. RESULTS: Statistical analysis of CK-MM value of the 13,110 neonates suggested that the cut-off value may be set as 472 ng/mL. 3 cases of DMD were screened among 13,110 newborns, all of whom had CK-MM levels >600 ng/mL. We detected 4 rare variants in DMD gene, including 2 exon deletions (deletion of exon 52 and deletion from exon 3 to exon 7) and 2 point variants (c.9568C>T and c.4030C>T). Two cases were all exon deletions, one case was compound heterozygous variants. CONCLUSIONS: The estimated incidence of male neonatal DMD was 1:4,370 in Henan province. NBS is of great value to the early intervention and treatment of the disease, and is fundamental to support public health decision-making. The experience from this study provided a model that will allow further expansion and facilitate establishment a universal public health screening in Henan hospital systems.

Response Mechanisms of Adventitious Root Architectural Characteristics of Nitraria tangutorum Shrubs to Soil Nutrients in Nabkha.

The adventitious roots of desert shrubs respond to a nabkhas soil environment by adjusting their configuration characteristics, but the mechanism of this response and the main influencing factors are still unclear. To illustrate this response pattern, Nitraria tangutorum Bobrov, Sovetsk. in West Ordos National Nature Reserve was studied, and the shrub was divided into three growth stages: the rudimental stage, developing stage, and stabilizing stage. A combination of total root excavation and root tracing was used to investigate their adventitious root morphology. The results show the following: (1) As the shrub grows, the ability to accumulate sand into nabkhas increases. (2) The soil nutrient accumulation capacity increased with shrub growth. The "fertilizer island effect" was formed in the nutrient developing stage and stabilizing stage of nabkhas soil, but the rudimental stage was not formed. (3) The adventitious root architecture of N. tangutorum at different growth stages was all herringbone with a simple branch structure. With the growth in N. tangutorum, the root diameter of each level gradually increased, the branches of the shrub grew gradually complicated, and the range of resource utilization gradually expanded. (4) Redundancy analysis (RDA) results show that soil organic carbon (SOC) was the main factor affecting the adventitious root architecture. The results of this study reveal the adjustments the adventitious root architecture of N. tangutorum make in order to adapt to the stress environment and provide data support for the protection of natural vegetation in West Ordos.

The Hydrophobic Residues in Amino Terminal Domains of Cx46 and Cx50 Are Important for Their Gap Junction Channel Ion Permeation and Gating.

Lens gap junctions (GJs) formed by Cx46 and Cx50 are important to keep lens transparency. Functional studies on Cx46 and Cx50 GJs showed that the Vj-gating, single channel conductance (γj), gating polarity, and/or channel open stability could be modified by the charged residues in the amino terminal (NT) domain. The role of hydrophobic residues in the NT on GJ properties is not clear. Crystal and cryo-EM GJ structures have been resolved, but the NT domain structure has either not been resolved or has showed very different orientations depending on the component connexins and possibly other experimental conditions, making it difficult to understand the structural basis of the NT in Vj-gating and γj. Here, we generated missense variants in Cx46 and Cx50 NT domains and studied their properties by recombinant expression and dual whole-cell patch clamp experiments on connexin-deficient N2A cells. The NT variants (Cx46 L10I, N13E, A14V, Q15N, and Cx50 I10L, E13N, V14A, N15Q) were all able to form functional GJs with similar coupling%, except Cx46 N13E, which showed a significantly reduced coupling%. The GJs of Cx46 N13E, A14V and Cx50 E13N, N15Q showed a reduced coupling conductance. Vj-gating of all the variant GJs were similar to the corresponding wild-type GJs except Cx46 L10I. The γj of Cx46 N13E, A14V, Cx50 E13N, and N15Q GJs was reduced to 51%, 82%, 87%, and 74%, respectively, as compared to their wild-type γjs. Structural models of Cx46 L10I and A14V predicted steric clashes between these residues and the TM2 residues, which might be partially responsible for our observed changes in GJ properties. To verify the importance of hydrophobic interactions, we generated a variant, Cx50 S89T, which also shows a steric clash and failed to form a functional GJ. Our experimental results and structure models indicate that hydrophobic interactions between the NT and TM2 domain are important for their Vj-gating, γj, and channel open stability in these and possibly other GJs.

[Effect of knee arthroscopy on subsequent total knee arthroplasty: Meta-analysis].

OBJECTIVE: To evaluate effect of knee arthroscopy on prognosis of subsequent total knee arthroplasty (total knee arthroplasty, TKA) by Meta-analysis. METHODS: Databases including PubMed, Embase, Cochrane Library, CNKI, Wanfang and other databases were searched by computer from establishing to October 2020 to collect literatures on effect of knee arthroscopy on prognosis of subsequent TKA. Quality evaluation and data extraction were carried out according to inclusion, exclusion criteria and literature screening. Newcastle-Ottawa Scale (NOS) was used to evaluate literature quality of non-randomized controlled studies. RevMan 5.3 software was applied to Meta-analysis on revision rate, reoperation rate, postoperative stiffness rate, periprosthetic infection rate, postoperative venous thrombosis venous thromboembolism(VTE) rate and postoperative knee flexion range of motion after TKA. RESULTS: Eight literatures were finally included with totally sample size of 182 815 patients. Among them, 6 998 patients were in knee arthroscopy group and 175 817 patients were in knee arthroscopy group. Meta-analysis results showed that there were statistical differences in revision rate after TKA[OR=1.66, 95%CI(1.37, 2.00), P<0.000 01], re-operation rate[OR=2.31, 95%CI(1.59, 3.36), P<0.000 1], postoperative stiffness rate[OR=1.78, 95%CI(1.02, 3.11), P=0.04] and infection rate around prosthesis[OR=1.40, 95%CI(1.19, 1.66), P<0.000 1]. While there were no difference in VTE rate[OR=1.06, 95%CI(0.83, 1.35), P=0.64], postoperative knee flexion range of motion[MD=-1.21, 95%CI(-3.07, 0.65), P=0.20]. CONCLUSION: Knee arthroscopy has a negative impact on subsequent TKA surgery. Previous arthroscopic increased risk of stiffness, periprosthetic joint infection, revision and reoperation after TKA, but there was no significant difference in postoperative knee flexion range of motion and incidence of VTE.

Time-dependent Effects of Moderate- and High-intensity Exercises on Myocardial Transcriptomics.

The heart is a highly adaptable organ that responds to changes in functional requirements due to exposure to internal and external stimuli. Physical exercise has unique stimulatory effects on the myocardium in both healthy individuals and those with health disorders, where the effects are primarily determined by the intensity and recovery time of exercise. We investigated the time-dependent effects of different exercise intensities on myocardial transcriptional expression in rats. Moderate intensity exercise induced more differentially expressed genes in the myocardium than high intensity exercise, while 16 differentially expressed genes were down-regulated by moderate intensity exercise but up-regulated by high intensity exercise at 12 h post- exercise. Both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that moderate intensity exercise specifically regulated gene expression related to heart adaptation, energy metabolism, and oxidative stress, while high intensity exercise specifically regulated gene expression related to immunity, inflammation, and apoptosis. Moreover, there was increased expression of Tbx5, Casq1, Igsf1, and Ddah1 at all time points after moderate intensity exercise, while there was increased expression of Card9 at all time points after high intensity exercise. Our study provides a better understanding of the intensity dependent effects of physical exercise of the molecular mechanisms of cardiac adaptation to physical exercise.

Successful treatment of pleural empyema and necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus infection following influenza A virus infection: A case report and literature review.

With the rapid increase in the number of infections, children with Staphylococcus aureus (S. aureus) infection secondary to Influenza A virus (IAV), appear to have a great possibility of causing severe complications and illness. Despite some cases and research findings regarding the death of children with IAV and S. aureus, coinfection included, there were few details about successful treatment of pleural empyema and necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) infection following IAV. In this case report, we describe the clinical symptoms and treatment of a teenager with pleural empyema and necrotizing pneumonia related to S. aureus secondary infection who was initially infected by IAV. This case highlights the importance of early recognition and application of thoracoscopy for this potentially fatal pleural empyema caused by MRSA and IAV coinfection. We conclude that this is a significant case that contributes to raising awareness regarding rarely occurring severe respiratory infections by MRSA in a child with normal immune function after IAV. In addition, further studies are needed to explore risk factors for IAV coinfection with S. aureus.

Identification of phenylketonuria patient genotypes using single-gene full-length sequencing.

BACKGROUND: Phenylketonuria (PKU) is a common, autosomal recessive inborn error of metabolism caused by PAH gene variants. After routine genetic analysis methods were applied, approximately 5% of PKU patients were still not diagnosed with a definite genotype. METHODS: In this study, for the first time, we identified PKU patients with unknown genotypes via single-gene full-length sequencing. RESULTS: The detection rate of PKU genotype increased from 94.6 to 99.4%, an increase of approximately 5%. The variants c.1199 + 502A > T and 1065 + 241C > A were found at a high frequency in Chinese PKU patients. CONCLUSION: Our study suggest that single-gene full-length sequencing is a rapid, efficient and cost-effective tool to improve the genotype detection rate of PKU patients. Moreover, we provides additional case data to support pathogenicity of deep intronic variants in PAH.

[Analysis of GCH1 gene variant in a consanguineous Chinese pedigree affected with tetrahydrobiopterin deficiency].

OBJECTIVE: To explore the genetic basis for a child featuring tetrahydrobiopterin deficiency and global developmental delay. METHODS: Clinical and laboratory examinations were carried out for the child. Genomic DNA of the patient was subjected to high-throughput sequencing to identify genetic variants associated with hyperphenylalaninemia. Candidate variants were verified by Sanger sequencing. RESULTS: The result of blood tandem mass spectrometry showed that the Phenylalanine in the blood was 642.7 µmol/l, and the ratio of Phenylalanine/Tyrosine was 5.42. Analysis of urinary pterin: neopterin 0.09 mmol/mol Cr, biopterin 0.04 mmol/mol Cr, biopterin% 77%, which suggested tetrahydrobiopterin deficiency. The parents of the proband were first cousins. DNA sequencing revealed that the proband has harbored homozygous c.353A>T variants in exon 2 of the GCH1 gene, for which his great grandmother, grandfather, mother, uncle, father and elder brother were heterozygous carriers with normal phenotype and no clinical symptoms associated with dopa responsive dystonia. CONCLUSION: The homozygous c.353A>T variant of the GCH1 gene probably underlay the tetrahydrobiopterin deficiency in this pedigree of consanguineous marriage.

Genomic analysis of 9 infants with hypermethioninemia by whole-exome sequencing among in Henan, China.

BACKGROUND: Hypermethioninemia is an inborn error of metabolism with elevated plasma methionine (Met) caused by methionine adenosyltransferase deficiency. Methionine adenosyltransferase (MAT) I/III deficiency is the most common cause of hypermethioninemia. Except for increased blood Met, most patients have no symptoms, but a small number have nervous system complications, including cognitive impairment and mental retardation. OBJECTIVE: To investigate the gene variation of patients with hypermethioninemia in newborns in Henan province. METHODS: 9 cases of hypermethioninemia were screened for amino acids profile and acyl carnitine by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed whole-exome sequencing on 9 families of infants with hypermethioninemia. We identified mutated genes under different models of inheritance and further assessed these mutations through Sanger sequencing and association analysis. RESULTS: The incidence of neonatal hypermethioninemia was 1:27 228 in Henan province. A total of ten mutations in the MAT1A gene in the 9 patients were identified, including nine reported mutations (c.1070C > T, c.895C > T, c.100 T > A, c.315C > A, c.529C > T, c.623A > C, c.407G > T, c.1066C > T, 867G > T) and one novel mutations (c.772G > C). c.772G > C was detected in 2 families and is the most common variant. 7 infants (7/9) with hypermethioninemia were genetically autosomal dominant, and 2 infants (2/9) with hypermethioninemia were genetically autosomal recessive. CONCLUSION: Our findings expand the mutational spectrum of hypermethioninemia, with the description of one new mutation. They improve the understanding of the genetic background and clinical manifestation of MAT1A in Chinese patients.