Evaluating the impact of automatic positive airway pressure therapy on cardiovascular risk index and vascular behavior in patients with obstructive sleep apnea: a study on heterogeneity in the therapeutic response.

STUDY OBJECTIVES: This study investigated the impact of APAP therapy on vascular behavior and its potential to lower cardiovascular risk in patients with OSA, as well as differentiating APAP therapy heterogeneity. METHODS: All participants were diagnosed with OSA by portable monitoring, and pulse wave parameters and cardiac risk composite parameter index (CRI) were obtained by photoplethysmography before and after APAP. Clustering analysis of pulse wave parameters before APAP in the high-risk population was performed using k-means clustering. Linear regression was used to assess the associations of changes in CRI and pulse wave parameters with clinical characteristics. RESULTS: Eighty-two patients with OSA underwent APAP therapy. The CRI after APAP was significantly lower than before APAP (0.38± 0.33 and 0.58 ± 0.31, respectively; p < 0.001). All pulse wave parameters (except irregular pulse) were significantly different (p < 0.001) in patients with OSA and in the high-risk responders group after versus before APAP. The differences in pulse wave parameters after versus before APAP were not significant in the high-risk non-responders group, except for RCRD and pulse rate variability. Four clusters were obtained from the clustering analysis of pulse wave parameters before APAP in the high-risk responders group. CONCLUSIONS: APAP reduces the CRI in patients with OSA by altering vascular behavior. Overnight photoplethysmography monitoring of pulse wave parameters can be used to assess whether patients with OSA will benefit from APAP.

miR-26a-5p inhibits the proliferation of psoriasis-like keratinocytes in vitro and in vivo by dual interference with the CDC6/CCNE1 axis.

Psoriasis is a chronic inflammatory proliferative dermatological ailment that currently lacks a definitive cure. Employing data mining techniques, this study identified a collection of substantially downregulated miRNAs (top 10). Notably, 32 targets were implicated in both the activation of the IL-17 signaling pathway and cell cycle dysregulation. In silico analysis revealed that one of these miRNAs, miR-26a-5p, is a highly conserved cross-species miRNA. Strikingly, the miR-26a-5p sequences in humans and mice are identical, and mmu-miR-26a-5p was found to target the same 7 cell cycle targets as its human counterpart, hsa-miR-26a-5p. Among these targets, CDC6 and CCNE1 were the most effective targets of miR-26a-5p, which was further validated in vitro using a dual luciferase reporter system and qPCR assay. The therapeutic assessment of miR-26a-5p revealed its remarkable efficacy in inhibiting the proliferation and G1/S transition of keratinocytes (HaCaT and HEKs) in vitro. In vivo experiments corroborated these findings, demonstrating that miR-26a-5p effectively suppressed imiquimod (IMQ)-induced psoriasis-like skin lesions in mice over an 8-day treatment period. Histological analysis via H&E staining revealed that miR-26a-5p treatment resulted in reduced keratinocyte thickness and immune cell infiltration into the spleens of IMQ-treated mice. Mechanistic investigations revealed that miR-26a-5p induced a cascade of downregulated genes associated with the IL-23/IL-17A axis, which is known to be critical in psoriasis pathogenesis, while concomitantly suppressing CDC6 and CCNE1 expression. These findings were corroborated by qPCR and Western blot analyses. Collectively, our study provides compelling evidence supporting the therapeutic potential of miR-26a-5p as a safe and reliable endogenous small nucleic acid for the treatment of psoriasis.

The C-terminal selenenylsulfide of extracellular/non-reduced thioredoxin reductase endows this protein with selectivity to small-molecule electrophilic reagents under oxidative conditions.

Mammalian cytosolic thioredoxin reductase (TrxR1) serves as an antioxidant protein by transferring electrons from NADPH to various substrates. The action of TrxR1 is achieved via reversible changes between NADPH-reduced and non-reduced forms, which involves C-terminal selenolthiol/selenenylsulfide exchanges. TrxR1 may be released into extracellular environment, where TrxR1 is present mainly in the non-reduced form with active-site disulfide and selenenylsulfide bonds. The relationships between extracellular TrxR1 and tumor metastasis or cellular signaling have been discovered, but there are few reports on small-molecule compounds in targeted the non-reduced form of TrxR1. Using eight types of small-molecule thiol-reactive reagents as electrophilic models, we report that the selenenylsulfide bond in the non-reduced form of TrxR1 functions as a selector for the thiol-reactive reagents at pH 7.5. The non-reduced form of TrxR1 is resistant to hydrogen peroxide/oxidized glutathione, but is sensitive to certain electrophilic reagents in different ways. With 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) and S-nitrosoglutathione (GSNO), the polarized selenenylsulfide bond breaks, and selenolate anion donates electron to the dynamic covalent bond in DTNB or GSNO, forming TNB-S-Se-TrxR1 complex or ON-Se-TrxR1 complex. The both complexes lose the ability to transfer electrons from NADPH to substrate. For diamide, the non-reduced TrxR1 actually prevents irreversible damage by this oxidant. This is consistent with the regained activity of TrxR1 through removal of diamide via dialysis. Diamide shows effective in the presence of human cytosolic thioredoxin (hTrx1), Cys residue(s) of which is/are preferentially affected by diamide to yield disulfide, hTrx1 dimer and the mixed disulfide between TrxR1-Cys497/Sec498 and hTrx1-Cys73. In human serum samples, the non-reduced form of TrxR1 exists as dithiothreitol-reducible polymer/complexes, which might protect the non-reduced TrxR1 from inactivation by certain electrophilic reagents under oxidative conditions, because cleavage of these disulfides can lead to regain the activity of TrxR1. The details of the selective response of the selenenylsulfide bond to electrophilic reagents may provide new information for designing novel small-molecule inhibitors (drugs) in targeted extracellular/non-reduced TrxR1.

Variable Control and Its Influence Before Urine Sample Analysis in a Field Environment.

Background and Objectives: The aim of the study was to store urine samples at different temperatures and humidity levels and analyze common biochemical test results and point-of-care testing (POCT) indicators according to different storage times and evaluate whether the samples should be centrifuged to study the best storage conditions for urine samples. Methods: Random midstream urine samples (100 mL) were collected from 10 healthy individuals. A portion of the samples was centrifuged. The remaining samples were not centrifuged and were stored under different temperature and humidity conditions for different periods. We measured urine indicators ([Na+], [K+], [Cl-], gamma-glutamyl transpeptidase [GGT], urea, and creatinine [Cr]) at 2, 4, 24, and 72 hours and 7 and 55 days, and we used POCT to measure myoglobin (Mb) and microalbumin (mAlb) concentrations. Results: Centrifugation of urine samples decreased the measured GGT and increased the measured Mb. In urine samples stored at 4°C and room temperature, electrolyte concentrations were scarcely affected by storage time. After storage at 50°C for 24 hours, the measured [Na+] and [Cl-] levels changed. Metabolites (urea and Cr) underwent no obvious change across temperatures. GGT did not change during long-term storage at 4°C. The mAlb level changed significantly only after storage at 4°C. When stored at 4°C, Mb changed little within 4 hours. Under humid conditions, [Na+] and [Cl-] increased significantly after 24 hours, and urea decreased significantly after 7 days of storage. Under dry storage conditions, urinary Cr and GGT decreased, and under humid conditions, these concentrations increased. At high humidity, mAlb increased significantly after 72 hours. Conclusions: Electrolyte and amino acid metabolite concentrations were less affected by storage time at 4°C and room temperature than at other temperatures. Some proteins are sensitive to environmental changes; samples collected for quantification of these proteins can be stored briefly at 4°C after centrifugation. Normal humidity conditions meet most physiological testing requirements.

Both epilepsy and anti-seizure medications affect bone metabolism in children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.

Associations between Borg's rating of perceived exertion and changes in urinary organic acid metabolites after outdoor weight-bearing hiking.

BACKGROUND: Developing methods to monitor exercise load and evaluate body fatigue and muscle injury over time in hiking training remains a key problem to be solved. A widely used psycho-physical tool to assess the subjective perception of effort during exercise is Borg's rating of perceived exertion (BRPE) scale. Data on the relationships and validity of the BRPE compared to objectively assessed metabolic criteria are still lacking, especially urinary organic acid concentrations. AIM: To verify whether the BRPE scale could be used in the prescription of outdoor hiking with weight-bearing and reveal the relationship between the BRPE scale and urinary physiological measures. METHODS: Eighty-nine healthy men (average age: 22 years) were enrolled in a 40 km (6 h) hiking training exercise with a 20 kg load. After training, the BRPE scale (6-20) was completed. All participants were divided into three groups according to the rating of the BRPE scale. Urine samples were collected before and after training. Urinary myoglobin levels were measured immediately using the fluorescent immunoassay method. The remaining urine was subpacked and frozen for the subsequent detection of urinary organic acids using gas chromatography and mass spectrometry. RESULTS: The contents of organic acids and myoglobin in urine were significantly increased after participants hiked 40 km (6 h) with a 20 kg load. Only orthogonal partial least-squares discrimination analysis performed well in separating the group with a BRPE score of 6-12 from the group with a BRPE score of 13-20. Significant differences in the urine levels of several organic acids were observed between the two groups, and the heatmap also presented different metabolic profiles based on BRPE. According to the standard of a variable importance in the projection > 1, fold change > 1.5 and P < 0.05, 19 different metabolites of urinary organic acids were screened and enriched in pathways mainly including the citrate cycle (tricarboxylic acid cycle) and alanine, aspartate and glucose metabolism. CONCLUSION: The BRPE scale identified significantly different urinary organic acid profiles between the higher and lower BRPE value groups, and, thus, could be used to monitor body fatigue in individuals participating in long-distance outdoor hiking with weight bearing.

A Case of Multidrug-Resistant Klebsiella pneumoniae Treated with Carrimycin.

One of the most pressing emerging issues in bacterial resistance is multidrug-resistant Klebsiella pneumoniae. The treatment of K. pneumoniae infections is often problematic because of the lack of available therapeutic options, leading to negative effects on morbidity, mortality, and healthcare-associated costs. Carrimycin is a macrolide antibiotic with good antibacterial effects. In this study, we report a patient diagnosed with multidrug-resistant K. pneumoniae infection who was treated with carrimycin. The patient presented with cough, expectoration, dyspnea, and severe hypoxemia requiring noninvasive ventilation. We successively used a variety of antibiotics, including meropenem, tigecycline, and polymyxin, with unsatisfactory results. Finally, we used carrimycin, and the patient's condition improved, resulting in hospital discharge. Therefore, for patients with multidrug-resistant K. pneumoniae infection that does not respond to conventional anti-infective treatments, carrimycin can be considered a treatment option.

Estrogen ameliorates sepsis-induced vascular hyporeactivity in thoracic aorta of female rats via permissive effect of GRα expression.

OBJECTIVE: Estrogen is correlated to the lower mortality and disease severity of female than that of male, which indicates the potential therapeutic role of estrogen supplement therapy in sepsis. The structure of Daidzein is similar to that of 17ß estradiol (E2), an estrogen in human body, causing the exogenous Daidzein can interact with estrogen receptor as well as E2 in the body. We aim to explore the therapeutic role of estrogen in sepsis-induced vascular dysfunction. Also, we wonder if estrogen regulates blood pressure via glucocorticoid-mediated vascular reactivity. METHODS: Female SD rats received ovariectomy (OVX) to induce estrogen deficiency. After 12 weeks of administration, cecal ligation and puncture (CLP) was used to establish the in vivo model of sepsis. Lipopolysaccharide (LPS) was used to construct the in vitro model of sepsis in vascular smooth muscle cells (VSMCs). E2 and Daidzein were used for estrogen supplement therapy. RESULTS: E2 and Daidzein significantly inhibited inflammation infiltration and histopathological injury in thoracic aorta in the rat model with CLP. E2 and Daidzein improved carotid pressure and vascular hyporeactivity in sepsis rats with OVX. Importantly, E2 and Daidzein promoted glucocorticoid permissive action and increased glucocorticoid receptor α (GRα) expression in thoracic aorta smooth muscle cells. E2 and Daidzein upregulated GRα, and inhibits cytokine production, proliferative phenotype and cell migration in LPS-induced VSMCs. CONCLUSION: Estrogen improved vascular hyporeactivity in thoracic aorta induced by sepsis via permissive effect of GRα expression.

Identification of a novel mutation in the FGF10 gene in a Chinese family with obvious congenital lacrimal duct dysplasia in lacrimo-auriculo-dento-digital syndrome.

AIM: To identify the pathogenic gene variant in a family with lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] showing congenital lacrimal duct dysplasia as the main clinical manifestation and lay the foundation for future research on the pathogenic gene. METHODS: Ophthalmological examinations, including slit-lamp biomicroscopy and lacrimal duct probing, and computed tomography dacryocystography (CT-DCG) were performed for all participants. The family pedigree was drawn, genetic features were analyzed, and the genomic DNA of the subjects was extracted. Pathogenic genes were screened via whole exome sequencing (WES) and confirmed using Sanger sequencing. RESULTS: Six patients belonged to this three-generation family, and their clinical manifestations included congenital nasolacrimal duct obstruction, congenital absence of lacrimal puncta and canaliculi, lacrimal fistulae, and limb deformities. This pattern indicates autosomal dominant inheritance. Diagnosis was based on the clinical characteristics of LADD syndrome, which presented in all the patients in this family. A novel frameshift mutation in the FGF10 gene (NM_004465.1), c.234dupC (p.Trp79Leus*15), was identified in all patients via WES. The variant was confirmed by Sanger sequencing and classified as a "pathogenic mutation" according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines. CONCLUSION: A novel frameshift mutation in the FGF10 gene is found in all patients. This finding helps this family with LADD syndrome receiving a more accurate clinical diagnosis and genetic counseling by extending the mutation range of the FGF10 gene.

Application of Nonlinear Models Combined with Conventional Laboratory Indicators for the Diagnosis and Differential Diagnosis of Ovarian Cancer.

Existing biomarkers for ovarian cancer lack sensitivity and specificity. We compared the diagnostic efficacy of nonlinear machine learning and linear statistical models for diagnosing ovarian cancer using a combination of conventional laboratory indicators. We divided 901 retrospective samples into an ovarian cancer group and a control group, comprising non-ovarian malignant gynecological tumor (NOMGT), benign gynecological disease (BGD), and healthy control subgroups. Cases were randomly assigned to training and internal validation sets. Two linear (logistic regression (LR) and Fisher's linear discriminant (FLD)) and three nonlinear models (support vector machine (SVM), random forest (RF), and artificial neural network (ANN)) were constructed using 22 conventional laboratory indicators and three demographic characteristics. Model performance was compared. In an independent prospectively recruited validation set, the order of diagnostic efficiency was RF, SVM, ANN, FLD, LR, and carbohydrate antigen 125 (CA125)-only (AUC, accuracy: 0.989, 95.6%; 0.985, 94.4%; 0.974, 93.4%; 0.915, 82.1%; 0.859, 80.1%; and 0.732, 73.0%, respectively). RF maintained satisfactory classification performance for identifying different ovarian cancer stages and for discriminating it from NOMGT-, BGD-, or CA125-positive control. Nonlinear models outperformed linear models, indicating that nonlinear machine learning models can efficiently use conventional laboratory indicators for ovarian cancer diagnosis.

Atomically dispersed Mn atoms coordinated with N and O within an N-doped porous carbon framework for boosted oxygen reduction catalysis.

Developing efficient and robust catalysts to replace Pt group metals for the oxygen reduction reaction (ORR) is conducive to achieving highly efficient energy conversion. Here, we develop a general ion exchange strategy to construct highly efficient ORR catalysts consisting of various atomically dispersed metal atoms anchored on N-doped porous carbon (M-SAs/NC) to investigate the atomic structure-catalytic activity relationship. The structure characterization results demonstrated that the achieved atomic structure varied due to the presence of different metal centers. Mn-SAs/NC consists of MnN3O1 centers, in which the Mn single atoms are stabilized by 3 N and 1 O. In contrast, the center metals in Fe-/Co-/Cu single-atom catalysts are coordinated by merely N atoms. Mn-SAs/NC delivers superior performance for the ORR with a half-wave potential (E1/2) of 0.91 V vs. RHE in 0.1 M KOH solution, outperforming that of the commercial Pt/C catalyst and the control Fe-/Co-/Cu single-atom catalysts. Furthermore, Mn-SAs/NC also shows excellent methanol tolerance and stability up to 5000 cycles. Density functional theory (DFT) calculations reveal that Mn single atom catalysts with MnN3O1 centers contributed to the superior ORR performance with lower energy barriers and optimized adsorption capacity of intermediates. These findings provide insights into the design and development of specific coordinated structures of atomically dispersed catalysts to facilitate the practical applications of energy conversion.

An integrated Mg battery-powered iontophoresis patch for efficient and controllable transdermal drug delivery.

Wearable transdermal iontophoresis eliminating the need for external power sources offers advantages for patient-comfort when deploying epidermal diseases treatments. However, current self-powered iontophoresis based on energy harvesters is limited to support efficient therapeutic administration over the long-term operation, owing to the low and inconsistent energy supply. Here we propose a simplified wearable iontophoresis patch with a built-in Mg battery for efficient and controllable transdermal delivery. This system decreases the system complexity and form factors by using viologen-based hydrogels as an integrated drug reservoir and cathode material, eliminating the conventional interface impedance between the electrode and drug reservoir. The redox-active polyelectrolyte hydrogel offers a high energy density of 3.57 mWh cm-2, and an optimal bioelectronic interface with ultra-soft nature and low tissue-interface impedance. The delivery dosage can be readily manipulated by tuning the viologen hydrogel and the iontophoresis stimulation mode. This iontophoresis patch demonstrates an effective treatment of an imiquimod-induced psoriasis mouse. Considering the advantages of being a reliable and efficient energy supply, simplified configuration, and optimal electrical skin-device interface, this battery-powered iontophoresis may provide a new non-invasive treatment for chronic epidermal diseases.

Machine-learning models utilizing CYP3A4*1G show improved prediction of hypoglycemic medication in Type 2 diabetes.

The effectiveness and side effects of Type 2 diabetes (T2D) medication are related to individual genetic background. SNPs CYP3A4 and CYP2C19 were introduced to machine-learning models to improve the performance of T2D medication prediction. Two multilabel classification models, ML-KNN and WRank-SVM, trained with clinical data and CYP3A4/CYP2C19 SNPs were evaluated. Prediction performance was evaluated with Hamming loss, one-error, coverage, ranking loss and average precision. The average precision of ML-KNN and WRank-SVM using clinical data was 92.74% and 92.9%, respectively. Combined with CYP2C19*2*3, the average precision dropped to 88.84% and 89.93%, respectively. While combined with CYP3A4*1G, the average precision was enhanced to 97.96% and 97.82%, respectively. Results suggest that CYP3A4*1G can improve the performance of ML-KNN and WRank-SVM models in predicting T2D medication performance.

About 10% of adults around the world are living with Type 2 Diabetes (T2D). Due to the huge number of patients and the complexity of individual makeup, it is a challenge for doctors to prescribe appropriate hypoglycemic drugs. To aid prescribing, machine-learning models were developed to predict medication schemes based on patients' demographic information and laboratory test results. These models treat prediction as a multilabel classification problem, with each class of medication as a label. This work was designed to determine whether the introduction of genetic information would improve prediction performance. The machine-learning models were trained using datasets with and without genetic information and their performance was compared. The performance of the machine-learning models was improved by incorporating the SNP CYP3A4*1G into the datasets. Thus, this work demonstrates a novel strategy to improve the prediction of T2D hypoglycemic medication performance and provides new ideas for how to support the T2D health system with machine-learning techniques.

Relationship between serum indirect bilirubin and prostate volume in patients with benign prostatic hyperplasia: a cross-sectional study.

Background: Due to its anti-oxidative effects, bilirubin may protect against a spectrum of diseases. However, the role of bilirubin in patients with benign prostatic hyperplasia (BPH) is poorly explored. This study aimed to investigate the cross-sectional associations between serum indirect bilirubin (IBIL) and prostate volume (PV) in patients with BPH. Methods: The medical records of 722 BPH patients were retrospectively analyzed. Body mass index (BMI) was calculated as body weight (kg)/height (m)2. PV was obtained as height (cm) × width (cm) × length (cm) × π/6. Other biochemical indexes were measured by the automatic biochemical analyzer. A univariable linear regression analysis was performed to detect confounders. The IBIL-PV relationship was examined using unadjusted and covariate-adjusted regression models. Furthermore, a segmented linear regression was conducted to analyze the linear trend of IBIL levels and PV. Finally, the sensitivity analysis was stratified by BMI and low-density lipoprotein cholesterol (LDL-C) cutoffs. Results: In this study, the mean age of the patients was 68 (range, 43-93) years. By univariable line regression test, we observed that PV was positively correlated with age, BMI, and LDL-C (ß=0.113, 0.096, and 0.135, respectively). IBIL was negatively associated with PV in full adjusted model in men age ≤75 years (ß=-1.01; 95% CI: -1.81, -0.22; P=0.01). A statistically significant inverse trend was observed between serum IBIL intervals and PV in patients aged ≤75 years (adjusted for age, BMI, and LDL-C, P for trend =0.015). In sensitivity analysis, significantly negative IBIL-PV relationship only existed in men with normal BMI (adjusted ß=-1.328; 95% CI: -2.467, -0.190; P=0.022), overweight men (adjusted ß=-1.296; 95% CI: -2.519, -0.074; P=0.038), and men with normal LDL-C level (adjusted ß=-1.017; 95% CI: -1.869, -0.164; P=0.019). Conclusions: IBIL is negatively associated with PV in the non-obese population ≤75 years with normal LDL-C. These results suggest that higher serum IBIL possibly provides a degree of protection to BPH by mitigating oxidative stress (OS) related to aging and lipid peroxidation. Nevertheless, these preliminary findings from a single-center, retrospective study have limitations and need to be confirmed by future studies.

A preliminary investigation of amino acid and acylcarnitine levels in neonates from the Tibet autonomous.

Background: The purpose of the study was to investigate the levels of amino acids and acylcarnitines in newborns of the Tibet Autonomous Region for the first time and to provide an experimental basis for the diagnosis of genetic metabolic diseases. Methods: We detected concentrations of 43 kinds of amino acids, acylcarnitines and succinylacetone in the dried blood spots of 18482 newborns using liquid chromatography tandem mass spectrometry and diagnose the case by gene sequencing. We compared the indexes between Tibet and our lab, where most data come from an inland area and Han Chinese people. Then we compared amino acid and acylcarnitine levels of seven regions in Tibet and explored their impact factors. Results: We described the levels of amino acids and acylcarnitines in Tibet newborns using 95% confidence intervals. The distribution of amino acid and acylcarnitines were different in Tibet. Conclusion: This study has contributed to filling in the blanks of Tibet newborn screening, which should be considered in the newborn metabolic disease screening in this area.

Graphene-containing metal-organic framework nanocomposites for enhanced microwave ablation of salivary adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (SACC), one of the most common malignant tumors in the head and neck region, is characterized by high postoperative recurrence rate and poor prognosis. Microwave (MW) ablation possesses advantages in preserving SACC patients' facial aesthetics and oral function, but unfortunately, it suffers from low therapeutic efficacy due to the limited MW-thermal efficiency. Moreover, the insufficient thermal ablation may aggravate hypoxic state in tumors, which is deleterious to the treatment of residual tumors and aggressive tumors. Hence, MW ablation has been rarely applied in treating head and neck tumors in recent years. To minimize the unfavorable outcomes and maximize the therapeutic effects of MW ablation, a MW sensitizer coupled with a self-sufficient oxygen nanoagent was employed for the first time in MW ablation to treat head and neck tumors. We prepared a graphene-containing metal-organic framework (ZIF67@Gr-PEG), which exhibited excellent MW thermal conversion ability endowed by the incorporated Gr and showed in situ oxygen generation capacity derived from the ZIF67 matrix. In an animal experiment, ZIF67@Gr-PEG-based MW ablation with a temperature up to 66.1 °C exhibited a high tumor ablation rate. More importantly, insufficient MW ablation-induced high expressions of HIF-1α and VEGF were observed in our experiment, whereas the levels of tumor hypoxia and angiogenesis were efficiently decreased in MW ablation with the assistance of ZIF67@Gr-PEG nanocomposites (NCs). Notably, our strategy for MW ablation not only evidences the great potential of ZIF67@Gr-PEG but also promotes the translation of thermotherapeutic graphene from basic research to clinical practice.

[Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria].

OBJECTIVE: To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant. METHODS: A retrospective study on the clinical manifestations, complications, treatment, and outcome in 164 patients of cblC type with MMACHC c.609G>A homologous variant was conducted. The patients were diagnosed by biochemical and genetic analysis from January 1998 to December 2020. RESULTS: Among the 164 patients, 2 cases were prenatally diagnosed and began treatment after birth. They are 3 and 12 years old with normal physical and mental development. Twenty-one cases were diagnosed by newborn screening. Among them, 15 cases had with normal development. They were treated from the age of two weeks at the asymptomatic period. Six cases began treatment aged 1 to 3 months after onset. Their development was delayed. One hundred and forty-one cases were clinically diagnosed. Their onset age ranges from a few minutes after birth to 6 years old. 110 cases had early-onset (78.0%). 31 cases had late-onset (22.0%). Five of them died. 24 patients lost to follow-up. Of the 141 clinically diagnosed patients, 130 (92.2%) with psychomotor retardation, 69 (48.9%) with epilepsy, 39 (27.7%) with anemia, 30 (21.3%) had visual impairment, 27 (19.1%) had hydrocephalus, 26 (18.4%) had feeding difficulties, 7 (5.0%) with liver damage, and 5 (3.5%) with metabolic syndrome. The frequency of hydrocephalus and seizures was significantly higher in the early-onset group. The urinary methylmalonic acid increased significantly in the patients with epilepsy. During the long-term follow-up, the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group, the difference had a statistical significance (P<0.05). CONCLUSION: Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease, with a high mortality and disability rate. If not treated in time, it will lead to neurological damage, resulting in epilepsy, mental retardation, hydrocephalus, and multiple organ damage. Pre-symptomatic diagnosis and treatment are crucial to prevent irreversible neurological damage. Neonatal screening and prenatal diagnosis are important to improve the outcome of the patients.

Current care practices for patients with Duchenne muscular dystrophy in China.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has presented challenges in the care of patients with chronic diseases. We identified the challenges faced by Chinese patients with Duchenne muscular dystrophy (DMD) during the pandemic. METHODS: An online cross-sectional survey was conducted between March 27 and June 30, 2021. RESULTS: Of the 2105 valid questionnaire responses, 2,056 patients were from non-lockdown areas. In these areas, 42.8% reduced outside daily activities, 49.4% reduced rehabilitation service use, 39.7% postponed regular follow-ups, and 40.8% reported accelerated motor function decline. These figures generally increased for patients from lockdown areas-67.3% reduced outside daily activities, 44.9% reduced rehabilitation service use, 79.6% postponed regular follow-ups, and 55.1% reported accelerated motor function decline. Ambulation loss was most commonly reported in September and March before 2020; however, this trend was absent in 2020. Regarding the informed prices of disease-modifying drugs in Europe and the United States, 86.7% could afford a maximum of one-twentieth of the prices, 8.0% could afford one-tenth of the prices, and only 0.6% of the patients could afford the full prices. CONCLUSIONS: Implementation of standardized care for DMD in China is consistent with global practices, and the COVID-19 pandemic has affected the care of patients with chronic diseases worldwide, particularly in lockdown areas. Telemedicine is an effective model for providing healthcare to such patients. Healthcare workers should assist patients and establish more robust chronic disease management systems. Collaboration between governmental and non-governmental entities could address the cost of disease-modifying drugs in China and other developing countries.

Identification of novel variations in SLC6A8 and GAMT genes causing cerebral creatine deficiency syndrome.

Cerebral creatine deficiency syndromes (CCDSs) are a group of rare mendelian disorders mainly characterized by intellectual disability, movement anomaly, behavior disorder and seizures. SLC6A8, GAMT, and GATM are known genes responsible for CCDS. In this study, seven pediatric patients with developmental delay were recruited and submitted to a series of clinical evaluation, laboratory testing, and genetic analysis. The clinical manifestations and core biochemical indications of each child were basically consistent with the diagnosis of CCDS. Genetic diagnosis determined that all patients were positive for SLC6A8 or GAMT variation. A total of 12 variants were identified in this cohort, including six novel ones. The frequency of these variants, the Revel scores and the conservatism of the affected amino acids support their pathogenicity. Our findings expanded the mutation spectrum of CCDS disorders, and provided solid evidence for the counseling to affected families.