Silver-Promoted Three-Component Synthesis of Perfluoroalkenyl Pyrroles through Partial Defluorinative Functionalization of Perfluoroalkyl Halides.

A silver-promoted three-component heterocyclization of alkynes, perfluoroalkyl halides, and 1,3-dinucleophiles was developed for the efficient synthesis of privileged (E)-perfluoroalkenyl pyrroles. The reaction proceeded through a rationally designed sequence of radical perfluoroalkylation and intramolecular defluorinative [3 + 2]-heterocyclization. The utility of perfluoroalkyl halide as a perfluoroalkenyl reagent, by selective and controllable functionalization of two inert C(sp3)-F bonds at vicinal carbon centers on the perfluoroalkyl chain, provides a new reaction mode for the synthesis of value-added organofluorides starting from the easily available and low-cost fluorinated feedstock.

Releasing Free Radicals in Precursor Triggers the Formation of Closed Pores in Hard Carbon for Sodium-Ion Batteries.

Increasing closed pore volume in hard carbon is considered to be the most effective way to enhance the electrochemical performance in sodium-ion batteries. However, there is a lack of systematic insights into the formation mechanisms of closed pores at molecular level. In this study, a regulation strategy of closed pores via adjustment of the content of free radicals is reported. Sufficient free radicals are exposed by part delignification of bamboo, which is related to the formation of well-developed carbon layers and rich closed pores. In addition, excessive free radicals from nearly total delignification lead to more reactive sites during pyrolysis, which competes for limited precursor debris to form smaller microcrystals and therefore compact the material. The optimal sample delivers a large closed pore volume of 0.203 cm3 g-1, which leads to a high reversible capacity of 350 mAh g-1 at 20 mA g-1 and enhanced Na+ transfer kinetics. This work provides insights into the formation mechanisms of closed pores at molecular level, enabling rational design of hard carbon pore structures.

A comprehensive clinical evaluation of HER2-TKIs in patients with previously treated HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor 2-tyrosine kinase inhibitors (HER2-TKIs) have been extensively utilized for treating HER2-positive metastatic breast cancer (MBC), with numerous clinical trial reports available. We aim to systematically perform a comprehensive clinical evaluation on HER2-TKIs, provide a reference for the clinical rational use of drugs, and serve for the decision-making of the national drug policy. We performed comprehensive clinical evaluation in six dimensions including safety, effectiveness, economy, suitability, accessibility, and innovation through meta-analysis, literature review, drug administration websites, and other relevant medication data to analyze HER2-TKIs in treating HER2-positive MBC. For safety, the risk of ≥ grade 3 adverse events among pyrotinib, lapatinib, and neratinib is not significantly different. Furthermore, pyrotinib and neratinib were found to be higher in the risk of ≥ grade 3 diarrhea than lapatinib, however the risk could be reversed and prevented with loperamide. Regarding effectiveness and economy, pyrotinib was confirmed to have the best efficacy and cost-utility value, neratinib the second, and lapatinib the third. As regards innovation and suitability, pyrotinib showed better than other HER2-TKIs. In addition, pyrotinib received a higher recommendation than other HER2-TKIs in patients with HER2-positive MBC. The accessibility of pyrotinib was found to be the best with better urban, rural, and national affordability and lower annual treatment costs. Pyrotinib is more valuable in clinics with better safety, effectiveness, economy, suitability, accessibility, and innovation in HER2-positive MBC. This study could provide references for the clinical application of HER2-TKIs in treating HER2-positive MBC.

[The technique and application of individualized tympanic membrane flap in the repair of tympanic membrane under endoscopy ear surgery].

Objective:To investigate the technique of personalized flap making under otoscopy and its clinical application. Methods:The clinical data of patients who underwent 301 Military Hospital myringoplasty in the Department of otoendoscopic surgery, Department of Otorhinolaryngology, head and neck surgery, Department of Otorhinolaryngology, from October 2022 to 2023 August were analyzed retrospectively, all enrolled patients were performed independently by the same skilled otoendoscopic surgeon. The patients' general condition, medical history, tympanic membrane perforation scope, perforation size, need for tympanic cavity exploration, thickness of skin flap, tympanic cavity lesion scope, skin flap making method and postoperative rehabilitation were collected. Results:Many factors such as the location of tympanic membrane perforation, the thickness of the skin flap, the degree of curvature or stricture of the ear canal and the extent of the lesion in the tympanic cavity should be considered in the manufacture of the individualized tympanic membrane skin flap, the way of skin flap making does not affect the long-term postoperative rehabilitation, but it can effectively avoid unnecessary ear canal skin flap injury and improve the operation efficiency. Conclusion:Scientific flap fabrication is important for improving surgical efficiency and enhancing surgical confidence.

A Case of Oropharyngeal Syphilis.

We present a case of a 50-year-old male who complained of a sore throat persisting for 2 months. Upon physical examination, multiple mucous patches were observed in the oropharynx region, but no skin lesions were found. Fiberoptic laryngoscopy confirmed these findings. The Treponema pallidum particle agglutination test and toluidine red unheated serum test (TRUST) were positive with a titer of TRUST 1:64. The patient admitted to engaging in extramarital sexual activities with several females but no males. Based on the clinical manifestations and laboratory test results, a diagnosis of secondary syphilis of the oropharynx was established. He was treated with 2.4 million units of benzathine penicillin G by intramuscular injection once a week for 3 weeks. After 1 month, the lesions completely disappeared without any symptoms. The titer of TRUST reduced to 1:2 in 1-year follow-up. This report aims to enhance physicians' understanding and recognition of oropharyngeal syphilis, enabling timely diagnosis and effective management.

Screening of 1.17 million newborns for inborn errors of metabolism using tandem mass spectrometry in Shanghai, China: A 19-year report.

BACKGROUND: Inborn errors of metabolism (IEMs) frequently result in progressive and irreversible clinical consequences if not be diagnosed or treated timely. The tandem mass spectrometry (MS/MS)-based newborn screening (NBS) facilitates early diagnosis and treatment of IEMs. The aim of this study was to determine the characteristics of IEMs and the successful deployment and application of MS/MS screening over a 19-year time period in Shanghai, China, to inform national NBS policy. METHODS: The amino acids and acylcarnitines in dried blood spots from 1,176,073 newborns were assessed for IEMs by MS/MS. The diagnosis of IEMs was made through a comprehensive consideration of clinical features, biochemical performance and genetic testing results. The levels of MS/MS testing parameters were compared between various IEM subtypes and genotypes. RESULTS: A total of 392 newborns were diagnosed with IEMs from January 2003 to June 2022. There were 196 newborns with amino acid disorders (50.00%, 1: 5910), 115 newborns with organic acid disorders (29.59%, 1: 10,139), and 81 newborns with fatty acid oxidation disorders (20.41%; 1:14,701). Phenylalanine hydroxylase deficiency, methylmalonic acidemia and primary carnitine deficiency were the three most common disorders. Some hotspot variations in eight IEM genes (PAH, SLC22A5, MMACHC, MMUT, MAT1A, MCCC2, ACADM, ACAD8), 35 novel variants and some genotype-biochemical phenotype associations were identified. CONCLUSIONS: A total of 28 types of IEMs were identified, with an overall incidence of 1: 3000 in Shanghai, China. Our study offered clinical guidance for the implementation of MS/MS-based NBS and genetic counseling for IEMs in this city.

Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort.

BACKGROUND: The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (MMACHC) c.482G > A mutation in 195 Chinese cases with CblC disease. METHODS: We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months. RESULTS: Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group). CONCLUSIONS: The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. Video Abstract (MP4 136794 kb).

Newborn screening of maple syrup urine disease and the effect of early diagnosis.

BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease for which newborn screening (NBS) is feasible but not universally applied in China. We shared our experiences with MSUD NBS. METHODS: Tandem mass spectrometry-based NBS for MSUD was implemented in January 2003, and diagnostic methods included urine organic acid analysis via gas chromatography-mass spectrometry and genetic analysis. RESULTS: Six MSUD patients were identified from 1.3 million newborns, yielding an incidence of 1:219,472, in Shanghai, China. The areas under the curve (AUCs) of total leucine (Xle), Xle/phenylalanine ratio, and Xle/alanine ratio were all 1.000. Some amino acid and acylcarnitine concentrations were markedly low in MSUD patients. 47 MSUD patients identified here and in other centers were investigated, which included 14 patients identified by NBS and 33 patients diagnosed clinically. Forty-four patients were subclassified into classic (n = 29), intermediate (n = 11) and intermittent (n = 4) subtypes. Due to earlier diagnosis and treatment, screened classic patients showed a higher survival rate (62.5%, 5/8) than clinically diagnosed classic patients (5.2%, 1/19). Overall, 56.8% (25/44) of MSUD patients and 77.8% (21/27) of classic patients carried variants in the BCKDHB gene. Among 61 identified genetic variants, 16 novel variants were identified. CONCLUSION: MSUD NBS in Shanghai, China, enabled earlier detection and increased survivorship in the screened population.

Comparison of Depth-Specific Prediction of Soil Properties: MIR vs. Vis-NIR Spectroscopy.

The prediction of soil properties at different depths is an important research topic for promoting the conservation of black soils and the development of precision agriculture. Mid-infrared spectroscopy (MIR, 2500-25000 nm) has shown great potential in predicting soil properties. This study aimed to explore the ability of MIR to predict soil organic matter (OM) and total nitrogen (TN) at five different depths with the calibration from the whole depth (0-100 cm) or the shallow layers (0-40 cm) and compare its performance with visible and near-infrared spectroscopy (vis-NIR, 350-2500 nm). A total of 90 soil samples containing 450 subsamples (0-10 cm, 10-20 cm, 20-40 cm, 40-70 cm, and 70-100 cm depths) and their corresponding MIR and vis-NIR spectra were collected from a field of black soil in Northeast China. Multivariate adaptive regression splines (MARS) were used to build prediction models. The results showed that prediction models based on MIR (OM: RMSEp = 1.07-3.82 g/kg, RPD = 1.10-5.80; TN: RMSEp = 0.11-0.15 g/kg, RPD = 1.70-4.39) outperformed those based on vis-NIR (OM: RMSEp = 1.75-8.95 g/kg, RPD = 0.50-3.61; TN: RMSEp = 0.12-0.27 g/kg; RPD = 1.00-3.11) because of the higher number of characteristic bands. Prediction models based on the whole depth calibration (OM: RMSEp = 1.09-2.97 g/kg, RPD = 2.13-5.80; TN: RMSEp = 0.08-0.19 g/kg, RPD = 1.86-4.39) outperformed those based on the shallow layers (OM: RMSEp = 1.07-8.95 g/kg, RPD = 0.50-3.93; TN: RMSEp = 0.11-0.27 g/kg, RPD = 1.00-2.24) because the soil sample data of the whole depth had a larger and more representative sample size and a wider distribution. However, prediction models based on the whole depth calibration might provide lower accuracy in some shallow layers. Accordingly, it is suggested that the methods pertaining to soil property prediction based on the spectral library should be considered in future studies for an optimal approach to predicting soil properties at specific depths. This study verified the superiority of MIR for soil property prediction at specific depths and confirmed the advantage of modeling with the whole depth calibration, pointing out a possible optimal approach and providing a reference for predicting soil properties at specific depths.

Selective and Controllable Defluorophosphination and Defluorophosphorylation of Trifluoromethylated Enones: An Auxiliary Function of the Carbonyl Group.

The auxiliary function of a carbonyl group in the tunable defluorophosphination and defluorophosphorylation of trifluoromethylated enones with P(O)-containing compounds was demonstrated. Controlled replacement of one or two fluorine atoms in trifluoromethylated enones while maintaining high chemo- and stereoselectivity was achieved under mild conditions, thus enabling diversity-oriented synthesis of skeletally diverse organophosphorus libraries─(Z)-difluoro-1,3-dien-1-yl phosphinates, (1Z,3E)-4-phosphoryl-4-fluoro-buta-1,3-dien-1-yl phosphinates, and (E)-4-phosphoryl-4-fluoro-1,3-but-3-en-1-ones─in good yields with excellent functional group tolerance.

Overexpression of ClWRKY48 from Cunninghamia lanceolata improves Arabidopsis phosphate uptake.

MAIN CONCLUSION: Our findings suggested that ClWRKY48 promoted the expression level of Arabidopsis phosphate transporter genes, enhanced phosphate uptake, and delayed the transition from the vegetative stage to the reproductive phase in Arabidopsis. Phosphorus (P) is an essential mineral for plants that influences their growth and development. ClWRKY48, one of the most highly expressed genes in the leaf, was identified by RT-PCR from Chinese fir [Cunninghamia lanceolata (Lamb.) Hook] (C. lanceolata). Furthermore, when treating C. lanceolata with increasing phosphate (Pi) concentration, the expression level of ClWRKY48 rose in leaves, the trends followed the increasing phosphate concentration treatment. ClWRKY48 is a transcription factor in C. lanceolata, according to the results of a yeast one hybridization experiment. Based on subcellular localization studies, ClWRKY48 is a nuclear-localized protein. Under Pi deficiency conditions, the phosphorus concentration of ClWRKY48 overexpressing Arabidopsis increased by 43.2-51.1% compared to the wild-type. Moreover, under Pi limiting conditions, the phosphate transporter genes AtPHT1;1 (Arabidopsis Phosphate transporter 1;1), AtPHT1;4, and AtPHO1 (Arabidopsis PHOSPHATE 1) were expressed 2.1-2.5, 2.2-2.7, and 6.7-7.3-fold greater than the wild-type in ClWRKY48 transgenic Arabidopsis, respectively. Under Pi-sufficient conditions, the phosphorus concentration and phosphate transporter genes of ClWRKY48 overexpression in Arabidopsis are not significantly different from the wild type. These findings indicated that ClWRKY48 increased phosphate absorption in transgenic Arabidopsis. Furthermore, compared to the wild type, the ClWRKY48 transgenic Arabidopsis not only had a delayed flowering time characteristic but also had lower expression of flowering-related genes AtFT (FLOWERING LOCUS T), AtFUL (FRUITFUL), and AtTSF (TWIN SISTER OF FT). Our findings show that ClWRKY48 enhances phosphate absorption and slows the transition from the vegetative to the reproductive stage in ClWRKY48 transgenic Arabidopsis.

Haplotype Analysis Sheds Light on the Genetic Evolution of the Powdery Mildew Resistance Locus Pm60 in Triticum Species.

Wheat powdery mildew (Blumeria graminis f. sp. tritici, Bgt, recently clarified as B. graminis s. str.), is one of the most destructive diseases of wheat. Pm60 is a nucleotide-binding leucine-rich repeat (NLR) gene that confers race-specific resistance to Bgt. Allelic variants (Pm60, Pm60a, and Pm60b) were found in Triticum urartu and T. dicoccoides, the wild progenitors of wheat. In the present study, we studied the diversity of the Pm60 locus in a large set of wheat germplasm and found 20 tetraploid wheats harboring the Pm60 alleles, which correspond to three novel haplotypes (HapI-HapIII). HapI (Pm60 allele) and HapII (Pm60a allele) were present in domesticated tetraploid wheats, whereas HapIII (Pm60a allele) was identified in wild tetraploid T. araraticum. A sequence comparison of HapII and HapIII revealed that they differed by three SNPs and a GCC deletion. Results of the phylogenetic analysis revealed that HapII was more closely related to the functional haplotype MlIW172. Infection tests showed that HapII-carrying lines display a partial resistance response to Bgt#GH, while HapI was susceptible. Our results provide insights into the genetic evolution of the Pm60 locus and potential valuable alleles for powdery mildew resistance breeding.

Clinical, biochemical, and molecular genetic characteristics of patients with primary carnitine deficiency identified by newborn screening in Shanghai, China.

Background: Primary carnitine deficiency (PCD) is an autosomal recessive disease caused by mutations in the SLC22A5 gene, which encodes the organic cation transporter 2 (OCTN2). Patients with PCD may be at risk of skeletal or cardiac myopathy, metabolic decompensation, and even sudden death. This study aimed to analyze the biochemical, clinical, and genetic characteristics of PCD patients identified by newborn screening (NBS) in Shanghai. Methods: Dried blood spot (DBS) samples of newborns were analyzed through tandem mass spectrometry (MS/MS) from January 2003 to December 2021. Newborns with low free carnitine (C0) levels were recalled. Mutation in the SLC22A5 gene was analyzed on suspected positive newborns with low C0 levels after recall. Results: 1,247,274 newborns were screened by MS/MS and 40 newborns were diagnosed with PCD, therefore the incidence of PCD in Shanghai was approximately 1:31,200. The mean C0 level in newborns with PCD was 5.37 ± 1.79 µmol/L before treatment and increased to 24.45 ± 10.87 µmol/L after treatment with L-carnitine. Twenty-three different variants were identified in the SLC22A5 gene, including 8 novel variants, of which c.51C>G (p.F17L) was the most frequent (27.27%, 18/66), followed by c.1400C>G (p.S467C) (25.76%, 17/66). Almost all the screened PCD patients were asymptomatic. Conclusion: NBS via MS/MS was a quick and efficient method for the early diagnosis of PCD. The incidence of PCD in Shanghai was 1:31,200. Eight novel variants were identified, which greatly expanded the variant spectrum of SLC22A5. MS/MS combined with genetic testing could effectively improve the diagnostic accuracy of PCD.

Corrigendum: Case report: Primary aldosteronism and subclinical cushing syndrome in a 49-year-old woman with hypertension plus hypokalaemia.

[This corrects the article DOI: 10.3389/fcvm.2022.911333.].

Research Progress of PI3K/PTEN/AKT Signaling Pathway Associated with Renal Cell Carcinoma.

Renal cell carcinoma is a common renal malignancy of the urinary system and the most malignant type of kidney cancer. Phosphatidylinositol 3-kinase (PI3K) is an intracellular phosphatidylinositol kinase associated with oncogene products such as v-src and with serine/threonine kinase activity, and its increased activity correlates with the development of several cancers. Protein kinase B (AKT) is a cyclic guanosine phosphate-dependent protein kinase that plays an important role in cell survival and apoptosis. Phosphatase and tensin homolog (PTEN), a newly discovered oncogene in recent years, participates in tumorigenesis and development by competing with tyrosine kinases for common substrates. The product encoded by PTEN was found to negatively regulate the PI3K/Akt signaling pathway, thereby inhibiting cell proliferation and promoting apoptosis. The PI3K/PTEN/AKT signaling pathway has also been identified in several studies as being involved in the development of several malignancies, including renal cell carcinoma. Radiotherapy is currently one of the most effective means of treatment for renal cell carcinoma, whereas it is predisposed to significant tolerance during the course of radiotherapy, thereby leading to treatment failure. Therefore, new treatment options may potentiate the efficiency of renal cell carcinoma treatment. With the development of tumor molecular biology, targeted biological therapy for malignant tumors has gradually become a research hotspot. Given the above research background, this study reviews the application of the PI3K/PTEN/AKT signaling pathway in renal cell carcinoma, aiming to provide more references for the treatment of clinical renal cell carcinoma.

Association of the triglyceride-glucose index and vascular target organ damage in a Beijing community-based population.

Objective: We aimed to explore the association between the triglyceride-glucose (TyG) index, a marker of insulin resistance (IR), and vascular target organ damage (TOD) in a Beijing community-based population, China. Methods: A total of 6,015 participants from an atherosclerosis cohort survey performed in the Shijingshan District in Beijing, China were included in our analysis. Vascular TOD, such as carotid-femoral pulse wave velocity (cfPWV), brachial-ankle pulse wave velocity (baPWV), and the urine albumin-to-creatinine ratio (UACR) were all evaluated. Results: The overall mean age of all the participants was 62.35 years, 3,951 (65.69%) were female, and mean TyG index was 8.81. In univariable regression analyzes, an increased TyG index was associated with higher cfPWV, baPWV, lnUACR, and higher risk of cfPWV ≥ 10 m/s, baPWV ≥ 1,800 cm/s, and UACR ≥ 30 mg/g, respectively. Multivariable regression analyzes showed subjects with the TyG index in top tertile had a significant increase in cfPWV (ß = 0.29 m/s; 95% confidence interval [95% CI] 0.19-0.40; p fortrend < 0.001), baPWV (ß = 69.28 cm/s; 95% CI 50.97-87.59; p fortrend < 0.001), lnUACR (ß = 0.23; 95% CI 0.13-0.34; p fortrend < 0.001), and had a higher risk of cfPWV ≥ 10 m/s (odds ratio [OR] = 1.47; 95% CI 1.17-1.85; p fortrend < 0.001), baPWV ≥ 1,800 cm/s (OR = 1.79; 95% CI 1.48-2.17; p fortrend < 0.001), and UACR ≥ 30 mg/g (OR = 1.71; 95% CI 1.30-2.24; p fortrend < 0.001) after fully adjusting for age, sex, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), estimated glomerular filtration rate (eGFR), self-reported coronary heart disease (CHD) and stroke, antihypertensive drugs, hypoglycemic drugs, and lipid-lowering drugs. Consistent conclusions were obtained in the subgroups without hypoglycemic and lipid-lowering medications or aged younger than 65 years old. Conclusions: The TyG index was positively associated with artery stiffness and nephric microvascular damage in a Beijing community-based population in China. This result provides evidence that the TyG index may serve as a simple and effective indicator to reflect vascular TOD.

Prenatal Diagnosis of Isovaleric Acidemia From Amniotic Fluid Using Genetic and Biochemical Approaches.

Background: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and different approaches have been applied to its prenatal diagnosis. However, systemic application of a biochemical strategy is rare. To evaluate its reliability and validity, we conducted a retrospective study of our experience with metabolite measurement together with genetic analysis in IVA prenatal diagnosis at a single center. Methods: A total of eight pregnancies whose probands were diagnosed as IVA were referred to our center for prenatal diagnosis. Prenatal data of genetic analysis and metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) in amniotic fluid (AF) samples were retrospectively reviewed. Results: Genetic and biochemical results were both available in these eight at-risk fetuses. Among them, two fetuses had higher levels of isovalerylcarnitine (C5) and C5/acetylcarnitine (C2) in AF compared with normal reference range and, thus, were determined to be affected, both of whom were found to carry compound heterogeneous mutations according to genetic analysis. The remaining six fetuses were determined to be unaffected based on a normal AF metabolite profile, except one showed slightly elevated C5 and they were found to be carriers according to genetic analysis. However, the level of isovalerylglycine (IVG) could not be detected at all in both groups. Conclusion: The biochemical analysis, as a quick and convenient method, could be an additional reliable option for the prenatal diagnosis of IVA, especially in families with inconclusive genetic results, and can achieve a more precise diagnosis in conjunction with mutation analysis.

Case Report: Primary Aldosteronism and Subclinical Cushing Syndrome in a 49-Year-Old Woman With Hypertension Plus Hypokalaemia.

Background: Coexisting primary aldosteronism (PA) and subclinical Cushing's syndrome (SCS) caused by bilateral adrenocortical adenomas have occasionally been reported. Precise diagnosis and treatment of the disease pose a challenge to clinicians due to its atypical clinical manifestations and laboratory findings. Case Summary: A 49-year-old woman was admitted to our hospital due to fatigue, increased nocturia and refractory hypertension. The patient had a history of severe left hydronephrosis 6 months prior. Laboratory examinations showed hypokalaemia (2.58 mmol/L) and high urine potassium (71 mmol/24 h). Adrenal computed tomography (CT) showed bilateral adrenal masses. Undetectable ACTH and unsuppressed plasma cortisol levels by dexamethasone indicated ACTH-independent Cushing's syndrome. Although the upright aldosterone-to-renin ratio (ARR) was 3.06 which did not exceed 3.7, elevated plasma aldosterone concentrations (PAC) with unsuppressed PAC after the captopril test still suggested PA. Adrenal venous sampling (AVS) without adrenocorticotropic hormone further revealed hypersecretion of aldosterone from the right side and no dominant side of cortisol secretion. A laparoscopic right adrenal tumor resection was performed. The pathological diagnosis was adrenocortical adenoma. After the operation, the supine and standing PAC were normalized; while the plasma cortisol levels postoperatively were still high and plasma renin was activated. The patient's postoperative serum potassium and 24-h urine potassium returned to normal without any pharmacological treatment. In addition, the patient's blood pressure was controlled normally with irbesartan alone. Conclusion: Patients with refractory hypertension should be screened for the cause of secondary hypertension. AVS should be performed in patients in which PA is highly suspected to determine whether there is the option of surgical treatment. Moreover, patients with PA should be screened for hypercortisolism, which can contribute to a proper understanding of the AVS result.

The Follow-Up of Chinese Patients in cblC Type Methylmalonic Acidemia Identified Through Expanded Newborn Screening.

Objective: The cblC type of combined methylmalonic acidemia and homocystinuria, an inherited disorder with variable phenotypes, is included in newborn screening (NBS) programs at multiple newborn screening centers in China. The present study aimed to investigate the long-term clinical benefits of screening individual. Methods: A national, retrospective multi-center study of infants with confirmed cblC defect identified by NBS between 2004 and 2020 was conducted. We collected a large cohort of 538 patients and investigated their clinical data in detail, including disease onset, biochemical metabolites, and gene variation, and explored different factors on the prognosis. Results: The long-term outcomes of all patients were evaluated, representing 44.6% for poor outcomes. In our comparison of patients with already occurring clinical signs before treatment to asymptomatic ones, the incidence of intellectual impairment, movement disorders, ocular complications, hydrocephalus, and death were significantly different (p < 0.01). The presence of disease onset [Odd ratio (OR) 12.39, 95% CI 5.15-29.81; p = 0.000], variants of c.609G>A (OR 2.55, 95% CI 1.49-4.35; p = 0.001), and c.567dupT (OR 2.28, 95% CI 1.03-5.05; p = 0.042) were independently associated with poor outcomes, especially for neurodevelopmental deterioration. Conclusion: NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have protective effects on the prognosis of infants with cblC defect.

Association Between Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations and Cardiovascular Events in Cardiovascular Disease: A Systemic Review and Meta-Analysis.

Background: A large amount of evidence suggests that proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors have clinical benefits in patients with cardiovascular disease (CVD). However, whether PCSK9 concentrations predict future cardiovascular (CV) events remains unclear. Methods: We conducted a meta-analysis to investigate the ability of PCSK9 concentrations to predict future CV events in patients with established CVD. A comprehensive search of electronic databases was conducted in June 2021. We included relative risk (RR) estimates with 95% CI or events of interest. Results: Eleven cohort studies including 8,471 patients with CVD were enrolled. The pooled RR of CV events for the increase in the circulating baseline PCSK9 concentrations by 1 SD showed a positive association in a random-effect model (RR 1.226, 95% CI: 1.055-1.423, P = 0.008). Similarly, the risk of the total CV events increased by 52% in the patients in the highest tertile compared with those in the lowest tertile of circulating PCSK9 concentrations (RR 1.523, 95% CI: 1.098-2.112, P = 0.012). The association between PCSK9 and CV events was stronger in stable patients with CVD, patients treated with statins, and Asian patients. Conclusions: High PCSK9 concentrations are significantly related to the increased risk of future CV events. These results enrich the knowledge of PCSK9 function and suggest the further possible clinical role of PCSK9 inhibitors.