Publications by authors named "Junling Wang"

309 Publications

Factors associated with medication nonadherence among Medicare low-income subsidy beneficiaries with diabetes, hypertension, and/or heart failure.

J Manag Care Spec Pharm 2021 Aug;27(8):971-981

Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center College of Pharmacy, Memphis.

Previous studies have documented factors influencing medication nonadherence among the Medicare population, but few studies have examined medication nonadherence among the Medicare low-income subsidy (LIS) population. Furthermore, little is known about the factors associated with nonadherence among this population, especially those with prevalent chronic conditions such as type 2 diabetes, hypertension, or heart failure. To examine factors associated with the likelihood of medication nonadherence among Medicare LIS recipients with type 2 diabetes, hypertension, or heart failure. This was a retrospective analysis of 2012-2013 Medicare Parts A, B, and D claims (most recent available for this research) linked to the Area Health Resources Files. Beneficiaries aged 65 years or older with continuous Medicare coverage and receiving any LIS were included. Individuals were categorized into full LIS or partial LIS groups. Nonadherence was determined by the proportion of days covered less than 80% for specified oral type 2 diabetes, hypertension, and heart failure medications, as defined by the Pharmacy Quality Alliance. A multivariate logistic regression was used to determine and compare individual-level and community-level characteristics associated with nonadherence among the entire study sample, the full LIS group, and the partial LIS group. The study sample included 505,771 Medicare beneficiaries, with 448,509 (88.7%) receiving full LIS and 57,262 (11.3%) receiving partial LIS. The proportion of individuals nonadherent was higher among the full LIS population (33.2%) than that of the partial LIS population (30.8%). Among the entire population, younger age was associated with nonadherence (OR = 0.98; 95% CI = 0.98-0.99). Men were more likely to be nonadherent than women (OR = 1.12; 95% CI = 1.11-1.14). Compared with non-Hispanic Whites, racial/ethnic minorities had higher nonadherence. Compared with beneficiaries who were non-Hispanic White, the ORs for those who were Black, Hispanic, Asian, and other were 1.41 (95% CI = 1.38-1.43), 1.58 (95% CI = 1.55-1.61), 1.08 (95% CI = 1.05-1.11), and 1.63 (95% CI = 1.56-1.70), respectively. There were higher nonadherence rates among patients living in communities with lower socioeconomic characteristics, such as a metropolitan statistical area (MSA vs non-MSA; OR = 1.05, 95% CI = 1.04-1.07). A higher risk adjustment summary score, indicating worse health status, was associated with an increased likelihood of medication nonadherence (OR = 1.21; 95% CI = 1.20-1.22). These patterns were similar among the full and partial LIS groups. Individual- and community-level characteristics were associated with the likelihood of medication nonadherence among Medicare LIS recipients with type 2 diabetes, hypertension, or heart failure. These characteristics included younger age, male sex, racial/ethnic minorities, living in lower socioeconomic communities, and a higher risk adjustment summary score. This study provided insight into medication nonadherence within the Medicare LIS population and identified the need to consider these factors when developing future policies to improve medication adherence. This study was funded by the Pharmaceutical Research & Manufacturers of America (PhRMA), which was involved in the preparation and revision of the manuscript. Dougherty is employed by PhRMA. Todor was a PQA-CVS Health Foundation Scholar who was funded to work on this study. Hines is employed by Pharmacy Quality Alliance. Wang reports grants from AbbVie, Curo, Bristol Myers Squibb, and Pfizer, during the time of this study, and fees from the PhRMA Foundation for work on its Heath Outcomes Research Advisor Committee. The other authors have nothing to disclose. This study was presented as a poster at the online 2020 PQA Annual Meeting, May 7, 2020.
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http://dx.doi.org/10.18553/jmcp.2021.27.8.971DOI Listing
August 2021

Biallelic -Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.

Front Genet 2021 12;12:685035. Epub 2021 Jul 12.

Department of Neurology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.

Objective: The cytochrome c oxidase assembly factor 7 ( gene encodes a protein localized to mitochondria that is involved in the assembly of mitochondrial respiratory chain complex IV. Here, we report the clinical, genetic and biochemical analysis of a female patient with suspected mitochondrial disorder and novel variants in , that presented with a considerably different phenotype and age of onset than the five patients reported to date.

Methods: We performed trio-exome sequencing in the affected patient and both parents. To verify the pathogenicity of the detected variants in , mitochondrial enzyme activities and oxygen consumption rate were investigated in fibroblasts of the patient and her parents.

Results: A Chinese girl was referred at 9 months of age with a history of developmental delay and regression since 3 months of age. In the following months, she lost previously acquired skills and developed progressive spasticity of the lower extremities. Trio-exome sequencing revealed compound heterzygous variants in (c.511G > A/p.Ala171Thr and c.566A > G/p.Asn189Ser). Functional validation experiments revealed isolated complex IV deficiency and a significantly reduced mitochondrial respiration rate in patient-derived fibroblasts.

Interpretation: Hitherto, characteristic features of patients were described as slowly progressing neuropathy and spinocerebellar ataxia, starting at the toddler age and progressing into adulthood. In contrast, our patient was reported to show developmental delay from 3 months of age, which was found to be due to a rapidly progressive encephalopathy and brain atrophy seen at 9 months of age. Unexpectedly, the genetic investigation revealed a associated mitochondrial disease, which was confirmed functionally. Thus, this report broadens the genetic and clinical spectrum of this heterogeneous mitochondriopathy and highlights the value of the presented unbiased approach.
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http://dx.doi.org/10.3389/fgene.2021.685035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312223PMC
July 2021

Report of the Largest Chinese Cohort With Gene Defect and Literature Review.

Front Genet 2021 1;12:683255. Epub 2021 Jul 1.

Department of Neurology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype.
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http://dx.doi.org/10.3389/fgene.2021.683255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281341PMC
July 2021

Mutation spectrum of amyotrophic lateral sclerosis in Central South China.

Neurobiol Aging 2021 Jun 19. Epub 2021 Jun 19.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Laboratory of Medical Genetics, Central South University, Changsha, Hunan, People's Republic of China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, People's Republic of China; National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. Electronic address:

To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.008DOI Listing
June 2021

Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth disease from central south China.

Eur J Neurol 2021 Jul 13. Epub 2021 Jul 13.

Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China.

Background And Purpose: The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China.

Methods: In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis.

Results: Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype.

Conclusions: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.
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http://dx.doi.org/10.1111/ene.15024DOI Listing
July 2021

Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis.

Front Neurol 2021 24;12:628710. Epub 2021 Jun 24.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.
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http://dx.doi.org/10.3389/fneur.2021.628710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264193PMC
June 2021

Supramolecular wrapped sandwich like SW-SiN hybrid sheets as advanced filler toward reducing fire risks and enhancing thermal conductivity of thermoplastic polyurethanes.

J Colloid Interface Sci 2021 Jun 29;603:844-855. Epub 2021 Jun 29.

State Key Laboratory of Fire Science, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei 230026, China. Electronic address:

A sandwich-like melamine/phytic acid/silicon nitride hybrid (SW-SiN) sheets were prepared by supramolecular wrapping as the hybrid flame retardants for thermoplastic polyurethane (TPU). The introduction of SiN sheets as a template could not only induce the generation of two-dimensional phytic/melamine (PAMA) capping layers, but also produce the synergistic flame-retardant effect on TPU composites. Cone test showed that heat release rate (HRR), smoke production rate (SPR) and total smoke production (TSP) values of TPU were decreased obviously by adding SW-SiN. TG-IR test indicated the dramatic inhibition of aromatic compound, hydrocarbons, CO and HCN release. Besides, the thermal conductivity of composites was obviously improved by adding SW-SiN. This work may provide better reference for developing multi-functional TPU composites for diverse application.
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http://dx.doi.org/10.1016/j.jcis.2021.06.153DOI Listing
June 2021

Corrigendum: Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With Mutations Presenting With Leigh/Leigh-Like Syndrome.

Front Pharmacol 2021 10;12:686933. Epub 2021 Jun 10.

Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

[This corrects the article DOI: 10.3389/fphar.2021.605803.].
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http://dx.doi.org/10.3389/fphar.2021.686933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223874PMC
June 2021

The role of frontotemporal dementia associated genes in patients with Alzheimer's disease.

Neurobiol Aging 2021 May 30. Epub 2021 May 30.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China; Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China. Electronic address:

Alzheimer's disease (AD) and frontotemporal dementia (FTD) overlap clinically and pathologically. However, the role of FTD-associated genes in patients with AD remained unclear. To explore the relationship between FTD-associated genes and AD risk, we investigated 14 FTD-associated genes via targeted next-generation sequencing panel or whole-genome sequencing in a total of 721 AD patients and 1391 controls. Common variant-based association analysis and gene-based association test of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal (SKAT-O test) respectively. As a result, 2 common variants, UBQLN1 rs1044175 (p value = 2.76 × 10) and MAPT rs2258689 (p value = 5.71 × 10), differed significantly between AD patients and controls. Additionally, gene-based analysis aggregating rare variants demonstrated that HNRNPA1 reached statistical significance in the SKAT-O test (p value = 2.24 × 10). Protein-protein interaction analysis showed that UBQLN1, MAPT, and HNRNPA1 interacted with proteins encoded by well-recognized AD-associated genes. Our study indicated that UBQLN1, MAPT, and HNRNPA1 are implicated in the pathogenesis of AD in the mainland Chinese population.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.05.016DOI Listing
May 2021

Spin pinning effect to reconstructed oxyhydroxide layer on ferromagnetic oxides for enhanced water oxidation.

Nat Commun 2021 Jun 15;12(1):3634. Epub 2021 Jun 15.

School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore.

Producing hydrogen by water electrolysis suffers from the kinetic barriers in the oxygen evolution reaction (OER) that limits the overall efficiency. With spin-dependent kinetics in OER, to manipulate the spin ordering of ferromagnetic OER catalysts (e.g., by magnetization) can reduce the kinetic barrier. However, most active OER catalysts are not ferromagnetic, which makes the spin manipulation challenging. In this work, we report a strategy with spin pinning effect to make the spins in paramagnetic oxyhydroxides more aligned for higher intrinsic OER activity. The spin pinning effect is established in oxide/oxyhydroxide interface which is realized by a controlled surface reconstruction of ferromagnetic oxides. Under spin pinning, simple magnetization further increases the spin alignment and thus the OER activity, which validates the spin effect in rate-limiting OER step. The spin polarization in OER highly relies on oxyl radicals (O∙) created by 1 dehydrogenation to reduce the barrier for subsequent O-O coupling.
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http://dx.doi.org/10.1038/s41467-021-23896-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206068PMC
June 2021

Mitochondrial genome variations are associated with amyotrophic lateral sclerosis in patients from mainland China.

J Neurol 2021 Jun 15. Epub 2021 Jun 15.

Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, People's Republic of China.

Background: Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS.

Methods: The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants.

Results: A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS.

Conclusions: This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.
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http://dx.doi.org/10.1007/s00415-021-10659-7DOI Listing
June 2021

Identification of a Novel Variant in Causing MELAS.

Front Genet 2021 12;12:638749. Epub 2021 May 12.

Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease. Most cases of MELAS are caused by the m.3243A > G variant in the gene encoding tRNALeu. However, the genetic cause in 10% of patients with MELAS is unknown. We investigated the pathogenicity of the novel mtDNA variant m.9396G > A/ (p.E64K), which affects an extremely conserved amino acid in the CO3 subunit of mitochondrial respiratory chain (MRC) complex IV (CIV) in a patient with MELAS. Biochemical assays of a muscle biopsy confirmed remarkable CIV deficiency, and pathological examination showed ragged red fibers and generalized COX non-reactive muscle fibers. Transfer of the mutant mtDNA into cybrids impaired CIV assembly, followed by remarkable mitochondrial dysfunction and ROS production. Our findings highlight the pathogenicity of a novel m.9396G > A variant and extend the spectrum of pathogenic mtDNA variants.
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http://dx.doi.org/10.3389/fgene.2021.638749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153374PMC
May 2021

Effects of the Medicare Part D comprehensive medication review on medication adherence among patients with Alzheimer's disease.

Curr Med Res Opin 2021 Jun 24:1-8. Epub 2021 Jun 24.

Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA.

Objective: Older patients with Alzheimer's disease (AD) are challenged with adhering to complex medication regimens. We examined effects of Comprehensive Medication Review (CMR), a required Medicare Part D Medication Therapy Management (MTM) program component, on medication adherence among AD patients.

Methods: This retrospective study analyzed 100% of 2016-2017 Medicare claims covering the entire United States, linked to Area Health Resources Files. Medicare beneficiaries aged ≥65 years were included. Propensity score matching identified comparable intervention and comparison groups with the intervention defined as receiving a CMR in 2017. A difference-in-differences analysis included in multivariate logistic regressions an interaction term between CMR receipt and year 2017. The outcome measured was nonadherence to diabetes, hypertension and hyperlipidemia medications, with nonadherence defined as proportion of days covered <80% for study medications.

Results: Unadjusted comparisons indicated the proportion of nonadherence for intervention group members decreased from 2016 to 2017 but increased for the comparison group. In adjusted analyses, reduction in medication nonadherence among the intervention group remained higher: odds ratios for the interaction term were 0.62 (95% confidence interval [CI] = 0.54-0.71), 0.54 (95% CI = 0.50-0.58) and 0.50 (95% CI = 0.47-0.53) respectively for diabetes, hypertension and hyperlipidemia medications. This suggests that the likelihood of nonadherence in the intervention group was respectively reduced by 38%, 46% and 50% more than the comparison group.

Conclusions: CMR was found to reduce nonadherence to diabetes, hypertension and hyperlipidemia medications among older Medicare beneficiaries with AD. This provides evidence that the MTM program is effective for a population with unique medication compliance challenges.
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http://dx.doi.org/10.1080/03007995.2021.1935224DOI Listing
June 2021

Characterizing the seizure onset zone and epileptic network using EEG-fMRI in a rat seizure model.

Neuroimage 2021 08 2;237:118133. Epub 2021 May 2.

Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China; Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing Institute of Brain Disorders, Beijing, China; Neuroelectrophysiological Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China. Electronic address:

Accurate epileptogenic zone (EZ) or seizure onset zone (SOZ) localization is crucial for epilepsy surgery optimization. Previous animal and human studies on epilepsy have reported that changes in blood oxygen level-dependent (BOLD) signals induced by epileptic events could be used as diagnostic markers for EZ or SOZ localization. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) recording is gaining interest as a non-invasive tool for preoperative epilepsy evaluation. However, EEG-fMRI studies have reported inconsistent and ambiguous findings. Therefore, it remains unclear whether BOLD responses can be used for accurate EZ or SOZ localization. In this study, we used simultaneous EEG-fMRI recording in a rat model of 4-aminopyridine-induced acute focal seizures to assess the spatial concordance between individual BOLD responses and the SOZ. This was to determine the optimal use of simultaneous EEG-fMRI recording in the SOZ localization. We observed a high spatial consistency between BOLD responses and the SOZ. Further, dynamic BOLD responses were consistent with the regions where the seizures were propagated. These results suggested that simultaneous EEG-fMRI recording could be used as a noninvasive clinical diagnostic technique for localizing the EZ or SOZ and could be an effective tool for mapping epileptic networks.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118133DOI Listing
August 2021

The role of NOTCH3 variants in Alzheimer's disease and subcortical vascular dementia in the Chinese population.

CNS Neurosci Ther 2021 Aug 4;27(8):930-940. Epub 2021 May 4.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Aims: NOTCH3 gene mutations predominantly cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a common etiology of subcortical vascular dementia (SVaD). Besides, there may be a pathogenic link between NOTCH3 variants and Alzheimer's disease (AD). We aimed to study the role of NOTCH3 variants in AD and SVaD patients.

Methods: We recruited 763 patients with dementia (667 AD and 96 SVaD) and 365 healthy controls from the Southern Han Chinese population. Targeted capture sequencing was performed on NOTCH3 coding and adjacent intron regions to detect the pathogenic variants in AD and SVaD. The relationship between common or rare NOTCH3 variants and AD was further analyzed using Plink1.9.

Results: Five known pathogenic variants (p.R182C, p.C201S, p.R544C, p.R607C, and p.R1006C) and two novel likely pathogenic variants (p.C201F and p.C1061F) were detected in 16 SVaD patients. Additionally, no pathogenic or likely pathogenic variants were found in AD patients. NOTCH3 was not associated with AD in either single-variant association analysis or gene-based association analysis.

Conclusion: Our findings broaden the mutational spectrum of NOTCH3 and validate the pathogenic role of NOTCH3 mutations in SVaD, but do not support the notion that NOTCH3 variation influences the risk of AD.
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http://dx.doi.org/10.1111/cns.13647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265940PMC
August 2021

Arginyltransferase (Ate1) regulates the RGS7 protein level and the sensitivity of light-evoked ON-bipolar responses.

Sci Rep 2021 Apr 30;11(1):9376. Epub 2021 Apr 30.

Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Regulator of G-protein signaling 7 (RGS7) is predominately present in the nervous system and is essential for neuronal signaling involving G-proteins. Prior studies in cultured cells showed that RGS7 is regulated via proteasomal degradation, however no protein is known to facilitate proteasomal degradation of RGS7 and it has not been shown whether this regulation affects G-protein signaling in neurons. Here we used a knockout mouse model with conditional deletion of arginyltransferase (Ate1) in the nervous system and found that in retinal ON bipolar cells, where RGS7 modulates a G-protein to signal light increments, deletion of Ate1 raised the level of RGS7. Electroretinographs revealed that lack of Ate1 leads to increased light-evoked response sensitivities of ON-bipolar cells, as well as their downstream neurons. In cultured mouse embryonic fibroblasts (MEF), RGS7 was rapidly degraded via proteasome pathway and this degradation was abolished in Ate1 knockout MEF. Our results indicate that Ate1 regulates RGS7 protein level by facilitating proteasomal degradation of RGS7 and thus affects G-protein signaling in neurons.
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http://dx.doi.org/10.1038/s41598-021-88628-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087773PMC
April 2021

Genetic effect of C677T, A1298C, and A1793G polymorphisms on the age at onset, plasma homocysteine, and white matter lesions in Alzheimer's disease in the Chinese population.

Aging (Albany NY) 2021 04 4;13(8):11352-11362. Epub 2021 Apr 4.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Background: Three polymorphisms in the gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population.

Method: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients.

Results: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls ( = 0.040), while no statistical difference was observed in A1298C and A1793G ( > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls ( = 0.021, = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers ( = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers ( = 0.034, = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level ( = 0.036) and higher Fazekas score ( = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score ( = 0.013).

Conclusions: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.
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http://dx.doi.org/10.18632/aging.202827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109119PMC
April 2021

Mosaic ring chromosome 18 in a Chinese child with epilepsy: a case report and review of the literature.

Neurol Sci 2021 Apr 8. Epub 2021 Apr 8.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Background: Ring chromosome 18 (r[18]) is a rare syndrome in which one or both ends of chromosome 18 are lost and the remaining chromosome rejoins to form ring-shaped figures. It is characterized by developmental delay/cognitive disability, facial dysmorphisms, and immunological problems. The phenotype associated with epilepsy is rare and has not yet been reported in China.

Methods: We report herein the case of a 12-year-old Chinese girl who presented with typical facial dysmorphisms, developmental delay, cognitive disability, hyperactivity, and epilepsy and discuss the clinical features of r(18) syndromes through comparison with previously described cases worldwide.

Results: We describe the characteristics of all seizures that have been reported in these cases and propose that the appearance of epilepsy in r(18) patients may be associated with the abnormality of chromosome karyotypes. Further studies are warranted to confirm this.
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http://dx.doi.org/10.1007/s10072-021-05143-zDOI Listing
April 2021

Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With Mutations Presenting With Leigh/Leigh-Like Syndrome.

Front Pharmacol 2021 8;12:605803. Epub 2021 Mar 8.

Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

3-Hydroxyisobutyryl-CoA hydrolase (, NM_014362.3) gene mutation can cause HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series have investigated the relationship between metabolites and clinical phenotypes or the effects of treatment, although 34 patients with mutations from 27 families have been reported. The purpose of this study was to analyze the phenotypic spectrum, follow-up results, metabolites, and genotypes of patients with HIBCH deficiency presenting with Leigh/Leigh-like syndrome and explore specific metabolites related to disease diagnosis and prognosis through retrospective and longitudinal studies. Applying next-generation sequencing, we identified eight patients with mutations from our cohort of 181 cases of genetically diagnosed Leigh/Leigh-like syndrome. Six novel mutations were identified: c.977T>G [p.Leu326Arg], c.1036G>T [p.Val346Phe], c.750+1G>A, c.810-2A>C, c.469C>T [p.Arg157*], and c.236delC [p.Pro79Leufs*5]. The Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) was employed to assess disease progression and clinical outcomes. The non-invasive approach of metabolite analysis showed that levels of some were associated with clinical phenotype severity. Five (5/7) patients presented with elevated C4-OH in dried blood spots, and the level was probably correlated with the NPMDS scores during the peak disease phase. 2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients and elevated S-(2-caboxypropyl)cysteamine in urine was found in three patients (3/3). The median age at initial presentation was 13 months (8-18 months), and the median follow-up was 2.3 years (range 1.3-7.2 years). We summarized and compared with all reported patients with mutations. The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties. We administered drug and dietary treatment. During follow-up, five patients responded positively to treatment with a significant decrease in NPMDS scores. Our research is the largest case series of patients with mutations.
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http://dx.doi.org/10.3389/fphar.2021.605803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982470PMC
March 2021

Downregulation of TOP2 modulates neurodegeneration caused by GGGGCC expanded repeats.

Hum Mol Genet 2021 May;30(10):893-901

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.
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http://dx.doi.org/10.1093/hmg/ddab079DOI Listing
May 2021

Earlyonset familial Alzheimers disease in a family with mutation of presenilin 2 gene.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021 Feb;46(2):189-194

Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2021.190616DOI Listing
February 2021

Low molecular weight-PAHs induced inflammation in A549 cells by activating PI3K/AKT and NF-κB signaling pathways.

Toxicol Res (Camb) 2021 Jan 25;10(1):150-157. Epub 2021 Jan 25.

Department of Toxicology, School of Public Health, Lanzhou University, No. 199 Donggang West Road, Lanzhou 730000, Gansu, China.

Our previous study has demonstrated that two low molecular weight-polycyclic aromatic hydrocarbons (LMW-PAHs), phenanthrene (Phe) and fluorene (Flu), alone and as a mixture could induce oxidative damage and inflammation in A549 cells. However, the associated mechanisms have not been well discussed. The aim of this study was to further investigate the roles of PI3K/AKT and NF-κB signaling pathways in the inflammatory effects in A549 cells induced by Phe, Flu and their mixture. The results indicated that Phe, Flu and their mixture significantly activated PI3K/AKT and NF-κB signaling pathways by increasing the phosphorylation levels of PI3K, AKT, IκBα and NF-κB p65. In addition, pro-inflammatory cytokine expressions of TNF-α and IL-6 induced by the binary mixture of Phe and Flu were all alleviated by co-treatment with PI3K/AKT and NF-κB specific inhibitors (LY294002 and BAY11-7082). The results suggested that PI3K/AKT and NF-κB signaling pathways played an important role in LMW-PAHs induced inflammation in A549 cells.
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http://dx.doi.org/10.1093/toxres/tfaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885328PMC
January 2021

Upregulated Expression of Toll-Like Receptor 7 in Peripheral Blood Basophils of Patients With Allergic Rhinitis.

Am J Rhinol Allergy 2021 Feb 8:1945892421993034. Epub 2021 Feb 8.

Department of Immunology, Translational Medicine Institute, Shenyang Medical College, Shenyang, China.

Background: Recently, it has been reported that Toll-like receptor 7 (TLR7) agonists can improve allergic rhinitis (AR) symptoms by up-regulation of Th1 cytokine release and suppression of Th2 cell functions. However, little is known of the expression of TLR7 in basophils of AR.

Objective: To explore the expression of TLR7 in basophils of AR, and influence of allergens on TLR7 expression.

Methods: The expression levels of TLR7 in basophils of patients with AR were determined by flow cytometry, and the influence of allergens on TLR7 expression was examined by real time (q) PCR.

Results: The percentages of TLR7CCR3 cells ( < 0.001 and  = 0.011), TLR7CD123HLA-DR cells ( = 0 .016 and  = 0.042) and TLR7CCR3CD123HLA-DR cells ( = 0.046 and  = 0.035) in blood granulocyte and mononucleated cell populations of the patients with AR were increased, respectively compared with HC subjects. TLR7 MFI on CCR3 cells ( = 0.050 and  = 0.043), CD123HLA-DR cells ( < 0.001 and  = 0.002) and CCR3CD123HLA-DR cells ( < 0.001 and  = 0.003) were enhanced compared with HC subjects. Allergens Der p1 and OVA provoked upregulation of TLR7 expression at both protein and mRNA levels and IL-13 production in KU812 cells. House Dust Mite extract (HDME), Artemisia sieversiana wild allergen extract (ASWE), IL-31, IL-33, IL-37, and TSLP provoked elevation of IL-6 release from KU812 cells following 2 h incubation period.

Conclusions: The percentage of TLR7 basophils and TLR7 expression intensity in a single basophil are both increased in the blood of patients with AR, indicating that basophils likely contribute to the pathogenesis of AR via TLR7.
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http://dx.doi.org/10.1177/1945892421993034DOI Listing
February 2021

Ferroelastic-switching-driven large shear strain and piezoelectricity in a hybrid ferroelectric.

Nat Mater 2021 May 11;20(5):612-617. Epub 2021 Jan 11.

School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore.

Materials that can produce large controllable strains are widely used in shape memory devices, actuators and sensors, and great efforts have been made to improve the strain output. Among them, ferroelastic transitions underpin giant reversible strains in electrically driven ferroelectrics or piezoelectrics and thermally or magnetically driven shape memory alloys. However, large-strain ferroelastic switching in conventional ferroelectrics is very challenging, while magnetic and thermal controls are not desirable for practical applications. Here we demonstrate a large shear strain of up to 21.5% in a hybrid ferroelectric, CHN(CH)CdCl, which is two orders of magnitude greater than that in conventional ferroelectric polymers and oxides. It is achieved by inorganic bond switching and facilitated by structural confinement of the large organic moieties, which prevents undesired 180° polarization switching. Furthermore, Br substitution can soften the bonds, allowing a sizable shear piezoelectric coefficient (d ≈ 4,830 pm V) at the Br-rich end of the solid solution, CHN(CH)CdBrCl. The electromechanical properties of these compounds suggest their potential in lightweight and high-energy-density devices, and the strategy described here could inspire the development of next-generation piezoelectrics and electroactive materials based on hybrid ferroelectrics.
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http://dx.doi.org/10.1038/s41563-020-00875-3DOI Listing
May 2021

Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy.

Mitochondrion 2021 03 2;57:222-229. Epub 2021 Jan 2.

Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. Electronic address:

Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities is an extremely rare autosomal recessive mitochondrial disease caused by biallelic mutations in MECR. Using whole-exome sequencing, we identified a novel homozygous MECR mutation (c.910G > T, p.Asp304Tyr) in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy. With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed. To our knowledge, this is the first study about MECR-related mitochondrial disease in a Chinese patient and the first to report that supplementation with lipoic acid is a possible effective therapeutic strategy for this disease.
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http://dx.doi.org/10.1016/j.mito.2020.12.014DOI Listing
March 2021

Hepatocyte CD1d protects against liver immunopathology in mice with schistosomiasis japonica.

Immunology 2021 Mar 22;162(3):328-338. Epub 2020 Dec 22.

Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, China.

Schistosomiasis is a neglected tropical disease with over 250 million people infected worldwide. The main clinically important species Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum) cause inflammatory responses against tissue-trapped eggs, resulting in formation of granulomas mainly in host liver. Persistent granulomatous response results in severe fibrosis in the liver, leading to irreversible impairment of the liver and even death of the host. CD1d, a highly conserved MHC class I-like molecule, is expressed by both haematopoietic and non-haematopoietic cells. CD1d on antigen-presenting cells (APCs) of haematopoietic origin presents pathogen-derived lipid antigens to natural killer T (NKT) cells, which enables them to rapidly produce large amounts of various cytokines and facilitate CD4 T helper (Th) cell differentiation upon invading pathogens. Noteworthy, hepatocytes of non-haematopoietic origin have recently been shown to be involved in maintaining liver NKT cell homeostasis through a CD1d-dependent manner. However, whether hepatocyte CD1d-dependent regulation of NKT cell homeostasis also modulates CD4 Th cell responses and liver immunopathology in murine schistosomiasis remains to be addressed. Here, we show in mice that CD1d expression on hepatocytes was decreased dramatically upon S. japonicum infection, accompanied by increased NKT cells, as well as upregulated Th1 and Th2 responses. Overexpression of CD1d in hepatocytes significantly decreased local NKT numbers and cytokines (IFN-γ, IL-4, IL-13), concomitantly with downregulation of both Th1 and Th2 responses and alleviation in pathological damage in livers of S. japonicum-infected mice. These findings highlight the potential of hepatocyte CD1d-targeted therapies for liver immunopathology control in schistosomiasis.
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http://dx.doi.org/10.1111/imm.13288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884646PMC
March 2021

Racial/ethnic disparities in measure calculations for Part D Star Ratings among Medicare beneficiaries with diabetes, hypertension, and/or hyperlipidemia.

Res Social Adm Pharm 2021 08 10;17(8):1469-1477. Epub 2020 Nov 10.

Department of Clinical Pharmacy and Translational Science, University of Tennessee College of Pharmacy, 881 Madison Avenue, Room 221, Memphis, TN, 38163, United States. Electronic address:

Background: Previous literature reported racial/ethnic disparities in the measure assessment of diabetes medication adherence in the Medicare Part D Star Ratings program.

Objective: This study examined the likelihood of inclusion in measure calculation across racial/ethnic groups for adherence metrics in Part D Star Ratings among individuals with diabetes, hypertension, and/or hyperlipidemia.

Methods: This was a retrospective cross sectional analysis of a 10% random sample of 2017 Medicare claims linked to Area Health Resources Files. Inclusion in measure calculation was determined based on inclusion/exclusion criteria in adherence metrics for adherence medications for diabetes, hypertension, and hyperlipidemia in Part D Star Ratings developed by the Pharmacy Quality Alliance. Logistic regression and multinomial logistic regression were used to adjust for patient/community characteristics.

Results: The study sample size was 2 707 216. Compared to Non-Hispanic White (White) beneficiaries, minorities were more likely to be excluded from measure calculation among individuals with 1 condition. For example, among individuals with hypertension, compared to White individuals, the adjusted odds ratios for exclusion for Black, Hispanic, Asian/Pacific Islander and other individuals were 1.46 (95% confidence interval, or CI = 1.42-1.50), 1.38 (95% CI = 1.33-1.43), 1.28 (95% CI = 1.21-1.35), and 1.08 (95% CI = 1.02-1.15), respectively. Among individuals with more than 1 chronic condition, minorities were more likely to be included in fewer calculations for medication adherence measures. For example, among individuals with all 3 conditions, the adjusted relative risk ratios for Black, compared to White, beneficiaries for being included in 0, 1, and 2 measures, versus all 3 measures, were 2.14 (95% CI = 1.99-2.30), 1.49 (95% CI = 1.41-1.56), 1.20 (95% CI = 1.18-1.23), respectively.

Conclusions: Compared to White beneficiaries, racial/ethnic minorities are more likely to be excluded from the calculation for adherence measures among individuals with diabetes, hypertension, and/or hyperlipidemia. Future studies should examine whether such disparities exacerbate existing racial/ethnic disparities in health outcomes and devise solutions for these disparities.
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http://dx.doi.org/10.1016/j.sapharm.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107189PMC
August 2021

Upregulation of the expression of Toll-like receptor 9 in basophils in patients with allergic rhinitis: An enhanced expression by allergens.

Scand J Immunol 2021 Mar 11;93(3):e13003. Epub 2020 Dec 11.

Department of Pathophysiology, Translational Medicine Institute, Shenyang Medical College, Shenyang, China.

It was reported that the expression of Toll-like receptor (TLR) 9 may be related to Th2-type allergic inflammation including allergic rhinitis (AR). However, little is known about the expression of TLR9 in the basophils in AR. In the present study, the expression of TLR9 was examined by flow cytometry analysis, and the expression of TLR9 mRNA in KU812 was determined by quantitative real-time PCR. The results showed that the percentage of TLR9 CCR3 cells in blood granulocytes increased by 46% in patients with AR, but not in peripheral blood mononuclear cells (PBMCs). Allergens namely Dermatophagoide allergen extract (DAE) and Platanus pollen allergen extract (PPAE) upregulated the expression of TLR9 in CCR3 granulocytes by 76% and 84%, respectively. DAE and PPAE also enhanced the proportions of TLR9 CD123 HLA-DR cells and TLR9 CCR3 CD123 HLA-DR cells in granulocytes and PBMCs of patients with AR. In order to investigate the actions of allergens on basophils, KU812 cells were used. It was observed that all KU812 cells expressed TLR9, and the expression intensity of TLR9 in a single KU812 cell was elevated by CpG. IL-37, IL-31, IL-33, Artemisia sieversiana wild allergen extract (ASWAE), DAE, OVA and Der p 1 induced an increase in the expression of TLR9 mRNA and IL-6 production in KU812 cells. It was shown that the percentage of TLR9-expressing basophils increased in the blood of ovalbumin (OVA)-sensitized mice. In conclusion, an increased expression of TLR9 and the production of IL-6 in basophils implicate that the contribution of basophils to AR is likely via TLR9.
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http://dx.doi.org/10.1111/sji.13003DOI Listing
March 2021
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