Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon-level Array, and RNA sequencing.

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.

Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation.

OBJECTIVES: Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes. METHODS: We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial. RESULTS: Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-ß, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54. CONCLUSIONS: Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.

Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.

Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for a panel of genes implicated in peroxisomal diseases are critical tools for the early and accurate detection of these disorders. It is therefore essential to evaluate the clinical validity of the genes included in sequencing panels for peroxisomal disorders. The Peroxisomal Gene Curation Expert Panel (GCEP) assessed genes frequently included on clinical peroxisomal testing panels using the Clinical Genome Resource (ClinGen) gene-disease validity curation framework and classified gene-disease relationships as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. Subsequent to gene curation, the GCEP made recommendations to update the disease nomenclature and ontology in the Monarch Disease Ontology (Mondo) database. Thirty-six genes were assessed for the strength of evidence supporting their role in peroxisomal disease, leading to 36 gene-disease relationships, after two genes were removed for their lack of a role in peroxisomal disease and two genes were curated for two different disease entities each. Of these, 23 were classified as Definitive (64%), one as Strong (3%), eight as Moderate (23%), two as Limited (5%), and two as No known disease relationship (5%). No contradictory evidence was found to classify any relationships as Disputed or Refuted. The gene-disease relationship curations are publicly available on the ClinGen website (https://clinicalgenome.org/affiliation/40049/). The changes to peroxisomal disease nomenclature are displayed on the Mondo website (http://purl.obolibrary.org/obo/MONDO_0019053). The Peroxisomal GCEP-curated gene-disease relationships will inform clinical and laboratory diagnostics and enhance molecular testing and reporting. As new data will emerge, the gene-disease classifications asserted by the Peroxisomal GCEP will be re-evaluated periodically.

Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.

Conversion of drylands to paddy fields on former wetlands restores soil organic carbon by accumulating labile carbon fractions in the Sanjiang Plain, northeast China.

BACKGROUND: Since the 1990s, drylands have been extensively converted to rice paddy fields on the former wetlands in the Sanjiang Plain of northeast China. However, the influence of this successiveland-use change from native wetlands to drylands to rice paddy fields on soil organic carbon (C) dynamics remains unexplored. Here, we compared the difference in soil organic C stock among native wetlands, drylands, and paddy fields, and then used a two-step acid hydrolysis approach to examine the effect of this land-use change on labile C I (LPI-C), labile C II (LPII-C), and recalcitrant C (RP-C) fractions at depths of 0-15 cm, 15-30 cm, and 30-50 cm. RESULTS: Soil organic C stock at a depth of 0-50 cm was reduced by 79% after the conversion of wetlands to drylands but increased by 24% when drylands were converted to paddy fields. Compared with wetlands, paddy fields had 74% lower soil organic C stock at a depth of 0-50 cm. The conversion of wetlands to drylands reduced the concentrations of LPI-C, LPII-C, and RP-C fractions at each soil depth. However, land-use change from drylands to paddy fields only increased the concentrations of LPI-C and LPII-C fractions at the 0-15 cm and 30-50 cm depths. CONCLUSION: The conversion of drylands to paddy lands on former wetlands enhances the soil organic C stock by promoting labile C fraction accumulation, and labile C fractions are more sensitive to this successive land-use change than recalcitrant C fractions in the Sanjiang Plain of northeast China. © 2022 Society of Chemical Industry.

Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database.

The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma (MTC) onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature. The classifications for the 166 single unique variants in the MEN2 RET database were reanalyzed using the MEN2 RET specifically modified ACMG/AMP classification guidelines (version 1). Applying these guidelines added two new variant classifications to the database (likely benign and likely pathogenic) and resulted in clinically significant classification changes (e.g., from pathogenic to uncertain) in 15.7% (26/166) of the original variants. Of those clinically significant changes, the highest percentage of changes, 46.2% (12/26), were changes from uncertain to benign or likely benign. The modified ACMG/AMP criteria with MEN2 RET specifications will optimize and standardize RET variant classifications.

De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder.

TATA-binding protein associated factor 4 (TAF4) is a subunit of the Transcription Factor IID (TFIID) complex, a central player in transcription initiation. Other members of this multimeric complex have been implicated previously as monogenic disease genes in human developmental disorders. TAF4 has not been described to date as a monogenic disease gene. We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD). Common features include intellectual disability, abnormal behavior, and facial dysmorphisms. We propose TAF4 as a novel dominant disease gene for NDD, and coin this novel disorder "TAF4-related NDD" (T4NDD). We place T4NDD in the context of other disorders related to TFIID subunits, revealing shared features of T4NDD with other TAF-opathies.

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Evaluating use of changing technologies for rapid next-generation sequencing in pediatrics.

BACKGROUND: Rapid next-generation sequencing (NGS) offers the potential to shorten the diagnostic process and improve the care of acutely ill children. The goal of this study was to report our findings, including benefits and limitations, of a targeted NGS panel and rapid genome sequencing (rGS) in neonatal and pediatric acute clinical care settings. METHODS: Retrospective analysis of patient characteristics, diagnostic yields, turnaround time, and changes in management for infants and children receiving either RapSeq, a targeted NGS panel for 4500+ genes, or rGS, at the University of Utah Hospital and Primary Children's Hospital, from 2015 to 2020. RESULTS: Over a 5-year period, 142 probands underwent rapid NGS: 66 received RapSeq and 76 rGS. Overall diagnostic yield was 39%. In the majority of diagnostic cases, there were one or more changes in clinical care management. Of note, 7% of diagnoses identified by rGS would not have been identified by RapSeq. CONCLUSIONS: Our results indicate that rapid NGS impacts acute pediatric care in real-life clinical settings. Although affected by patient selection criteria, diagnostic yields were similar to those from clinical trial settings. Future studies are needed to determine relative advantages, including cost, turnaround time, and benefits for patients, of each approach in specific clinical circumstances. IMPACT: The use of comprehensive Mendelian gene panels and genome sequencing in the clinical setting allows for early diagnosis of patients in neonatal, pediatric, and cardiac intensive care units and impactful change in management. Diagnoses led to significant changes in management for several patients in lower acuity inpatient units supporting further exploration of the utility of rapid sequencing in these settings. This study reviews the limitations of comparing sequencing platforms in the clinical setting and the variables that should be considered in evaluating diagnostic rates across studies.

Genetic testing for inherited colorectal cancer and polyposis, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and 30% of all cases of CRC are believed to have a familial component and up to one-third of these (10%) are hereditary. Pathogenic germline variants in multiple genes have been associated with predisposition to hereditary CRC or polyposis. Lynch syndrome (LS) is the most common hereditary CRC syndrome, caused by variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 and is inherited in a dominant manner. Heritable conditions associated with colonic polyposis include familial adenomatous polyposis (FAP) associated with APC pathogenic variants, MUTYH-associated polyposis (MAP) caused by biallelic MUTYH pathogenic variants, and polymerase proofreading-associated polyposis (PPAP) caused by POLE or POLD1 pathogenic variants. Given the overlapping phenotypes of the cancer syndromes along with the limited sensitivity of using clinical criteria alone, a multigene panel testing approach to diagnose these conditions using next-generation sequencing (NGS) is effective and efficient. This technical standard is not recommended for use in the clinic for patient evaluation. Please refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine an appropriate testing strategy and guide medical screening and management. This 2021 edition of the American College of Medical Genetics and Genomics (ACMG) technical standard supersedes the 2013 edition on this topic.

Effects of long-term nitrogen addition on dissolved organic matter characteristics in a temperate wetland of Northeast China.

Dissolved organic matter (DOM) plays an indispensable role in ecosystem services and functions in wetlands. While most wetlands have undergone increased nitrogen (N) loading due to intensive human activities, the response of DOM characteristics to long-term N addition remains unexplored. In this study, we assessed the changes in dissolved organic carbon (DOC), NH4+, NO3-, dissolved organic N (DON), dissolved total N (DTN), and dissolved total phosphorus (DTP) in surface water and soil pore water at 15 cm depth after 10 years of N addition at four levels (0, 60, 120, and 240 kg N hm-2 year-1) in a freshwater marsh of Northeast China. We also examined the effect of N addition on DOM aromaticity and humification by measuring the specific UV absorbance at 254 nm (SUVA254), the color per C unit (C/C ratio), and the fulvic acid/humic acid ratio (E4/E6 ratio). Our results showed that N addition significantly altered DOM properties, but the direction and magnitude of these changes generally did not vary with the N addition level. During the growing season, DOC, NH4+, NO3-, DON, and DTN concentrations in both surface water and soil pore water were increased by N addition. Accordingly, N addition increased the DOC/DTP and DTN/DTP ratios but decreased the DOC/DTN ratio in surface water and soil pore water. In addition, the SUVA254 value and C/C ratio increased, while the E4/E6 ratio reduced after N addition in surface water and soil pore water, indicating increases in DOM aromaticity and humification. These observations suggest that long-term N addition changes DOM characteristics by causing stoichiometric imbalances and increasing recalcitrant compounds in temperate freshwater wetlands, which may then deteriorate water quality, alter microbial-mediated ecological processes, and impact downstream aquatic ecosystem structures.

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.

Mitochondrial DNA (mtDNA) variant pathogenicity interpretation has special considerations given unique features of the mtDNA genome, including maternal inheritance, variant heteroplasmy, threshold effect, absence of splicing, and contextual effects of haplogroups. Currently, there are insufficient standardized criteria for mtDNA variant assessment, which leads to inconsistencies in clinical variant pathogenicity reporting. An international working group of mtDNA experts was assembled within the Mitochondrial Disease Sequence Data Resource Consortium and obtained Expert Panel status from ClinGen. This group reviewed the 2015 American College of Medical Genetics and Association of Molecular Pathology standards and guidelines that are widely used for clinical interpretation of DNA sequence variants and provided further specifications for additional and specific guidance related to mtDNA variant classification. These Expert Panel consensus specifications allow for consistent consideration of the unique aspects of the mtDNA genome that directly influence variant assessment, including addressing mtDNA genome composition and structure, haplogroups and phylogeny, maternal inheritance, heteroplasmy, and functional analyses unique to mtDNA, as well as specifications for utilization of mtDNA genomic databases and computational algorithms.

[Clinical practice guideline for stable chronic obstructive pulmonary disease with traditional Chinese medicine (draft version for comments)].

By referring to the standards and procedures of WHQ Handbook for Guideline Development, under the guidance of relevant laws, regulations, and technical documents, in line with the principle of "evidence-based, consensus-based, experience-based", and based on the best available evidences, fully combined with expert experience and patient preferences, we summarized eight clinical questions in this paper: can traditional Chinese medicine(TCM) treatment improve the clinical symptoms and the degree of dyspnea in patients with stable chronic obstructive pulmonary disease(COPD) Can TCM treatment reduce the number of exacerbations in patients with stable COPD? Can TCM treatment improve the exercise tolerance of patients with stable COPD? Can TCM treatment improve the quality of life of patients with stable COPD? Can TCM treatment delay the decline of lung function in patients with stable COPD? Can TCM treatment improve anxiety and depression in patients with stable COPD? Does the point application therapy benefit patients with stable COPD? Can non-pharmacological treatment benefit patients with stable COPD? Based on these eight clinical problems, the cha-racteristics of TCM itself, and actual clinical situation, the recommendations of TCM to treat the stable COPD were formed in this guideline, with intention to provide advice and guidance to clinicians in the use of TCM to treat stable COPD, to relieve symptoms, improve exercise tolerance, improve health status, prevent disease progression, prevent and treat exacerbations, and improve clinical efficacy. Due to the influence of the user's region, nationality, race and other factors, the implementation of this guideline should be based on the actual situations.

[Editorial explanation for clinical practice guideline for stable chronic obstructive pulmonary disease with traditional Chinese medicine].

As an important auxiliary document in the process of guideline development, the editorial explanation is the extension and complement to the content of the guideline, a basis for fully understanding the technical content of the guideline, an indispensable document for the guideline's traceability. The project team of this guideline, while formulating the Clinical practice guideline for stable chronic obstructive pulmonary disease with traditional Chinese medicine(draft version for comments), also has written the corresponding editorial explanation. In order to enable the relevant medical workers to more accurately understand and apply the guideline, but also to provide readers with a more in-depth understanding of the reasons and processes for the development of the guideline, the paper will give a detailed introduction to the compilation process about the guideline, includes: work overview(project background, task source, drafting and collaboration unit, project team members and their division of labor), main technical content(the basis and principles of guideline development, technical route), main compilation process(the establishment of project team, the formulation of the guideline plan, the project approval and the registration of research programme, the construction of clinical issues and the selection of outcome indicators, evidence search screening and synthesis, evidence evaluation and grading, the formation of recommendations, the writing of exposure draft, external review and self-assessment, etc), expert consensus implementation requirements and measure suggestions(promotion and implementation measures, and post-effect evaluation), other issues need to be explained and so on.

[Systematic review and Meta-analysis on efficacy and safety of Liujunzi Decoction combined with Western medicine for stable chronic obstructive pulmonary disease].

To systematically review the efficacy and safety of Liujunzi Decoction combined with Western medicine in the treatment of stable chronic obstructive pulmonary disease(COPD). Three English databases and four Chinese databases were systematically searched from the database establishment to April 1, 2020. We screened randomized controlled trial(RCT) according to the pre-determined inclusion and exclusion criteria, then extracted data. Methodological quality of included studies was assessed with Cochrane bias risk evaluation tool. Data were analyzed by using RevMan 5.3. A total of 401 articles were retrieved and finally 17 RCTs were included in this study, involving 1 447 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in reducing traditional Chinese medicine symptom score, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing the grade of modified medical research council(mMRC), Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing COPD assessment test(CAT) score, Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone. In delaying the decline of forced expiratory volume in one second(FEV_1) or % in the expected value, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In delaying the decline of ratio of FEV_1 to forced vital capacity(FEV_1/FVC), Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone, but there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing acute exacerbation rate, there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. On the other outcome measures of Liujunzi Decoction combined with other Western medicine, Meta-analysis could not be conducted and conclusions due to the inclusion of only one study. In terms of the occurrence of adverse reactions, some studies did not mention, so the safety of Liujunzi Decoction combined with Wes-tern medicine could not be determined in this paper. Due to the limitations of the quality and quantity of inclu-ded studies, the efficacy of Liujunzi Decoction combined with Western medicine for COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

[Systematic review and Meta-analysis on efficacy and safety of Buzhong Yiqi Decoction for stable chronic obstructive pulmonary disease].

To systematically review the efficacy and safety of Buzhong Yiqi Decoction in the treatment of stable chronic obstructive pulmonary disease(COPD) at the stable stage. Three English databases and four Chinese databases were systematically searched from the database establishment to August 1, 2020. Randomized controlled trials(RCTs) were screened according to the pre-determined inclusion and exclusion criteria, and then the data were extracted. Methodological quality of the included studies was assessed based on Cochrane bias risk tool, and RevMan 5.3 was used for data analysis. A total of 389 articles were retrieved and finally 18 RCTs were included in this study, involving 1 566 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in terms of improving 6-minute walk distance(6 MWD), and delaying the decline of forced expiratory volume in one second(FEV_1) or its % in the expected value as well as the decline in ratio of FEV_1 to forced vital capacity(FVC), Buzhong Yiqi Decoction alone or in combination with conventional Western medicine was superior to conventional therapy Western medicine alone. Subgroup analysis showed that, in terms of reducing traditional Chinese medicine symptom scores, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of reducing the grade of modified medical research council(mMRC), Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of improving 6 MWD, Buzhong Yiqi Decoction combined with conventional treatment or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment alone or Tiotropium Bromide Powder for Inhalation alone. In terms of delaying the decline of FEV_1 or its % in the expected value, Buzhong Yiqi Decoction combined with conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation alone, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. In terms of delaying the decline in FEV_1/FVC, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. Meta-analysis of other outcome measures was not available and no conclusion can be drawn due to the inclusion of only one study. As some studies did not mention the adverse reactions, no safety comments can be made for Buzhong Yiqi Decoction alone or combined with conventional Western medicine. Due to the limitations of the quality and quantity of included studies, the conclusions of this research should be treated with caution. The efficacy of Buzhong Yiqi Decoction for stable COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

[Analysis of acupoint selection of plaster therapy in treatment of stable chronic obstructive pulmonary disease based on data mining].

This article analyze acupoint selection and characteristics of plaster therapy for stable chronic obstructive pulmonary di-sease(COPD) by data mining. The CNKI, VIP, CBM, WanFang, PubMed, EMbase, Cochrane Library were retrieved for collecting clinical studies of plaster therapy for stable COPD. After literature screening, a total of 46 systematic reviews were included. Frequency statistics, cluster analysis, and Apriori correlation analysis were used to analyze the pattern and characteristics of plaster therapy for stable COPD. The result showed that the main acupoints for stable COPD were BL13, Dingchuan, CV22, BL23 and BL20. The acupoints used are mainly concentrated on the chest and back. The most frequently used meridian is the bladder meridian. Analysis of the acupoints yielded 27 correlation rules. And cluster analysis grouped the high frequency acupoints into 5 categories. The results of the study showed that the current choice of acupoints is rather concentrated. "Local acupuncture points" and "matching points with front and back" were the main acupoint selection rules. The choice of acupuncture points reflected the traditional Chinese medicine treatment principle of strengthening healthy Qi to eliminate pathogenic factor, treating both manifestation and root cause of disease, and preventing measure taken after the occurrence of disease.

Circulating plasmablasts are elevated and produce pathogenic anti-endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating pulmonary vascular disease in which autoimmune and inflammatory phenomena are implicated. B cells and autoantibodies have been associated with IPAH and identified as potential therapeutic targets. However, the specific populations of B cells involved and their roles in disease pathogenesis are not clearly defined. We aimed to assess the levels of activated B cells (plasmablasts) in IPAH, and to characterize recombinant antibodies derived from these plasmablasts. Blood plasmablasts are elevated in IPAH, remain elevated over time, and produce IgA autoantibodies. Single-cell sequencing of plasmablasts in IPAH revealed repertoires of affinity-matured antibodies with small clonal expansions, consistent with an ongoing autoimmune response. Recombinant antibodies representative of these clonal lineages bound known autoantigen targets and displayed an unexpectedly high degree of polyreactivity. Representative IPAH plasmablast recombinant antibodies stimulated human umbilical vein endothelial cells to produce cytokines and overexpress the adhesion molecule ICAM-1. Together, our results demonstrate an ongoing adaptive autoimmune response involving IgA plasmablasts that produce anti-endothelial cell autoantibodies in IPAH. These antibodies stimulate endothelial cell production of cytokines and adhesion molecules, which may contribute to disease pathogenesis. These findings suggest a role for mucosally-driven autoimmunity and autoimmune injury in the pathogenesis of IPAH.

Misattributed parentage as an unanticipated finding during exome/genome sequencing: current clinical laboratory practices and an opportunity for standardization.

PURPOSE: Clinical laboratories performing exome or genome sequencing (ES/GS) are familiar with the challenges associated with proper consenting for and reporting of medically actionable secondary findings based on recommendations from the American College of Medical Genetics and Genomics (ACMG). Misattributed parentage is another type of unanticipated finding a laboratory may encounter during family-based ES/GS; however, there are currently no professional recommendations related to the proper consenting for and reporting of misattributed parentage encountered during ES/GS. METHODS: We surveyed 10 clinical laboratories offering family-based ES/GS regarding their consent language, discovery, and reporting of misattributed parentage. RESULTS: Many laboratories have already developed their own practices/policies for these issues, which do not necessarily agree with those from other labs. CONCLUSION: There are several other possibilities besides true misattributed parentage that could result in similar laboratory findings, and laboratories often feel they lack sufficient information to make formal conclusions on a report regarding the true genetic relatedness of the submitted samples. However, understanding the genetic relatedness (or lack thereof) of the samples submitted for family-based ES/GS has medical relevance. Therefore, professional recommendations for the appropriate handling of suspected misattributed parentage encountered during ES/GS are needed to help standardize current clinical laboratory practices.

Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future.

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.