A rapid and simple endoscopic resection of gastric fundus submucosal tumors.

A 56-year-old male patient was diagnosed with a submucosal tumor in the fundus of the stomach. The conventional operation method is endoscopic submucosal dissection. We present a case of rapid tumor resection without employing traditional endoscopic submucosal dissection instruments such as a mucotomy knife and endoscopic injection needle, resulting in substantial cost savings for the patients.

Campanophyllummicrosporum (Agaricales, Agaricomycetes), Caloceramultiramosa, and Dacrymycesnaematelioides (Dacrymycetales, Dacrymycetes), three new species from Yunnan Province, southwestern China.

Three new species belonging to Basidiomycota from southwestern China are described based on morphological and molecular data. Campanophyllummicrosporum is morphologically characterized by dorsally pseudostipitate, pale orange to brownish orange pileus, excentric to lateral pseudostipe, crowded lamellae, cylindrical-ellipsoid basidiospores 3.0-4.2 × 1.7-2.2 µm, narrowly clavate to clavate basidia 14.5-23.0 × 3.0-4.2 µm, and cylindrical to clavate cheilocystidia 22.0-55.0 × 5.0-10.8 µm. Caloceramultiramosa is morphologically characterized by stipitate, yellowish to orange, dendroid, and dichotomously branched basidiomata, cylindrical to clavate basidia 36.5-52.5 × 3.8-6.1 µm, navicular or reniform, 1-5-septate mature basidiospores 10.4-16.7 × 5.2-7.4 µm. Dacrymycesnaematelioides is morphologically characterized by stipitate and cerebriform, orange to light brown basidiomata, cylindrical to clavate, smooth or roughened basidia 38.5-79.5 × 6.5-10.6 µm, broadly and elliptic-fusiform, 7-septate mature basidiospores 18.5-28.6 × 8.9-13.8 µm. These three new species are supported by the phylogenetic analyses using maximum likelihood (ML) and Bayesian inference (BI) analyses with combined nuclear ribosomal DNA (rDNA) internal transcribed spacer (ITS) and large ribosomal subunit (LSU) sequences. Full descriptions and photographs of these new species are provided.

The effects of baicalin in depression: preclinical evidence construction based on meta-analysis.

Background: Depression manifests as a mental disorder characterized by a low mood, suicidal tendencies, disturbances in sleep-wake cycles, psychomotor agitation, and pronounced feelings of hopelessness and anhedonia. Baicalin, a natural flavonoid compound, shows significant promise in alleviating depressive symptoms in animals. This study aims to assess the impact of baicalin on experimental models of depression. Methods: A systematic search of electronic databases was conducted using the search terms "baicalin" AND "depression" OR "depressed" OR "anti-depression". Preclinical animal models representing experimental depression were included in the analysis. The risk of bias in the included studies was evaluated using the CAMARADES tools. Results: Baicalin significantly increased sucrose preference test (SPT) [SMD= 21.31, 95%CI (16.32, 26.31), P < 0.00001]. mThe tail suspension test (TST) duration significantly decreased in the baicalin group compared to the model group [SMD = -39.3, 95%CI (-49.71, -28.89), P < 0.0001]. Furthermore, baicalin reduced immobility time in rats subjected to the forced swim test (FST) [SMD = -39.73, 95%CI (-48.77, -30.69) P < 0.0001]. Compared to the model group, baicalin treatment also significantly increased the frequency of crossings in the open field test (OFT) [SMD = 32.44, 95%CI (17.74, 47.13), P < 0.00001]. Conclusion: Baicalin significantly improves the manifestations of depressive symptoms. The effect of baicalin against depression is exerted through its anti-inflammatory actions, inhibition of oxidative stress, regulation of the HPA axis, and restoration of neuroplasticity. Future studies will be needed to further explore how these promising preclinical findings can be translated into clinical treatment for depression. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023472181.

Scientific misconduct responsibility attribution: An empirical study on byline position and team identity in Chinese medical papers.

OBJECTIVE: The primary objective of this inquiry was to explore the nexus between authorship attribution in medical literature and accountability for scientific impropriety while assessing the influence of authorial multiplicity on the severity of sanctions imposed. METHODS: Probit regression models were employed to scrutinize the impact of authorship on assuming accountability for scientific misconduct, and unordered multinomial logistic regression models were used to examine the influence of authorship and the number of bylines on the severity of punitive measures. RESULTS: First authors and corresponding authors were significantly more likely to be liable for scientific misconduct than other authors and were more likely to be penalized particularly severely. Furthermore, a negative correlation was observed between the number of authors' affiliations and the severity of punitive measures. CONCLUSION: Authorship exerts a pronounced influence on the attribution of accountability in scientific research misconduct, particularly evident in the heightened risk of severe penalties confronting first and corresponding authors owing to their principal roles. Hence, scientific research institutions and journals must delineate authorship specifications meticulously, ascertain authors' contributions judiciously, bolster initiatives aimed at fostering scientific research integrity, and uphold an environment conducive for robust scientific inquiry.

Chemerin Enhances Migration and Invasion of OC Cells via CMKLR1/RhoA/ROCK-Mediated EMT.

Chemerin is a newly described adipokine with significant effects on obesity, metabolic disorders, and immune trafficking. Recently, chemerin has gained prominence for its potential roles in cancer and tumorigenesis with pro- or antitumor effects. To date, most referenced multifunctions of chemerin are attributed to the chemokine-like receptor 1 (CMKLR1), distributing broadly in many tissues. This study investigates the in vitro roles of chemerin treatment on migration and invasion of ovarian carcinoma cells (OVCAR-3 and SK-OV-3) and potential underlying mechanisms. Herein, exogenous chemerin treatment promotes growth and invasion of SK-OV-3 cells but has no significant effects on OVCAR-3 cells. SK-OV-3 cells undergo morphological elongation characterized by epithelial-to-mesenchymal transition (EMT) and Ras homologous genome members A (RhoA)/Rho protein-related curl spiral kinase-1 (ROCK1) activation. Furthermore, chemerin-enhanced invasion and EMT of SK-OV-3 cells are effectively blocked by C3 transferase (C3T) and Y27632 and RhoA and ROCK1 inhibitor, respectively. More importantly, RhoA/ROCK1-EMT-mediated SK-OV-3 cell invasion is orchestrated by CMKLR1 upregulation after chemerin treatment (50 ng/mL). The silencing of CMKLR1 significantly (P < 0.0001) reverses the chemerin-enhanced invasion, EMT, and RhoA/ROCK1 activation of SK-OV-3 cells. Our study indicates that chemerin promotes invasion of OC cells via CMKLR1-RhoA/ROCK1-mediated EMT, offering a novel potential target for metastasis of OC.

[Genetic Variation of SH2B3 in Patients with Myeloid Neoplasms].

OBJECTIVE: To observe the genetic variation of SH2B3 in patients with myeloid neoplasms. METHODS: The results of targeted DNA sequencing associated with myeloid neoplasms in the Department of Hematology, Xuanwu Hospital, Capital Medical University from November 2017 to November 2022 were retrospectively analyzed, and the patients with SH2B3 gene mutations were identified. The demographic and clinical data of these patients were collected, and characteristics of SH2B3 gene mutation, co-mutated genes and their correlations with diseases were analyzed. RESULTS: The sequencing results were obtained from 1 005 patients, in which 19 patients were detected with SH2B3 gene mutation, including 18 missense mutations (94.74%), 1 nonsense mutation (5.26%), and 10 patients with co-mutated genes (52.63%). Variant allele frequency (VAF) ranged from 0.03 to 0.66. The highest frequency mutation was p.Ile568Thr (5/19, 26.32%), with an average VAF of 0.49, involving 1 case of MDS/MPN-RS (with SF3B1 mutation), 1 case of MDS-U (with SF3B1 mutation), 1 case of aplastic anemia with PNH clone (with PIGA and KMT2A mutations), 2 cases of MDS-MLD (1 case with SETBP1 mutation). The other mutations included p.Ala567Thr in 2 cases (10.53%), p.Arg566Trp, p.Glu533Lys, p.Met437Arg, p.Arg425Cys, p.Glu314Lys, p.Arg308*, p.Gln294Glu, p.Arg282Gln, p.Arg175Gln, p.Gly86Cys, p.His55Asn and p.Gln54Pro in 1 case each. CONCLUSION: A wide distribution of genetic mutation sites and low recurrence of SH2B3 is observed in myeloid neoplasms, among of them, p.Ile568Thr mutation is detected with a higher incidence and often coexists with characteristic mutations of other diseases.

GPX4 allosteric activators inhibit ferroptosis and exert myocardial protection in doxorubicin-induced myocardial injury mouse model.

Ferroptosis is a unique type of non-apoptotic form of cell death characterized by increased lipid hydroperoxide levels. It has relevance for a number of pathological conditions including multiple organ injuries and degenerative diseases. GPX4 plays an important role in ferroptosis by repairing lipid hydroperoxides. Based on the reported allosteric sites, we obtained the GPX4 allosteric activator hit compound A9 through virtual screening. A9 can bind to GPX4 and prevent RSL3-induced lipid peroxidation production in HT-1080 cells. In addition, A9 can specifically rescue erastin-induced cell death. Further chemical modification and structure-activity relationship studies afforded the optimized compound C3. C3 showed the activity of alleviating myocardial injury in the doxorubicin-induced myocardial injury mouse model. This study demonstrated that inhibiting ferroptosis by activating GPX4 is expected to be a potential solution to treat myocardial injury.

Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms.

The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner's fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.

A shape memory cationized chitosan sponge loaded with thrombin for high-effective hemostasis and antibacterial activity.

This study presents a thrombin-loaded cationized chitosan (TCCS) sponge with highly effective hemostatic and antibacterial activity. The TCCS sponge, prepared using a multistep method, features a porous structure, favorable mechanical properties, excellent water absorption ability, and shape recovery triggered by water or blood. The TCCS sponge exhibited strong antibacterial activity against Methicillin-resistant Staphylococcus aureus and Escherichia coli. Additionally, it demonstrated enhanced procoagulant and hemostatic efficacy in rat tail amputation and rat liver perforation wound models compared to commercial hemostats. Furthermore, the sponge exhibited favorable biocompatibility and biosafety. These findings suggest that the TCCS sponge has substantial potential for practical applications in managing severe hemorrhages and bacterial infections.

Research Progress on the Pathogenesis and Treatment of Neoatherosclerosis.

Neoatherosclerosis (NA) within stents has become an important clinical problem after coronary artery stent implantation. In-stent restenosis and in-stent thrombosis are the two major complications following coronary stent placement and seriously affect patient prognosis. As the common pathological basis of these two complications, NA plaques, unlike native atherosclerotic plaques, often grow around residual oxidized lipids and stent struts. The main components are foam cells formed by vascular smooth muscle cells (VSMCs) engulfing oxidized lipids at lipid residue sites. Current research mainly focuses on optical coherence tomography (OCT) and intravascular ultrasound (IVUS), but the specific pathogenesis of NA is still unclear. A thorough understanding of the pathogenesis and pathological features of NA provides a theoretical basis for clinical treatment. This article reviews the previous research of our research group and the current situation of domestic and foreign research.

Evolution of digital twins in precision health applications: a scoping review study.

An increasing amount of research is incorporating the concept of Digital twin (DT) in biomedical and health care applications. This scoping review aims to summarize existing research and identify gaps in the development and use of DTs in the health care domain. The focus of this study lies on summarizing: the different types of DTs, the techniques employed in DT development, the DT applications in health care, and the data resources used for creating DTs. We identified fifty studies, which mainly focused on creating organ- (n=15) and patient-specific twins (n=30). The research predominantly centers on cardiology, endocrinology, orthopedics, and infectious diseases. Only a few studies used real-world datasets for developing their DTs. However, there remain unresolved questions and promising directions that require further exploration. This review provides valuable reference material and insights for researchers on DTs in health care and highlights gaps and unmet needs in this field.

Tauroursodeoxycholic Acid Improves Nonalcoholic Fatty Liver Disease by Regulating Gut Microbiota and Bile Acid Metabolism.

Tauroursodeoxycholic acid (TUDCA) is a synthetic bile salt that has demonstrated efficacy in the management of hepatobiliary disorders. However, its specific mechanism of action in preventing and treating nonalcoholic fatty liver disease (NAFLD) remains incompletely understood. This research revealed that TUDCA treatment can reduce obesity and hepatic lipid buildup, enhance intestinal barrier function and microbial balance, and increase the presence of Allobaculum and Bifidobacterium in NAFLD mouse models. TUDCA can influence the activity of farnesoid X receptor (FXR) and cholesterol 7α-hydroxylase (CYP7A1), resulting in higher hepatic bile acid levels and increased expression of sodium taurocholate cotransporting polypeptide (NTCP), leading to elevated concentrations of liver-bound bile acids in mice. Furthermore, TUDCA can inhibit the expression of FXR and fatty acid transport protein 5 (FATP5), thereby reducing fatty acid absorption and hepatic lipid accumulation. This investigation provides new insights into the potential of TUDCA for preventing and treating NAFLD.

A high-frequency sense list.

A number of high-frequency word lists have been created to help foreign language learners master English vocabulary. These word lists, despite their widespread use, did not take word meaning into consideration. Foreign language learners are unclear on which meanings they should focus on first. To address this issue, we semantically annotated the Corpus of Contemporary American English (COCA) and the British National Corpus (BNC) with high accuracy using a BERT model. From these annotated corpora, we calculated the semantic frequency of different senses and filtered out 5000 senses to create a High-frequency Sense List. Subsequently, we checked the validity of this list and compared it with established influential word lists. This list exhibits three notable characteristics. First, it achieves stable coverage in different corpora. Second, it identifies high-frequency items with greater accuracy. It achieves comparable coverage with lists like GSL, NGSL, and New-GSL but with significantly fewer items. Especially, it includes everyday words that used to fall off high-frequency lists without requiring manual adjustments. Third, it describes clearly which senses are most frequently used and therefore should be focused on by beginning learners. This study represents a pioneering effort in semantic annotation of large corpora and the creation of a word list based on semantic frequency.

Exploration of the potential mechanism of aqueous extract of Artemisia capillaris for the treatment of non-alcoholic fatty liver disease based on network pharmacology and experimental verification.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a nutritional and metabolic disease with a high prevalence today. Artemisia capillaris has anti-inflammatory, antioxidant, and other effects. However, the mechanism of A. capillaris in treating NAFLD is still poorly understood. METHODS: This study explored the mechanism of A. capillaris in the treatment of NAFLD through network pharmacology and molecular docking, and verified the results through in vivo experiments using a high-fat diet-induced mouse model and in vitro experiments using an oleic acid-induced HepG2 cell model. KEY FINDINGS: Aqueous extract of A. capillaris (AEAC) can reduce blood lipids, reduce liver lipid accumulation and liver inflammation in NAFLD mice, and improve NAFLD. Network pharmacology analysis revealed that 51 drug ingredients in A. capillaris correspond to 370 targets that act on NAFLD. GEO data mining obtained 93 liver differentially expressed genes related to NAFLD. In the UHPLC-MS detection results, 36 components were characterized and molecular docked with JNK. Verified in vitro and in vivo, the results show that JNK and the phosphorylation levels of IL-6, IL-1ß, c-Jun, c-Fos, and CCL2 are key targets and pathways. CONCLUSIONS: This study confirmed that AEAC reduces lipid accumulation and inflammation in the liver of NAFLD mice by inhibiting the JNK/AP-1 pathway.

Early Diagnostic Markers for Esophageal Squamous Cell Carcinoma: CNA Gene Identification and cfDNA Detection.

The high mortality rate of esophageal squamous cell carcinoma (ESCC) is exacerbated by the absence of early diagnostic markers. The pronounced heterogeneity of mutations in ESCC renders copy number alterations (CNAs) more prevalent among patients. The identification of CNA genes within esophageal squamous dysplasia (ESD), a precancerous stage of ESCC, is crucial for advancing early detection efforts. Utilization of liquid biopsies via droplet-based digital PCR (ddPCR) offers a novel strategy for detecting incipient tumor traces. This study undertook a thorough investigation of CNA profiles across ESCC development stages, integrating data from existing databases and prior investigations to pinpoint and confirm CNA markers conducive to early detection of ESCC. Targeted sequencing was employed to select potential early detection genes, followed by the establishment of prediction models for ESCC early detection using ddPCR. Our analysis reveals widespread CNAs during the ESD stage, mirroring the CNA landscape observed in ESCC. A total of 40 CNA genes were identified as highly frequent in both ESCC and ESD lesions, through a comprehensive gene-level CNA analysis encompassing ESD and ESCC tissues, ESCC cell lines, and pan-cancer datasets. Subsequent validation of five candidate markers via ddPCR underscored the efficacy of combined predictive models-encompassing PIK3CA, SOX2, EGFR, MYC, and CCND1-in early ESCC screening, as evidenced by the area under the curve (AUC) values exceeding 0.92 (p<0.0001) across various detection contexts. The findings highlight the significant utility of CNA genes in the early screening of ESCC, presenting robust models that could facilitate early detection, broad-scale population screening, and adjunctive diagnosis.

PC4C_CAPSI: Image data of capsicum plant growth in protected horticulture.

Feeding the increasing global population and reducing the carbon footprint of agricultural activities are two critical challenges of our century. Growing crops under protected horticulture and precise crop monitoring have emerged to address these challenges. Crop monitoring in commercial protected facilities remains mostly manual and labour intensive. Using computer vision to solve specific problems in image-based crop monitoring in these compact and complex growth environments is currently hindered by the scarcity of available data. We collected an RGBD dataset for vertically supported, hydroponically-grown capsicum plants in a commercial-scale glasshouse facility to fill this gap. Data were collected weekly using a single top-angled stereo camera mounted on a mobile platform running between the hydroponic gutters. The RGBD streams covered 80 % of the crop growing season in three different light conditions. The metadata include camera configurations and light condition information. Manually measured plant heights of ten selected plants per gutter are provided as ground truth. The images covered the whole plants and focused on the top third. This dataset will support research on plant height estimation, plant organ identification, object segmentation, organ measurements, 3D reconstruction, 3D data processing, and depth noise reduction. The usability of the dataset has been successfully demonstrated in a previously published study on plant height estimation using machine learning and 3D point cloud.

Extracting Pulmonary Nodules and Nodule Characteristics from Radiology Reports of Lung Cancer Screening Patients Using Transformer Models.

 Pulmonary nodules and nodule characteristics are important indicators of lung nodule malignancy. However, nodule information is often documented as free text in clinical narratives such as radiology reports in electronic health record systems. Natural language processing (NLP) is the key technology to extract and standardize patient information from radiology reports into structured data elements. This study aimed to develop an NLP system using state-of-the-art transformer models to extract pulmonary nodules and associated nodule characteristics from radiology reports. We identified a cohort of 3080 patients who underwent LDCT at the University of Florida health system and collected their radiology reports. We manually annotated 394 reports as the gold standard. We explored eight pretrained transformer models from three transformer architectures including bidirectional encoder representations from transformers (BERT), robustly optimized BERT approach (RoBERTa), and A Lite BERT (ALBERT), for clinical concept extraction, relation identification, and negation detection. We examined general transformer models pretrained using general English corpora, transformer models fine-tuned using a clinical corpus, and a large clinical transformer model, GatorTron, which was trained from scratch using 90 billion words of clinical text. We compared transformer models with two baseline models including a recurrent neural network implemented using bidirectional long short-term memory with a conditional random fields layer and support vector machines. RoBERTa-mimic achieved the best F1-score of 0.9279 for nodule concept and nodule characteristics extraction. ALBERT-base and GatorTron achieved the best F1-score of 0.9737 in linking nodule characteristics to pulmonary nodules. Seven out of eight transformers achieved the best F1-score of 1.0000 for negation detection. Our end-to-end system achieved an overall F1-score of 0.8869. This study demonstrated the advantage of state-of-the-art transformer models for pulmonary nodule information extraction from radiology reports. Supplementary Information: The online version contains supplementary material available at 10.1007/s41666-024-00166-5.

Past and present: a bibliometric study on the treatment of recurrent ovarian cancer.

Background: Ovarian cancer (OC) is a gynecological malignancy with a high mortality rate worldwide. The unfavorable prognosis of OC is mainly attributed to the recurrent propensity. Recently, mortality from OC has exhibited a downward trend. These favorable patterns are likely to be driven by advancements in novel therapeutic regimens. However, there is a lack of visualize analysis of the application of these new drugs on women with recurrent OC (ROC). Therefore, we aimed to provide a bibliometric analysis of the evolving paradigms in the ROC treatment. Methods: Documents on ROC treatment were systematically collected from the MEDLINE database and Web of Science Core Collection (WOSCC). The retrieved documents were exported in the plain text file format, and files were named and saved to the paths specified by the Java application. Microsoft Excel (version 2010), Citespace (6.2.R4) and VOSviewer (1.6.19) were used for data analysis, and included the following: 1) annual publication trend; 2) contributions of countries, institutions and authors; 3) co-citation of journals and references; and 4) co-occurrence of keywords. Results: A total of 914 documents published in the MEDLINE and 9,980 ones in WOSCC were retrieved. There has been an upward trend in the productivity of publications on ROC treatment on by years. The United States was the leading contributor in this field, and the University of Texas System stood out as the most productive institution. Giovanni Scambia and Maurie Markman were the research leaders in the field of ROC treatment. The journal Gynecologic Oncology had the highest citation frequency. The reference entitled with "Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer" got highest centrality of 0.14 in the co-citation network. Keyword analysis revealed that the focus of current ROC treatment was on platinum-based anticancer drugs, paclitaxel, angiogenesis inhibitors (AIs), immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase inhibitors (PARPis). Conclusion: Scholars from a multitude of countries have been instrumental in the advancement of ROC treatment. The research hotspots and trend in the field of predominantly originated from leading international journals and specialized periodicals focused on gynecologic oncology. Maintenance therapy using AIs or (and) PARPis has emerged as a significant complement to platinum-based chemotherapy for patients with ROC.

Novel de novo SPAST mutation in a Han Chinese SPG4 patient: a case report.

Spastic paraplegia type 4 (SPG4), the predominant form of Autosomal Dominant Hereditary spastic paraplegia (AD-HSP), is characterized by variants in the SPAST gene. This study reports a unique case of a late-onset SPG4 in a Han Chinese male, manifesting primarily as gait disturbances from lower extremity spasticity. Uncovered through whole-genome sequencing, a previously undocumented frameshift variant, c.1545dupA in exon 14 of the SPAST gene, was identified. Notably, this variant was absent in asymptomatic parents with confirmed paternity and maternity status, suggesting a de novo variant occurrence. This discovery emphasizes the potential of de novo variants to exhibit a late-onset pure pattern, extending the SPG4 variant spectrum, and consideration of such variants should be given in HSP patients with a negative family history.