Background: Hearing loss (HL) is one of the most common sensory disorders, affecting over 5-8% of the world's population. Approximately half of HL cases are attributed to genetic factors. In hereditary deafness, about 75-80% is inherited through autosomal recessive inheritance, and common pathogenic genes include GJB2 and SLC26A4. Pathogenic variants in the SLC26A4gene are the leading cause of hereditary hearing loss in humans, second only to the GJB2 gene. Variants in the SLC26A4gene cause hearing loss, which can be non-syndromic autosomal recessive deafness (DFNB4, OMIM #600791) associated with enlarged vestibular aqueduct (EVA) or Pendred syndrome (Pendred, OMIM #605646). DFNB4 is characterized by sensorineural hearing loss combined with EVA or less common cochlear malformation defect. Pendred syndrome is characterized by bilateral sensorineural hearing loss with EVA and an iodine defect that can lead to thyroid goiter. Currently, it is known that EVA is associated with variants in the SLC26A4 gene and is a penetrant feature of SLC26A4-related HL. Predominant mutations in these genes differ significantly across populations. For instance, predominant SLC26A4 mutations differ among populations, including p.T416P and c.1001G>A in Caucasians, p.H723R in Japanese and Koreans, and c.919-2A>G in Han Taiwanese and Han Chinese. On the other hand, there has been no study of hearing loss related to SLC26A4 gene variants among Mongolians, which is the basis of our research. Aim: We aimed to identify the characteristics of the SLC26A4 gene variants in Mongolian people with Enlarged vestibular aqueduct and Mondini malformation. Materials and Methods: In 2022-2024, We included 13 people with hearing loss and enlarged vestibular aqueduct, incomplete cochlea (1.5 turns of the cochlea with cystic apex- incomplete partition type II- Mondini malformation) were examined by CT scan of the temporal bone in our study. WES (Whole exome sequencing) analysis was performed in the Genetics genetic-laboratory of the National Taiwan University Hospital. Results: Genetic analysis revealed 26 confirmed pathogenic variants of bi-allelic SLC26A4 gene of 8 different types in 13 cases, and c.919-2A>G variant was dominant with 46% (12/26) in allele frequency, and c.2027T>A (p.L676Q) variant 19% (5/26), c.1318A>T(p.K440X) variant 11% (3/26), c.1229C>T (p.T410M) variant 8% (2/26) ) , c.716T>A (p.V239D), c.281C>T (p.T94I), c.1546dupC, and c.1975G>C (p.V659L) variants were each 4% (1/26)- revealed. Two male children, 11 years old (SLC26A4: c.919-2A>G) and 7 years old (SLC26A4: c.919-2A>G:, SLC26A4: c.2027T>A (p.L676Q))had history of born normal hearing and progressive hearing loss. Conclusions 1. 26 variants of bi-allelic SLC26A4 gene mutation were detected in Mongolian people with EVA and Mondini malformation, and c.919-2A>G was the most dominant allele variant, and rare variants such as c.1546dupC, c.716T>A (p.V239D) were detected. 2. Our study shows that whole-exome sequencing (WES) can identify gene mutations that are not detected by polymerase chain reaction (PCR) or NGS analysis.

BACKGROUND: The FAVOR (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) III China trial demonstrated that percutaneous coronary intervention (PCI) lesion selection using quantitative flow ratio (QFR) measurement, a novel angiography-based approach for estimating fractional flow reserve, improved two-year clinical outcomes compared with standard angiography guidance. This study aimed to assess the cost-effectiveness of QFR-guided PCI from the perspective of the current Chinese healthcare system. METHODS: This study is a pre-specified analysis of the FAVOR III China trial, which included 3825 patients randomized between December 25, 2018, and January 19, 2020, from 26 centers in China. Patients with stable or unstable angina pectoris or those ≥72 hours post-myocardial infarction who had at least one lesion with a diameter stenosis between 50% and 90% in a coronary artery with a ≥2.5 mm reference vessel diameter by visual assessment were randomized to a QFR-guided strategy or an angiography-guided strategy with 1:1 ratio. During the two-year follow-up, data were collected on clinical outcomes, quality-adjusted life-years (QALYs), estimated costs of index procedure hospitalization, outpatient cardiovascular medication use, and rehospitalization due to major adverse cardiac and cerebrovascular events (MACCE). The primary analysis calculated the incremental cost-effectiveness ratio (ICER) as the cost per MACCE avoided. An ICER of ¥10,000/MACCE event avoided was considered economically attractive in China. RESULTS: At two years, the QFR-guided group demonstrated a reduced rate of MACCE compared to the angiography-guided group (10.8% vs . 14.7%, P <0.01). Total two-year costs were similar between the groups (¥50,803 ± 21,121 vs . ¥50,685 ± 23,495, P = 0.87). The ICER for the QFR-guided strategy was ¥3055 per MACCE avoided, and the probability of QFR being economically attractive was 64% at a willingness-to-pay threshold of ¥10,000/MACCE avoided. Sensitivity analysis showed that QFR-guided PCI would become cost-saving if the cost of QFR were below ¥3682 (current cost: ¥3800). Cost-utility analysis yielded an ICER of ¥56,163 per QALY gained, with a 53% probability of being cost-effective at a willingness-to-pay threshold of ¥85,000 per QALY gained. CONCLUSION: In patients undergoing PCI, a QFR-guided strategy appears economically attractive compared to angiographic guidance from the perspective of the Chinese healthcare system. TRIAL REGISTRATION ClinicalTrials.gov , NCT03656848.
Humans ; Cost-Benefit Analysis ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Angiography/methods* ; Middle Aged ; Aged ; Coronary Artery Disease/surgery* ; Quality-Adjusted Life Years ; Fractional Flow Reserve, Myocardial/physiology*

Purpose: Men are increasingly turning toward online direct-to-consumer (DTC) men’s health platforms to fulfill their health needs. Research surrounding these platforms is lacking and the motivations and predictors underlying this online health-seeking behavior is largely unknown. This review scopes the existing literature concerning DTC men’s health and identifies factors influencing engagement, as well as health outcomes of this platform. Materials and Methods: A structured search was performed following PRISMA guidelines. CINAHL via EBSCO, Embase, MEDLINE via Ovid, PsycINFO, PubMed and Web of Science were searched. Results: Peer-reviewed quantitative and qualitative studies with a focus on demographics and characteristics of those using DTC men’s health platforms, as well as studies related to patient outcomes using such platforms, were included. Ten of the 3,003 studies identified met the inclusion and exclusion criteria. Four cross-sectional descriptive studies evaluated the motivations behind men’s engagement with DTC platforms. Convenience, embarrassment and health motivation were identified as predominant factors associated with DTC platform use. The review identified a lack of qualitative studies, and major limitations were noted in the quantitative studies that impacted the accuracy of findings. Six further quantitative studies explored the quality of care provided by DTC platforms. DTC platforms were found to have a varying level of adherence to established clinical guidelines, but appeared to provide satisfactory patient outcomes with low levels of patient-reported side effects and adverse events. Conclusions There is a lack of research within the DTC men’s health space given the infancy of the field. Important predictors and motivations underlying men’s choices in accessing these platforms have been noted across several studies. However, further studies need to be conducted to investigate the psychosocial underpinnings of this behavior. Studies across a wider variety of male health conditions treated by these platforms will also help to provide insights to guide patient-centered care within the DTC landscape.

OBJECTIVE: To measure the burden of hepatitis C-associated diseases in China from 1990 to 2019, and to predict its changes from 2020 to 2044, so as to provide insights into formulation of the targeted hepatitis C control strategy. METHODS: The total burden due to hepatitis C-associated diseases in China from 1990 to 2019 were extracted from the Global Burden of Disease 2019 (GBD 2019) data resources, and the trends in age-standardized prevalence, incidence, mortality and disability-adjusted life years (DALYs) rate of hepatitis C-associated acute hepatitis C (AHC), chronic liver diseases (CLD) and liver cancer in China from 1990 to 2019 were evaluated in China from 1990 to 2019 using estimated annual percentage change (EAPC). In addition, the changes in the burden of hepatitis C-associated diseases were predicted in China from 2020 to 2044 using a Bayesian model. RESULTS: The prevalence, incidence, mortality and DALY rate of hepatitis C-associated diseases all appeared an overall tendency towards a decline in China from 1990 to 2019 (EAPC = -2.64%, -2.24%, -3.81% and -3.90%, respectively); however, there was a minor rise in the incidence and prevalence of hepatitis C-associated diseases from 2015 to 2019. The overall prevalence of hepatitis C-associated diseases reduced from 2 152.7/10⁵ in 1990 to 1 254.1/10⁵ in 2019 in China, with a reduction of 41.7%. The overall incidence reduced from 87.9/10⁵ in 1990 to 55.0/10⁵ in 2019 in China, with a reduction of 37.4%, and the highest incidence was seen for AHC, followed by CLD and liver cancer. The overall mortality and DALY rate of hepatitis C-associated diseases was 4.0/10⁵ and 100.8/10⁵ in China from 1990 to 2019, with CLD showing the largest contributions to the gross mortality and DALY. The mortality and DALY rate of hepatitis C-associated diseases were 5.5/10⁵ and 142.4/10⁵ among men in China in 2019, which were both much higher than among women (2.8/10⁵ and 60.3/10⁵, respectively), and the overall prevalence (1 604.9/10⁵), mortality (30.2/10⁵) and DALYs (437.1/10⁵) of hepatitis C-associated diseases were all highest among patients at ages of 70 years and older, and the highest incidence was seen among patients at ages of 0 to 9 years (167.3/10⁵). The incidence of hepatitis C-associated diseases was predicted to rise in China from 2020 to 2044; however, the DALY rate was projected to appear a tendency towards a decline. CONCLUSIONS Although the burden of hepatitis C-associated diseases showed a tendency towards a decline in China from 1990 to 2019, the burden remained high, and was predicted to slightly rise from 2020 to 2044. High attention should be paid to screening of hepatitis C among infants and treatment among adults.
Male ; Adult ; Infant ; Humans ; Female ; Bayes Theorem ; Quality-Adjusted Life Years ; Hepatitis C/epidemiology* ; Liver Neoplasms/epidemiology* ; China/epidemiology* ; Incidence

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [e.g., cytochrome P450 3A4 (CYP3A4)] and transporters. Although the regulation of PXR target genes is well-characterized, less is known about the regulation of PXR protein level. By screening an RNAi library, we identified the F-box-only protein 44 (FBXO44) as a novel E3 ligase for PXR. PXR abundance increases upon knockdown of FBXO44, and, inversely, decreases upon overexpression of FBXO44. Further analysis revealed that FBXO44 interacts with PXR, leading to its ubiquitination and proteasomal degradation, and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction. In summary, FBXO44 regulates PXR protein abundance, which has downstream consequences for CYP3A4 levels and drug-drug interactions. The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3 ubiquitin ligase activities will affect PXR-mediated drug metabolism.

Objective: To investigate the clinicopathological features, immunophenotype and gene alterations of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA). Methods: Fifteen case of TL-LGNPPA diagnosed at Zhejiang Cancer Hospital (5 cases) and the First Affiliated Hospital, Zhejiang University School of Medicine (10 cases) from November 2011 to August 2020 were collected. Clinical and pathological examinations, immunohistochemical staining and next-generation sequencing were performed. The clinicopathological and molecular characteristics were summarized, and relevant literature was reviewed. Results: Fifteen patients were identified and included. Their median age was 36 years (range, 20-60 years). The male-female ratio was 1.0∶1.1. The most common symptoms were epistaxis and nasal obstruction. The neoplasms were located on the roof of the nasopharynx or the posterior margin of the nasal septum. The pathological features included complex papillary and glandular structures mainly composed of single or pseudostratified cubic and columnar cells, with mild to moderate cytological atypia. In some cases, spindle cell features, nuclear grooves, ground glass nuclei, squamous metaplasia, or scattered psammoma bodies were identified. In addition, nuclear polar reversal cells, hobnail cells and micropapillary structures were found, but have not been reported in previous literature. Immunohistochemistry showed that the tumor cells were diffusely positive for TTF1, CK7, vimentin and CKpan; focally positive for p40, CK5/6 and p16; and negative for Tg, NapsinA, CK20, CDX2, S-100 and PAX8. The Ki-67 positive rates ranged from 1% to 20% and were≤10% in thirteen cases (13/15). EBER in situ hybridization was negative in all cases. DNA sequencing of 6 specimens was performed and all specimens were found harboring gene mutations (EWSR1, SMAD2, ROS1, JAK3, GRIN2A, ERRCC5, STAT3, and TET2), but no hot spot gene alterations were found. No MSI-H and MMR related gene changes were detected. All tumors showed low tumor mutation burden. All 15 patients underwent endoscopic surgery, and only 1 of them underwent radiotherapy postoperatively. All patients were recurrence free and alive at the end of follow-up periods (range: 23 to 129 months). Conclusions: TL-LGNPPA is a rare indolent tumor of the nasopharynx and exhibits a unique morphology and immunophenotype. Endoscopic resection is an effective treatment for TL-LGNPPA with excellent overall prognosis.
Humans ; Male ; Female ; Adult ; Thyroid Gland/pathology* ; Adenocarcinoma, Papillary/pathology* ; Nasopharyngeal Neoplasms/pathology* ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins ; Nasopharynx/pathology* ; Biomarkers, Tumor

As total mesorectal excision (TME) for rectal cancer is widely carried out in China, lateral ligament of rectum, as an important anatomical structure of the lateral rectum with certain anatomical value and clinical significance, has been the focus of attention. In this paper, by comparing and analyzing the characteristics about ligaments of the abdomen and pelvis, reviewing the membrane anatomy and the theory of primitive gut rotation, and combining clinical observations and histological studies, the author came to a conclusion that lateral ligament of rectum does not exist, but is only a relatively dense space on the rectal side accompanied by numerous tiny nerve plexuses and small blood vessels penetrating through it.
Humans ; Rectum/anatomy & histology* ; Pelvis/anatomy & histology* ; Rectal Neoplasms/surgery* ; Peritoneum ; Collateral Ligaments ; Cognition

Human salivary histatin 1 (Hst1) exhibits a series of cell-activating properties, such as promoting cell spreading, migration, and metabolic activity. We recently have shown that fluorescently labeled Hst1 (F-Hst1) targets and activates mitochondria, presenting an important molecular mechanism. However, its regulating signaling pathways remain to be elucidated. We investigated the influence of specific inhibitors of G protein-coupled receptors (GPCR), endocytosis pathways, extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, p38 signaling, mitochondrial respiration and Na+/K+-ATPase activity on the uptake, mitochondria-targeting and -activating properties of F-Hst1. We performed a siRNA knockdown (KD) to assess the effect of Sigma-2 receptor (S2R) /Transmembrane Protein 97 (TMEM97)-a recently identified target protein of Hst1. We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1. Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1. The inhibitors of GPCR, ERK1/2, phagocytosis, and clathrin-mediated endocytosis (CME) as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake, which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity. Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1. We further showed the intracellular trafficking and targeting process of F-Hst1, in which early endosome plays an important role. Overall, phagocytosis, CME, GPCR, ERK signaling, and S2R/TMEM97 are involved in the internalization of Hst1, while only CME and S2R/TMEM97 are critical for its subcellular targeting. The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.
Endocytosis/physiology* ; Histatins/pharmacology* ; Humans ; Membrane Proteins ; Mitochondria/metabolism* ; RNA, Small Interfering/pharmacology* ; Receptors, G-Protein-Coupled/metabolism* ; Receptors, sigma

Background: and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.