RNA m6A modification regulates L1 retrotransposons in human spermatogonial stem cell differentiation in vitro and in vivo.

The maintenance of genome integrity in the germline is crucial for mammalian development. Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element that makes up about 17% of the human genome and poses a threat to genome integrity. N6-methyl-adenosine (m6A) plays an essential role in regulating various biological processes. However, the function of m6A modification in L1 retrotransposons and human germline development remains largely unknown. Here we knocked out the m6A methyltransferase METTL3 or the m6A reader YTHDF2 in human embryonic stem cells (hESCs) and discovered that METTL3 and YTHDF2 are crucial for inducing human spermatogonial stem cells (hSSCs) from hESCs in vitro. The removal of METTL3 or YTHDF2 resulted in increased L1 retrotransposition and reduced the efficiency of SSC differentiation in vitro. Further analysis showed that YTHDF2 recognizes the METTL3-catalyzed m6A modification of L1 retrotransposons and degrades L1 mRNA through autophagy, thereby blocking L1 retrotransposition. Moreover, the study confirmed that m6A modification in human fetal germ cells promotes the degradation of L1 retrotransposon RNA, preventing the insertion of new L1 retrotransposons into the genome. Interestingly, L1 retrotransposon RNA was highly expressed while METTL3 was significantly downregulated in the seminal plasma of azoospermic patients with meiotic arrest compared to males with normal fertility. Additionally, we identified some potentially pathogenic variants in m6A-related genes in azoospermic men with meiotic arrest. In summary, our study suggests that m6A modification serves as a guardian of genome stability during human germline development and provides novel insights into the function and regulatory mechanisms of m6A modification in restricting L1 retrotransposition.

Effect of artificial intelligence on novice-performed colonoscopy: a multicenter randomized controlled tandem study.

BACKGROUND AND AIMS: The efficacy and safety of colonoscopy performed by artificial intelligence (AI)-assisted novices remain unknown. The aim of this study was to compare the lesion detection capability of novices, AI-assisted novices, and experts. METHODS: This multicenter, randomized, noninferiority tandem study was conducted across 3 hospitals in China from May 1, 2022, to November 11, 2022. Eligible patients were randomized into 1 of 3 groups: the CN group (control novice group, withdrawal performed by a novice independently), the AN group (AI-assisted novice group, withdrawal performed by a novice with AI assistance), or the CE group (control expert group, withdrawal performed by an expert independently). Participants underwent a repeat colonoscopy conducted by an AI-assisted expert to evaluate the lesion miss rate and ensure lesion detection. The primary outcome was the adenoma miss rate (AMR). RESULTS: A total of 685 eligible patients were analyzed: 229 in the CN group, 227 in the AN group, and 229 in the CE group. Both AMR and polyp miss rate were lower in the AN group than in the CN group (18.82% vs 43.69% [P < .001] and 21.23% vs 35.38% [P < .001], respectively). The noninferiority margin was met between the AN and CE groups of both AMR and polyp miss rate (18.82% vs 26.97% [P = .202] and 21.23% vs 24.10% [P < .249]). CONCLUSIONS: AI-assisted colonoscopy lowered the AMR of novices, making them noninferior to experts. The withdrawal technique of new endoscopists can be enhanced by AI-assisted colonoscopy. (Clinical trial registration number: NCT05323279.).

Validation of Artificial Intelligence-based Bowel Preparation Assessment in Screening Colonoscopy.

BACKGROUND AND AIMS: Accurate bowel preparation assessment is essential for determining colonoscopy screening intervals. Patients with suboptimal bowel preparation are at a high risk of missing >5mm adenomas, and should undergo an early repeat colonoscopy. In this study, we employed artificial intelligence (AI) to evaluate bowel preparation and validated the ability of the system in accurately identifying patients who are at high risk of missing >5mm adenoma due to inadequate bowel preparation. PATIENTS AND METHODS: This prospective, single-center, observational study was conducted at the Eighth Affiliated Hospital, Sun Yat-sen University from October 8, 2021, to November 9, 2022. Eligible patients underwent screening colonoscopy were consecutively enrolled. The AI assessed bowel preparation using e-Boston Bowel Preparation Scale (BBPS) while endoscopists evaluated using BBPS. If both BBPS and e-BBPS deemed preparation adequate, the patient immediately underwent a second colonoscopy, otherwise the patient underwent bowel re-cleansing before the second colonoscopy. RESULTS: Among the 393 patients, 72 ＞5mm adenomas were detected, while 27 ＞5mm adenomas were missed. In unqualified-AI patients, the >5mm AMR was significantly higher than in qualified-AI patients (35.71% vs 13.19%, p=0.0056, OR 0.2734, 95% CI 0.1139, 0.6565), as were the AMR (50.89% vs 20.79%, p<0.001, OR 0.2532, 95% CI 0.1583, 0.4052) and >5mm PMR (35.82% vs 19.48%, p=0.0152, OR 0.4335, 95% CI 0.2288, 0.8213). CONCLUSIONS: This study confirmed that patients classified as inadequate by AI showed unacceptable >5mm AMR, provided key evidence for implementing AI in guiding the bowel re-cleansing, potentially standardizing the future colonoscopy screening; ClincialTrials.gov, NCT05145712.

Assessment of the role of false-positive alerts in computer-aided polyp detection for assistance capabilities.

BACKGROUND AND AIM: False positives (FPs) pose a significant challenge in the application of artificial intelligence (AI) for polyp detection during colonoscopy. The study aimed to quantitatively evaluate the impact of computer-aided polyp detection (CADe) systems' FPs on endoscopists. METHODS: The model's FPs were categorized into four gradients: 0-5, 5-10, 10-15, and 15-20 FPs per minute (FPPM). Fifty-six colonoscopy videos were collected for a crossover study involving 10 endoscopists. Polyp missed rate (PMR) was set as primary outcome. Subsequently, to further verify the impact of FPPM on the assistance capability of AI in clinical environments, a secondary analysis was conducted on a prospective randomized controlled trial (RCT) from Renmin Hospital of Wuhan University in China from July 1 to October 15, 2020, with the adenoma detection rate (ADR) as primary outcome. RESULTS: Compared with routine group, CADe reduced PMR when FPPM was less than 5. However, with the continuous increase of FPPM, the beneficial effect of CADe gradually weakens. For secondary analysis of RCT, a total of 956 patients were enrolled. In AI-assisted group, ADR is higher when FPPM ≤ 5 compared with FPPM > 5 (CADe group: 27.78% vs 11.90%; P = 0.014; odds ratio [OR], 0.351; 95% confidence interval [CI], 0.152-0.812; COMBO group: 38.40% vs 23.46%, P = 0.029; OR, 0.427; 95% CI, 0.199-0.916). After AI intervention, ADR increased when FPPM ≤ 5 (27.78% vs 14.76%; P = 0.001; OR, 0.399; 95% CI, 0.231-0.690), but no statistically significant difference was found when FPPM > 5 (11.90% vs 14.76%, P = 0.788; OR, 1.111; 95% CI, 0.514-2.403). CONCLUSION: The level of FPs of CADe does affect its effectiveness as an aid to endoscopists, with its best effect when FPPM is less than 5.

Corrections to the Bekenstein-Hawking Entropy of the HNUTKN Black Hole Due to Lorentz-Breaking Fermionic Einstein-Aether Theory.

A hot NUT-Kerr-Newman black hole is a general stationary axisymmetric black hole. In this black hole spacetime, the dynamical equations of fermions at the horizon are modified by considering Lorentz breaking. The corrections to the Hawking temperature and Bekenstein-Hawking entropy at the horizon of the black hole are studied in depth. Based on the semiclassical theory correction, the Bekenstein-Hawking entropy of this black hole is quantum-corrected by considering the perturbation effect of the Planck constant ℏ. The latter part of this paper presents a detailed discussion of the obtained results and their physical implications.

sncRNAs in Epididymosomes: The Contribution to Embryonic Development and Offspring Health.

Much progress has been made in determining that paternal environmental exposures can remodel their spermatozoa small noncoding RNAs (sncRANs) and, in turn, affect the phenotypes of their offspring. Studies have shown that changes in the spermatozoa sncRNAs profile occur during passing through the epididymis. Due to the absence of transcription and translation in the epididymis, spermatozoa remodel their sncRNAs profile through communication with the epididymal microenvironment. Since epididymosomes contribute to the process of spermatozoa maturation by mediating the crosstalk between the epididymis and the passing spermatozoa, they are considered to be the leading candidate to mediate these changes. Previous studies and reviews on the role of epididymal transfer proteins in sperm maturation and function are myriad. This review focuses on the role and mechanisms of epididymosome-mediated transfer of sncRNAs cargoes onembryonic development and offspring health.

Transfer- or 'transmission'-RNA fragments? The roles of tsRNAs in the reproductive system.

Transfer-RNAs (tRNAs) help ribosomes decode mRNAs and synthesize proteins; however, tRNA fragments produced under certain conditions, known as tRNA-derived small RNAs (tsRNAs), have been found to play important roles in pathophysiological processes. In the reproductive system, tsRNAs are abundant in gametes and embryos and at the maternal-fetal interface, as well as in microvesicles like epididymosomes, seminal plasma exosomes, and syncytiotrophoblast-derived extracellular vesicles. tsRNAs can affect gamete cell maturation, zygote activation, and early embryonic development. tsRNAs can transmit epigenetic information to later generations. In particular, exposure to environmental factors such as nutrition, isoproterenol, and poly(I:C) may allow tsRNAs to transfer information to the gametes or placenta to alter offspring phenotype. The underlying mechanisms of tsRNAs action include transposon silencing, translation regulation, and target mRNA degradation. Herein, we review the currently reported tsRNAs in the reproductive system, their validated functions, and potential roles. A better understanding of this field may help to provide useful recommendations or develop strategies to increase fertility and conception of healthy babies.

The effect of tibolone treatment on lipid profile in women: A systematic review and dose-response meta-analysis of randomized controlled trials.

Inconsistencies exist with regard to influence of tibolone treatment on the lipid profile. The reasons for these inconsistencies might derive from several factors, i.e., differences in baseline variables, intervention duration, participants' health status or baseline body mass index (BMI). To address these inconsistencies, based on a systematic search in Scopus, PubMed/Medline, Web of Science, and Embase for papers published until 21 December 2020, we conducted the current dose-response meta-analysis of randomized controlled trials (RCTs) to determine the impact of tibolone treatment on the lipid profile. The overall findings were derived from 26 RCTs. Tibolone administration decreased total cholesterol (TC) (weighted mean difference, WMD: -18.55 mg/dL, CI: -25.95 to -11.16, P < 0.001), high-density lipoprotein-cholesterol (HDL-C) (WMD: -9.42 mg/dL, CI: -11.83 to -7.01, P < 0.001) and triglyceride (TG) (WMD: -21.43 mg/dL, CI: -27.15 to -15.70, P < 0.001) levels. A significant reduction in LDL-C occurred when tibolone was prescribed for ≤ 26 weeks (WMD: -7.64 mg/dL, 95% CI: -14.58 to -0.70, P = 0.031) versus > 26 weeks (WMD: -8.84 mg/dL, 95% CI: -29.98, 12.29, P = 0.412). The decrease in TG (WMD: -22.64 mg/dL) and TC (-18.55 mg/dL) concentrations was more pronounced in patients with BMI ≥ 25 kg/m2versus BMI < 25 kg/m2. This systematic review and meta-analysis discovered that tibolone decreases TC, HDL-C and TG levels. LDL-C concentrations are significantly reduced when tibolone administration lasts for ≤ 26 weeks.

[Processing of impedance cardiogram differential for non-invasive cardiac function detection].

The precise recognition of feature points of impedance cardiogram (ICG) is the precondition of calculating hemodynamic parameters based on thoracic bioimpedance. To improve the accuracy of detecting feature points of ICG signals, a new method was proposed to de-noise ICG signal based on the adaptive ensemble empirical mode decomposition and wavelet threshold firstly, and then on the basis of adaptive ensemble empirical mode decomposition, we combined difference and adaptive segmentation to detect the feature points, A, B, C and X, in ICG signal. We selected randomly 30 ICG signals in different forms from diverse cardiac patients to examine the accuracy of the proposed approach and the accuracy rate of the proposed algorithm is 99.72%. The improved accuracy rate of feature detection can help to get more accurate cardiac hemodynamic parameters on the basis of thoracic bioimpedance.

Prediction of ESRD in IgA Nephropathy Patients from an Asian Cohort: A Random Forest Model.

BACKGROUND/AIMS: There is an increasing risk of end-stage renal disease (ESRD) among Asian people with immunoglobulin A nephropathy (IgAN). A computer-aided system for ESRD prediction in Asian IgAN patients has not been well studied. METHODS: We retrospectively reviewed biopsy-proven IgAN patients treated at the Department of Nephrology of the Second Xiangya Hospital from January 2009 to November 2013. Demographic and clinicopathological data were obtained within 1 month of renal biopsy. A random forest (RF) model was employed to predict the ESRD status in IgAN patients. All cases were initially trained and validated, taking advantage of the out-of-bagging(OOB) error. Predictors used in the model were selected according to the Gini impurity index in the RF model and verified by logistic regression analysis. The area under the receiver operating characteristic(ROC) curve (AUC) and F-measure were used to evaluate the RF model. RESULTS: A total of 262 IgAN patients were enrolled in this study with a median follow-up time of 4.66 years. The importance rankings of predictors of ESRD in the RF model were first obtained, indicating some of the most important predictors. Logistic regression also showed that these factors were statistically associated with ESRD status. We first trained an initial RF model using gender, age, hypertension, serum creatinine, 24-hour proteinuria and histological grading suggested by the Clinical Decision Support System for IgAN (CDSS, www.IgAN.net). This 6-predictor model achieved a F-measure of 0.8 and an AUC of 92.57%. By adding Oxford-MEST scores, this model outperformed the initial model with an improved AUC (96.1%) and F-measure (0.823). When C3 staining was incorporated, the AUC was 97.29% and F-measure increased to 0.83. Adding the estimated glomerular filtration rate (eGFR) improved the AUC to 95.45%. We also observed improved performance of the model with additional inputs of blood urea nitrogen (BUN), uric acid, hemoglobin and albumin. CONCLUSION: In addition to the predictors in the CDSS, Oxford-MEST scores, C3 staining and eGFR conveyed additional information for ESRD prediction in Chinese IgAN patients using a RF model.

Effects of RAAS Inhibitors in Patients with Kidney Disease.

Proteinuria and decline of renal function are associated with progression of kidney disease. The Renin Angiotensin Aldosterone System (RAAS) plays an important role in blood pressure regulation, fluid volume, and sodium balance. Overactivity of RAAS contributes to the pathogenesis of a variety of clinical conditions including progress of chronic kidney disease (CKD). This review summarizes the use of RAAS inhibitors as dual therapy or monotherapy in different stages of kidney disease. Experimental and clinical studies have demonstrated RAAS inhibitors prevent proteinuria, kidney fibrosis and slow decline of renal function and thus play a protective role in both early and end stages of kidney disease. While combination use of RAAS inhibitors showed higher efficiency compared with monotherapy, it is also associated with higher incidence of adverse events. Besides ACEI/ARBs, more mechanism research of mineralocorticoid receptor antagonists in kidney disease should be performed.

Hookworm Infection Caused Acute Intestinal Bleeding Diagnosed by Capsule: A Case Report and Literature Review.

Hookworm infections are rare causes of acute gastrointestinal bleeding. We report a middle aged man with primary nephrotic syndrome and pulmonary embolism. During the treatment with steroids and anticoagulants, the patient presented acute massive hemorrhage of the gastrointestinal tract. The results of gastroscopy showed red worms in the duodenum. Colonoscopy and CT angiogram of abdomen were unremarkable. Capsule endoscopy revealed fresh blood and multiple hookworms in the jejunum and ileum. Hookworms caused the acute intestinal bleeding. The patient responded well to albendazole. Hematochezia was markedly ameliorated after eliminating the parasites. Hence, hookworm infection should be considered in the differential diagnosis of a patient with obscure gastrointestinal bleeding. Capsule endoscopy may offer a better means of diagnosis for intestinal hookworm infections.

[Changes in peripheral hemogram among workers with short-term lead exposure].

OBJECTIVE: To examine the effect of short-term occupational lead exposure on the inflammatory response system in blood among workers. METHODS: A total of 255 lead-exposed workers (length of service ≤1 year) at an electronics factory in Dongguan, China (exposure group), as well as 205 managers without any occupational exposure at another factory (control group), were included in the study. Occupational physical examination was done to get peripheral blood counts. The blood lead levels of workers were determined by atomic absorption spectrometry. The relationship between blood lead and peripheral hemogram was analyzed using SPSS software. RESULTS: The exposure group had blood lead levels of 0.07∼1.70 µmol/L, falling within the normal range. The leukocyte count, percentage of granulocytes, and absolute value of granulocytes were significantly higher in the exposure group than in the control group, and the results remained unchanged after adjustment for age and sex (P < 0.05). There were no significant differences in red blood cell count and hemoglobin value between the two groups (P > 0.05). CONCLUSION: Short-term occupational lead exposure may increase the counts of inflammatory cells in blood, but it has little effect on red blood cells and hemoglobin.

Free vibration analysis of Timoshenko pipes with fixed boundary conditions conveying high velocity fluid.

Sever vibration will be induced due to the high flow velocity in the pipe. When the flow velocity exceeds the critical value, the static equilibrium configuration of the pipe loses its stability, and the vibration properties change accordingly. In this paper, the free vibration characteristics of the pipe with fixed-fixed ends are revealed in the supercritical regime. Based on the Timoshenko beam theory, the governing equations of the nonlinear vibration near the non-trivial static equilibrium configuration are established. The influences of system parameters on equilibrium configuration, critical velocity, and free vibration frequency is analyzed. The effects of supercritical velocity in different ranges on the natural frequencies are revealed. In addition, the comparison with the Euler-Bernoulli pipe model shows that the differences in critical velocity, equilibrium configuration, and frequency are still significant even the length-diameter ratio is large. The increase of the flow velocity reduces the difference of non-trivial static equilibrium configurations, but eventually aggravates the difference of natural frequencies. Within a certain supercritical velocity range, the vibration difference between the two pipe models is small, beyond this range, the vibration difference increases significantly.

Preconception paternal mental disorders and child health: Mechanisms and interventions.

Mental illness is a significant global health issue with a steady prevalence. High heritability is suspected, but genome-wide association studies only identified a small number of risk genes associated with mental disorders. This 'missing inheritance' can be partially explained by epigenetic heredity. Evidence from numerous animal models and human studies supports the possibility that preconception paternal mental health influences their offspring's mental health via nongenetic means. Here, we review two potential pathways, including sperm epigenetics and seminal plasma components. The current review highlights the role of sperm epigenetics and explores epigenetic message origination and susceptibility to chronic stress. Meanwhile, possible spatiotemporal windows and events that induce sexually dimorphic modes and effects of paternal stress transmission are inferred in this review. Additionally, we discuss emerging interventions that could potentially block the intergenerational transmission of paternal psychiatric disorders and reduce the incidence of mental illness. Understanding the underlying mechanisms by which preconception paternal stress impacts offspring health is critical for identifying strategies supporting healthy development and successfully controlling the prevalence of mental illness.

Expression of Testis-specific Serine/Threonine Kinases during the Reproductive and Nonreproductive Seasons and Their Localization in Mature Spermatozoa of Tree Shrews (Tupaia belangeri).

Tree shrews display obvious reproductive cycles, and sexually mature male tree shrews produce little or no sperm with extremely low motility during the nonreproductive season; the mechanism underlying this phenomenon remains unknown. Because testis-specific serine/threonine kinases (TSSK) are specifically expressed in the testis and male germ cells of mammals, we hypothesized that they may have an important role in spermatogenesis or sperm function regulation in tree shrews. In addition, the expression, distribution, subcellular localization, and dynamic changes of TSSK in tree shrew sperm are unclear. Here we show that during the reproductive season, the seminiferous tubules were significantly larger as compared with the nonreproductive season and contained mature sperm and other germ cells. The mRNA expression of Tssk genes in testis was significantly higher than that in other tissues, and the mRNA level in the testis during the reproductive season was significantly higher than that in nonreproductive season. In addition, the mRNA level of Tssk3 in the testis and sperm was significantly higher than that of other members. Specifically, Tssk1 mRNA was distributed in the acrosome and throughout the flagellum of tree shrew sperm, Tssk2 was present in the acrosome, Tssk3 was localized to postacrosomal region and relocated to the main part of the flagellum after capacitation, and Tssk6 was distributed in the acrosome and postacrosomal region. These results indicate that the TSSK are important regulating reproductive function in tree shrews.

Coexistence of anomalous muscle, persistent median artery, bifid median nerve causing carpal tunnel syndrome: A case report and literature review.

Carpal tunnel syndrome (CTS) is an upper extremity median nerve entrapment disorder that is rare in children and adolescents. Anatomical variations of the wrist, such as anomalous muscles, persistent median artery (PMA), and bifid median nerves (BMN), are rare etiology of CTS. Coexistence of all three variants combined with CTS in adolescents has been rarely reported. Case description: A 16-year-old right-hand dominant male presented to our clinic with several years of bilateral thenar muscle atrophy and weakness but no paresthesia or pain in his both hands. Ultrasonography showed that the right median nerve become significantly thinner, and the left median nerve was split into two branches by PMA. Magnetic resonance imaging (MRI) revealed that anomalous muscles in the bilateral wrist extending to the carpal tunnel, causing compression of the median nerve. Considering the possibility of CTS clinically, the patient underwent bilateral open carpal tunnel release without resection of anomalous muscles and PMA. The patient has no discomfort after 2 years. This suggests that anatomical variations of the carpal tunnel may contribute to CTS, which can be confirmed by preoperative ultrasonography and MRI, and the possibility of carpal tunnel anatomical variations should be considered when CTS occurs in adolescents. Open carpal tunnel release is an effective treatment for juvenile CTS without the need to resect abnormal muscle and PMA during the operation.

A novel dose fall-off index and preliminary application in brain and lung stereotactic radiotherapy.

BACKGROUND: Stereotactic radiotherapy (SRT) has been widely used for the treatment of brain metastases and early stage non-small-cell lung cancer (NSCLC). Excellent SRT plans are characterized by steep dose fall-off, making it critical to accurately and comprehensively predict and evaluate dose fall-off. PURPOSE: A novel dose fall-off index was proposed to ensure high-quality SRT planning. METHODS: The novel gradient index (NGI) had two different modes: NGIx V for three-dimensions and NGIx r for one-dimension. NGIx V and NGIx r were defined as the ratios of the decreased percentage dose (x%) to the corresponding isodose volume and equivalent sphere radii, respectively. A total of 243 SRT plans at our institution between April 2020 and March 2022 were enrolled, including 126 brain and 117 lung SRT plans. Measurement-based verifications were performed using SRS MapCHECK. Ten plan complexity indexes were calculated. Dosimetric parameters related to radiation injuries were also extracted, including the normal brain volume exposed to 12 Gy (V12 ) and 18 Gy (V18 ) during single-fraction SRT (SF-SRT) and multi-fraction SRT (MF-SRT), respectively, and the normal lung volume exposed to 12 Gy (V12 ). The performance of NGI and other common dose fall-off indexes, gradient index (GI), R50% and D2cm were evaluated using Spearman correlation analysis to explore their correlations with the PTV size, gamma passing rate (GPR), plan complexity indexes, and dosimetric parameters. RESULTS: There were statistically significant correlations between NGI and PTV size (r = -0.98, P < 0.01 for NGI50 V and r = -0.93, P < 0.01 for NGI50 r), which were the strongest correlations compared with GI (r = 0.11, P = 0.13), R50% (r = -0.08, P = 0.19) and D2cm (r = 0.84, P < 0.01). The fitted formulas of NGI50 V = 23.86V-1.00 and NGI50 r = 113.5r-1.05 were established. The GPRs of enrolled SRT plans were 98.6 ± 1.7%, 94.2 ± 4.7% and 97.1 ± 3.1% using the criteria of 3%/2 mm, 3%/1 mm, and 2%/2 mm, respectively. NGI50 V achieved the strongest correlations with various plan complexity indexes (|r| ranged from 0.67 to 0.91, P < 0.01). NGI50 V also showed the highest r values with V12 (r = -0.93, P < 0.01) and V18 (r = -0.96, P < 0.01) of the normal brain during SF-SRT and MF-SRT, respectively, and V12 (r = -0.86, P < 0.01) of the normal lung during lung SRT. CONCLUSIONS: Compared with GI, R50% and D2cm , the proposed dose fall-off index, NGI, had the strongest correlations with the PTV size, plan complexity and V12 /V18 of the normal tissues. These correlations established on NGI are more helpful and reliable for SRT planning, quality control, and reducing the risk of radiation injuries.