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OBJECTIVE: A hedgehog family ligand, namely, sonic hedgehog (SHH), was reported to be important in the development of bladder and ureter smooth muscle. In this prospective study, we aimed to determine protein expression of SHH in resected ureterovesical junction (UVJ) segments of children with vesicoureteral reflux (VUR). MATERIALS AND METHODS: The study group included 19 children; 12 (63%) girls, 7 (37%) boys, who had ureteroneocystostomy operation; 3 (15.7%) right sided, 7 (36.8%) left sided, 9 (47.3%) bilateral, due to primary VUR between years 2015 and 2018. Totally, 28 UVJ segments were examined for Western Blot analysis to determine related protein expression levels. RESULTS: The mean Western blot band area of SHH gene pathway related protein was 3880.69 (2059.55-13941.61) while the mean area of ß-Actin, the house-keeping gene, was 20180.25 (9530.39-26709.75) (p = 0.001). Correlation analyses between grade of reflux and protein expression of SHH gene pathways revealed no significant relation (p = 0.300). When the UV samples were grouped as low- and high-grade reflux and compared in terms of SHH protein expression levels, no statistically significant difference was found between groups (p = 0.818). CONCLUSION: We concluded that SHH signaling molecule which is effective in development of bladder and ureter smooth musculature might also be effective in etiopathology of reflux.

OBJETIVO: Se ha informado que el ligando sonic hedgehog (SHH) es importante en el desarrollo de los músculos lisos de la vejiga y el uréter. Nuestro objetivo fue determinar la expresión proteica de SHH en los segmentos de la unión ureterovesical de niños con reflujo vesicoureteral (RVU). MATERIALES Y MÉTODOS: El grupo de estudio incluyó a 19 niños; 12 (63%) niñas, 7 (37%) niños, que tuvieron operación de ureteroneocistostomía (UNC); 3 (15.7%) derecho, 7 (36.8%) izquierdo, 9 (47.3%) bilateral, por RVU primario entre los años 2015-2018. Se examinaron un total de 28 segmentos de la unión ureterovesical para análisis de transferencia Western para determinar los niveles de expresión de proteínas relacionadas en las muestras. RESULTADOS: El área media de la banda de transferencia Western de la proteína relacionada con la vía del gen SHH fue de 3880.69 (2059.55-13941.61), mientras que el área media de la ß-actina, el gen de limpieza, fue de 20180.25 (9530.39-26709.75) (p = 0.001). Los análisis de correlación entre el grado de reflujo y la expresión de proteínas de las vías del gen SHH no revelaron una relación significativa (p = 0.300). CONCLUSIÓN: Concluimos que la molécula de señalización SHH también podría ser efectiva en la etiopatología del reflujo vesicoureteral.

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OBJECTIVE: An investigation of the diagnostic and clinical value of cell cycle-dependent kinase 1 (CDK1) in small cell lung cancer (SCLC). METHODS: A large tertiary hospital in Jiangxi Province enrolled 80 SCLC cases, 105 cases of non-small cell lung cancer (NSCLC), 114 cases of pulmonary nodule (PN) and 60 control cases from December 2022 to December 2023. ELISA was used to measure CDK1 levels in serum. The expression levers of neuron-specific enolase (NSE), Pro gastrin-releasing peptide (ProGRP), squamous cell carcinoma antigen (SCCA), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199) and cytokeratin 19 fragment (YFRA21-1) were detected by electrochemiluminescence immunoassay. RESULTS: ①CDK1, ProGRP, NSE, and CA199 expressions were significantly higher in the SCLC group compared to the NSCLC, PN and Control groups (P < 0.01). ②Spearman correlation analysis showed that serum levels of CDK1, NSE, and ProGRP were associated with clinical staging and lymph node metastasis in SCLC patients (P < 0.05). ③The serum levels of CDK1, NSE, and ProGRP in patients with extensive-disease (ED) SCLC were higher than those in patients with limited-disease (LD) SCLC (P < 0.05), and the serum levels of CDK1, NSE, and ProGRP in SCLC patients with lymph node metastasis were higher than those without lymph node metastasis (P < 0.05). ④Compared with the NSCLC group, the AUC of subjects diagnosed with SCLC by CDK1 was the largest and the sensitivity was the highest, 0.831 and 72.50%, the specificity of ProGRP in diagnosing SCLC is the highest, at 95.20% (P < 0.01). Compared with the PN group, CDK1 had the highest AUC, sensitivity, and specificity in diagnosing SCLC, with values of 0.93%, 88.80%, and 94.70%, respectively (P < 0.01). ⑤The combination of CDK1, ProGRP and NSE had the highest AUC and sensitivity of 0.903 and 86.30% for the diagnosis of SCLC (P < 0.01). CONCLUSION: CDK1 not only plays an important role in assisting the diagnosis of SCLC but also in the differential diagnosis between SCLC and NSCLC. The combination of CDK1 and NSE and ProGRP can significantly improve the diagnostic performance and provide new ideas for the clinical diagnosis of SCLC.

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Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses.

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Aims: Rheumatic mitral stenosis (MS) frequently leads to impaired left atrial (LA) function because of pressure overload, highlighting the underlying atrial pathology. Two-dimensional speckle tracking echocardiography (2D-STE) offers early detection of LA dysfunction, potentially improving risk assessment in patients with MS. This study aims to evaluate the predictive value of LA function assessed by 2D-STE for clinical outcomes in patients with MS. Methods and results: Between 2011 and 2021, patients with MS underwent LA function assessment using 2D-STE, with focus on the reservoir phase (LASr). Atrial fibrillation (AF) development constituted the primary outcome, with death or valve replacement as the secondary outcome. Conditional inference trees were employed for analysis, validated through sample splitting. The study included 493 patients with MS (mean valve area 1.1 ± 0.4 cm2, 84% female). At baseline, 166 patients (34%) had AF, with 62 patients (19%) developing AF during follow-up. LASr emerged as the primary predictor for new-onset AF, with a threshold of 17.9%. Over a mean 3.8-year follow-up, 125 patients (25%) underwent mitral valve replacement, and 32 patients (6.5%) died. A decision tree analysis identified key predictors such as age, LASr, severity of tricuspid regurgitation (TR), net atrioventricular compliance (C n), and early percutaneous mitral valvuloplasty, especially in patients aged ≤49 years, where LASr, with a threshold of 12.8%, significantly predicted adverse outcomes. Conclusion: LASr emerged as a significant predictor of cardiovascular events in this MS cohort, validated through a decision tree analysis. Patients were stratified into low- or high-risk categories for adverse outcomes, taking into account LASr, age, TR severity, and C n.

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INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

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PURPOSE: The tonsoku-like DNA repair protein (TONSL) encoded by the TONSL gene, located on chromosome 8q24.3, is crucial for repairing DNA double-strand breaks through homologous recombination. However, TONSL overexpression in lung adenocarcinoma (LUAD) promotes tumor development, leading to a poor prognosis. METHODS: TONSL was verified as a reliable prognostic marker for LUAD using bioinformatics, and clinical features related to LUAD prognosis were screened from the TCGA database to establish the relationship between risk factors and TONSL expression. In addition, TONSL expression in normal and LUAD tissues was verified using real-time quantitative polymerase chain reaction and immunohistochemistry. To elucidate the possible functions of TONSL, TONSL-related differentially expressed genes were screened, and functional enrichment analysis was performed. Subsequently, siRNA was used to knock down TONSL expression in lung cancer cells for cytobehavioral experiments. The effects of TONSL expression on tumor immune escape were analyzed using the ESTIMATE algorithm and tumor immune-infiltration analysis. In addition, the half-maximal inhibitory concentration of LUAD with varying TONSL expression levels in response to first-line chemotherapeutic drugs and epidermal growth factor receptor-tyrosine kinase inhibitors was analyzed for drug sensitivity. RESULTS: Up-regulation of TONSL in LUAD promotes the proliferation, migration, and invasion of lung cancer cells, thereby contributing to a poor prognosis. Furthermore, TONSL overexpression promotes immune escape and drug sensitivity in LUAD. CONCLUSION: TONSL serves as a reliable prognostic marker for LUAD, and its up-regulation is associated with increased immune escape and drug sensitivity. These findings suggest that TONSL holds potential as a novel therapeutic target for LUAD.

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INTRODUCTION: Atrophic acne scarring, a common sequela of acne, can be treated by different interventions, including microneedling and laser resurfacing. OBJECTIVES: We sought to evaluate the comparative efficacy of microneedling versus fractional CO2 laser in treating atrophic acne facial scars using imaging with high and ultra-high frequency ultrasound. METHODS: Participants received 2 sessions, separated by 1 month, of microneedling on the left side of the face and fractional CO2 laser on the right. Color Doppler ultrasound evaluations (24 and 70 MHz) were conducted at baseline and 3 months after treatment. Each patient completed questionnaires on satisfaction, pain, and adverse effects. RESULTS: Nine subjects were enrolled. The frequency order of scar types was boxcar, ice-pick, and rolling. At 3 months, using the acne scar clinical evaluation scale, a decrease in scar scores of both methods was observed for total scars (P = 0.0005), ice-pick scars (P = 0.0128), and rolling scars (P = 0.0007). Twenty-two scars analyzed by ultrasound demonstrated a trend to decrease in size; however, no significant changes were observed for either microneedling or CO2 laser treatments. Moreover, there were no significant differences between these methods. Both treatments were rated as good or very good by patient assessments. There was a low frequency of pain and hyperpigmentation reported with both modalities, albeit somewhat higher with microneedling. CONCLUSIONS: Both microneedling and CO2 laser improved atrophic acne scars. Ultrasound did not show significant differences between these modalities.

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BACKGROUND: There are no randomized studies comparing the maintenance of sinus rhythm after catheter ablation (CA) concerning treatment with antiarrhythmic drugs (AA) in elderly patients with paroxysmal atrial fibrillation (AF). OBJECTIVES: To compare the clinical results of pulmonary vein (PV) isolation with the second-generation PVAC Gold catheter against AA treatment in elderly people with recurrent symptomatic paroxysmal AF, refractory to at least one AA, and without structural heart disease. METHODS: Sixty patients with paroxysmal AF ≥ 65 years old were randomized to two forms of treatment: group 1: CA and group 2: AA drugs. The primary outcome was the AF recurrence-free rate after at least one year of follow-up. Secondary outcomes were: progression to persistent forms of AF, impact on quality of life (QOLF), and complications. The significance level adopted in the statistical analysis was 5% (p<0.05). RESULTS: The AF recurrence-free rate was 80% (10% with amiodarone) in the CA group, after 1.3 procedures per patient and 65% in the AA group (60% with amiodarone), (p = 0.119) in an average follow-up of 719 days (Q1: 566; Q3: 730). The persistent AF free rate was 83.4% in the AC group and 67.7% in the AA group (p = 0.073) Both strategies showed an improvement in the AFQoL score during follow-up (p < 0.001), with no difference between the groups. Although without clinical repercussions or impact on the intellectual assessment test, 25% of patients in the CA group showed signs of cerebral embolization on brain MRI. CONCLUSIONS: Both strategies for maintaining sinus rhythm promoted an improvement in the quality of life of elderly patients with symptomatic AF, with no statistical difference in the clinical outcomes. Additional studies using technologies with a better safety profile are needed to evaluate the benefits of CA in elderly patients with AF.

FUNDAMENTO: Não existem estudos randomizados comparando a manutenção do ritmo sinusal após ablação por cateter (AC) em relação ao tratamento com fármacos antiarrítmicos (AA) em pacientes idosos portadores fibrilação atrial (FA) paroxística. OBJETIVOS: Comparar os resultados clínicos do isolamento das veias pulmonares (VPs) com o cateter PVAC Gold de segunda geração com o uso de AA em idosos com FA paroxística sintomática, recorrente, apesar do uso de fármacos AA. MÉTODOS: Sessenta pacientes com FA paroxística ≥ 65 anos e sem cardiopatias estruturais foram randomizados para duas formas de tratamento: grupo 1: AC e grupo 2: AA. O desfecho primário foi a taxa livre de recorrência de FA após pelo menos um ano de seguimento. Os desfechos secundários foram: progressão para formas persistentes de FA, impacto na qualidade de vida (QVFA) e complicações. O nível de significância adotado na análise estatística foi de 5% (p<0,05). RESULTADOS: A taxa livre de recorrência de FA foi de 80% (10% com amiodarona) no grupo AC, após 1,3 procedimentos por paciente e de 65% no grupo AA (60% com amiodarona), (p = 0,119) num seguimento médio de 719 dias (Q1: 566; Q3: 730). A taxa livre de FA persistente foi de 83,4% no grupo AC e de 67,7% no grupo AA (p = 0,073). Ambas as estratégias apresentaram melhora no escore de QVFA durante o seguimento (p < 0,001), sem diferença entre os grupos. Embora sem repercussão clínica ou impacto no teste de avaliação intelectual, 25% dos pacientes do grupo PVAC apresentou sinais de embolização cerebral na RNM cerebral. CONCLUSÕES: Ambas as estratégias para manutenção do ritmo sinusal promoveram melhora na qualidade de vida de pacientes idosos com FA sintomática, sem diferença estatística nos desfechos clínicos preconizados. Estudos adicionais usando tecnologias com melhor perfil de segurança são necessários para avaliar os benefícios da AC em pacientes idosos com FA.

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OBJECTIVE: To investigate the efficacy of cluster nursing intervention based on Enhanced Recovery After Surgery (ERAS) for xerostomia in chronic rhinosinusitis after nasal endoscopic surgery. METHODS: A total of 80 patients with chronic rhinosinusitis who underwent functional nasal endoscopic surgery between January 2020 and December 2021 were selected and randomly divided into a control group (n = 40) and an experimental group (n = 40). Patients in the control group were treated with general nursing, while ERAS-based cluster nursing intervention was adopted for the experimental group, in addition to general nursing. Xerostomia stage and comfort level were observed at 2 h, 6 h, 24 h and 48 h after surgery; negative emotions before and after nursing were also observed. RESULTS: After the intervention, the xerostomia stage and comfort level at 6, 24 and 48 after surgery were higher in the experimental group (p < 0.05). Negative emotions in the experimental group were lower after nursing (p < 0.001). The self-rating depression scale and self-rating anxiety scale scores increased after nursing in both two groups (p < 0.05). CONCLUSION: Enhanced recovery after surgery-based cluster nursing intervention can alleviate xerostomia, improve patients' comfort levels, reduce their negative emotions and accelerate postoperative recovery.

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PURPOSE: This study aimed to develop a tumor radiomics quality and quantity model (RQQM) based on preoperative enhanced CT to predict early recurrence after radical surgery for colorectal liver metastases (CRLM). METHODS: A retrospective analysis was conducted on 282 cases from 3 centers. Clinical risk factors were examined using univariate and multivariate logistic regression (LR) to construct the clinical model. Radiomics features were extracted using the least absolute shrinkage and selection operator (LASSO) for dimensionality reduction. The LR learning algorithm was employed to construct the radiomics model, RQQM (radiomics-TBS), combined model (radiomics-clinical), clinical risk score (CRS) model and tumor burden score (TBS) model. Inter-model comparisons were made using area under the curve (AUC), decision curve analysis (DCA) and calibration curve. Log-rank tests assessed differences in disease-free survival (DFS) and overall survival (OS). RESULTS: Clinical features screening identified CRS, KRAS/NRAS/BRAF and liver lobe distribution as risk factors. Radiomics model, RQQM, combined model demonstrated higher AUC values compared to CRS and TBS model in training, internal and external validation cohorts (Delong-test P < 0.05). RQQM outperformed the radiomics model, but was slightly inferior to the combined model. Survival curves revealed statistically significant differences in 1-year DFS and 3-year OS for the RQQM (P < 0.001). CONCLUSIONS: RQQM integrates both "quality" (radiomics) and "quantity" (TBS). The radiomics model is superior to the TBS model and has a greater impact on patient prognosis. In the absence of clinical data, RQQM, relying solely on imaging data, shows an advantage in predicting early recurrence after radical surgery for CRLM.

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This study aims to address a critical gap in the literature by examining the incorporation of uncertainty in measuring carbon emissions using the greenhouse gas (GHG) Protocol methodology across all three scopes. By comprehensively considering the various dimensions of CO2 emissions within the context of organizational activities, our research contributes significantly to the existing body of knowledge. We address challenges such as data quality issues and a high prevalence of missing values by using information entropy, techniques for order preference by similarity to ideal solution (TOPSIS), and an artificial neural network (ANN) to analyze the contextual variables. Our findings, derived from the data sample of 56 companies across 18 sectors and 13 Brazilian states between 2017 and 2019, reveal that Scope 3 emissions exhibit the highest levels of information entropy. Additionally, we highlight the pivotal role of public policies in enhancing the availability of GHG emissions data, which, in turn, positively impacts policy-making practices. By demonstrating the potential for a virtuous cycle between improved information availability and enhanced policy outcomes, our research underscores the importance of addressing uncertainty in carbon emissions measurement for advancing effective climate change mitigation strategies.

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Chronic hepatitis B virus infection (CHB) remains a global health concern, with currently available antiviral therapies demonstrating limited effectiveness in preventing hepatocellular carcinoma (HCC) development. Two primary challenges in CHB treatment include the persistence of the minichromosome, covalently closed circular DNA (cccDNA) of the hepatitis B virus (HBV), and the failure of the host immune response to eliminate cccDNA. Recent findings indicate several host and HBV proteins involved in the epigenetic regulation of cccDNA, including HBV core protein (HBc) and HBV x protein (HBx). Both proteins might contribute to the stability of the cccDNA minichromosome and interact with viral and host proteins to support transcription. One potential avenue for CHB treatment involves the utilization of therapeutic vaccines. This paper explores HBV antigens suitable for epigenetic manipulation of cccDNA, elucidates their mechanisms of action, and evaluates their potential as key components of epigenetically-driven vaccines for CHB therapy. Molecular targeted agents with therapeutic vaccines offer a promising strategy for addressing CHB by targeting the virus and enhancing the host's immunological response. Despite challenges, the development of these vaccines provides new hope for CHB patients by emphasizing the need for HBV antigens that induce effective immune responses without causing T cell exhaustion.

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Surface water and sediments from the Jackpile mine, St. Anthony mine, Rio Paguate, Rio Moquino, and Mesita Dam areas near Pueblo of Laguna, New Mexico, were analyzed for 226Ra and U using gamma (γ) spectroscopy and inductively coupled plasma mass spectroscopy, respectively. Activity ratios for 226Ra/238U for solid samples range from 0.34 ± 0.13 to 16 ± 2.9, which reflect uranium transport and accumulation (<1), relatively pristine material in secular equilibrium (1), and removal of uranium by weathering (>1). Concentrations ranging from 80 to 225 µg L-1 U were detected in unfiltered water samples near the Jackpile mine. Water samples upstream and downstream from the mine contained concentrations ranging from 12 to 15 µg L-1 U. Water samples collected from the North Pit standing pond in the Jackpile mine contained as much as 1560 pCi L-1 of 226Ra, and passing the water through a 0.2 µM filter did not substantially reduce the activity of 226Ra in the water. 234Th and 226Ra are in secular equilibrium in this water, while radon gas was lost from the water. The results of the current study provide insight into the distribution of U-series radionuclides in the Pueblo of Laguna area, including detection of high levels of radioactivity in water at some locations within the Jackpile mine.

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OBJECTIVES: Allergic diseases and Meniere's disease found to have a possible link in observational study. However, the potential causal relationship between the two is unclear. Therefore, we aimed to explore the causal relationship between allergic diseases and Meniere's disease using a new data analysis technique called bidirectional Mendelian randomization study. METHOD: Summary-level statistics for Meniere's disease and three allergic diseases (asthma, allergic rhinitis, eczema/dermatitis) were obtained from large-scale genome-wide association studies. The inverse variance weighted method was used as the primary measure, supplemented by MR-Egger regression and the weighted median method. To ensure the reliability of the conclusions, Cochran's Q, MR-Egger intercept, MR-PRESSO test, leave-one-out test, and MR Steiger test were used. RESULTS: Inverse-variance weighted method showed asthma (p = 0.008, OR = 3.908, 95% CI 1.424-10.724, adjust_p = 0.024), allergic rhinitis (p = 0.026, OR = 24.714, 95% CI 1.479-412.827, adjust_p = 0.026) and eczema/dermatitis (p = 0.019, OR = 3725.954, 95% CI 3.795 to 3,658,399.580, adjust_p = 0.029) all had a significant effect on Meniere's disease. Reverse Mendelian randomization studies have shown that Meniere's disease does not increase the risk of three allergic diseases. Sensitivity analysis showed no horizontal pleiotropy and heterogeneity for each trait. CONCLUSION: Our Mendelian randomization analysis supports a positive causal relationship between three allergic diseases (asthma, allergic rhinitis, eczema/dermatitis) and Meniere's disease. This suggests that physicians should pay more attention to the Meniere's patient's allergy history and consider allergy avoidance as part of their treatment plan. LEVEL OF EVIDENCE: Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

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OBJECTIVE: This study mainly explores (2R,6R; 2S,6S)-HNK and its compounds whether there are antidepressant effects. METHODS: Four HNK compounds were obtained from 2-(Chlorophenyl) Cyclopentylmethanone. Forced swimming test, locomotor sensitization test, and conditioned location preference test were used to screen the antidepressant activity of the synthesized target compounds. RESULTS: In the case of 10 mg HNK treatment, compared with saline, the immobile time of mice in the HNK group, I5 group and I6 group at 1 h and 7 days had statistical significance. In the case of 10 mg HNK treatment, compared with saline, the immobile time of compound C and D groups in the glass cylinder area was significantly different. In the locomotor sensitization test, the movement distance of compound C and D groups on day 15 and day 7 mice increased significantly compared with the first day. In the conditioned place preference experiment, compound C and compound D induced conditioned place preference in mice compared with the Veh group. CONCLUSION: The results of the forced swimming test, locomotor sensitization test, and conditioned location preference test showed that compounds C and D may have certain anti-depressant activity. However, HNK exerts a rapid and significant antidepressant effect within 1 week, but the duration is short.

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BACKGROUND: Catheter ablation of parahisian accessory pathways (PHAP) are challenging due to their proximity to the normal conduction system. Retrospective studies suggest that cryoablation has a better safety profile but a higher recurrence rate when compared to radiofrequency ablation (RFCA). The objective of this study was to compare the results of parahisian AP ablation performed by electrophysiologists with experience in both technologies. METHODS: Prospective single-center, non-blinded and 1:1 model was used. Patients included had parahisian AP confirmed by an electrophysiological study and referred for radiofrequency or cryotherapy ablation according to current guidelines, under fluoroscopic guidance. No electroanatomic mapping was used. RESULTS: A total of 30 patients (mean age of 25±9.4 years; 90% male) were enrolled between Oct/2018 to Feb/2020. Acute success rate between RFCA and CRYO were similar (93% vs. 87%, p = 0.54). A nonsignificant reduction in short-term recurrence rate for RFCA (14% vs. 30%, p = 0.3) and mechanical trauma (6% vs. 20%; p = 0.28) was observed. Long-term recurrence rate and event-free survival time were similar in both groups after 1-year follow-up (p = 0.286). No persistent complete AV block or conduction disturbance was also observed. CONCLUSION: Considering the limitation of a small sample size and the lack of use of electroanatomic mapping for RFCA, the efficacy and safety profile of parahisian AP ablation with RFCA was not different from CRYO, when performed by experienced electrophysiologists. No cases of permanent complete AV block were reported with either energy modalities.

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BACKGROUND: Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes. RESULTS: The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1. CONCLUSIONS: These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.

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OBJECTIVE: This meta-analysis aims to evaluate the safety and efficacy of restarting immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) after experiencing immune-related adverse events (irAEs). METHODS: A comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library was conducted to identify studies investigating the safety and efficacy of restarting ICIs in NSCLC patients after irAEs. Outcome measures, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) after ICI restarting, were extracted. Meta-analysis was performed using the R meta-package. RESULTS: Four studies involving a total of 326 subjects were included, comprising 137 patients who restarted ICI treatment after irAEs and 189 patients who did not restart ICI treatment. The results revealed that ICI restarting was associated with an increased ORR (OR = 2.36, 95% CI 1.49-3.84), prolonged PFS (HR = 0.60, 95% CI 0.42-0.86), and prolonged OS (HR = 0.65, 95% CI 0.43-0.99) compared to non-restarting. The incidence of irAEs after ICI restarting was 45% (95% CI 0.27-0.63). CONCLUSION: Restarting ICI treatment after discontinuation due to previous irAEs appears to be a reasonable option for NSCLC patients. However, a comprehensive assessment of the potential benefits and risks to individual patients is crucial, and close monitoring of irAEs is warranted.

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