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BACKGROUND: The aim of this study was to assess factors associated with higher odds of undergoing repeat general anesthesia (GA2) for dental treatments. METHODS: The authors studied children up to age 48 months of age enrolled in Medicaid who underwent dental treatment under first general anesthesia (GA1). The authors used a case-control design to compare children who had a GA2 within 48 months of GA1 (case patients) with those who did not (control patients). RESULTS: In total, 60 case patients were age and sex matched to 120 control patients. Mean (SD) age at GA1 was 38 (5.2) months for case participants and 40 (4.7) months for control participants (P = .08). Higher caries involvement of maxillary incisors (P = .04), and lower caries involvment of canines (P = .003), first molars (P = .012), and second molars (P < .001) at GA1 was associated with higher odds of occurrence of GA2. There was a significant inverse association between full-coverage restoration on canines (P = .003), first molars (P = .001), and second molars (P = .002) at GA1 and occurrence of GA2. There was a significant direct association between the use of composites or sealants on second molars in GA1 and occurrence of GA2 (P = .02). The number of extractions at GA1 was not associated significantly with the occurrence of GA2. CONCLUSIONS: The use of full-coverage restorations on primary molars and canines under general anesthesia (GA) was associated with lower odds of occurrence of GA2. Resin restorations and sealants on primary second molars were associated with higher odds of occurrence repeat GA. The findings support preferential use of full-coverage restorations for young children undergoing dental GA. PRACTICAL IMPLICATIONS: Full-coverage restorations should be considered strongly for young children undergoing GA for dental treatments to reduce the risk of requiring GA2.
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Purpose: The purpose of this study was to explore the perceived value of clinical photographs for traumatic dental injuries (TDIs). Methods: A survey was sent to members of the American Academy of Pediatric Dentistry (AAPD). The survey collected respondents' responses to case-based questions with and without photographs, and opinions about the value of photography for TDI. Results: A total of 496 respondents (5.8 percent response) completed the survey. Overall, no significant difference in correct answers was observed between cases with and without a photograph (P=0.09). The majority of respondents (82.2 percent) agreed that photographs should be taken for the management of TDIs, with 88.7 percent stating that the photographs aided in the diagnosis of TDIs. The majority of respondents acknowledged the time-saving (80.9 percent) and legal importance (77.0 percent) of photographs. Conclusion: Photographs should be taken in the management of traumatic dental injuries when possible for history and documentation purposes.
Subject(s)
Photography, Dental , Tooth Injuries , Humans , Tooth Injuries/therapy , Child , Attitude of Health Personnel , Pediatric Dentistry , Photography , DocumentationABSTRACT
Purpose: To identify pandemic-related behavioral and attitudinal changes in caregivers. Methods: A 38-question cross-sectional survey was developed and distributed to English-speaking caregivers accompanying children for dental care in a hospital dental clinic. The questionnaire surveyed caregiver beliefs and behaviors regarding COVID19, whether the pandemic altered their use of medical and dental care or at-home health habits, as well as their attitudes toward medical and dental teams. Results: The 594 respondents varied in age, marital status, education and income level. Trust was high regarding medical and dental teams, government public health management and mask policies for children. However, those respondents who did not think children should be required to wear masks at school if the health department recommended it and respondents who did not think that government agencies would protect them if another pandemic happened were less likely to change perceptions on dental care, preventive dentistry, sugar intake and toothbrushing (P<0.05). No other strong and consistent relationships were found. Conclusions: In a safety-net dental clinic population, over half of caregivers changed dental behaviors and attitudes following the pandemic. Caregivers cynical of mask mandates and governmental pandemic management were not in the group to change their dental attitudes and behaviors. No other consistent pattern of demographic variables offered a clear profile of group beliefs and behaviors, suggesting the necessity of inquiring individuals and families about their oral health perceptions and behaviors.
Subject(s)
COVID-19 , Caregivers , Humans , COVID-19/prevention & control , Cross-Sectional Studies , Male , Female , Caregivers/psychology , Adult , Surveys and Questionnaires , Middle Aged , Health Knowledge, Attitudes, Practice , Child , SARS-CoV-2 , Masks , Dental Care for Children/psychology , Young Adult , Adolescent , Health Behavior , PandemicsABSTRACT
A palladium-catalyzed cascade carbonylation reaction of 2-bromo-N-(2-iodophenyl)benzamides with benzylidenecyclopropanes for the synthesis of fused isoindolinone derivatives has been developed. A broad range of 6/5/6/6 tetracyclic isoindolinone products were efficiently prepared in moderate to good yields with diverse substitution. Two carbonyl groups were incorporated into the substrates in a single step with the formation of four carbon-carbon bonds and two carbon-heteroatom bonds.
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A common life-threatening hereditary disease, Cystic Fibrosis (CF), affects primarily Caucasian infants. High sweat-salt levels are observed as a result of a single autosomal mutation in chromosome 7 that affects the critical function of the cystic fibrosis transmembrane regulator (CFTR). For establishing tailored treatment strategies, it is important to understand the broad range of CFTR mutations and their impacts on disease pathophysiology. This study thoroughly investigates the six main classes of classification of CFTR mutations based on their functional effects. Each class is distinguished by distinct molecular flaws, such as poor protein synthesis, misfolding, gating defects, conduction defects, and decreased CFTR expression at the apical membrane. Furthermore, this paper focuses on the emerging field of CFTR modulators, which intend to restore CFTR function or mitigate its consequences. These modulators, which are characterized by the mode of action and targeted mutation class, have the potential to provide personalized therapy regimens in CF patients. This review provides valuable insights into the genetic basis of CF pathology, and highlights the potential for precision medicine methods in CF therapy by thoroughly investigating CFTR mutation classification and related modulators.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Mutation , Humans , Cystic Fibrosis/genetics , Cystic Fibrosis/therapy , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Precision Medicine/methodsABSTRACT
Silicone rubber has broad applications in the field of industrial engineering due to its stable physical and chemical properties. However, the superhydrophobic properties, of silicone rubber, especially large deformation superhydrophobic properties, were not satisfactory for many harsh application environments and complex engineering structures. Here, we report the preparation of superhydrophobic tensile designable silicone rubber composites by a mixed deposition process that included powder deposition and smoke deposition. The infrared test showed that the deposited powder from silicone rubber combustion was mainly composed of SiO2 and short chain siloxane. The mixed deposited surface with a rich micro-nanostructure, which was the key to the formation of superhydrophobic properties. The water contact angle (WCA) and sliding angle (SA) of coating surface could reach 157.6° and 5° ± 1°, respectively, and the tensile designability of superhydrophobic surface is closely related to the prestretched process. In addition, bounce tests, high temperature tests, and solvent resistance tests showed the application potential of modified silicone rubber composites in the field of engineering.
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BACKGROUND: Isolated splenic abscesses are rare, but increasingly reported with newer organisms and changes in mechanisms involved. We conducted a comparative review of publications from 1900-1977, 1977-1986, 1987-1995, and 1996-2022. METHODS: A systematic search in Embase and PubMed resulted in 522 publications (1111 cases). Data was tabulated, analysed, and compared. RESULTS: Patient demographics and symptoms remain unchanged although more Asian patients were reported. Metastatic infections remain the main cause, but COVID-19-linked and iatrogenic causes post bariatric surgery and splenic artery embolization are increasingly reported. Aerobic organisms remain the commonest (68%), with a variety of exotic organisms reported. Splenectomy remains the definitive treatment, although antibiotics only and percutaneous aspiration/catheter-drainage are increasingly used with reasonable outcomes, with salvage splenectomy for therapeutic failures not having significantly higher mortality than upfront splenectomy. CONCLUSIONS: Isolated splenic abscesses continue to be uncommon, with diagnosis requiring a high degree of suspicion. Non-surgical options for treatment can sometimes be definitive.
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2,3-Allenamides are an important class of unsaturated group-substituted carbonyl compounds. A palladium-catalyzed aminocarbonylation of propargyl acetates with amines for the synthesized tri-/tetrasubstituted 2,3-allenamides has been developed. A broad range of tri-/tetrasubstituted 2,3-allenamides have been prepared from propargyl acetates in good to excellent yields. The reaction featured mild reaction conditions and good functional group tolerance. The applicability of this methodology was further highlighted by the late-stage modification of several natural products and pharmaceuticals.
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BACKGROUND: Acute pancreatitis is one of the most common diseases requiring emergency surgery. Rapid and accurate recognition of acute pancreatitis can help improve clinical outcomes. This study aimed to develop a deep learning-powered diagnostic model for acute pancreatitis. MATERIALS AND METHODS: In this investigation, we enrolled a cohort of 190 patients with acute pancreatitis who were admitted to Sichuan Provincial People's Hospital between January 2020 and December 2021. Abdominal computed tomography (CT) scans were obtained from both patients with acute pancreatitis and healthy individuals. Our model was constructed using two modules: (1) the acute pancreatitis classifier module; (2) the pancreatitis lesion segmentation module. Each model's performance was assessed based on precision, recall rate, F1-score, Area Under the Curve (AUC), loss rate, frequency-weighted accuracy (fwavacc), and Mean Intersection over Union (MIOU). RESULTS: Upon admission, significant variations were observed between patients with mild and severe acute pancreatitis in inflammatory indexes, liver, and kidney function indicators, as well as coagulation parameters. The acute pancreatitis classifier module exhibited commendable diagnostic efficacy, showing an impressive AUC of 0.993 (95%CI: 0.978-0.999) in the test set (comprising healthy examination patients vs. those with acute pancreatitis, P < 0.001) and an AUC of 0.850 (95%CI: 0.790-0.898) in the external validation set (healthy examination patients vs. patients with acute pancreatitis, P < 0.001). Furthermore, the acute pancreatitis lesion segmentation module demonstrated exceptional performance in the validation set. For pancreas segmentation, peripancreatic inflammatory exudation, peripancreatic effusion, and peripancreatic abscess necrosis, the MIOU values were 86.02 (84.52, 87.20), 61.81 (56.25, 64.83), 57.73 (49.90, 68.23), and 66.36 (55.08, 72.12), respectively. These findings underscore the robustness and reliability of the developed models in accurately characterizing and assessing acute pancreatitis. CONCLUSION: The diagnostic model for acute pancreatitis, driven by deep learning, exhibits excellent efficacy in accurately evaluating the severity of the condition. TRIAL REGISTRATION: This is a retrospective study.
Subject(s)
Deep Learning , Pancreatitis , Tomography, X-Ray Computed , Humans , Pancreatitis/diagnostic imaging , Male , Female , Tomography, X-Ray Computed/methods , Middle Aged , Adult , Acute Disease , Aged , Retrospective StudiesABSTRACT
The relationship between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) has long been extensively recognized, but their crosstalk mechanisms based on gene regulation remain elusive. In our study, for the first time, bulk RNA-seq and single-cell RNA-seq data were used to explore the shared molecular mechanisms between T2DM and CRC. Moreover, Connectivity Map and molecular docking were employed to determine potential drugs targeting the candidate targets. Eight genes (EVPL, TACSTD2, SOX4, ETV4, LY6E, MLXIPL, ENTPD3, UGP2) were identified as characteristic comorbidity genes for T2DM and CRC, with EVPL and ENTPD3 further identified as core comorbidity genes. Our results demonstrated that upregulation of EVPL and downregulation of ENTPD3 were intrinsic molecular features throughout T2DM and CRC and were significantly associated with immune responses, immune processes, and abnormal immune landscapes in both diseases. Single-cell analysis highlighted a cancer-associated fibroblast (CAF) subset that specifically expressed ENTPD3 in CRC, which exhibited high heterogeneity and unique tumor-suppressive features that were completely different from classical cancer-promoting CAFs. Furthermore, ENTPD3+ CAFs could notably predict immunotherapy response in CRC, holding promise to be an immunotherapy biomarker at the single-cell level. Finally, we identified that droperidol may be a novel drug simultaneously targeting EVPL and ENTPD3. In conclusion, previous studies have often focused solely on metabolic alterations common to T2DM and CRC. Our study establishes EVPL and ENTPD3 as characteristic molecules and immune biomarkers of comorbidity in T2DM and CRC patients, and emphasizes the importance of considering immunological mechanisms in the co-development of T2DM and CRC.
Subject(s)
Colorectal Neoplasms , Diabetes Mellitus, Type 2 , Single-Cell Analysis , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Comorbidity , Gene Expression Regulation, Neoplastic , Molecular Docking Simulation , MaleABSTRACT
The membrane-associated RING-CH 8 protein (MARCH8), a member of the E3 ubiquitin ligase family, has broad-spectrum antiviral activity. However, some viruses hijack MARCH8 to promote virus replication, highlighting its dual role in the viral lifecycle. Most studies on MARCH8 have focused on RNA viruses, leaving its role in DNA viruses largely unexplored. Pseudorabies virus (PRV) is a large DNA virus that poses a potential threat to humans. In this study, we found that MARCH8 inhibited PRV replication at the cell-to-cell fusion stage. Interestingly, our findings proved that MARCH8 blocks gB cleavage by recruiting furin but this activity does not inhibit viral infection in vitro. Furthermore, we confirmed that MARCH8 inhibits cell-to-cell fusion independent of its E3 ubiquitin ligase activity but dependent on the interaction with the cell-to-cell fusion complex (gB, gD, gH, and gL). Finally, we discovered that the distribution of the cell-to-cell fusion complex is significantly altered and trapped within the trans-Golgi network. Overall, our results indicate that human MARCH8 acts as a potent antiviral host factor against PRV via trapping the cell-to-cell fusion complex in the trans-Golgi network.
Subject(s)
Cell Fusion , Herpesvirus 1, Suid , Ubiquitin-Protein Ligases , Virus Replication , trans-Golgi Network , Animals , Humans , Cell Line , Herpesvirus 1, Suid/physiology , trans-Golgi Network/metabolism , trans-Golgi Network/virology , Ubiquitin-Protein Ligases/metabolismABSTRACT
The membrane-associated RING-CH (MARCH) family of proteins are members of the E3 ubiquitin ligase family and are essential for a variety of biological functions. Currently, MARCH proteins are discovered to execute antiviral functions by directly triggering viral protein degradation or blocking the furin cleavage of viral class I fusion proteins. Here, we report a novel antiviral mechanism of MARCH1 and MARCH2 (MARCH1/2) in the replication of Pseudorabies virus (PRV), a member of the Herpesviridae family. We discovered MARCH1/2 restrict PRV replication at the cell-to-cell fusion step. Furthermore, MARCH1/2 block gB cleavage, and this is dependent on their E3 ligase activity. Interestingly, the blocking of gB cleavage by MARCH1/2 does not contribute to their antiviral activity in vitro. We discovered that MARCH1/2 are associated with the cell-to-cell fusion complex of gB, gD, gH, and gL and trap these viral proteins in the trans-Golgi network (TGN) rather than degrading them. Overall, we conclude that MARCH1/2 inhibit PRV by trapping the viral cell-to-cell fusion complex in TGN.
Subject(s)
Herpesvirus 1, Suid , Ubiquitin-Protein Ligases , Virus Replication , trans-Golgi Network , Herpesvirus 1, Suid/physiology , Animals , trans-Golgi Network/virology , trans-Golgi Network/metabolism , Ubiquitin-Protein Ligases/metabolism , Cell Fusion , Swine , Cell Line , Humans , Viral Proteins/metabolism , Viral Proteins/genetics , HEK293 Cells , Pseudorabies/virologyABSTRACT
Voice assistant technologies (VAT) has been part of our daily lives, as a virtual assistant to complete requested tasks. The integration of VAT in dental offices has the potential to augment productivity and hygiene practices. Prior to the adoption of such innovations in dental settings, it is crucial to evaluate their applicability. This study aims to assess dentists' perceptions and the factors influencing their intention to use VAT in a clinical setting. A survey and research model were designed based on an extended Unified Theory of Acceptance and Use of Technology (UTAUT). The survey was sent to 7,544 Ohio-licensed dentists through email. The data was analyzed and reported using descriptive statistics, model reliability testing, and partial least squares regression (PLSR) to explain dentists' behavioral intention (BI) to use VAT. In total, 257 participants completed the survey. The model accounted for 74.2% of the variance in BI to use VAT. Performance expectancy and perceived enjoyment had significant positive influence on BI to use VAT. Perceived risk had significant negative influence on BI to use VAT. Self-efficacy had significantly influenced perceived enjoyment, accounting for 35.5% of the variance of perceived enjoyment. This investigation reveals that performance efficiency and user enjoyment are key determinants in dentists' decision to adopt VAT. Concerns regarding the privacy of VAT also play a crucial role in its acceptance. This study represents the first documented inquiry into dentists' reception of VAT, laying groundwork for future research and implementation strategies.
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Cortical bone loss is intricately associated with ageing and coincides with iron accumulation. The precise role of ferroptosis, characterized by iron overload and lipid peroxidation, in senescent osteocytes remains elusive. We found that ferroptosis was a crucial mode of osteocyte death in cortical bone during ageing. Using a single-cell transcriptome analysis, we identified activating transcription factor 3 (ATF3) as a critical driver of osteocyte ferroptosis. Elevated ATF3 expression in senescent osteocytes promotes iron uptake by upregulating transferrin receptor 1 while simultaneously inhibiting solute carrier family 7-member 11-mediated cystine import. This process leads to an iron overload and lipid peroxidation, culminating in ferroptosis. Importantly, ATF3 inhibition in aged mice effectively alleviated ferroptosis in the cortical bone and mitigated cortical bone mass loss. Taken together, our findings establish a pivotal role of ferroptosis in cortical bone loss in older adults, providing promising prevention and treatment strategies for osteoporosis and fractures.
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Background: The combination therapy of immunotherapy and drug-eluting bead bronchial artery chemoembolization (DEB-BACE) or microwave ablation (MWA) has been attempted as an effective and safe approach for advanced non-small cell lung cancer (NSCLC). However, the outcomes of immunotherapy plus multiple interventional techniques for advanced NSCLC remain unclear. This retrospective study thus aimed to investigate the effectiveness and safety of the maintenance treatment of programmed cell death protein 1 (PD-1) blockade after MWA plus DEB-BACE for advanced NSCLC. Methods: This retrospective cohort study consists of 95 patients with advanced NSCLC who were treated with DEB-BACE between April 2017 and October 2022 and who were allocated to three groups: group A (MWA + DEB-BACE + PD-1 blockade; n=15), group B (MWA + DEB-BACE; n=25), and group C (DEB-BACE alone; n=55). The adverse events (AEs) were compared between the three groups. The outcomes were compared via Kaplan-Meier methods, including median progression-free survival (PFS) and overall survival (OS). Survival analyses were performed via the univariate and multivariate analyses to investigate the prognostic predictors. Results: The overall incidence of AEs in the groups A-C was 53.3% (8/15), 36.0% (9/25), and 32.7% (18/55), respectively, which did not represent a significant difference (P=0.42). No severe AEs (SAEs) occurred. Group A, compared with group B and group C, had a significantly longer estimated median PFS (33.0 vs. 7.0 vs. 3.0 months; P<0.001) and OS (33.0 vs. 13.0 vs. 6.0 months; P=0.002). PD-1 blockade (P=0.006), tumor number (P=0.01), and DEB-BACE/bronchial artery infusion (BAI) chemotherapy cycles (P=0.04) were identified as the predictors of PFS, while the predictors of OS were PD-1 blockade (P<0.001), number of metastases (P<0.001), tumor diameter (P<0.001), and DEB-BACE/BAI cycles (P=0.02). Conclusions: Compared with that of advanced NSCLC treated with MWA plus DEB-BACE or DEB-BACE alone, the maintenance treatment of immunotherapy after MWA plus DEB-BACE might provide a superior prognosis without increasing the risk of AEs.
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Atrial fibrillation (AF) is the most common arrhythmia and its incidence increases with sepsis. However, data on new-onset AF during sepsis hospitalization remain limited in China. We aimed to evaluate the incidence, risk factors, and associated mortality of new-onset AF in sepsis patients in China. We conducted a retrospective study using the National Data Center for Medical Service system, from 1923 tertiary and 2363 secondary hospitals from 31 provinces in China from 2017 to 2019.In total we included 1,425,055 sepsis patients ≥ 18 years without prior AF. The incidence of new-onset AF was 1.49%. Older age, male sex, hypertension, heart failure, coronary disease, valvular disease, and mechanical ventilation were independent risk factor. New-onset AF was associated with a slight increased risk of mortality (adjusted RR 1.03, 95% CI 1.01-1.06). Population attributable fraction suggested AF accounted for 0.2% of sepsis deaths. In this large nationwide cohort, new-onset AF occurred in 1.49% of sepsis admissions and was associated with a small mortality increase. Further research should examine whether optimized AF management can improve sepsis outcomes in China.
Subject(s)
Atrial Fibrillation , Hospital Mortality , Sepsis , Humans , Atrial Fibrillation/mortality , Atrial Fibrillation/epidemiology , Atrial Fibrillation/complications , Sepsis/mortality , Sepsis/complications , Sepsis/epidemiology , Male , Female , Middle Aged , Aged , Risk Factors , China/epidemiology , Retrospective Studies , Incidence , Adult , Aged, 80 and over , Hospitalization/statistics & numerical dataABSTRACT
Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.
Subject(s)
Deep Learning , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Precancerous Conditions , Humans , Middle Aged , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Prospective Studies , Precancerous Conditions/pathologyABSTRACT
BACKGROUND: There are few large-scale analyses comparing local tumor destruction (LTD) or local tumor enucleation/excision (LTE) relative to partial nephrectomy (PN) for patients with T1a renal masses in terms of cancer-specific survival (CSS) and overall survival (OS). We aimed to compare CSS and OS after LTD versus LTE versus PN. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019), we identified patients with clinical T1a renal masses and histologically confirmed kidney cancer treated with LTD, LTE or PN. After 1:1 ratio propensity score matching (PSM), comparisons between the groups were conducted. Kaplan-Meier analysis and log-rank tests were used to compare survival in the matched population. RESULTS: In the overall cohort of 3717 LTD patients versus 1993 LTE patients versus 26935 PN patients, 77.3% of LTD-treated patients and 74.4% of LTE-treated patients were over 60 years old, while only 50.3% of PN-treated patients were over 60 years old. PN was more strongly associated with CSS (hazard ratio (HR)=1.276, P<0.001) and OS (HR=1.112, P<0.001)) than was LTD, while PN was less strongly associated with CSS (HR=1.040, P=0.230) and OS (HR=0.888, P=0.002) than was LTE, not only in the PSM cohort but also in the subgroups of patients with a tumor size ≤3 cm and patients with a tumor size of 3.1-4 cm. CONCLUSIONS: In clinical T1a solid renal mass patients, LTD was associated with lower CSS and OS than LTE and PN, while LTE demonstrated noninferior CSS and superior OS to PN regardless of tumor size.