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Importance: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. Objective: To investigate the genetics of APs and affiliated arrhythmias. Design, Setting, and Participants: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. Exposures: Sequence variants. Main Outcomes and Measures: Genome-wide significant association of sequence variants with APs. Results: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. Conclusions and Relevance: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

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This study was performed to evaluate the impact on the upper airway and nasal cavity of a new minimally invasive surgical and miniscrew-assisted rapid palatal expansion (MISMARPE) technique for the treatment of adult patients with transverse maxillary deficiency, in comparison to surgically assisted rapid palatal expansion (SARPE). Computed tomography scans of 21 MISMARPE and 16 SARPE patients were obtained preoperatively (T0) and at the end of the activation period (T1) and analysed. Linear and volumetric measurements were performed in the dental, alveolar, nasal cavity, and oropharynx regions. Generalised estimating equations were used to consider the intervention time and surgery type, and their interaction. In both groups, measurements were increased at T1 (P < 0.001), except for oropharynx volume (P > 0.05). A greater expansion in nasal cavity floor and median palatal suture was shown for MISMARPE when compared to SARPE (P < 0.001), with the same degree of expander activation (P = 0.094). A trapezoidal (coronal plane) and 'V' shape (axial plane) expansion pattern, was observed after MISMARPE. Both surgical techniques were effective for maxillary expansion in adults. However, MISMARPE was performed without osteotomy of the pterygomaxillary suture, in an outpatient setting and with local anaesthesia.

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Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

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Although a number of high-risk breast cancer genes have been identified, including BRCA1 and BRCA2, the risk profile of many high-risk families cannot be explained using known breast cancer genes. Previously, we have shown strong indications of new breast cancer risk loci at chromosomes 2p, 6q, and 14q in a family of six generations including 10 breast cancer cases. In this study, we identified and traced four new family branches descending from siblings of the parents in the top generation of the studied family. One distantly related branch included four breast cancer cases, two of whom were diagnosed at age < 45 years. DNA samples from the cases were typed at selected polymorphic markers from all three chromosome loci, to test identical origin of the haplotypes. All four cases were shown to segregate a common 6q haplotype with a region identical to the previously identified 6q haplotype. The data strongly support a new breast cancer locus at 6q, and narrow it down to a 17 MB interval at 6q15-q21.

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Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure: Genotype. Main Outcomes and Measures: Pericarditis. Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein ß (encoded by CEBPB). Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.

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The present study highlighted the repositioning of the drug dapsone (DDS) for cancer therapy. Due to its mechanism of action, DDS has a dual effect as an antibiotic and as an anti-inflammatory/immunomodulator; however, at high doses, it has important adverse effects. The derivative DDS-13 [N,N'-(sulfonyl bis (4,1-phenylene)) dioctanamide] was synthesized through an N-acylation reaction to compare it with DDS. Its cytotoxic effects in cancer cells (DU145 and HeLa) and non-cancer cells (HDFa) were observed at concentrations ranging 0.01-100 µM and its physicochemical/pharmacokinetic properties were analyzed using the SwissADME tool. The objectives of the present study were to evaluate the anticancer activity of both DDS and DDS-13 and to identify the physicochemical and pharmacokinetic properties of DDS-13. The results showed that DDS-13 presented a cytotoxic effect in the DU145 cell line (IC50=19.06 µM), while DDS showed a cytotoxic effect on both the DU145 (IC50=11.11 µM) and HeLa (IC50=13.07 µM) cell lines. DDS-13 appears to be a good cytotoxic candidate for the treatment of prostate cancer, while DDS appears to be a good candidate for both cervical and prostate cancer. Neither candidate showed a cytotoxic effect in non-cancerous cells. The different pharmacokinetic properties of DDS-13 make it a new candidate for evaluation in preclinical models for the treatment of cancer.

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Estrogen receptor-positive (ER+) breast cancer generally confers a more favorable prognosis than ER-negative cancer, however, a different picture is emerging for BRCA2 mutation carriers and young patients. We used nationwide data from population-based registries to study prognostic effects in those two groups. Of all 2817 eligible women diagnosed with breast cancer in Iceland during 1980-2004, 85% had been tested for the Icelandic 999del5 BRCA2 (c.771_775delTCAAA) founder pathogenic variant. We compared breast cancer-specific survival, effects of ER status, other clinical parameters, and treatment, between three mutually exclusive groups: BRCA2-carriers, non-carriers diagnosed 40 years or younger, and older non-carriers. Prevalence of the BRCA2 mutation among tested patients <=40 years of age was 21.0%, but it was 5.4% among women diagnosed >40 years of age. For ER+ cancer, breast cancer-specific 15-year survival was 49.7%, 55.2%, and 74.7%, among BRCA2-carriers, young and older non-carriers, respectively, whereas for ER-negative cancer, survival was similar (64.0-69.3%) for all three groups. Neither BRCA2 carriers nor young non-carriers did tumor grade 3 predict worse survival than did tumor grade 1. The adverse outcome for the young cases cannot be explained by BRCA2 mutations, as carriers were excluded from the group. Those two clinically important patient groups need special attention with respect to treatment choices, in particular, if diagnosed with ER+ tumors. It is thus advisable to have knowledge of BRCA2 status when treatment decisions are made. Finally, it is important to understand the biological basis for the specific nature of ER+ tumors in young women and BRCA2 carriers.

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The disruption of endoplasmic reticulum (ER) homeostasis occurs in many human diseases. Atlastins (ATLs) maintain the branched network of the ER. The dysregulation of ATL2, located at ER network junctions, has been associated with cancer. ATL2 is necessary for lipid droplet formation in murine breast tissue. Thus, we analyzed whether ATL2 has a role in human breast cancer (BC) pathology. The expression of ATL2 variant ATL2-2 was analyzed in breast tumors from the BC cohorts of the TCGA, METABRIC, and two independent Icelandic cohorts, Cohort 1 and 2; its association with clinical, pathological, survival, and cellular pathways was explored. ATL2-2 mRNA and protein expression were higher in breast tumors than in normal tissue. ATL2-2 mRNA associated with tumor characteristics that indicate a worse prognosis. In METABRIC, high ATL2-2 mRNA levels were associated with shorter BC-specific survival (BCSS) in patients with estrogen-receptor-positive luminal breast tumors, which remained significant after correction for grade and tumor size (HR 1.334, CI 1.063-1.673). Tumors with high ATL2 mRNA showed an upregulation of hallmark pathways MYC targets v1, E2F targets, and G2M checkpoint genes. Taken together, the results suggest that high levels of ATL2-2 may support BC progression through key cancer driver pathways.

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Background Long-QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1, KCNH2, and SCN5A. The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ1, 3 in KCNH2, 2 in cardiomyopathy genes MYBPC3 and PKP2, and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms (P=4.2×10-7; odds ratio [OR], 38.6; P=8.4×10-10, OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death (P=0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval (P=1.8×10-44; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation.

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AIMS: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. METHODS AND RESULTS: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. CONCLUSION: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.

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INTRODUCTION: Several UK military expeditions have successfully used physiological sensors to monitor participant's physiological responses to challenging environmental conditions. This article describes the development and trial of a multimodal wearable biosensor that was used during the first all-female unassisted ski crossing of the Antarctic land mass. The project successfully transmitted remote real-time physiological data back to the UK. The ergonomic and technical lessons identified have informed recommendations for future wearable devices. METHOD: The biosensor devices were designed to be continuously worn against the skin and capture: HR, ECG, body surface temperature, bioimpedance, perspiration pH, sodium, lactate and glucose. The data were transmitted from the devices to an android smartphone using near-field technology. A custom-built App running on an android smartphone managed the secure transmission of the data to a UK research centre, using a commercially available satellite transceiver. RESULTS: Real-time physiological data, captured by the multimodal device, was successfully transmitted back to a UK research control centre on 6 occasions. Postexpedition feedback from the participants has contributed to the ergonomic and technical refinement of the next generation of devices. CONCLUSION: The future success of wearable technologies lies in establishing clinical confidence in the quality of the measured data and the accurate interpretation of those data in the context of the individual, the environment and activity being undertaken. In the near future, wearable physiological monitoring could improve point-of-care diagnostic accuracy and inform critical medical and command decisions.

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Dentoskeletal changes in minimally invasive surgically assisted rapid palatal expansion (SARPE) were evaluated using cone beam computed tomography (CBCT). This was a prospective study of 30 patients who underwent minimally invasive SARPE performed under local anaesthesia plus sedation by the same surgeon, in an ambulatory setting. Pre- and postoperative CBCT images were obtained for each patient. A statistically significant increase in the linear transverse dimensions of the maxilla occurred systematically. In the canine region, a mean increase of 5.84 mm occurred at the apex level and 7.82 mm at the crown level. These dimensions were 4.83 mm and 7.68 mm, respectively, in the molar region. The cross-sectional area of the maxilla increased by a mean 12.9 mm2 at the palate level and 23.3 mm2 at the crown level. Dental inclination to the buccal aspect was detected (mean 6.1° at the canines and 8.4° at the first molars). The alveolar process tipped buccally 10° at the molar level. Nasal width increased a mean of 3.0 mm at the canine level. Through a three-dimensional analysis, this study found that minimally invasive SARPE was effective in the correction of transverse maxillary discrepancies> 5 mm in non-growing patients. Although dental inclination to the buccal aspect occurred, significant expansion of the maxilla at the skeletal and dentoalveolar levels was confirmed.

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The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

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Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

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En un trabajo anterior (Caballo et al., 2021) comprobamos la eficacia del programa de Intervención multidimensional para la ansiedad social (IMAS) en la reducción de los síntomas de ansiedad social. En este estudio cuasiexperimental, con medidas pre/postratamiento y seguimiento, hallamos el impacto del programa IMAS en otros problemas relacionados con la ansiedad social. 57 personas diagnosticadas con un trastorno de ansiedad social (TAS), según el DSM-5, contestaron a cuestionarios que medían habilidades sociales, depresión, síntomas del trastorno de la personalidad por evitación, alcoholismo, autoestima, sensibilidad personal, preocupaciones y calidad de vida. Diferentes terapeutas llevaron a cabo el tratamiento en Ecuador, España y Paraguay. Los resultados mostraron importantes mejoras en el postratamiento en prácticamente todos los aspectos evaluados, mejoras que se mantenían a los seis meses. Los tamaños del efecto sobre la eficacia del tratamiento iban de medianos a grandes. Se comparó también el programa IMAS con terapia cognitivo conductual individual y tratamiento farmacológico, con resultados favorables para el programa IMAS. Este nuevo programa para el tratamiento de la ansiedad social tiene un impacto importante en otros problemas relacionados habitualmente con el TAS.

In a previous work (Caballo et al., 2021) we tested the effectiveness of the Multidimensional Intervention for Social Anxiety (MISA) program in reducing social anxiety symptoms. In this quasi-experimental study, with pre/post-treatment and follow-up measures, we examined the impact of the MISA program on other problems related to social anxiety. 57 people diagnosed with social anxiety disorder (SAD), according to DSM-5, were assessed with a diagnostic interview and questionnaires measuring social skills, depression, avoidant personality disorder symptoms, alcoholism, self-esteem, personal sensitivity, worries, and quality of life. Different therapists carried out the treatment in Ecuador, Spain, and Paraguay. The results showed significant improvements at post-treatment in virtually all measures assessing the above variables, improvements that were maintained at six months. Effect sizes on treatment effectiveness ranged from medium to large. The MISA program was also compared with individual cognitive behavioral therapy and pharmacological treatment, with favorable results for the MISA program. In conclusion, this new program for the treatment of social anxiety has a significant impact on other problems usually related to SAD.

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BACKGROUND: The management of hemorrhoidal disease (HD) in patients with bleeding disorders (BD) is challenging. Polidocanol foam sclerotherapy (PFS) is associated with a low rate of bleeding complications. The aim of this study was to compare the efficacy and safety of PFS in the treatment of HD in patients with and without BD. METHODS: This prospective, multicenter, cohort study enrolled patients with (group B) and without (group A) BD, with symptomatic internal HD grades I-III over an 18-month period. All patients were treated with PFS. Patients with congenital BD did not undergo prior replacement therapy and those with acquired BD due to antithrombotic drugs, did not discontinue therapy. Efficacy outcomes included therapeutic success and HD recurrence during a 1-year follow-up period. To evaluate safety the complications related to PFS were recorded. RESULTS: We included 228 patients (group A: 155, group B: 73; male/female: 114/114; mean age: 59.4 ± 15.9 years). The baseline hemorrhoidal disease bleeding grade (p < 0.001) and Sodergren hemorrhoidal symptom severity score (p = 0.019) were higher for group B. The overall therapeutic success rate was 93.4% with an average number of sessions of 1.51 ± 0.74, significantly higher for group B (1.68 ± 0.86 vs 1.43 ± 0.65, p = 0.013). Complications occurred in 11.4% of the patients, with bleeding reported in 4.8%. The majority of complications were mild (96.2%). No significant differences between the two groups were observed for therapeutic success, recurrence, or complication rate. CONCLUSIONS: Patients with BD may have more symptomatic HD at baseline. Even so, PSF showed similar effectiveness and safety in patients with BD compared to patients without BD.

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