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The prevalence, etiologies and clinical consequences of tricuspid regurgitation associated with severe degenerative mitral regurgitation
No full textAims The prevalence, the aetiologies, and the clinical features of tricuspid regurgitation (TR) in the context of concomitant degenerative mitral valve (MV) disease are poorly defined. This paper aims to assess the prevalence, determinants, and clinical consequences of TR in severe degenerative mitral regurgitation (DMR) Methods and results Clinical and echocardiographic characteristics were collected among patients with severe DMR. A total of 884 patients were included in our study, 31% with >= moderate TR. Tricuspid valve prolapse (TVP) was the most common aetiology (487 patients, 55%), followed by atrial functional TR (AFTR, 172 patients, 19%) and ventricular functional TR (VFTR, 42 patients, 5%), while TR aetiology was classified as mixed in 183 (21%) patients. Patients with TVP were younger and had a better clinical presentation, few comorbidities, and less haemodynamically relevant TR. Patients with VFTR were characterized by older age, worse clinical presentation, and both highest comorbidity rate and prevalence of >mild TR. Patients with AFTR showed an intermediate profile of clinical presentation and comorbidities and the largest tricuspid annulus (TA) diameter. MV surgery was performed in 785 (88%) patients; 132 (15%) underwent simultaneous TV intervention, more often patients with AFTR (32%). TA dilatation [odds ratio (OR) 3.68, 95% confidence interval (CI) 2.05-6.62, P < 0.001] and >mild TR (OR 9.30, 95% CI 5.10-16.95, P < 0.001) were independently associated with TV intervention. Conclusion In patients with severe DMR, TR presents with different aetiologies, clinical features, and echocardiographic phenotypes that require a comprehensive assessment at the time of DMR surgery to ensure the best management for these patients.Aims The prevalence, the aetiologies, and the clinical features of tricuspid regurgitation (TR) in the context of concomitant degenerative mitral valve (MV) disease are poorly defined. This paper aims to assess the prevalence, determinants, and clinical consequences of TR in severe degenerative mitral regurgitation (DMR) Methods and results Clinical and echocardiographic characteristics were collected among patients with severe DMR. A total of 884 patients were included in our study, 31% with >= moderate TR. Tricuspid valve prolapse (TVP) was the most common aetiology (487 patients, 55%), followed by atrial functional TR (AFTR, 172 patients, 19%) and ventricular functional TR (VFTR, 42 patients, 5%), while TR aetiology was classified as mixed in 183 (21%) patients. Patients with TVP were younger and had a better clinical presentation, few comorbidities, and less haemodynamically relevant TR. Patients with VFTR were characterized by older age, worse clinical presentation, and both highest comorbidity rate and prevalence of >mild TR. Patients with AFTR showed an intermediate profile of clinical presentation and comorbidities and the largest tricuspid annulus (TA) diameter. MV surgery was performed in 785 (88%) patients; 132 (15%) underwent simultaneous TV intervention, more often patients with AFTR (32%). TA dilatation [odds ratio (OR) 3.68, 95% confidence interval (CI) 2.05-6.62, P mild TR (OR 9.30, 95% CI 5.10-16.95, P < 0.001) were independently associated with TV intervention. Conclusion In patients with severe DMR, TR presents with different aetiologies, clinical features, and echocardiographic phenotypes that require a comprehensive assessment at the time of DMR surgery to ensure the best management for these patients.[GRAPHICS]
Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA
Get PDFClinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL
Gender Differences in Obstructive Sleep Apnea: A Preliminary Clinical and Polysomnographic Investigation
No full textBackground/Objectives: Gender differences influence the clinical manifestations, progression, and treatment response in obstructive sleep apnea (OSA) syndrome, suggesting the existence of distinct gender-related phenotypes potentially driven by anatomical, physiological, and hormonal factors. However, the impact of gender on OSA-related cognitive profiles remains unknown. This study aimed to investigate the neuropsychological and polysomnographic (PSG) differences between OSA females and males in order to detect the impact of gender on clinical manifestation and PSG features. Methods: Data were collected from 28 OSA patients (14 females and 14 males matched for age, education, and disease severity). All patients performed a complete neuropsychological evaluation, Epworth sleepiness scale, and whole-night PSG. To evaluate the relationship between specific sleep profiles and cognitive performance, PSG parameters were correlated to scores obtained on neuropsychological tests. Results: Both male and female groups performed within the normal range across all administered neuropsychological tests, according to Italian normative values. Compared with OSA males, female patients showed significantly lower values on the Rey–Osterrieth Complex Figure (ROCF) Recall Test. By contrast, no significant statistical clinical difference emerged between the two OSA groups in terms of clinical manifestation and sleep parameters. Conclusions: This study improves the knowledge on gender-related cognitive impairment in OSA patients. Our preliminary findings demonstrate that the ROCF Recall Test may be altered in OSA females, but not in males. Further longitudinal studies are needed to investigate whether OSA female patients will develop a frank dementia over time
Roles for the long non-coding RNA Pax6os1/PAX6-AS1 in pancreatic beta cell function
Get PDFLong non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell function. Here, we show that an lncRNA-transcribed antisense to Pax6, annotated as Pax6os1/PAX6-AS1, was upregulated by high glucose concentrations in human as well as murine beta cell lines and islets. Elevated expression was also observed in islets from mice on a high-fat diet and patients with type 2 diabetes. Silencing Pax6os1/PAX6-AS1 in MIN6 or EndoC-βH1 cells increased several beta cell signature genes’ expression. Pax6os1/PAX6-AS1 was shown to bind to EIF3D, indicating a role in translation of specific mRNAs, as well as histones H3 and H4, suggesting a role in histone modifications. Important interspecies differences were found, with a stronger phenotype in humans. Only female Pax6os1 null mice fed a high-fat diet showed slightly enhanced glucose clearance. In contrast, silencing PAX6-AS1 in human islets enhanced glucose-stimulated insulin secretion and increased calcium dynamics, whereas overexpression of the lncRNA resulted in the opposite phenotype
Every minute counts: a network meta-analysis comparing the effect of prophylactic endovascular procedures in abnormal placentation
Get PDFBackground: Preventing postpartum haemorrhage remains a high priority worldwide. We aimed to provide all available evidence comparing maternal and neonatal outcomes of different prophylactic endovascular procedures in patients with abnormal placentation. Methods: Pubmed, Embase and ClinicalTrials.gov databases were searched from inception to Nov, 2024, using relevant key words. Studies comparing outcomes of women undergoing or not prophylactic endovascular procedures in planned cesarean delivery in patients with antenatally suspected or confirmed PAS, placenta previa or both were included. An arm-based random effect frequentist network meta-analysis was performed. All available maternal and neonatal outcomes were evaluated. Results: Three randomized controlled trials and 59 observational studies were eligible reporting on 6973 women (42.9% did not undergo any endovascular procedure, 26.7% underwent aortic balloon occlusion, REBOA, 16.6%, internal iliac balloon occlusion, PBO-IIA, 5.8%, common iliac artery occlusion, PBO-CIA, placement, and 7.8% underwent uterine artery embolization, UAE). The pooled network analysis showed that all prophylactic endovascular procedures were associated with reduced perioperative blood loss, with proximal balloon occlusion (REBOA) having the strongest effect (SMD −1.80 L, 95%CI −2.38;-1.21; I2 = 97.2%). Also, peripartum hysterectomy rates were significantly lower in women undergoing prophylactic UAE and REBOA compared to the control group; moreover, patients with placenta previa without any prophylactic endovascular procedure had a 4 to fivefold increased risk of peripartum hysterectomy compared to the REBOA group (I2 = 20.6%). REBOA was associated with a significant decrease in massive transfusion rates (I2 = 0%), surgery-related complications (I2 = 0%), ICU admissions (I2 = 40.3%), and units of red blood cells transfused (I2 = 92.8%), compared to PBO-IIA and control groups. The control group versus women undergoing prophylactic UAE showed a significant increase in total operative time (I2 = 96.5%) and Clavien-Dindo grade IV post-operative complications (I2 = 26%), compared to REBOA. All prophylactic endovascular procedures had a comparable risk ratio in terms of units of platelets transfused, maternal mortality, and use of additional post-operative bilateral uterine artery embolization among the treatment groups. As for neonatal outcomes, no significant differences were detected. Conclusions: Although the preponderance of observational studies suggests caution in interpreting the results of this meta-analysis, our findings suggest that prophylactic endovascular interventional procedures, particularly aortic balloon occlusion, may substantially improve clinical outcomes in women with PAS, placenta previa or both. PROSPERO registration number: CRD4202457398
Controversies in NEN: An ENETS position statement on the management of locally advanced neuroendocrine neoplasia of the small intestine and pancreas without distant metastases
No full textLocally advanced neuroendocrine neoplasms (NENs) are defined by extensive local invasion in the absence of distant metastases, although specific definitions may vary among study groups. While most patients with NENs present with localized or metastatic disease, a smaller subset is diagnosed with locally advanced tumors. Management of this subgroup remains particularly challenging, owing to the limited evidence base and lack of consensus regarding optimal therapeutic strategies. This guidance document synthesizes the current evidence and expert knowledge on the management of locally advanced NENs of the small intestine and pancreas, addressing four clinically relevant key questions that aim to inform best practice in these patients
Sexually transmitted infections in men who have sex with men with tenofovir/emtricitabine- or cabotegravir-resistant HIV
No full textObjective: Sexually transmitted infections (STIs) are associated with an increased risk of HIV transmission, raising concerns in case of virus resistant (R) to the drugs currently approved for pre-exposure prophylaxis (PrEP). We explored the incidence of STIs in men who have sex with men with HIV (MSMWH) and resistance to tenofovir/emtricitabine (TXF/FTC) and/or cabotegravir (CAB). Design: Retrospective, cohort study on MSMWH on antiretroviral treatment (ART) with ≥1 genotyping resistance test (GRT) including integrase. Methods: The following STIs were included in the analysis: Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma/Ureaplasma spp. (only if symptomatic), early syphilis (primary, secondary, or early latent), and mpox infections. Poisson regression modeled incidence rates (IRs) and 95% confidence intervals (95%CIs). Results: Overall, 638 MSMWH evaluated: 67 (10.5%) TXF/FTC-R, 4 (0.6%) CAB-R, and 13 (2.0%) TXF/FTC+CAB-R. During a median follow-up of 9.6 (7.3-11.7) years [5908 person-years-of-follow-up (PY)], 307/638 (48.1%) individuals developed 744 STIs: IR = 12.6 (95%CI = 11.7-13.5)/100 PY. Among 307 MSMWH who developed STIs, 34 (11.1%) had ≥1 STI at HIV load ≥200 copies/mL [21 (6.8%) ≥1000 copies/mL]. Thirty-two (10.4%) of 307 individuals with ≥1 incident STI had TXF/FTC- and/or CAB-R strains; 5 (15.6%) of these developed STIs at HIV load ≥200 copies/mL (specifically, ≥1000 copies/mL). STI incidence was significantly lower in presence of drug resistance [either TXF/FTC- or CAB-R: IR = 8.2 (95%CI = 6.2-10.5)/100 PY and IRR = 0.6 (95%CI = 0.5-0.8); TXF/FTC+CAB-R: IR = 2.9 (95%CI = 0.8-7.3)/100 PY and IRR = 0.2 (95%CI = 0.1-0.5)]. Conclusions: In our cohort of MSMWH, STI incidence was non-negligible, although reduced, in presence of resistance to TXF/FTC and/or CAB. Discussion of HIV resistance test results should include the risk of sexual transmission uncontrolled by pre-exposure prophylaxis
Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS
No full textImportance: Early treatment choice in relapsing-remitting multiple sclerosis (RRMS) is prognostically crucial, yet robust comparative data on cladribine vs sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive patients with RRMS are limited. Objective: To compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS. Design, setting, and participants: This comparative effectiveness research study used data from 108 Italian multiple sclerosis (MS) centers affiliated with the Italian Multiple Sclerosis and Related Disorders Register. All treatment-naive patients with RRMS who initiated cladribine or an S1PRM (fingolimod, ozanimod, or ponesimod) between January 2011 and October 2021 and had at least 12 months of follow-up were included. Propensity score matching and pairwise censoring were used to balance baseline differences and follow-up duration. Patient data were extracted from the register in September 2024. Exposure: Initiation of cladribine or an S1PRM, with duration reflecting clinical practice. Main outcomes and measures: The primary outcome was no evidence of disease activity (NEDA-3) and its subcomponents. Secondary analyses evaluated disability accrual subdivided into progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW), plus variables associated with treatment response. Cox proportional hazards models, adjusted for visit and magnetic resonance imaging (MRI) frequency, were used to compare outcomes. Results: Of the 1587 patients (485 taking cladribine and 1102 taking S1PRMs), matching yielded 475 pairs (950 individuals; mean [SD] age, 34.7 [10.7] years; 686 female [72.2%]), with a median (IQR) follow-up period of 25 (12-60) months. For the cladribine vs S1PRM groups, no significant differences were observed in relapse rates (72 patients [15.2%] vs 76 patients [16.0%]), MRI activity (137 patients [31.3%] vs 145 patients [34.8%]), or NEDA-3 loss (194 patients [44.4% vs 219 patients [52.2%]). Cladribine was associated with a lower risk of disability worsening vs S1PRM (54 patients [11.4%] vs 70 patients [14.7%]; hazard ratio [HR], 0.64; 95% CI, 0.42-0.96; P = .03), a finding that was confirmed in sensitivity analyses for patients younger than 40 years, those whose diagnoses were made according to the 2017 McDonald Criteria, and those with Expanded Disability Status Scale score less than or equal to 3.0. This was mainly driven by reduced PIRA risk with cladribine (HR, 0.40; 95% CI, 0.20-0.79; P = .009), with no RAW difference. After 36 months, patients treated with cladribine showed higher relapse risk (HR, 1.81; 95% CI, 1.02-3.20; P = .04) and increased NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67; P = .01). Discontinuation rates were similar (HR, 0.92; 95% CI, 0.67-1.15; P = .58). Conclusions and relevance: These findings suggest cladribine was associated with superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control
Post-pandemic upsurge in Group A Streptococcus infections at an Italian tertiary university hospital
Get PDFStreptococcus pyogenes (Group A Streptococcus; GAS) is a pathogen of global significance. In the pre-antibiotic era, GAS was a major cause of childhood morbidity and mortality, but its spread rapidly declined until the mid-2010s. The continuing increase in GAS infections, associated with the expansion of the M1(UK) lineage, was observed first in the United Kingdom (UK) and, later, globally. Here, we endeavor to assess the various determinants underlying the post-pandemic GAS upsurge, with a focus on microbial genomic features. We performed an epidemiological analysis of all laboratory-confirmed GAS infections identified between June 2018 and June 2024 at a tertiary University Hospital located in Northern Italy, dividing them into three levels of severity: mild, moderate, and invasive GAS infections. A subset of 34 representative GAS isolates identified in the post-pandemic period were subjected to short- and long-read whole genome sequencing (WGS). Of the 531 GAS cases analyzed during this period, the majority (415, 78.2%) occurred in the last two years. This increase in GAS cases correlated with a significant shift in infection severity: among the 118 GAS cases identified in the June 2018-May 2022 period, only one resulted in an invasive infection (1/118, 0.8%). In contrast, among the 531 GAS cases identified in the June 2022-May 2024 period, 32 caused invasive infections (32/531, 7.9%). WGS of 34 isolates (including 15 invasive isolates) identified 11 different emm types, the most frequent being emm1 (9 isolates) followed by emm12 (7 isolates), then emm89 and emm28 (4 isolates each). Among the emm1 isolates, the M1(UK) sublineage was the most represented (8 out of 9 isolates), with the remaining "singleton" belonging to the M1(13SNP) sublineage
An International Expert-Based CONsensus on Indications and Techniques for aoRtic balloOn occLusion in the Management of Ruptured Abdominal Aortic Aneurysms (CONTROL-RAAA)
Get PDFObjective: To report on the recommendations of an expert-based consensus on the indications, timing, and techniques of aortic balloon occlusion (ABO) in the management of ruptured abdominal aortic aneurysms (rAAA). Methods: Eleven facilitators created appropriate statements regarding the study issues that were voted on using a 4-point Likert scale with open-comment fields, by a selected panel of international experts (vascular surgeons and interventional radiologists) using a 3-round modified Delphi consensus procedure (study period: January-April 2023). Based on the experts’ responses, only the statements reaching grade A (full agreement ≥75%) or B (overall agreement ≥80% and full disagreement <5%) were included in the final study report. The consistency of each round’s answers was also graded using Cohen’s kappa, the intraclass correlation coefficient, and, in case of double resubmission, Fleiss kappa. Results: Sixty-three experts were included in the final analysis and voted on 25 statements related to indication and timing (n=6), and techniques (n=19) of ABO in the setting of rAAA. Femoral sheath or ABO should be preferably placed in the operating room, via a percutaneous transfemoral access, on a stiff wire (grade B, consistency I), ABO placement should be suprarenal and last less than 30 minutes (grade B, consistency II), postoperative peripheral vascular status (grade A, consistency II) and laboratory testing every 6 to 12 hours (grade B, consistency) should be assessed to detect complications. Formal training for ABO should be implemented (grade B, consistency I). Most of the statements in this international expert-based Delphi consensus study might guide current choices for indications, timing, and techniques of ABO in the management of rAAA. Clinical practice guidelines should incorporate dedicated statements that can guide clinicians in decision-making. Conclusions: At arrival and during both open or endovascular procedures for rAAA, selective use of intra-aortic balloon occlusion is recommended, and it should be performed preferably by the treating physician in aortic pathology. Clinical Impact: This is the first consensus study of international vascular experts aimed at defining the indications, timing, and techniques of optimal use of ABO in the clinical setting of rAAA. Aortic occlusion by endovascular means (or ABO) is a quick procedure in properly trained hands that may play an important role as a temporizing measure until the definitive aortic repair is achieved, whether by endovascular or open means. Since data on its use in hemodynamically unstable patients are limited in the literature, owing to practical challenges in the performance of well-conducted prospective studies, understanding real-world use by experts is of importance in addressing critical issues and identifying main gaps in knowledge