Disorders of sex development : timing of diagnosis and management in a single large tertiary center

Background: We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center. Methods: DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts. Results: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 +/- 5.5 years), Klinefelter syndrome (14.5%, 6.8 +/- 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P <0.001). Conclusions: Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients' adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.Peer reviewe

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe

The Finnish Think Tank Landscape : A Mixture of Consensualism and Adversity?

As a common feature of Nordic countries, the Finnish landscape of thinks tanks has been populated by large corporatist interest organisations and government-funded research organisations. In addition to this, since 2005, party-affiliated think tanks form a notable part of the picture. Recently, several small think tanks that are oriented towards specific themes, such as international relations, the environment and feminism, have been founded. This article examines Finnish developments in the field of think tanks with two objectives. First, it gives a general overview of the Finnish think tank landscape. Second, by using interview data and public mission statements of the most prominent think tanks, it explores how these organisations see their role in Finnish society. What is their relationship with media and the political machinery, and how does this relate to their position and activities as either consensual or adversarial actors? It is concluded that redeeming the place of think tanks in the Finnish polity is a continuing challenge, and resorting to adversarial tactics is not a favourable way to do so. This approach has mostly been attempted by neoliberal think tanks that, in the past, have also profited from corporatist structures to enhance their objectives.Peer reviewe

Perioperative Bleeding Requiring Blood Transfusions is Associated With Increased Risk of Stroke After Transcatheter and Surgical Aortic Valve Replacement

Objectives: The authors aimed to investigate the impact of severe bleeding and use of red blood cell (RBC) transfusion on the development of postoperative stroke after surgical (SAVR) and transcatheter aortic valve replacement (TAVR), taken from the FinnValve registry. Design: Nationwide, retrospective observational study. Setting: Five Finnish university hospitals participated in the registry. Participants: A total of 6,463 patients who underwent SAVR (n = 4,333) or TAVR (n = 2,130). Interventions: Patients who underwent TAVR or SAVR with a bioprosthesis with or without coronary revascularization. Measurements and Main Results: The incidence of postoperative stroke after SAVR was 3.8%. In multivariate analysis, the number of trans-fused RBC units (odds ratio [OR], 1.098; 95% confidence interval [CI], 1.064-1.133) was one of the independent predictors of postoperative stroke. The incidence of stroke increased, along with the severity of perioperative bleeding, according to the European Coronary Artery Bypass Grafting (E-CABG) bleeding grades were as follows: grade 0, 2.2% (reference group); grade 1, 3.4% (adjusted OR, 1.841; 95% CI, 1.105-3.066); grade 2, 5.5% (adjusted OR, 3.282; 95% CI, 1.948-5.529); and grade 3, 14.8% (adjusted OR, 7.103; 95% CI, 3.612-13.966). The inci-dence of postoperative stroke after TAVR was 2.5%. The number of transfused RBC units was an independent predictor of stroke after TAVR (adjusted OR, 1.155; 95% CI, 1.058-1.261). The incidence of postoperative stroke increased, along with the severity of perioperative bleeding, as stratified by the E-CABG bleeding grades: E-CABG grade 0, 1.7%; grade 1, 5.3% (adjusted OR, 1.270; 95% CI, 0.532-3.035); grade 2, 10.0% (adjusted OR, 2.898; 95% CI, 1.101-7.627); and grade 3, 30.0% (adjusted OR, 10.706; 95% CI, 2.389-47.987). Conclusions: Perioperative bleeding requiring RBC transfusion and/or reoperation for intrathoracic bleeding is associated with an increased risk of postoperative stroke after SAVR and TAVR. Patient blood management and meticulous preprocedural planning and operative technique aiming to avoid significant perioperative bleeding may reduce the risk of cerebrovascular complications. (C) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Mid-term outcomes of Sapien 3 versus Perimount Magna Ease for treatment of severe aortic stenosis

BackgroundThere is limited information on the longer-term outcome after transcatheter aortic valve replacement (TAVR) with new-generation prostheses compared to surgical aortic valve replacement (SAVR). The aim of this study was to compare the mid-term outcomes after TAVR with Sapien 3 and SAVR with Perimount Magna Ease bioprostheses for severe aortic stenosis.MethodsIn a retrospective study, we included patients who underwent transfemoral TAVR with Sapien 3 or SAVR with Perimount Magna Ease bioprosthesis between January 2008 and October 2017 from the nationwide FinnValve registry. Propensity score matching was performed to adjust for differences in the baseline characteristics. The Kaplan-Meir method was used to estimate late mortality.ResultsA total of 2000 patients were included (689 in the TAVR cohort and 1311 in the SAVR cohort). Propensity score matching resulted in 308 pairs (STS score, TAVR 3.52.2% vs. SAVR 3.52.8%, p=0.918). In-hospital mortality was 3.6% after SAVR and 1.3% after TAVR (p=0.092). Stroke, acute kidney injury, bleeding and atrial fibrillation were significantly more frequent after SAVR, but higher rate of vascular complications was observed after TAVR. The cumulative incidence of permanent pacemaker implantation at 4years was 13.9% in the TAVR group and 6.9% in the SAVR group (p=0.0004). At 4-years, all-cause mortality was 20.6% for SAVR and 25.9% for TAVR (p=0.910). Four-year rates of coronary revascularization, prosthetic valve endocarditis and repeat aortic valve intervention were similar between matched cohorts.Conclusions p id=Par The Sapien 3 bioprosthesis achieves comparable midterm outcomes to a surgical bioprosthesis with proven durability such as the Perimount Magna Ease. However, the Sapien 3 bioprosthesis was associated with better early outcome.Trial registration p id=Par ClinicalTrials.gov Identifier: NCT03385915.Peer reviewe

Ten-year experience with transcatheter and surgical aortic valve replacement in Finland

Aim: We investigated the outcomes of transcatheter (TAVR) and surgical aortic valve replacement (SAVR) in Finland during the last decade. Methods: The nationwide FinnValve registry included data from 6463 patients who underwent TAVR or SAVR with a bioprosthesis for aortic stenosis from 2008 to 2017. Results: The annual number of treated patients increased three-fold during the study period. Thirty-day mortality declined from 4.8% to 1.2% for TAVR (p = .011) and from 4.1% to 1.8% for SAVR (p = .048). Two-year survival improved from 71.4% to 83.9% for TAVR (p <.001) and from 87.2% to 91.6% for SAVR (p = .006). During the study period, a significant reduction in moderate-to-severe paravalvular regurgitation was observed among TAVR patients and a reduction of the rate of acute kidney injury was observed among both SAVR and TAVR patients. Similarly, the rate of red blood cell transfusion and severe bleeding decreased significantly among SAVR and TAVR patients. Hospital stay declined from 10.4 +/- 8.4 to 3.7 +/- 3.4 days after TAVR (p <.001) and from 9.0 +/- 5.9 to 7.8 +/- 5.1 days after SAVR (p <.001). Conclusions: In Finland, the introduction of TAVR has led to an increase in the invasive treatment of severe aortic stenosis, which was accompanied by improved early outcomes after both SAVR and TAVR.Peer reviewe

Transcatheter and Surgical Aortic Valve Replacement in Patients with Recent Acute Heart Failure

Background. Patients with severe aortic stenosis and heart failure have poor prognosis, and their outcomes may be suboptimal even after transcatheter (TAVR) and surgical aortic valve replacement (SAVR). Methods. This is an analysis of the nationwide FinnValve registry, which included patients who underwent primary TAVR or SAVR with a bioprothesis for aortic stenosis. We evaluated the outcome of patients with acute heart failure (AHF) within 60 days prior to TAVR or SAVR. Results. The prevalence of recent AHF was 11.4% (484 of 4241 patients) in the SAVR cohort and 11.3% (210 of 1855 patients) in the TAVR cohort. In the SAVR cohort, AHF was associated with lower 30-day survival (91.3% vs 97.0%; adjusted odds ratio 1.801, 95% confidence interval [CI] 1.125-2.882) and 5-year survival (64.0% vs 81.2%; adjusted hazard ratio 1.482, 95% CI 1.207-1.821). SAVR patients with AHF had higher risk of major bleeding, need of mechanical circulatory support, acute kidney injury, prolonged hospital stay, and composite end-point (30-day mortality, stroke and/or acute kidney injury). Patients with AHF had a trend toward lower 30-day survival (crude rates 95.2% vs 97.9%; adjusted odds ratio 2.028, 95% CI 0.908-4.529) as well as significantly lower 5-year survival (crude rates 45.3% vs 58.5%; adjusted hazard ratio 1.530, 95% CI 1.185-1.976) also after TAVR. AHF increased the risk of acute kidney injury, prolonged hospital stay, and composite end-point after TAVR. Conclusions. Recent AHF is associated with increased risk of mortality and morbidity after SAVR and TAVR. These findings suggest that aortic stenosis patients should be referred for invasive treatment before the development of clinically evident heart failure.Peer reviewe

Transcatheter and surgical aortic valve replacement in patients with left ventricular dysfunction

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