Abstract Background Despite widespread adoption of the six-item erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a clinical trial end point, there are currently ...no objective data on what constitutes a minimal clinically important difference (MCID) in the EF domain. Objective Estimate the MCID for the IIEF EF domain. Design, setting, and participants Anchor-based MCIDs were estimated using data from 17 randomized, double-blind, placebo-controlled, parallel-group clinical trials of the phosphodiesterase type 5 inhibitor (PDE5-I) tadalafil for 3345 patients treated for 12 wk. Measurements The anchor for the MCID is the minimal improvement measure calculated using change from baseline to 12 wk on IIEF question 7: “Over the past 4 weeks, when you attempted sexual intercourse how often was it satisfactory for you?” MCIDs were developed using analysis of variance (ANOVA)– and receiver operating characteristic (ROC)–based methods in a subset of studies ( n = 11) by comparing patients with and without minimal improvement ( n = 863). MCIDs were validated in the remaining six studies ( n = 377). Results and limitations The ROC-based MCID for the EF domain was 4, with estimated sensitivity and specificity of 0.74 and 0.73, respectively. MCIDs varied significantly ( p < 0.0001) according to baseline ED severity (mild: 2; moderate: 5; severe: 7). MCIDs consistently distinguished between patients in the validation sample classified as no change or minimally improved overall and by geographic region, ED etiology, and age group. MCIDs did not differ by age group, geographic region, or ED etiology. Current analyses were based on 17 clinical trials of tadalafil. Results need to be replicated in studies using other PDE5-Is or in nonpharmacologic intervention studies. Conclusions The contextualization of treatment-related changes in terms of clinically relevant improvement is essential to understanding treatment efficacy, to interpreting results across studies, and to managing patients effectively. This analysis provides, for the first time, anchor-based estimates of MCIDs in the EF domain score of the IIEF.
Objectives We sought to identify factors associated with the timing and surgical outcomes of the superior cavopulmonary anastomosis. Methods The Pediatric Heart Network's Infant Single Ventricle ...trial database identified participants who underwent superior cavopulmonary anastomosis. Factors potentially associated with age at superior cavopulmonary anastomosis, length of stay and death by 14 months of age were evaluated. Factors included subject demographics, cardiac anatomy, measures from neonatal hospitalization and pre–superior cavopulmonary anastomosis visit, adverse events, echocardiographic variables, intraoperative variables, superior cavopulmonary anastomosis type, and number of concurrent cardiac surgical procedures. Age at superior cavopulmonary anastomosis was analyzed using Cox proportional hazards regression. Natural log length of stay was analyzed by multiple linear regression. Results Superior cavopulmonary anastomosis was performed in 193 subjects at 5.2 months of age (interquartile range, 4.2, 6.2) and weight of 5.9 kg (interquartile range, 5.3, 6.6). The median length of stay was 7 days (interquartile range, 6, 10). There were 3 deaths and 1 transplant during the superior cavopulmonary anastomosis hospitalization, and 3 deaths and 3 transplants between discharge and 14 months of age. Age at superior cavopulmonary anastomosis was associated with center and interstage adverse events. A longer length of stay was associated with younger age and greater case complexity. Superior cavopulmonary anastomosis type, valve regurgitation, ventricular ejection fraction, and ventricular end-diastolic pressure were not independently associated with age at superior cavopulmonary anastomosis or the length of stay. Conclusions Greater case complexity and more frequent interstage adverse events are associated with an earlier age at superior cavopulmonary anastomosis. Significant variation in age at superior cavopulmonary anastomosis among centers, independent of subject factors, highlights a lack of consensus regarding the optimal timing. Factors associated with length of stay could offer insights for improving presuperior cavopulmonary anastomosis care and surgical outcome.
Despite adoption of the successful vaginal insertion (Q2) and intercourse (Q3) items of the sexual encounter profile (SEP) as end points in clinical trials, there are no objective data on what ...constitute minimal clinically important differences (MCIDs) in these items.
The objective was to estimate the MCID for SEP Q2 and Q3.
Using data from 17 randomized, controlled trials of the phosphodiesterase type 5 inhibitor tadalafil, we estimated MCIDs for the SEP using anchor‐based approaches. The 17 studies included 3,345 patients treated for 12 weeks. The anchor for the MCID is the minimal improvement measure calculated using change from baseline to 12 weeks on the following question: “Over the past 4 weeks, when you attempted sexual intercourse how often was it satisfactory for you?” MCIDs were developed using analysis of variance‐ and receiver operating characteristic (ROC)‐based methods in a subset of studies (N = 11) by comparing patients with and without minimal improvement (N = 863). MCIDs were validated in the remaining six studies (N = 377).
The main outcome measures of this study are SEP Q2 and Q3.
Using the ROC‐based approach, the MCID for SEP Q2 was 21.4%, with estimated sensitivity of 0.55 and specificity of 0.73; the MCID for SEP Q3 was 23.0%, with estimated sensitivity of 0.72 and specificity of 0.78. MCIDs for SEP Q2/Q3 varied significantly (P < 0.001) according to baseline erectile dysfunction (ED) severity. MCIDs distinguished between patients in the validation sample classified as no change or minimally improved in each ED etiology, ED duration, and age group, but less well across geographic regions.
The contextualization of treatment‐related changes into clinically relevant terms is essential to understanding treatment efficacy, interpreting results across studies, and for effective patient management. Overall, there was a better balance between sensitivity and specificity of the MCIDs using the ROC‐based approach for the SEP intercourse success item than for the vaginal insertion item. Araujo AB, Allen KR, Ni X, and Rosen RC. Minimal clinically important differences in the vaginal insertion and successful intercourse items of the Sexual Encounter Profile. J Sex Med 2012;9:169–179.
Objective For infants with single ventricle malformations undergoing staged repair, interstage mortality is reported at 2% to 20%. The Single Ventricle Reconstruction trial randomized subjects with a ...single morphologic right ventricle undergoing a Norwood procedure to a modified Blalock–Taussig shunt (MBTS) or a right ventricle-to-pulmonary artery shunt (RVPAS). The aim of this analysis was to explore the associations of interstage mortality and shunt type, and demographic, anatomic, and perioperative factors. Methods Participants in the Single Ventricle Reconstruction trial who survived to discharge after the Norwood procedure were included (n = 426). Interstage mortality was defined as death postdischarge after the Norwood procedure and before the stage II procedure. Univariate analysis and multivariable logistic regression were performed adjusting for site. Results Overall interstage mortality was 50 of 426 (12%)—13 of 225 (6%) for RVPAS and 37 of 201 (18%) for MBTS (odds ratio OR for MBTS, 3.4; P < .001). When moderate to severe postoperative atrioventricular valve regurgitation (AVVR) was present, interstage mortality was similar between shunt types. Interstage mortality was independently associated with gestational age less than 37 weeks (OR, 3.9; P = .008), Hispanic ethnicity (OR, 2.6; P = .04), aortic atresia/mitral atresia (OR, 2.3; P = .03), greater number of post-Norwood complications (OR, 1.2; P = .006), census block poverty level ( P = .003), and MBTS in subjects with no or mild postoperative AVVR (OR, 9.7; P < .001). Conclusions Interstage mortality remains high at 12% and is increased with the MBTS compared with the RVPAS if postoperative AVVR is absent or mild. Preterm delivery, anatomic, and socioeconomic factors are also important. Avoiding preterm delivery when possible and close surveillance after Norwood hospitalization for infants with identified risk factors may reduce interstage mortality.
Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of ...karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.
Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This ...perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.
Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation ...analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.
Influenza is a viral respiratory disease having a major impact on public health. Influenza A virus (IAV) usually causes mild transitory disease in humans. However, in specific groups of individuals ...such as severely obese, the elderly, and individuals with underlying inflammatory conditions, IAV can cause severe illness or death. In this review, relevant small and large animal models for human IAV infection, including the pig, ferret, and mouse, are discussed. The focus is on the pig as a large animal model for human IAV infection as well as on the associated innate immune response. Pigs are natural hosts for the same IAV subtypes as humans, they develop clinical disease mirroring human symptoms, they have similar lung anatomy, and their respiratory physiology and immune responses to IAV infection are remarkably similar to what is observed in humans. The pig model shows high face and target validity for human IAV infection, making it suitable for modeling many aspects of influenza, including increased risk of severe disease and impaired vaccine response due to underlying pathologies such as low-grade inflammation. Comparative analysis of proteins involved in viral pattern recognition, interferon responses, and regulation of interferon-stimulated genes reveals a significantly higher degree of similarity between pig, ferret, and human compared with mice. It is concluded that the pig is a promising animal model displaying substantial human translational value with the ability to provide essential insights into IAV infection, pathogenesis, and immunity.
Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a ...major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.
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