Identifying Epidermolysis Bullosa Patient Needs and Perceived Treatment Benefits:An Explorative Study Using the Patient Benefit Index

Epidermolysis bullosa (EB) is a genetic blistering skin condition for which no cure exists. Symptom alleviation and quality of life are therefore central to EB care. This study aimed to gain insight into EB patient needs and benefits from current clinical care. Two questionnaires were administered cross-sectionally to adult EB patients at the Dutch expertise centre for blistering diseases. Patient needs and benefits were analyzed using the patient benefit index survey (PBI-S). Ancillary data were compiled pertaining to self-reported EB severity, pain and pruritus, as well as current and previous treatments. In total, 104 participants were included (response rate 69.8%). Sixty-eight participants comprised the analyzed cohort (n = 36 omitted from analysis). The needs given the highest importance were to get better skin quickly (64.7%) and to be healed of all skin alterations (61.8%). A positive correlation between pain and EB severity and the importance of most needs was observed. Minimal clinically important differences within the PBI-S, relating to reported benefits from clinical care, were reported by 60.3% of the cohort. This study highlights a discrepancy between patient needs and feasible treatment outcomes. Utilizing the PBI-S in conjunction with well-established multidisciplinary care may catalyze the process of tailoring treatments to the needs of individual patients

Paraneoplastic pemphigus associated with post-transplant lymphoproliferative disorder after small bowel transplantation

Background PNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. Methods Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy. Results The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. Conclusion It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation

Gain-of-function mutation in ubiquitin ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues

The start codon c.1A>G mutation in KLHL24, encoding ubiquitin ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon. In skin, KLHL24-ΔN28 leads to gain of function, excessively targeting intermediate filament keratin-14 for proteasomal degradation and ultimately causing epidermolysis bullosa simplex (EBS). The majority of patients with EBS are also diagnosed with dilated cardiomyopathy (DCM), but the pathological mechanism in the heart is unknown. As desmin is the cardiac homolog of keratin-14, we hypothesized that KLHL24-ΔN28 leads to excessive degradation of desmin, resulting in DCM. Dynamically loaded engineered heart tissues (dyn-EHTs) were generated from human-induced pluripotent stem cell–derived (hiPSC-derived) cardiomyocytes from 2 patients and 3 nonfamilial controls. Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients’ explanted heart. This was accompanied by tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation. KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. To conclude, presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function, which can be prevented by restoring desmin protein levels

Assessing the Effects of Personal Characteristics and Context on U.S. House Speakers’ Leadership Styles, 1789-2006

Research on congressional leadership has been dominated in recent decades by contextual interpretations that see leaders’ behavior as best explained by the environment in which they seek to exercise leadership—particularly, the preference homogeneity and size of their party caucus. The role of agency is thus discounted, and leaders’ personal characteristics and leadership styles are underplayed. Focusing specifically on the speakers of the U.S. House of Representatives from the first to the 110th Congress, we construct measures of each speaker’s commitment to comity and leadership assertiveness. We find the scores reliable and then test the extent to which a speaker’s style is the product of both political context and personal characteristics. Regression estimates on speakers’ personal assertiveness scores provide robust support for a context-plus-personal characteristics explanation, whereas estimates of their comity scores show that speakers’ personal backgrounds trump context

Burden of non-communicable disease studies in Europe: a systematic review of data sources and methodological choices

Background: Assessment of disability-adjusted life years (DALYs) resulting from non-communicable diseases (NCDs) requires specific calculation methods and input data. The aims of this study were to (i) identify existing NCD burden of disease (BoD) activities in Europe; (ii) collate information on data sources for mortality and morbidity; and (iii) provide an overview of NCD-specific methods for calculating NCD DALYs. Methods: NCD BoD studies were systematically searched in international electronic literature databases and in grey literature. We included all BoD studies that used the DALY metric to quantify the health impact of one or more NCDs in countries belonging to the European Region. Results: A total of 163 BoD studies were retained: 96 (59%) were single-country or sub-national studies and 67 (41%) considered more than one country. Of the single-country studies, 29 (30%) consisted of secondary analyses using existing Global Burden of Disease (GBD) results. Mortality data were mainly derived (49%) from vital statistics. Morbidity data were frequently (40%) drawn from routine administrative and survey datasets, including disease registries and hospital discharge databases. The majority (60%) of national BoD studies reported mortality corrections. Multimorbidity adjustments were performed in 18% of national BoD studies. Conclusion: The number of national NCD BoD assessments across Europe increased over time, driven by an increase in BoD studies that consisted of secondary data analysis of GBD study findings. Ambiguity in reporting the use of NCD-specific BoD methods underlines the need for reporting guidelines of BoD studies to enhance the transparency of NCD BoD estimates across Europe

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies

Burden of disease attributable to risk factors in European countries: a scoping literature review

Objectives: Within the framework of the burden of disease (BoD) approach, disease, and injury burden estimates attributable to risk factors are a useful guide for policy formulation and priority setting in disease prevention. Considering the important differences in methods, and their impact on burden estimates, we conducted a scoping literature review to: (1) map the BoD assessments including risk factors performed across Europe, and (2) identify the methodological choices in comparative risk assessment (CRA) and risk assessment methods. Methods: We searched multiple literature databases, including grey literature websites, and targeted public health agencies' websites. Results: A total of 113 studies were included in the synthesis and further divided into independent BoD assessments (54 studies) and studies linked to the Global Burden of Disease (59 papers). Our results showed that the methods used to perform CRA varied substantially across independent European BoD studies. While there were some methodological choices that were more common than others, we did not observe patterns in terms of country, year, or risk factor. Each methodological choice can affect the comparability of estimates between and within countries and/or risk factors since they might significantly influence the quantification of the attributable burden. From our analysis, we observed that the use of CRA was less common for some types of risk factors and outcomes. These included environmental and occupational risk factors, which are more likely to use bottom-up approaches for health outcomes where disease envelopes may not be available. Conclusions: Our review also highlighted misreporting, the lack of uncertainty analysis, and the under-investigation of causal relationships in BoD studies. Development and use of guidelines for performing and reporting BoD studies will help understand differences, and avoid misinterpretations thus improving comparability among estimates.info:eu-repo/semantics/publishedVersio

Burden of disease attributable to risk factors in European countries: a scoping literature review

Objectives: Within the framework of the burden of disease (BoD) approach, disease, and injury burden estimates attributable to risk factors are a useful guide for policy formulation and priority setting in disease prevention. Considering the important differences in methods, and their impact on burden estimates, we conducted a scoping literature review to: (1) map the BoD assessments including risk factors performed across Europe, and (2) identify the methodological choices in comparative risk assessment (CRA) and risk assessment methods. Methods: We searched multiple literature databases, including grey literature websites, and targeted public health agencies' websites. Results: A total of 113 studies were included in the synthesis and further divided into independent BoD assessments (54 studies) and studies linked to the Global Burden of Disease (59 papers). Our results showed that the methods used to perform CRA varied substantially across independent European BoD studies. While there were some methodological choices that were more common than others, we did not observe patterns in terms of country, year, or risk factor. Each methodological choice can affect the comparability of estimates between and within countries and/or risk factors since they might significantly influence the quantification of the attributable burden. From our analysis, we observed that the use of CRA was less common for some types of risk factors and outcomes. These included environmental and occupational risk factors, which are more likely to use bottom-up approaches for health outcomes where disease envelopes may not be available. Conclusions: Our review also highlighted misreporting, the lack of uncertainty analysis, and the under-investigation of causal relationships in BoD studies. Development and use of guidelines for performing and reporting BoD studies will help understand differences, and avoid misinterpretations thus improving comparability among estimates.info:eu-repo/semantics/publishedVersio