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BACKGROUND: Primary endpoint measures in clinical trials are typically measures of disease severity, with patient reported outcome measures (PROMs) relegated as secondary endpoints. However validation of some PROMs may be more rigorous than that of disease severity measures, arguing for a primary role for PROMs. OBJECTIVES: This study reports on 24 peer reviewed journal articles that used the Dermatology Life Quality Index (DLQI) as primary outcome, derived from a systematic review of randomised controlled trials (RCTs) utlising DLQI covering all diseases and interventions. MATERIALS AND METHOD: The study protocol was prospectively published on the PROSPERO database, and the study followed PRISMA guidelines. Searches were made with Medline, Cochrane library, EMBASE, Web of Science, SCOPUS, CINAHL(EBSCO) and PsycINFO databases and records combined into an Endnote database. Records were filtered for duplicates and selected by study inclusion/exclusion criteria. Full text articles were sourced and data was extracted by two reviewers into a bespoke REDCap database, with a third reviewer adjudicating differences. The Jadad scoring method was used to determine risk of bias. RESULTS: Of the 3,220 publications retrieved from online searching, 457 articles met eligibility criteria and included 198,587 patients. DLQI scores were primary outcomes in 24 (5.3%) of these studies comprising 15 different diseases and 3,436 patients. Most study interventions (17/24 studies, 68%) were systemic drugs with biologics (liraglutide, alefacept, secukinumab, ustekinumab, adalimumab) accounting for five out of 25 pharmacological interventions (20%). Topical treaments comprised 32% (8 studies) whereas non-pharmacological interventions (8) were 24% of the total interventions (33). Three studies used non-traditional medicines. Eight studies were multicentred (33.3%), with trials conducted in at least 14 different countries, and four (16.7%) were conducted in multiple countries. The Jadad risk of bias scale showed that bias was uncertain or low, as 87.5% of studies had Jadad scores of ≥3. CONCLUSIONS: This study provides evidence for use of the DLQI as primary outcome in clinical trials to inform researchers' and clinicians' decisions for its further use.
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BACKGROUND: Over 29 years of clinical application, the Dermatology Life Quality Index (DLQI) has remained the most used patient-reported outcome (PRO) in dermatology due to its robustness, simplicity and ease of use. OBJECTIVES: To generate further evidence of the DLQI's utility in randomized controlled trials (RCTs) and to cover all diseases and interventions. METHODS: The methodology followed PRISMA guidelines and included seven bibliographical databases, searching articles published from 1 January 1994 until 16 November 2021. Articles were reviewed independently by two assessors, and an adjudicator resolved any opinion differences. RESULTS: Of 3220 screened publications, 454 articles meeting the eligibility criteria for inclusion, describing research on 198 190 patients, were analysed. DLQI scores were primary endpoints in 24 (5.3%) of studies. Most studies were of psoriasis (54.1%), although 69 different diseases were studied. Most study drugs were systemic (85.1%), with biologics comprising 55.9% of all pharmacological interventions. Topical treatments comprised 17.0% of total pharmacological interventions. Nonpharmacological interventions, mainly laser therapy and ultraviolet radiation treatment, comprised 12.2% of the total number of interventions. The majority of studies (63.7%) were multicentric, with trials conducted in at least 42 different countries; 40.2% were conducted in multiple countries. The minimal clinically importance difference (MCID) was reported in the analysis of 15.0% of studies, but only 1.3% considered full score meaning banding of the DLQI. Forty-seven (10.4%) of the studies investigated statistical correlation of the DLQI with clinical severity assessment or other PRO/quality of life tools; and 61-86% of studies had within-group scores differences greater than the MCID in 'active treatment arms'. The Jadad risk-of-bias scale showed that bias was generally low, as 91.8% of the studies had Jadad scores of ≥ 3; only 0.4% of studies showed a high risk of bias from randomization. Thirteen per cent had a high risk of bias from blinding and 10.1% had a high risk of bias from unknown outcomes of all participants in the studies. In 18.5% of the studies the authors declared that they followed an intention-to-treat protocol; imputation for missing DLQI data was used in 34.4% of studies. CONCLUSIONS: This systematic review provides a wealth of evidence of the use of the DLQI in clinical trials to inform researchers' and -clinicians' decisions for its further use. Recommendations are also made for improving the reporting of data from future RCTs using the DLQI.
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Dermatologia , Psoríase , Terapia Ultravioleta , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Psoríase/tratamento farmacológico , Qualidade de VidaRESUMO
Introduction: Skin diseases affect patients at any age, but as each period in life is different, tools used to assess quality of life impairment should be adjusted according to the particular age group. Adolescence is a unique time, when young individuals go through many changes, making them especially vulnerable to stress. Aim: Translation and validation of a Polish language version of the Teenagers Quality of Life questionnaire (T-QoL) questionnaire. Material and methods: T-QoL was translated following international guidelines. A group of 34 dermatological patients, aged 12-19 years old, with various skin diseases were given the T-QoL as well as the CDLQI or DLQI to complete. They were also asked to complete the T-QoL questionnaire for the second time after 3-5 days. Statistical analysis of the results was performed. Results: The Polish version of T-QoL is internally consistent (Cronbach α 0.893 for the whole questionnaire). Moreover, it presents very good convergent validity (ICC = 0.864). No statistically significant differences between each question were noticed between the first and second time of completing the form. T-QoL scores correlated significantly with DLQI (p = 0.008, r = 0.636) and CDLQI (p < 0.001, r = 0.777) scores. Conclusions: The Polish version of the T-QoL questionnaire is a reliable instrument with adequate convergent validity, consistency and reproducibility. It can be successfully used to measure quality of life impairment among teenagers.
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Chronic diseases have long-term consequences and can affect individuals' life course. The aim of this study was to create the Polish language version of a questionnaire estimating the impact of the disease on important life decisions-the major life changing decision profile (MLCDP). The translation of the MLCDP followed international guidelines. The created Polish language version of the questionnaire was administered to 32 nephrology and dermatology ward inpatients. To assess its properties, statistical analysis of the results obtained was conducted. The Polish language version of the MLCDP demonstrated very good internal consistency with a Cronbach α coefficient of 0.84. The questionnaire presented excellent test-retest reliability, established with a coefficient ICC of 0.97. The Polish language version of MLCDP has shown high internal consistency and reproducibility, and can be used effectively to assess the cumulative impact of the disease by indicating the number of major life decisions affected by chronic disease.
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Idioma , Qualidade de Vida , Humanos , Polônia , Reprodutibilidade dos Testes , Inquéritos e Questionários , TraduçõesRESUMO
Chronic diseases not only have a direct influence on patients' quality of life, but can also affect the life of family members. The aim of this study was to create the Polish language version of a questionnaire estimating impact of disease on quality of family life: the Family Reported Outcome Measure - 16 (FROM-16). A standard forward and backward translation procedure was used to convert the original English version of FROM-16 into the Polish language. Creation of the Polish version was performed in a group of 30 patients' family members. The Polish language version of FROM-16 showed very good internal consistency reliability, the Cronbach α coefficient was 0.89. Reproducibility level was established with an intraclass correlation coefficient of 0.98. The Polish language version of FROM-16 can potentially be used as a tool to assess quality of life of patients' family members.
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Idioma , Qualidade de Vida , Humanos , Medidas de Resultados Relatados pelo Paciente , Polônia , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Amyloid ß oligomers (AßOs) accumulate early in Alzheimer's disease (AD) and experimentally cause memory dysfunction and the major pathologies associated with AD, for example, tau abnormalities, synapse loss, oxidative damage, and cognitive dysfunction. In order to develop the most effective AßO-targeting diagnostics and therapeutics, the AßO structures contributing to AD-associated toxicity must be elucidated. Here, we investigate the structural properties and pathogenic relevance of AßOs stabilized by the bifunctional crosslinker 1,5-difluoro-2,4-dinitrobenzene (DFDNB). We find that DFDNB stabilizes synthetic Aß in a soluble oligomeric conformation. With DFDNB, solutions of Aß that would otherwise convert to large aggregates instead yield solutions of stable AßOs, predominantly in the 50-300 kDa range, that are maintained for at least 12 days at 37°C. Structures were determined by biochemical and native top-down mass spectrometry analyses. Assayed in neuronal cultures and i.c.v.-injected mice, the DFDNB-stabilized AßOs were found to induce tau hyperphosphorylation, inhibit choline acetyltransferase, and provoke neuroinflammation. Most interestingly, DFDNB crosslinking was found to stabilize an AßO conformation particularly potent in inducing memory dysfunction in mice. Taken together, these data support the utility of DFDNB crosslinking as a tool for stabilizing pathogenic AßOs in structure-function studies.
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Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Reagentes de Ligações Cruzadas/farmacologia , Neurônios/patologia , Animais , Humanos , Camundongos , RatosRESUMO
BACKGROUND: In adult patients, it is generally accepted that laparoscopic appendicectomy (LA) is the predominant operative pathway in treating acute appendicitis. The case for a similar pathway utilising LA in children is less clear. We investigate usage, trends and complications after LA in children in a single co-located adult/paediatric centre with contemporaneous adults as controls. METHODS: A retrospective case-control study was conducted over 12 years including patients who underwent appendicectomy, and the paediatric series (<16 years) was divided into age-groups-based quartiles. An anonymous questionnaire-based national survey was circulated among general and paediatric surgeons. RESULTS: Of the 5784 appendicectomy patients, 2960 were children. LA rate in paediatric appendicitis was 65%. Yearly trends in LA reached a steady state in both groups after 2010 (Δ 0-1%/year). Rates of LA and LA IAA (respectively) differed significantly between age groups: 60, 3% (0-9 years); 65, 1% (10-13 years); 71, 2% (14-16 years) and 93, 3% (>16 years) (p = 0.001, 0.02). The national survey showed respondents believed LA was not superior to OA in paediatric patients except in terms of cosmesis. There was strong support in the use of LA in older children and children >40 kg. CONCLUSION: The use of LA in paediatric appendicectomies in the study region is similar to international rates, but not increasing over time. Irish surgeons still favour OA in younger children and prefer a case-by-case approach rather LA being the preferred pathway. This is despite the regional and international evidence showing favourable outcomes with LA in children.
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Apendicectomia/tendências , Apendicite/cirurgia , Laparoscopia/tendências , Abscesso Abdominal/epidemiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apendicectomia/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The essential physical role, visibility and social importance of the hands place a major psychological burden on patients with hand eczema. OBJECTIVES: The aim of this study was to identify the psychological, social and clinical characteristics of patients with hand eczema, in particular the prevalences of depression, anxiety, suicidal ideation, and comorbidities. MATERIALS AND METHODS: Data on patients with hand eczema were analysed from a large European multicentre study conducted with dermatology outpatients from 13 countries. Groups of patients and controls were compared to analyse the psychological burden of hand eczema. RESULTS: Female patients with hand eczema had higher Hospital Anxiety and Depression Scale (HADS) scores for anxiety (n = 86, median = 7.0) than controls (n = 900, median = 5.0, P = .02), and for depression (median = 4.0) than controls (3.0, P < .001). Patients with high suicidal ideation, with low socioeconomic status and who were widowed or divorced were more likely to fulfil the HADS criteria for anxiety [odds ratio (OR) > 1, P = .038, P < .001, and P < .001, respectively]. The median Dermatology Life Quality Index score was 7.0 (n = 68). DISCUSSION: This study identifies a specific psychological burden experienced by hand eczema patients, highlighting the need for focused psychosocial interventions. Physicians in particular should be aware of the need to identify anxiety and depression in female patients.
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Ansiedade/psicologia , Depressão/psicologia , Eczema/psicologia , Dermatoses da Mão/psicologia , Adulto , Dermatite Alérgica de Contato/psicologia , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida/psicologia , Autoimagem , Distribuição por Sexo , Ideação SuicidaAssuntos
Fármacos Dermatológicos/uso terapêutico , Diferença Mínima Clinicamente Importante , Psoríase/tratamento farmacológico , Qualidade de Vida , Ensaios Clínicos como Assunto/métodos , Fármacos Dermatológicos/efeitos adversos , Determinação de Ponto Final , Humanos , Psoríase/diagnóstico , Psoríase/psicologia , Projetos de Pesquisa , Resultado do TratamentoRESUMO
OBJECTIVE: To assign clinical meanings to the Family Reported Outcome Measure (FROM-16) scores through the development of score bands using the anchor-based approach. DESIGN AND SETTING: A cross-sectional online study recruited participants through UK-based patient support groups, research support platforms (HealthWise Wales, Autism Research Centre-Cambridge University database, Join Dementia Research) and through social service departments in Wales. PARTICIPANTS: Family members/partners (aged ≥18 years) of patients with different health conditions. INTERVENTION: Family members/partners of patients completed the FROM-16 questionnaire and a Global Question (GQ). MAIN OUTCOME MEASURE: Various FROM-16 band sets were devised as a result of mapping of mean, median and mode of the GQ scores to FROM-16 total score, and receiver operating characteristic-area under the curve cut-off values. The band set with the best agreement with GQ based on weighted kappa was selected. RESULTS: A total of 4413 family members/partners (male=1533, 34.7%; female=2858, 64.8%; Prefer not to say=16, 0.4%; other=6, 0.14%) of people with a health condition (male=1994, 45.2%; female=2400, 54.4%; Prefer not to say=12, 0.3%; other=7, 0.16%) completed the online survey: mean FROM-16 score=15.02 (range 0-32, SD=8.08), mean GQ score=2.32 (range 0-4, SD=1.08). The proposed FROM-16 score bandings are: 0-1=no effect on the quality of life of family member; 2-8=small effect on family member; 9-16=moderate effect on family member; 17-25=very large effect on family member; 26-32=extremely large effect on family member (weighted kappa=0.60). CONCLUSION: The FROM-16 score descriptor bands provide new information to clinicians about interpreting scores and score changes, allowing better-informed treatment decisions for patients and their families. The score banding of FROM-16, along with a short administration time, demonstrates its potential to support holistic clinical practice.
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Família , Qualidade de Vida , Humanos , Masculino , Feminino , Adolescente , Adulto , Estudos Transversais , País de Gales , Medidas de Resultados Relatados pelo PacienteRESUMO
Limb-Girdle Muscular Dystrophy Type-2B/2R is caused by mutations in the dysferlin gene ( DYSF ). This disease has two known pathogenic missense mutations that occur within dysferlin's C2A domain, namely C2A W52R and C2A V67D . Yet, the etiological rationale to explain the disease linkage for these two mutations is still unclear. In this study, we have presented evidence from biophysical, computational, and immunological experiments which suggest that these missense mutations interfere with dysferlin's ability to repair cells. The failure of C2A W52R and C2A V67D to initiate membrane repair arises from their propensity to form stable amyloid. The misfolding of the C2A domain caused by either mutation exposes ß-strands, which are predicted to nucleate classical amyloid structures. When dysferlin C2A amyloid is formed, it triggers the NLRP3 inflammasome, leading to the secretion of inflammatory cytokines, including IL-1ß. The present study suggests that the muscle dysfunction and inflammation evident in Limb-Girdle Muscular Dystrophy types-2B/2R, specifically in cases involving C2A W52R and C2A V67D , as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.
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SpyCEP is a Streptococcus pyogenes protease that cleaves CXCL8/IL-8 and its activity is associated with human invasive disease severity. We investigated the role of SpyCEP in S. pyogenes necrotizing fasciitis and respiratory tract infection in mice using isogenic strains differing only in SpyCEP expression. SpyCEP cleaved human CXCL1, 2, 6 and 8 plus murine CXCL1 and 2 at a structurally conserved site. Mice were infected in thigh muscle with a strain of S. pyogenes that expresses a high level of SpyCEP, or with an isogenic non-SpyCEP expressing strain. SpyCEP expression by S. pyogenes hindered bacterial clearance from muscle, and enhanced bacterial spread, associated with cleavage of murine chemoattractant CXCL1. Mice were then infected with Lactococcus lactis strains that differed only in SpyCEP expression. In contrast to the parent L. lactis strain (lacks SpyCEP), which was avirulent when administered intramuscularly, infection with a strain that expressed SpyCEP heterologously led to dramatic systemic illness within 24 h, failure to clear bacteria from muscle and marked dissemination to other organs. In the upper airways, SpyCEP expression was required for survival of L. lactis but not S. pyogenes. However, dissemination of S. pyogenes to the lung was SpyCEP-dependent and was associated with evidence of chemokine cleavage. Taken together, the studies provide clear evidence that SpyCEP is necessary and sufficient for systemic bacterial dissemination from a soft tissue focus in this model and also underlies dissemination in the respiratory tract.
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Quimiocinas/metabolismo , Fasciite Necrosante/microbiologia , Peptídeo Hidrolases/metabolismo , Infecções Respiratórias/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/enzimologia , Fatores de Virulência/metabolismo , Sequência de Aminoácidos , Animais , Quimiocinas/antagonistas & inibidores , Contagem de Colônia Microbiana , Sequência Conservada , Feminino , Histocitoquímica , Humanos , Lactococcus lactis/genética , Lactococcus lactis/patogenicidade , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Microscopia , Dados de Sequência Molecular , Músculos/microbiologia , Músculos/patologia , Peptídeo Hidrolases/genética , Alinhamento de Sequência , Baço/microbiologia , Baço/patologia , Streptococcus pyogenes/genética , Streptococcus pyogenes/patogenicidade , Fatores de Virulência/genéticaRESUMO
OBJECTIVE: To test the hypothesis that therapeutic hypercapnia enhances the proinflammatory responses to endotoxemia in the lung and spleen of rats. DESIGN: Prospective randomized study. SETTINGS: Hospital research institute. SUBJECTS: Forty-eight adult male rats. INTERVENTIONS: Rats were randomly assigned for a 24-hr period to four breathing groups (n = 11/group), including air (controls), normoxic air with 5% CO2 (therapeutic hypercapnia), air and endotoxemia (5 mg/kg endotoxin), and therapeutic hypercapnia with endotoxemia. After euthanasia, the lung and spleen were removed for pro- and anti-inflammatory cytokine analyses and pulmonary histology evaluation. Four additional rats were used to examine changes in gas exchange and acid-base balance during exposure to therapeutic hypercapnia with and without endotoxemia before and at 4, 12, and 24 hrs into the study, using a permanently catheterized femoral artery. MEASUREMENTS AND MAIN RESULTS: The ratios of proinflammatory cytokines (interleukin-1ß [IL-1ß] and IL-6) and an anti-inflammatory cytokine (IL-10) in the lungs and spleen were used as indices of inflammatory status. The wet-weight to dry-weight ratios, histologic changes in lung interstitial inflammation, and alveolar structures were used as indices of endotoxin-induced acute lung injury. IL-1ß and IL-6 expression was significantly high in the lung of therapeutic hypercapnia-treated endotoxemic rats compared to the lung of rats subjected to only endotoxemia (p < .05 and p < .001, respectively). In the spleen, therapeutic hypercapnia-treated endotoxemic rats had low expression of IL-1ß and IL-6 compared to rats subjected to only endotoxemia (p > .05 and p < .001). Therapeutic hypercapnia following endotoxemic challenge was associated with a proinflammatory response in the lung and an anti-inflammatory response in spleen, as assessed by the ratios of IL-1ß and IL-6 to IL-10. The wet-weight to dry-weight ratio and the interstitial space were significantly increased only in therapeutic hypercapnia-treated endotoxemic rats (p < .05). The alveolar-septal thickness was significantly increased by 21% in endotoxemic rats (p < .001) and by 33% in therapeutic hypercapnia-treated endotoxemic rats (p < .001). CONCLUSIONS: A 24-hr exposure to therapeutic hypercapnia in endotoxin-stimulated, spontaneously breathing rats is associated with a proinflammatory immune response in the lung and anti-inflammatory response in the spleen as well as an increase in certain histologic indices of endotoxin-induced lung injury.
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Dióxido de Carbono/uso terapêutico , Endotoxemia/tratamento farmacológico , Endotoxemia/patologia , Infecções por Escherichia coli/tratamento farmacológico , Hipercapnia/induzido quimicamente , Pulmão/patologia , Animais , Citocinas/metabolismo , Endotoxemia/metabolismo , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/patologia , Pulmão/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Baço/metabolismo , Baço/patologiaRESUMO
OBJECTIVE: This study aimed to measure the impact of COVID-19 on the quality of life (QoL) of survivors and their partners and family members. DESIGN AND SETTING: A prospective cross-sectional global online survey using social media. PARTICIPANTS: Patients with COVID-19 and partners or family members (age ≥18 years). INTERVENTION: Online survey from June to August 2020. MAIN OUTCOME MEASURE: The EuroQol group five dimensions three level (EQ-5D-3L) to measure the QoL of survivors of COVID-19, and the Family Reported Outcome Measure (FROM-16) to assess the impact on their partner/family member's QoL. RESULTS: The survey was completed by 735 COVID-19 survivors (mean age=48 years; females=563) at a mean of 12.8 weeks after diagnosis and by 571 partners and 164 family members (n=735; mean age=47 years; females=246) from Europe (50.6%), North America (38.5%) and rest of the world (10.9%). The EQ-5D mean score for COVID-19 survivors was 8.65 (SD=1.9, median=9; range=6-14). 81.1% (596/735) reported pain and discomfort, 79.5% (584/735) problems with usual activities, 68.7% (505/735) anxiety and depression and 56.2% (413/735) problems with mobility. Hospitalised survivors (20.1%, n=148) and survivors with existing health conditions (30.9%, n=227) reported significantly more problems with mobility and usual activities (p<0.05), with hospitalised also experiencing more impact on self-care (p≤0.001). Among 735 partners and family members, the mean FROM-16 score (maximum score=highest impact =32) was 15 (median=15, range=0-32). 93.6% (688/735) reported being worried, 81.7% (601/735) frustrated, 78.4% (676/735) sad, 83.3% (612/735) reported impact on their family activities, 68.9% (507/735) on sleep and 68.1% (500/735) on their sex life. CONCLUSION: COVID-19 survivors reported a major persisting impact on their physical and psychosocial health. The lives of their partners and other family members were also severely affected. There is a need for a holistic support system sensitive to the needs of COVID-19 survivors and their family members who experience a major 'secondary burden'.
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COVID-19 , Qualidade de Vida , Adolescente , Estudos Transversais , Europa (Continente) , Família , Feminino , Humanos , Pessoa de Meia-Idade , América do Norte , Estudos Prospectivos , SARS-CoV-2 , Inquéritos e Questionários , SobreviventesRESUMO
Objective: Although many clinical metrics are associated with proximity to decompensation in heart failure (HF), none are individually accurate enough to risk-stratify HF patients on a patient-by-patient basis. The dire consequences of this inaccuracy in risk stratification have profoundly lowered the clinical threshold for application of high-risk surgical intervention, such as ventricular assist device placement. Machine learning can detect non-intuitive classifier patterns that allow for innovative combination of patient feature predictive capability. A machine learning-based clinical tool to identify proximity to catastrophic HF deterioration on a patient-specific basis would enable more efficient direction of high-risk surgical intervention to those patients who have the most to gain from it, while sparing others. Synthetic electronic health record (EHR) data are statistically indistinguishable from the original protected health information, and can be analyzed as if they were original data but without any privacy concerns. We demonstrate that synthetic EHR data can be easily accessed and analyzed and are amenable to machine learning analyses. Methods: We developed synthetic data from EHR data of 26,575 HF patients admitted to a single institution during the decade ending on 12/31/2018. Twenty-seven clinically-relevant features were synthesized and utilized in supervised deep learning and machine learning algorithms (i.e., deep neural networks [DNN], random forest [RF], and logistic regression [LR]) to explore their ability to predict 1-year mortality by five-fold cross validation methods. We conducted analyses leveraging features from prior to/at and after/at the time of HF diagnosis. Results: The area under the receiver operating curve (AUC) was used to evaluate the performance of the three models: the mean AUC was 0.80 for DNN, 0.72 for RF, and 0.74 for LR. Age, creatinine, body mass index, and blood pressure levels were especially important features in predicting death within 1-year among HF patients. Conclusions: Machine learning models have considerable potential to improve accuracy in mortality prediction, such that high-risk surgical intervention can be applied only in those patients who stand to benefit from it. Access to EHR-based synthetic data derivatives eliminates risk of exposure of EHR data, speeds time-to-insight, and facilitates data sharing. As more clinical, imaging, and contractile features with proven predictive capability are added to these models, the development of a clinical tool to assist in timing of intervention in surgical candidates may be possible.
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Dysferlin has been implicated in acute membrane repair processes, whereas myoferlin's activity is maximal during the myoblast fusion stage of early skeletal muscle cell development. Both proteins are similar in size and domain structure; however, despite the overall similarity, myoferlin's known physiological functions do not overlap with those of dysferlin. Here we present for the first time the X-ray crystal structure of human myoferlin C2A to 1.9 Å resolution bound to two divalent cations, and compare its three-dimensional structure and membrane binding activities to that of dysferlin C2A. We find that while dysferlin C2A binds membranes in a Ca2+-dependent manner, Ca2+ binding was the rate-limiting kinetic step for this interaction. Myoferlin C2A, on the other hand, binds two calcium ions with an affinity 3-fold lower than that of dysferlin C2A; and, surprisingly, myoferlin C2A binds only marginally to phospholipid mixtures with a high fraction of phosphatidylserine.
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Proteínas de Ligação ao Cálcio/química , Disferlina/química , Proteínas de Membrana/química , Proteínas Musculares/química , Sítios de Ligação , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Membrana Celular/metabolismo , Cristalografia por Raios X , Disferlina/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Modelos Moleculares , Proteínas Musculares/metabolismo , Ligação Proteica , Domínios ProteicosRESUMO
Since the early days of human life on the Earth, our skin has been exposed to different levels of light. Recently, due to inevitable consequences of modern life, humans are not exposed to adequate levels of natural light during the day but they are overexposed to relatively high levels of artificial light at night. Skin is a major target of oxidative stress and the link between aging and oxidative stress is well documented. Especially, extrinsic skin aging can be caused by oxidative stress. The widespread use of light emitting diodes (LEDs) and the rapidly increasing use of smartphones, tablets, laptops and desktop computers have led to a significant rise in the exposure of human eyes to short-wavelength visible light. Recent studies show that exposure of human skin cells to light emitted from electronic devices, even for exposures as short as 1 hour, may cause reactive oxygen species (ROS) generation, apoptosis, and necrosis. The biological effects of exposure to short-wavelength visible light in blue region in humans and other living organisms were among our research priorities at the Ionizing and Non-ionizing Radiation Protection Research Center (INIRPRC). Today, there is a growing concern over the safety of the light sources such as LEDs with peak emissions in the blue light range (400-490 nm). Recent studies aimed at investigating the effect of exposure to light emitted from electronic device on human skin cells, shows that even short exposures can increase the generation of reactive oxygen species. However, the biological effects of either long-term or repeated exposures are not fully known, yet. Furthermore, there are reports indicating that frequent exposure to visible light spectrum of the selfie flashes may cause skin damage and accelerated skin ageing. In this paper we have addressed the different aspects of potential effects of exposure to the light emitted from smartphones' digital screens as well as smartphones' photoflashes on premature aging of the human skin. Specifically, the effects of blue light on eyes and skin are discussed. Based on current knowledge, it can be suggested that changing the spectral output of LED-based smartphones' flashes can be introduced as an effective method to reduce the adverse health effects associated with exposure to blue light.
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Skin conditions may have a major impact on the psychologic well-being of patients, ranging from depression to anxiety. The Dermatology Life Quality Index (DLQI) is the most commonly used quality of life tool in dermatology, though it has yet to be correlated with psychiatric measures used in clinical therapeutic trials. We conducted a systematic review to determine whether there is any correlation between the DLQI and psychiatric measure scores, potentially allowing the DLQI to be used as a surrogate measure for depression or psychiatric screening. Six databases were searched using the following keywords: "DLQI," "Dermatology Life Quality Index," "Psych*," "depression," "anxiety," "stress," and "trial*." All randomized trials where full DLQI and psychiatric scores were provided were included. PRISMA guidelines were followed. In all, 462 records were screened, but only seven met inclusion criteria. Hospital Anxiety and Depression Scale (HADS) was the most commonly used psychiatric measure; the "depression" component score changes correlated strongly with the DLQI (r = 0.715). There needs to be guidance on psychiatric measurement and reporting in clinical trials. Although the DLQI correlated well with the "depression" domain of the HADS scale, interviews and screening for depression are still vital for full assessment of patient psychologic well-being.
Assuntos
Ansiedade/diagnóstico , Depressão/diagnóstico , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Dermatopatias/psicologia , Inquéritos e Questionários , Ansiedade/etiologia , Depressão/etiologia , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Ferlin proteins participate in such diverse biological events as vesicle fusion in C. elegans, fusion of myoblast membranes to form myotubes, Ca2+-sensing during exocytosis in the hair cells of the inner ear, and Ca2+-dependent membrane repair in skeletal muscle cells. Ferlins are Ca2+-dependent, phospholipid-binding, multi-C2 domain-containing proteins with a single transmembrane helix that spans a vesicle membrane. The overall domain composition of the ferlins resembles the proteins involved in exocytosis; therefore, it is thought that they participate in membrane fusion at some level. But if ferlins do fuse membranes, then they are distinct from other known fusion proteins. Here we show that the central FerA domain from dysferlin, myoferlin, and otoferlin is a novel four-helix bundle fold with its own Ca2+-dependent phospholipid-binding activity. Small-angle X-ray scattering (SAXS), spectroscopic, and thermodynamic analysis of the dysferlin, myoferlin, and otoferlin FerA domains, in addition to clinically-defined dysferlin FerA mutations, suggests that the FerA domain interacts with the membrane and that this interaction is enhanced by the presence of Ca2+.
Assuntos
Proteínas de Ligação ao Cálcio/química , Cálcio/metabolismo , Membrana Celular/metabolismo , Disferlina/química , Proteínas de Membrana/química , Proteínas Musculares/química , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Dicroísmo Circular , Disferlina/genética , Disferlina/metabolismo , Humanos , Fusão de Membrana , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Moleculares , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação , Domínios Proteicos , Estrutura Secundária de Proteína , Espalhamento a Baixo Ângulo , Termodinâmica , Difração de Raios XRESUMO
OBJECTIVES: Surgery for type A aortic dissection is associated with a high operative mortality, and a variety of predictive risk factors have been reported. We hypothesized that a combination of risk factors associated with organ malperfusion and severe acidosis that are not currently documented in databases would be associated with a level of extreme operative risk that would warrant the consideration of treatment paradigms other than immediate ascending aortic surgery. METHODS: Charts of patients undergoing repair of acute type A aortic dissection between January 1, 1996, and May 1, 2016, were queried for preoperative malperfusion, preoperative base deficit, pH, bicarbonate, cardiopulmonary resuscitation, severe aortic insufficiency, redo status, and preoperative intubation. Multivariable logistic analyses were considered to evaluate interested variables and operative mortality. RESULTS: Between January 1, 1996, and May 1, 2016, 282 patients underwent surgical repair of type A aortic dissection. A total of 66 patients had a calculated base deficit -5 or greater. Eleven of 12 patients (92%) with severe acidosis (base deficit ≥-10) with malperfusion had operative mortality. No patient with severe acidosis with abdominal malperfusion survived. Multivariable analyses identified base deficit, intubation, congestive heart failure, dyslipidemia/statin use, and renal failure as predictors of operative death. The most significant predictor was base deficit -10 or greater (odds ratio, 9.602; 95% confidence interval, 2.649-34.799). CONCLUSIONS: The combination of severe acidosis (base deficit ≥-10) with abdominal malperfusion was uniformly fatal. Further research is needed to determine whether the identification of extreme risk warrants consideration of alternate treatment options to address the cause of severe acidosis before ascending aortic procedures.