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Abstract Inborn errors of metabolism are predominantly autosomal-recessive disorders, but several follow an X-linked pattern of inheritance. They are called X-linked recessive, if the female carriers are asymptomatic, and are called X-linked dominant disorders, if almost all females are affected. Conditions, in which some females have symptoms while others are asymptomatic lifelong are simply referred to as X-linked. The aim of this review is to point out the variability in clinical manifestation of affected females in some X-linked metabolic disorders and to discuss on the basis of these examples possible mechanisms that may explain the broad phenotypic spectrum, such as the type of the underlying mutation, the issue of autonomous versus non-autonomous gene expression and the degree of skewing of X-inactivation. The use of the terms "X-linked dominant" and "X-linked recessive" will be discussed.
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BACKGROUND AND OBJECTIVES: Burnout is prevalent among clinicians and entails negative personal, professional, and organizational consequences. Assessments of burnout are typically anonymous to facilitate psychological safety. This limits the capacity of leadership to help struggling providers and reduces the level of demographic detail. Nonanonymous, confidential assessments may facilitate outreach to individuals or targeted interventions for at-risk populations. METHODS: We administered the Maslach Burnout Inventory to physician faculty and advanced practice providers in an academic department of family medicine. We identified a wellness officer within the department who served as an honest broker to keep nonanonymous survey responses confidential. Respondents had the option of taking the survey anonymously or confidentially. Anonymous respondents were allowed to withhold demographic information to ensure anonymity. RESULTS: Sixty-seven of 109 providers responded (61% response rate), with 46 (69%) doing so confidentially. Burnout rates were similar between groups: 48% among confidential respondents, and 43% among anonymous respondents (P=.71). Subscales of the MBI also showed no significant differences. Because a large proportion of anonymous respondents withheld demographic data, no demographic trends could be identified among them. Younger confidential respondents were more likely to exhibit depersonalization (P=.01). CONCLUSIONS: Most participants chose to respond confidentially. There was no significant difference in the level of burnout between confidential and anonymous respondents. Our findings refute the conventional wisdom that clinicians require anonymity to respond to burnout surveys. This finding has the potential to open a new line of inquiry regarding burnout, its drivers and potential solutions.
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Esgotamento Profissional , Médicos , Esgotamento Profissional/epidemiologia , Estudos Transversais , Docentes , Estudos de Viabilidade , Humanos , Inquéritos e QuestionáriosRESUMO
Coastal flood risks are rising rapidly. We provide high resolution estimates of the economic value of mangroves forests for flood risk reduction every 20 km worldwide. We develop a probabilistic, process-based valuation of the effects of mangroves on averting damages to people and property. We couple spatially-explicit 2-D hydrodynamic analyses with economic models, and find that mangroves provide flood protection benefits exceeding $US 65 billion per year. If mangroves were lost, 15 million more people would be flooded annually across the world. Some of the nations that receive the greatest economic benefits include the USA, China, India and Mexico. Vietnam, India and Bangladesh receive the greatest benefits in terms of people protected. Many (>45) 20-km coastal stretches particularly those near cities receive more than $US 250 million annually in flood protection benefits from mangroves. These results demonstrate the value of mangroves as natural coastal defenses at global, national and local scales, which can inform incentives for mangrove conservation and restoration in development, climate adaptation, disaster risk reduction and insurance.
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Inundações/economia , Inundações/prevenção & controle , Áreas Alagadas , Bangladesh , China , Conservação dos Recursos Naturais/economia , Humanos , Hidrodinâmica , Índia , México , Modelos Econômicos , Estados Unidos , VietnãRESUMO
Coral reefs can provide significant coastal protection benefits to people and property. Here we show that the annual expected damages from flooding would double, and costs from frequent storms would triple without reefs. For 100-year storm events, flood damages would increase by 91% to $US 272 billion without reefs. The countries with the most to gain from reef management are Indonesia, Philippines, Malaysia, Mexico, and Cuba; annual expected flood savings exceed $400 M for each of these nations. Sea-level rise will increase flood risk, but substantial impacts could happen from reef loss alone without better near-term management. We provide a global, process-based valuation of an ecosystem service across an entire marine biome at (sub)national levels. These spatially explicit benefits inform critical risk and environmental management decisions, and the expected benefits can be directly considered by governments (e.g., national accounts, recovery plans) and businesses (e.g., insurance).
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Antozoários/fisiologia , Recifes de Corais , Inundações , Movimentos da Água , Algoritmos , Animais , Conservação dos Recursos Naturais/economia , Conservação dos Recursos Naturais/métodos , Conservação dos Recursos Naturais/estatística & dados numéricos , Cuba , Geografia , Hidrodinâmica , Indonésia , Malásia , México , Modelos Teóricos , FilipinasRESUMO
Coastal communities in tropical environments are at increasing risk from both environmental degradation and climate change and require urgent local adaptation action. Evidences show coral reefs play a critical role in wave attenuation but relatively little direct connection has been drawn between these effects and impacts on shorelines. Reefs are rarely assessed for their coastal protection service and thus not managed for their infrastructure benefits, while widespread damage and degradation continues. This paper presents a systematic approach to assess the protective role of coral reefs and to examine solutions based on the reef's influence on wave propagation patterns. Portions of the shoreline of Grenville Bay, Grenada, have seen acute shoreline erosion and coastal flooding. This paper (i) analyzes the historical changes in the shoreline and the local marine, (ii) assess the role of coral reefs in shoreline positioning through a shoreline equilibrium model first applied to coral reef environments, and (iii) design and begin implementation of a reef-based solution to reduce erosion and flooding. Coastline changes in the bay over the past 6 decades are analyzed from bathymetry and benthic surveys, historical imagery, historical wave and sea level data and modeling of wave dynamics. The analysis shows that, at present, the healthy and well-developed coral reefs system in the southern bay keeps the shoreline in equilibrium and stable, whereas reef degradation in the northern bay is linked with severe coastal erosion. A comparison of wave energy modeling for past bathymetry indicates that degradation of the coral reefs better explains erosion than changes in climate and historical sea level rise. Using this knowledge on how reefs affect the hydrodynamics, a reef restoration solution is designed and studied to ameliorate the coastal erosion and flooding. A characteristic design provides a modular design that can meet specific engineering, ecological and implementation criteria. Four pilot units were implemented in 2015 and are currently being field-tested. This paper presents one of the few existing examples available to date of a reef restoration project designed and engineered to deliver risk reduction benefits. The case study shows how engineering and ecology can work together in community-based adaptation. Our findings are particularly important for Small Island States on the front lines of climate change, who have the most to gain from protecting and managing coral reefs as coastal infrastructure.
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Mudança Climática , Conservação dos Recursos Naturais , Recifes de Corais , Animais , Antozoários , Ecossistema , Inundações , Granada , HidrodinâmicaRESUMO
OBJECTIVE: The objective of our study was to determine the impact of embedding a pretest probability rule that is required during the computerized physician order-entry (CPOE) process on the appropriateness of CT angiography (CTA) of the pulmonary arteries for the diagnosis of pulmonary embolism (PE) in the emergency department (ED). MATERIALS AND METHODS: Data were obtained from the electronic medical records of all adults who visited the ED from October 17, 2010, through October 17, 2012 (n = 96,507). The primary outcome was the appropriateness of pulmonary CTA. Logistic regression was used to test whether rates of appropriate use, overuse, and underuse of pulmonary CTA improved significantly after the implementation of the decision support tool when controlling for other patient characteristics. RESULTS: Pulmonary CTA was appropriately used in 67.2% of patients with a modified Wells score of ≥ 4, a positive d-dimer test result, or both. CTA was overused in 19.3% of patients and underused in 13.5% of patients. Each additional month after the start of the intervention was associated with a 4-percentage point increase in the odds that the modified Wells score would indicate CTA had been used appropriately (odds ratio [OR] = 1.04; 95% CI, 1.01-1.07) and significantly lowered the odds of overuse of CTA (OR = 0.93; 95% CI, 0.90-0.96) based on the modified Wells score. These changes were not associated with any significant alteration in the level of CTA utilization or the positivity rate. CONCLUSION: The addition of a mandatory field in the CPOE record was associated with a significant improvement in the appropriate ordering of pulmonary CTA but did not change the PE positive rate or CTA utilization. It seems likely that physicians gradually inflated the modified Wells scores in spite of the fact that a threshold modified Wells score was not required to perform pulmonary CTA.
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Angiografia por Tomografia Computadorizada/estatística & dados numéricos , Técnicas de Apoio para a Decisão , Serviço Hospitalar de Emergência , Embolia Pulmonar/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Abstract Next-generation sequencing (NGS) panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders (LSDs). Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in LSDs. Given that NGS can be applied in a way that takes into account the many issues raised by international consensus guidelines, it can have a significant role even early in the course of the diagnostic process, in combination with biochemical and clinical data. Besides decreasing the delay in diagnosis for many patients, a precise molecular diagnosis is extremely important as new therapies are becoming available within the LSD spectrum for patients who share specific types of mutations. A genetic diagnosis is also the prerequisite for genetic counseling, family planning, and the individual choice of reproductive options in affected families.
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Abstract In the last decades, it has become more and more evident that lysosomal storage disorders and common neurodegenerative diseases such as Alzheimer and Parkinson diseases have clinical, neuropathological, and genetic features in common, including lysosomal dysfunction and impaired autophagy. Patients with Gaucher and even carriers of Gaucher disease have an increased risk to develop Parkinson disease. Likewise, individuals who are heterozygous for a mutation of a gene that causes an adult form of neuronal ceroid lipofuscinosis are more likely to be affected by a form of frontotemporal dementia in their later life. A further example is the gene NAGLU encoding the enzyme α-N-acetylglucosaminidase, which is deficient in patients with mucopolysaccharidosis type IIIB. Mutations of the NAGLU gene have been observed in patients affected by an axonal neuropathy. An interesting unexpected finding was the link between stuttering and genes that are essential for the function of all lysosomal enzymes. This review will present some example of the association of lysosomal storage disorders and neurodegenerative disease and discuss possible pathogenic mechanisms that are common to both conditions. The understanding of the pathophysiology of the endosomal-lysosomal-autophagic system may help to develop drugs, which might provide benefit not only for patients with rare lysosomal storage disorders but also for individuals affected by more common diseases.
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Abstract The Fabry Outcome Survey (FOS) is an international long-term observational registry sponsored by Shire for patients diagnosed with Fabry disease who are receiving or are candidates for therapy with agalsidase alfa (agalα). Established in 2001, FOS provides long-term data on agalα safety/efficacy and collects data on the natural history of Fabry disease, with the aim of improving clinical management. The FOS publications have helped establish prognostic and severity scores, defined the incidence of specific disease variants and implications for clinical management, described clinical manifestations in special populations, confirmed the high prevalence of cardiac morbidity, and demonstrated correlations between ocular changes and Fabry disease severity. These FOS data represent a rich resource with utility not only for description of natural history/therapeutic effects but also for exploratory hypothesis testing and generation of tools for diagnosis/management, with the potential to improve future patient outcomes.
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Henoch-Schönlein purpura is a common small-vessel vasculitis that presents in children as nonthrombocytopenic, nontender, and palpable purpura, arthritis/arthralgia, and abdominal pain. Central nervous system involvement is a reported, but likely, under-recognized complication. We present an 8-year-old boy with Henoch-Schönlein purpura and posterior reversible encephalopathy syndrome, after proposed mechanism and treatment considerations.
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Vasculite por IgA/complicações , Síndrome da Leucoencefalopatia Posterior/complicações , Biópsia , Criança , Diagnóstico Diferencial , Eletroencefalografia , Seguimentos , Glucocorticoides/uso terapêutico , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Síndrome da Leucoencefalopatia Posterior/tratamento farmacológico , Prednisolona/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Computer-based tools to assess venous thromboembolism (VTE) risk have been shown to increase VTE pharmacoprophylaxis rates and decrease VTE incidence in high-risk hospitalized patients. However, VTE risk may be underestimated using computer-based tools alone. We tested the effect of a provider-enhanced clinical decision support (CDS) tool on VTE pharmacoprophylaxis and VTE incidence in patients who would have been deemed "low risk" using a computer-based risk-assessment tool alone. METHODS: The study sample was adult patients hospitalized during a 13-month period who were determined to be at low risk for VTE with a computer-based risk-assessment tool. The provider-enhanced CDS tool was implemented 4 months into the study period and required providers to stratify patients as being at high, moderate, or low risk for VTE. We compared rates of VTE pharmacoprophylaxis and VTE incidence before and after implementation of the provider-enhanced CDS tool. RESULTS: There were 1322 patients in the 4-month pre-implementation period and 3347 patients in the 9-month post-implementation period who were determined to be at low risk for VTE based on a computer-based risk-assessment tool. Using the provider-enhanced CDS tool, providers stratified 31% of these computer-assigned low-risk patients as being at moderate risk for VTE and 7% as being at high risk for VTE. The rate of VTE pharmacoprophylaxis increased from 27% to 34% (P < 0.01). The venous thromboprophylaxis rate decreased from 0.98% to 0.42% after implementation of the provider-enhanced CDS tool (P < 0.02). CONCLUSION: Patients identified as being at low risk for VTE solely by computer-based algorithms may include patients whom providers determine to be at risk for VTE. Provider-enhanced CDS tools may outperform computer-based VTE risk-stratification algorithms.
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Anticoagulantes/uso terapêutico , Sistemas de Apoio a Decisões Clínicas , Gestão de Riscos/métodos , Tromboembolia Venosa/prevenção & controle , Adulto , Algoritmos , Feminino , Humanos , Incidência , Masculino , Pennsylvania/epidemiologia , Medição de Risco , Fatores de Risco , Interface Usuário-Computador , Tromboembolia Venosa/epidemiologiaRESUMO
OBJECTIVES: To assess the prevalence of cardiovascular signs and symptoms in a large group of patients with Hunter syndrome, an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. STUDY DESIGN: The Hunter Outcome Survey was established to characterize the natural history of Hunter syndrome and to assess the response to enzyme replacement therapy. Echocardiographic and electrocardiographic examination results were available for 102 patients who were enzyme replacement therapy-naïve in the Hunter Outcome Survey (median age at examination, approximately 8 years) as of Jan 23, 2009. RESULTS: The most common cardiovascular finding was valve disease, which was present in 63% of patients. Left ventricular hypertrophy (defined as left ventricular mass indexed to height(2.7) ≥50 g/m(2.7)) was found in 48% of patients <18 years old. Elevated blood pressure (defined as a Z score ≥2 for systolic blood pressure or diastolic blood pressure) was present in 25% of patients <18 years old. Other findings included abnormal heart frequency (7%), arrhythmia (5%), and congestive heart failure (6%). CONCLUSIONS: Treating physicians should be aware of the early emergence of cardiovascular manifestations in patients with Hunter syndrome so that appropriate treatment can be initiated.
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Cardiopatias/epidemiologia , Mucopolissacaridose II/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Ecocardiografia , Eletrocardiografia , Seguimentos , Alemanha/epidemiologia , Cardiopatias/diagnóstico , Cardiopatias/etiologia , Humanos , Iduronato Sulfatase/sangue , Masculino , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Fatores de Tempo , Estados Unidos/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. STUDY DESIGN: Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. RESULTS: After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p=.025) and 5.7 stairs per minute more 3MSC (p=.053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227+/-18 microg/mg more with rhASB than placebo (p<.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. CONCLUSION: rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.
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Mucopolissacaridose VI/tratamento farmacológico , N-Acetilgalactosamina-4-Sulfatase/uso terapêutico , Adolescente , Adulto , Análise de Variância , Criança , Método Duplo-Cego , Feminino , Seguimentos , Volume Expiratório Forçado , Glicosaminoglicanos/urina , Humanos , Modelos Lineares , Masculino , Proteínas Recombinantes , Segurança , CaminhadaRESUMO
OBJECTIVE: To confirm the efficacy and safety of recombinant human alpha-L-iduronidase (laronidase) in patients with mucopolysaccharidosis I (MPS I). STUDY DESIGN: This was a randomized, double-blinded, multinational study of 45 patients with MPS I administered 100 U/kg (0.58 mg/kg) laronidase, or placebo intravenously weekly for 26 weeks. The coprimary efficacy end points compared the median change from baseline to week 26 between groups in percentage of predicted normal forced vital capacity (FVC) and in 6-minute walk test (6MWT) distance through the use of the Wilcoxon rank sum test. RESULTS: The laronidase (n=22) and placebo (n=23) groups had similar baseline characteristics. After 26 weeks, patients receiving laronidase compared with placebo showed mean improvements of 5.6 percentage points in percent of predicted normal FVC (median, 3.0; P=.009) and 38.1 meters in 6MWT distance (median, 38.5; P=.066; P=.039, analysis of covariance). Laronidase also significantly reduced hepatomegaly and urinary glycosaminoglycans, and, in more severely affected patients, improved sleep apnea/hypopnea and shoulder flexion. Laronidase was well-tolerated. Nearly all patients receiving enzyme had development of IgG antibodies, without apparent clinical effects. CONCLUSIONS: In patients with MPS I, laronidase significantly improves respiratory function and physical capacity, reduces glycosaminoglycan storage, and has a favorable safety profile.