RESUMEN
Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.
RESUMEN
Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.
RESUMEN
5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.
Asunto(s)
Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Niño , Lactante , Humanos , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Inyecciones EspinalesRESUMEN
Influence of digital documentation on working hours and workflow in the intensive care unit: An observational pre-post-study Abstract: Background: The introduction of digital patient documentation systems in hospitals and intensive care units is increasing in Germany. The effects of these systems on the workflow of nurses have hardly been studied. Aim: It is analysed how high the workload is with a digital documentation system compared to paper-based documentation, how the workflow changes and how the digital documentation is evaluated in comparison to paper-based in terms of usability, time required and documentation quality. Methods: Before (to) and after the introduction of the digital patient documentation system (t1), the time for documentation and the documentation frequency was measured in a prospective pre-post observation study using an app configured specifically for this purpose, and both survey periods were statistically compared (Mann-Whitney-U-test). Furthermore, a survey of nursing staff on digital patient documentation was carried out. Results: The working time for the documentation remains the same after digitization. However, 80% of respondents state that the documentation time would have been reduced. Furthermore, the number of documentation processes decreases significantly (p = 0.03). In addition, a majority (55%) indicated an increase in documentation quality. Conclusions: Digital patient documentation does not necessarily save working time, but it defragments the process of documentation work and has the potential to positively influence the documentation workflow.
RESUMEN
Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
Asunto(s)
Estudios de Asociación Genética , Sarcoglicanopatías/epidemiología , Sarcoglicanopatías/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/genética , Estudios Retrospectivos , Sarcoglicanopatías/diagnóstico , Adulto JovenRESUMEN
The announcement of a hydrocephalus as a possible side effect in patients with spinal muscular atrophy (SMA) receiving the drug nusinersen, promoted major concern and warrants further evaluation. In this retrospective monocentric study, we analyzed clinical data, lumbar puncture opening pressure (LOP) measurement, and ophthalmologic and neuroimaging results in 34 patients with SMA types 1 to 3 undergoing treatment with nusinersen. None of the patients reported symptoms indicative of increased intracranial pressure. In our cohort, the LOP was >20 cm H2O in 25 patients (70.5%), and within this group ≥28 cm H2O in 12 patients (35.3%), in two patients, it was increased prior to treatment initiation. Signs of increased intracranial pressure in ophthalmological assessments or brain imaging were only seen in one patient. We did not identify a correlation between increased LOP and SMA type, scoliosis, or age of the patients; however, it was slightly higher in patients receiving sedation. Our results raise the question whether the LOP is generally increased in SMA as part of the underlying disease, if so, what the etiology is, and whether the increased LOP needs to be treated.
Asunto(s)
Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Humanos , Inyecciones Espinales/métodos , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/tratamiento farmacológico , Estudios Retrospectivos , Atrofias Musculares Espinales de la Infancia/terapia , Punción Espinal/efectos adversosRESUMEN
PURPOSE: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. METHODS: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. RESULTS: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. CONCLUSION: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
Asunto(s)
Fallo Hepático , Humanos , Hipotonía Muscular , Mutación , ConvulsionesRESUMEN
BACKGROUND: This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib. METHODS: Patients received oral dovitinib 500 mg day-1, 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment. RESULTS: Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2-66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1-11.9%), and 5.3% (n=2; 90% CI, 0.9-15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8-7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n=7), fatigue (n=5), vomiting (n=4), hypertriglyceridaemia (n=4), and γ-glutamyltransferase increase (n=4). CONCLUSIONS: Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib.
Asunto(s)
Bencimidazoles/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/farmacología , Quinolonas/farmacología , Terapia Recuperativa , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/metabolismo , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Passive fit of the prosthetic superstructure is important to avoid complications; however, evaluation of passive fit is not possible using conventional procedures. Thus, the aim of this study was to check and locate mechanical stress in bar restorations fabricated using two casting techniques. Fifteen patients received four implants in the interforaminal region of the mandible, and a bar was fabricated using either the cast-on abutment or lost-wax casting technique. The fit accuracy was checked according to the Sheffield's test criteria. Measurements were recorded on the master model with a gap-free, passive fit using foil strain gauges both before and after tightening the prosthetic screws. Data acquisition and processing was analyzed with computer software and submitted to statistical analysis (ANOVA). The greatest axial distortion was at position 42 with the cast-on abutment technique, with a mean distortion of 450 µm/m. The lowest axial distortion occurred at position 44 with the lost-wax casting technique, with a mean distortion of 100 µm/m. The minimal differences between the means of axial distortion do not indicate any significant differences between the techniques (P = 0.2076). Analysis of the sensor axial distortion in relation to the implant position produced a significant difference (P < 0.0001). Significantly higher measurements were recorded in the axial distortion analysis of the distal sensors of implants at the 34 and 44 regions than on the mesial positions at the 32 and 42 regions (P = 0.0481). The measuring technique recorded axial distortion in the implant-supported superstructures. Distortions were present at both casting techniques, with no significant difference between the sides.
Asunto(s)
Técnica de Colado Dental , Implantes Dentales , Prótesis Dental de Soporte Implantado , Retención de Dentadura/instrumentación , Pilares Dentales , Arco Dental/patología , Técnica de Impresión Dental , Adaptación Marginal Dental , Humanos , Mandíbula/patología , Programas Informáticos , Estrés Mecánico , Torque , Ceras/químicaRESUMEN
5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 'scoliosis' the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers.
Asunto(s)
Progresión de la Enfermedad , Aprendizaje Automático , Atrofia Muscular Espinal , Escoliosis , Humanos , Escoliosis/terapia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Masculino , Femenino , Niño , Terapia Genética/métodos , Adolescente , PreescolarRESUMEN
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease, causing progressive muscle weakness due to loss of lower motoneurons. Since 2017, three therapies, two modifying gene transcription and one adding the defective gene, have been approved with comparable efficacy on motor outcome. Data on cognitive outcomes of treated SMA type 1 patients is limited. The aim of this study was to evaluate cognitive function in symptomatic and presymptomatic SMA type 1 patients with two or three SMN2 copies who received SMN-modifying or gene-addition therapy in the first year of life. METHODS: Cognitive testing was performed in 20 patients, including 19 symptomatic SMA type 1 patients with up to three SMN2 copies and 1 pre-symptomatically treated patient. Children were tested using Bayley Scales of Infant Development (BSID-III) at the age of 2 or 3 years or the Wechsler Preschool and Primary Scale of Intelligence (WPSII-IV) at the of age of 5 years. RESULTS: 11/20 patients showed subnormal cognitive development. Boys had significantly lower cognitive scores. Patients requiring assisted ventilation or feeding support were more likely to have cognitive deficits. Achieving more motor milestones was associated with a better cognitive outcome. CONCLUSION: Treated patients with SMA type 1 have heterogeneous cognitive function with 55 % of patients showing deficits. Risk factors for cognitive impairment in our cohort were male gender and need for assisted ventilation or feeding support. Therefore, cognitive assessment should be included in the standard of care to allow early identification of deficits and potential therapeutic interventions.
Asunto(s)
Atrofias Musculares Espinales de la Infancia , Proteína 2 para la Supervivencia de la Neurona Motora , Humanos , Masculino , Femenino , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Preescolar , Lactante , Atrofias Musculares Espinales de la Infancia/terapia , Atrofias Musculares Espinales de la Infancia/genética , Atrofias Musculares Espinales de la Infancia/psicología , Terapia Genética/métodos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/terapia , Cognición/fisiología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapiaRESUMEN
Importance: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking. Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. Design, Setting, and Participants: This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months. Exposure: Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system. Main Outcomes: The primary end point was the achievement of motor milestones. Results: A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%). Conclusions and Relevance: This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group. Trial Registration: German Clinical Trials Register: DRKS00012699.
Asunto(s)
Tamizaje Neonatal , Humanos , Tamizaje Neonatal/métodos , Recién Nacido , Femenino , Masculino , Lactante , Alemania , Sistema de Registros , Atrofia Muscular Espinal/diagnóstico , Proyectos Piloto , Diagnóstico PrecozRESUMEN
Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Fenotipo , Humanos , Femenino , Masculino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Niño , Alemania , Secuenciación del Exoma/métodos , Adolescente , Estudios de Asociación Genética/métodos , Pruebas Genéticas/métodos , Preescolar , Estudios Prospectivos , Adulto , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Lactante , Adulto JovenRESUMEN
BACKGROUND: 2-8% of all children aged between 6 months and 5 years have febrile seizures. Often these seizures cease spontaneously, however depending on different national guidelines, 20-40% of the patients would need therapeutic intervention. For seizures longer than 3-5 minutes application of rectal diazepam, buccal midazolam or sublingual lorazepam is recommended. Benzodiazepines may be ineffective in some patients or cause prolonged sedation and fatigue. Preclinical investigations in a rat model provided evidence that febrile seizures may be triggered by respiratory alkalosis, which was subsequently confirmed by a retrospective clinical observation. Further, individual therapeutic interventions demonstrated that a pCO2-elevation via re-breathing or inhalation of 5% CO2 instantly stopped the febrile seizures. Here, we present the protocol for an interventional clinical trial to test the hypothesis that the application of 5% CO2 is effective and safe to suppress febrile seizures in children. METHODS: The CARDIF (CARbon DIoxide against Febrile seizures) trial is a monocentric, prospective, double-blind, placebo-controlled, randomized study. A total of 288 patients with a life history of at least one febrile seizure will be randomized to receive either carbogen (5% CO2 plus 95% O2) or placebo (100% O2). As recurrences of febrile seizures mainly occur at home, the study medication will be administered by the parents through a low-pressure can fitted with a respiratory mask. The primary outcome measure is the efficacy of carbogen to interrupt febrile seizures. As secondary outcome parameters we assess safety, practicability to use the can, quality of life, contentedness, anxiousness and mobility of the parents. PROSPECT: The CARDIF trial has the potential to develop a new therapy for the suppression of febrile seizures by redressing the normal physiological state. This would offer an alternative to the currently suggested treatment with benzodiazepines. This study is an example of academic translational research from the study of animal physiology to a new therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01370044.
Asunto(s)
Dióxido de Carbono/uso terapéutico , Convulsiones Febriles/terapia , Preescolar , Método Doble Ciego , Diseño de Equipo , Humanos , Lactante , Estudios Prospectivos , Calidad de Vida , Proyectos de Investigación , Investigación Biomédica Traslacional , Resultado del TratamientoRESUMEN
PURPOSE: With stage migration induced by early diagnosis of prostate-specific antigen, the course of disease for prostate cancer (PCa) patients has changed. Increasingly, patients undergo long-term androgen ablation with consecutive risks including osteoporosis and pathologic fractures. A recent randomized trial found that the RANK ligand inhibitor denosumab was more effective preventing skeletal-related events in patients with metastatic PCa as compared to treatment with the bisphosphonate zoledronic acid. This improved efficacy was linked to an increase of side effects. METHODS: The present analysis compares results reported for both substances using a number needed to treat analysis approach. Based upon these findings, risk-benefit calculations were performed. RESULTS: The results demonstrate that for patients with bone metastatic castration-resistant PCa, decision for or against treatment with either denosumab or zoledronic acid must not only consider efficacy but needs to balance the desired effects versus potential side effects. This is of specific relevance since life expectancy is limited in this patient cohort with end-stage disease. CONCLUSIONS: Further scientific efforts are necessary to identify optimal dosing and application intervals for denosumab and zoledronic acid as well as to answer the question of optimal duration of treatment. These findings will directly impact the risk versus benefit relations for both therapeutic options.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Hormonales/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Enfermedades Óseas/prevención & control , Difosfonatos/uso terapéutico , Imidazoles/uso terapéutico , Números Necesarios a Tratar , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/secundario , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Enfermedades Óseas/inducido químicamente , Denosumab , Difosfonatos/administración & dosificación , Difosfonatos/efectos adversos , Esquema de Medicación , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Esperanza de Vida , Masculino , Osteoporosis/inducido químicamente , Osteoporosis/prevención & control , Medición de Riesgo , Factores de Riesgo , Fracturas de la Columna Vertebral/inducido químicamente , Fracturas de la Columna Vertebral/prevención & control , Factores de Tiempo , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
Background/Objective: Neurofilament light chain (NfL) has been proposed as a biomarker reflecting disease severity and therapy response in children with spinal muscular atrophy type 1 and 2 (SMA1 and 2). The objective of this study was to examine how serum NfL changes after gene replacement therapy (GRT) with onasemnogene abeparvovec-xioi. Methods: We measured NfL in serum probes from 19 patients (10 SMA 1 and 6 SMA 2; 15 previously treated with nusinersen or risdiplam; 12 male) before and at variable time points after GRT. These values were related to motor scores (CHOP-Intend, HFMSE and RULM). Results: Median age at GRT was 19 months (range 2-46 months). Median NfL of all patients before GRT was 39 pg/ml (range 0-663 pg/ml; normal values <25 pg/ml), increased significantly to 297 pg/ml (range 61-1,696 pg/ml; p<0,002) 1 month after GRT, and decreased to 49 pg/ml (range 24-151 pg/ml) after 6 months. Subjects pre-treated with nusinersen or risdiplam had lower baseline NfL levels than naïve patients (p<0,005), but absolute increases of NfL were similar in both groups. While motor scores were improved in 14 out of 18 SMA patients (78%) 6 months after GRT NfL values differed not significantly from those measured at baseline (p = 0,959). Conclusion: Serum NfL showed a paradoxical transient increase after GRT in both, pre-treated and naïve patients, which may reflect an immunological reaction in the CNS related to transfection of neuronal cells by AAV9. The clinical meaning of this increase should be assessed in future studies. Our findings encourage regular monitoring of NfL in OA treated patients.
RESUMEN
BACKGROUND: In pediatric intensive care, prescription, administration, and interpretation of drug doses are weight dependent. The use of standardized concentrations simplifies the preparation of drugs and increases safety. For safe administration as well as easy interpretation of intravenous drug dosing regimens with standardized concentrations, the display of weight-related dose rates on the infusion device is of pivotal significance. OBJECTIVES: We report on challenges in the implementation of a new information technology-supported medication workflow. The workflow was introduced on eight beds in the pediatric heart surgery intensive care unit as well as in the pediatric anesthesia at the University of Bonn Medical Center. The proposed workflow utilizes medication labels generated from prescription data from the electronic health record. The generated labels include a two-dimensional barcode to transfer data to the infusion devices. METHODS: Clinical and technical processes were agilely developed. The reliability of the system under real-life conditions was monitored. User satisfaction and potential for improvement were assessed. In addition, a structured survey among the nursing staff was performed. The questionnaire addressed usability as well as the end-users' perception of the effects on patient safety. RESULTS: The workflow has been applied 44,111 times during the pilot phase. A total of 114 known failures in the technical infrastructure were observed. The survey showed good ratings for usability and safety (median "school grade" 2 or B for patient safety, intelligibility, patient identification, and handling). The medical management of the involved acute care facilities rated the process as clearly beneficial regarding patient safety, suggesting a rollout to all pediatric intensive care areas. CONCLUSION: A medical information technology-supported medication workflow can increase user satisfaction and patient safety as perceived by the clinical end-users in pediatric acute care. The successful implementation benefits from an interdisciplinary team, active investigation of possible associated risks, and technical redundancy.
Asunto(s)
Errores de Medicación , Seguridad del Paciente , Humanos , Niño , Errores de Medicación/prevención & control , Reproducibilidad de los Resultados , Unidades de Cuidado Intensivo Pediátrico , Cuidados CríticosRESUMEN
Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.
Asunto(s)
Atrofia Muscular Espinal , Recién Nacido , Humanos , Proyectos Piloto , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/terapia , Tamizaje Neonatal/métodos , Alemania , TiempoRESUMEN
The Helicobacter pylori protein CagA (cytotoxin-associated gene A) is associated with an increased risk for gastric cancer formation. After attachment to epithelial cells, the bacteria inject CagA via a type IV secretion apparatus into host cells, where it exerts its biological activity. Host cell responses to intracellular CagA have been linked exclusively to signaling motifs in the C terminus of the CagA protein. Little is known about the functional role of the remaining CagA protein. Using transgenic expression of CagA mutants in epithelial cells, we were able to identify a novel CagA inhibitory domain at the N terminus consisting of the first 200 amino acids. This domain localizes to cell-cell contacts and increases the rate and strength of cell-cell adhesion in epithelial cells. Thus, it compensates for the loss of cell-cell adhesion induced by the C terminus of the CagA protein. Consistent with its stabilizing role on cell-cell adhesion, the CagA N terminus domain reduces the CagA-induced ß-catenin transcriptional activity in the nucleus. Furthermore, it inhibits apical surface constriction and cell elongations, host cell phenotypes induced by the C terminus in polarized epithelia. Therefore, our study suggests that CagA contains an intrinsic inhibitory domain that reduces host cell responses to CagA, which have been associated with the formation of cancer.
Asunto(s)
Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Células Epiteliales/microbiología , Helicobacter pylori/fisiología , Interacciones Huésped-Patógeno , Transducción de Señal , Secuencias de Aminoácidos , Animales , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Línea Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Perros , Células Epiteliales/metabolismo , Mutación , Estructura Terciaria de Proteína , Factores de Riesgo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Transcripción Genética/genética , beta Catenina/biosíntesis , beta Catenina/genéticaRESUMEN
Recent years have witnessed major advances in the ability of computerized systems to track the positions of animals as they move through large and unconstrained environments. These systems have so far been a great boon in the fields of primatology, psychology, neuroscience, and biomedicine. Here, we discuss the promise of these technologies for animal welfare. Their potential benefits include identifying and reducing pain, suffering, and distress in captive populations, improving laboratory animal welfare within the context of the three Rs of animal research (reduction, refinement, and replacement), and applying our understanding of animal behavior to increase the "natural" behaviors in captive and wild populations facing human impact challenges. We note that these benefits are often incidental to the designed purpose of these tracking systems, a reflection of the fact that animal welfare is not inimical to research progress, but instead, that the aligned interests between basic research and welfare hold great promise for improvements to animal well-being.