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PURPOSE: Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition. METHODS: We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes. RESULTS: We identified 103 patients meeting eligibility criteria with median follow-up of 92 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46 mg/dL (95% CI - 77 to - 15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22). CONCLUSIONS: SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition.
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Neoplasias da Mama , Cetoacidose Diabética , Hiperglicemia , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Humanos , Feminino , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fosfatidilinositol 3-Quinases , Fosfatidilinositol 3-Quinase , Neoplasias da Mama/tratamento farmacológico , Hipoglicemiantes , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/tratamento farmacológico , Cetoacidose Diabética/epidemiologia , Glicemia , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , SódioRESUMO
Emerging evidence points out that the responses of soil organic carbon (SOC) to nitrogen (N) addition differ along the soil profile, highlighting the importance of synthesizing results from different soil layers. Here, using a global meta-analysis, we found that N addition significantly enhanced topsoil (0-30 cm) SOC by 3.7% (±1.4%) in forests and grasslands. In contrast, SOC in the subsoil (30-100 cm) initially increased with N addition but decreased over time. The model selection analysis revealed that experimental duration and vegetation type are among the most important predictors across a wide range of climatic, environmental, and edaphic variables. The contrasting responses of SOC to N addition indicate the importance of considering deep soil layers, particularly for long-term continuous N deposition. Finally, the lack of depth-dependent SOC responses to N addition in experimental and modeling frameworks has likely resulted in the overestimation of changes in SOC storage under enhanced N deposition.
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Carbono , Solo , Carbono/análise , Nitrogênio/análise , Florestas , Sequestro de Carbono , ChinaRESUMO
Phosphorus (P) limitation often constrains biological processes in Arctic tundra ecosystems. Although adsorption to soil minerals may limit P bioavailability and export from soils into aquatic systems, the contribution of mineral phases to P retention in Arctic tundra is poorly understood. Our objective was to use X-ray absorption spectroscopy to characterize P speciation and associations with soil minerals along hillslope toposequences and in undisturbed and disturbed low-lying wet sedge tundra on the North Slope, AK. Biogenic mats comprised of short-range ordered iron (Fe) oxyhydroxides were prevalent in undisturbed wet sedge meadows. Upland soils and pond sediments impacted by gravel mining or thermokarst lacked biogenic Fe mats and were comparatively iron poor. Phosphorus was primarily contained in organic compounds in hillslope soils but associated with Fe(III) oxyhydroxides in undisturbed wet sedge meadows and calcium (Ca) in disturbed pond sediments. We infer that phosphate mobilized through organic decomposition binds to Fe(III) oxyhydroxides in wet sedge, but these associations are disrupted by physical disturbance that removes Fe mats. Increasing disturbances of the Arctic tundra may continue to alter the mineralogical composition of soils at terrestrial-aquatic interfaces and binding mechanisms that could inhibit or promote transport of bioavailable P from soils to aquatic ecosystems.
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Ferro , Fósforo , Tundra , Fósforo/química , Regiões Árticas , Ferro/química , Ecossistema , Espectroscopia por Absorção de Raios X , Solo/química , Sedimentos Geológicos/químicaRESUMO
As global change processes modify the extent and functions of terrestrial-aquatic interfaces, the variability of critical and dynamic transitional zones between wetlands and uplands increases. However, it is still unclear how fluctuating water levels at these dynamic boundaries alter groundwater biogeochemical cycling. Here, we used high-temporal resolution data along gradients from wetlands to uplands and during fluctuating water levels at freshwater coastal areas to capture spatiotemporal patterns of groundwater redox potential (Eh). We observed that topography influences groundwater Eh that is higher in uplands than in wetlands; however, the high variability within TAI zones challenged the establishment of distinct redox zonation. Declining water levels generally decreased Eh, but most locations exhibited significant Eh variability, which is associated with rare instances of short-term water level fluctuations, introducing oxygen. The Eh-oxygen relationship showed distinct hysteresis patterns, reflecting redox poising capacity at higher Eh, maintaining more oxidizing states longer than the dissolved oxygen presence. Surprisingly, we observed more frequent oxidizing states in transitional areas and wetlands than in uplands. We infer that occasional oxygen entering specific wetland-upland boundaries acts as critical biogeochemical control points. High-resolution data can capture such rare yet significant biogeochemical instances, supporting redox-informed models and advancing the predictability of climate change feedback.
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RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.
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Citomegalovirus/fisiologia , Fibroblastos/imunologia , Fibroblastos/virologia , RNA Polimerase III/metabolismo , Animais , Chlorocebus aethiops , Citomegalovirus/imunologia , Células Dendríticas , Regulação Enzimológica da Expressão Gênica , Humanos , Mutação , RNA Polimerase III/genética , Células VeroRESUMO
Observations of woody plant mortality in coastal ecosystems are globally widespread, but the overarching processes and underlying mechanisms are poorly understood. This knowledge deficiency, combined with rapidly changing water levels, storm surges, atmospheric CO2 , and vapor pressure deficit, creates large predictive uncertainty regarding how coastal ecosystems will respond to global change. Here, we synthesize the literature on the mechanisms that underlie coastal woody-plant mortality, with the goal of producing a testable hypothesis framework. The key emergent mechanisms underlying mortality include hypoxic, osmotic, and ionic-driven reductions in whole-plant hydraulic conductance and photosynthesis that ultimately drive the coupled processes of hydraulic failure and carbon starvation. The relative importance of these processes in driving mortality, their order of progression, and their degree of coupling depends on the characteristics of the anomalous water exposure, on topographic effects, and on taxa-specific variation in traits and trait acclimation. Greater inundation exposure could accelerate mortality globally; however, the interaction of changing inundation exposure with elevated CO2 , drought, and rising vapor pressure deficit could influence mortality likelihood. Models of coastal forests that incorporate the frequency and duration of inundation, the role of climatic drivers, and the processes of hydraulic failure and carbon starvation can yield improved estimates of inundation-induced woody-plant mortality.
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Dióxido de Carbono , Ecossistema , Carbono , Secas , Árvores , ÁguaRESUMO
BACKGROUND: The sterilizing effect of cancer treatment depends mostly on the chemotherapy regimen and extent of radiotherapy. Prediction of long-term reproductive outcomes among cancer survivors according to chemo-radiotherapy regimen may improve pre-treatment fertility preservation counseling and future reproductive outcomes. METHODS: The aim of this study was to evaluate long term reproductive outcomes in cancer survivors according to gonadotoxicity risk estimation of the chemo-radiotherapy regimens utilized. This retrospective cohort study was comprised of post-pubertal female patients referred for fertility preservation during 1997 and 2017 was performed. Eligible adult patients were addressed and asked to complete a clinical survey regarding their ovarian function, menstruation, reproductive experience and ovarian tissue auto-transplantation procedures. Results were stratified according to the gonadotoxic potential of chemotherapy and radiotherapy they received-low, moderate and high-risk, defined by the regimen used, the cumulative dose of chemotherapy administered and radiation therapy extent. RESULTS: A total of 120 patients were eligible for the survey. Of those, 92 patients agreed to answer the questionnaire. Data regarding chemotherapy regimen were available for 77 of the 92 patients who answered the questionnaire. Menopause symptoms were much more prevalent in patients undergoing high vs moderate and low-risk chemotherapy protocol. (51.4% vs. 27.3% and 16.7%, respectively; p < 0.05). Spontaneous pregnancy rates were also significantly lower in the high-risk compared with the low-risk gonadotoxicity regimen group (32.0% vs. 58.3% and 87.5%, respectively; p < 0.05). CONCLUSION: Patients scheduled for aggressive cancer treatment have significantly higher rates of menopause symptoms and more than double the risk of struggling to conceive spontaneously. Improving prediction of future reproductive outcomes according to treatment protocol and counseling in early stages of cancer diagnosis and treatment may contribute to a tailored fertility related consultation among cancer survivors.
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Preservação da Fertilidade , Neoplasias , Adulto , Criopreservação , Feminino , Fertilidade , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Ovário , Gravidez , Estudos RetrospectivosRESUMO
Nasopharyngeal carcinoma (NPC) is a rare and locally aggressive form of childhood cancer. Treatment of NPC includes chemotherapy and radiotherapy. With current treatment protocols, survival rates for patients with nonmetastatic disease is over 80%. Data regarding very late events including long-term treatment-related morbidities and second malignancies are scarce. We present our data on 42 patients with NPC treated in Israel between 1989 and 2014, and followed until 2019. During follow up, five patients had disease recurrence, and four children developed secondary malignancy. Median time to diagnosis of secondary malignancy was 105 months. Eighty-eight percent of patients have long-term treatment-related morbidities.
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Quimiorradioterapia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Segunda Neoplasia Primária/mortalidade , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Israel/epidemiologia , Masculino , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/terapia , Estudos RetrospectivosRESUMO
Injuries of the hand and wrist are frequently encountered in radiology. Avulsions of the hand and wrist are a heterogeneous group of injuries, but they often have a characteristic imaging appearance that relates to the intricate bone and soft-tissue anatomy and the mechanism of injury. The imaging appearance and this intricate form and function dictate treatment of hand and wrist avulsions. This article reviews frequently and infrequently encountered avulsion injuries and describes abnormalities that may mimic the imaging appearance of avulsions. Specifically discussed entities include the Bennett and reverse Bennett fracture, ulnar collateral ligament avulsion, radial and ulnar styloid process avulsion, triquetral avulsion, mallet and jersey finger, central slip avulsion, and acute and chronic volar plate avulsion injuries. Uncommon avulsion injuries are also described and include avulsions of the scapholunate ligament, extensor carpi radialis longus and brevis tendons, trapeziometacarpal ligament, radial collateral ligament, and flexor digitorum profundus tendon. Emphasis is placed on the relevant anatomy and typical imaging findings for each diagnosis, with pertinent clinical history, pathophysiologic evaluation, and treatment discussed briefly. Understanding the anatomy and expected imaging findings can aid the radiologist in recognizing and characterizing these injuries.©RSNA, 2020.
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Traumatismos da Mão/diagnóstico por imagem , Traumatismos do Punho/diagnóstico por imagem , Diagnóstico Diferencial , Mãos/anatomia & histologia , Traumatismos da Mão/fisiopatologia , Traumatismos da Mão/terapia , Humanos , Punho/anatomia & histologia , Traumatismos do Punho/fisiopatologia , Traumatismos do Punho/terapiaRESUMO
BACKGROUND: Monocular vision has been found to have a negative effect on children's motion processing and motor functions. Yet, knowledge of motor function of survivors of retinoblastoma (RB) with monocular vision (due to enucleation, for example) is limited. This study examined motor function and its relationship to visual-related and health-related quality of life (HRQOL) in survivors of RB with monocular vision. PROCEDURE: Parents of 27 survivors of RB, who underwent an enucleation of one eye resulting in monocular vision, and of 21 typically developing children between the ages of 6 and 12, were administered questionnaires relating to their children's motor function (DCDQ), as well as vision-related function (CVFQ) and HRQOL (PedsQL). RESULTS: Of the 27 survivors of RB, 7 (25.6%) were found to have difficulties in motor functions, compared with 1 (4.8%) child in the control group. The difficulties were faced mainly in daily function requiring control during movement, including jumping, running, and ball playing. Additionally, significant correlations were found between motor functions and children's QOL. Finally, survivors of RB with monocular vision were found to have lower QOL, specifically physical- and school-related QOL. CONCLUSION: Survivors of RB who have monocular vision have a higher rate of decreased motor function and lower QOL. These results point to a need for ongoing assessment of survivors of RB to allow timely detection of motor deficits and to institute appropriate therapeutic interventions.
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Destreza Motora , Pais/psicologia , Qualidade de Vida , Neoplasias da Retina/fisiopatologia , Retinoblastoma/fisiopatologia , Sobreviventes/psicologia , Visão Monocular , Criança , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Neoplasias da Retina/psicologia , Retinoblastoma/psicologia , Inquéritos e QuestionáriosRESUMO
Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2-16) were applied. The main side effects were neutropenia (CTCAE grade 1-3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8-24) and the median overall survival is 15.6 months (range 6.9-28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Glioma/imunologia , Glioma/radioterapia , Humanos , Masculino , Intervalo Livre de Progressão , Estudos Prospectivos , Análise de SobrevidaRESUMO
Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition.
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Mutação em Linhagem Germinativa , Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Trombocitopenia/genética , Sequência de Aminoácidos , Estudos de Casos e Controles , Células HeLa , Humanos , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-ets/química , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
INTRODUCTION: Retinoblastoma (RB) is a malignant tumor presenting in the eyes of infants and children, which endangers life, the eye and vision. The treatment of RB has undergone marked changes in recent years, and great progress has been made in our ability to preserve eyes. Over the last three decades most Israeli patients with RB have been treated in the National Specialty Ocular Oncology Service at the Hadassah-Hebrew University Medical Center in Jerusalem. AIMS: To describe advances in the primary treatment of RB with an emphasis on eye-preserving treatments. METHODS: The study included a retrospective cohort of patients who were diagnosed and treated at our center over the last three decades. Review of patients' records was approved by the Hadassah IRB. RESULTS: From 1988 to 2014 we diagnosed 290 children (138 girls - 47.6%). The mean age at diagnosis (±SE) was 18.1±1.2 months, median 12.5 months. RB was unilateral in 55.6% of the cases, bilateral in 41.3% and unilateral multifocal in 3.1%. There was an even distribution of disease severity (IRB grouping). Since the advent of IV chemotherapy (IVC) there has been a decrease in the rate of eye enucleation from ~90% to ~30% of the children until the year 2000 with a stable rate thereafter. In the years 1990-2000 there was an increase followed by a decrease in the use of primary external beam radiotherapy (EBRT), and a parallel small increase in the use of brachytherapy from the mid '90s until today. The recently introduced novel treatments - intravitreal (IVitC) and intra-arterial chemotherapy (IAC) - were used as a complimentary treatment to IVC, and not yet as a single primary modality until 2014. CONCLUSIONS: IVC replaced the need to enucleate in most of the cases, but 30% of children still require a primary enucleation. DISCUSSION: IVC usually requires additive treatments (thermal-cryotherapy, trans-pupillary thermotherapy - TTT, brachytherapy and/or local chemotherapy - IVitC and IAC) and with the use of multi-modal therapy many eyes can be preserved. In the period reported in the current manuscript, the use of IAC as a primary treatment approach was only used in isolated cases. In Summary, There have been significant advances in our ability to save eyes, and the field continues to progress.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Enucleação Ocular/métodos , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Objective: Cross-national replication of the high rates of overweight/obesity among U.S. pediatric cancer survivors (PCS) is limited. Predictors of weight trajectories of Israeli PCS were examined from diagnosis and end of active cancer treatment to 3 years posttreatment. Methods: World Health Organization-derived body mass index (z-BMI) values were calculated at each time point from medical records of 135 Israeli PCS ( M diagnosis age = 11.4). A three-section piecewise multilevel model including age, ethnicity, gender, treatment length, and diagnosis as predictors was used to estimate z-BMI trajectories. Results: Most participants remained at a healthy weight at all time points. Differing weight trajectories emerged for PCS diagnosed with lymphoma/leukemia versus other cancer diagnoses from diagnosis to end of treatment, but similar weight change patterns were observed posttreatment. Conclusion: Replication of U.S. PCS weight trajectories was not observed in Israeli PCS, suggesting the importance of exploring environmental risk factors contributing to obesity among PCS.
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Sobreviventes de Câncer , Neoplasias/complicações , Obesidade Infantil/etiologia , Aumento de Peso , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Israel , Masculino , Modelos Estatísticos , Neoplasias/terapia , Sobrepeso/diagnóstico , Sobrepeso/epidemiologia , Sobrepeso/etiologia , Obesidade Infantil/diagnóstico , Obesidade Infantil/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: Our objective was to assess informed consent procedures for intravenous tissue plasminogen activator in acute stroke among New York State (NYS) Department of Health (DOH) designated stroke centers. METHODS: A 13-question survey stratified by 0- to 3-hour and 3.0- to 4.5-hour treatment windows was used to determine the type of consent or if no consent was required. RESULTS: Of the 117 hospitals, 111 responded (95%). All 111 hospitals provided treatment within the 3-hour window, whereas 97 (87%) provided treatment beyond the 3-hour window (P < .001). For hospitals that did provide treatment, there was a difference between the percentages of hospitals requiring consent (verbal or written) within 3 hours (82%) and beyond 3 hours (92%) (P = .04). Of the hospitals requiring consent, there was a difference in the type of consent: 31 of 91 (34%) required written consent within the 3-hour window, whereas 57 of 89 (64%) required written consent beyond the 3-hour window (P < .001). Within both treatment windows, 98% accepted a health-care proxy or surrogate in lieu of the patient. Of the hospitals with less than 500 beds, 11 of 81 (14%) did not require consent within the 3-hour treatment window, compared to hospitals with 500 or more beds where 9 of 30 (30%) did not require consent within the 3-hour treatment window (P < .05). Beyond the 3-hour treatment window, hospitals with more than 500 beds required written consent-2-fold increase "compared to less than 3 hour window" (P < .05). Fifty-five percent of the hospitals were academic, whereas 45% were nonacademic. Academic status was not related to the type of consent in either window. CONCLUSIONS: Significant variability exists in the types of informed consent based on hospital bed size and treatment windows across NYS DOH designated stroke centers.
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Fibrinolíticos/administração & dosagem , Hospitais/ética , Consentimento Livre e Esclarecido/ética , Avaliação de Processos em Cuidados de Saúde/ética , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/ética , Ativador de Plasminogênio Tecidual/administração & dosagem , Termos de Consentimento/ética , Pesquisas sobre Atenção à Saúde , Disparidades em Assistência à Saúde/ética , Número de Leitos em Hospital , Humanos , Infusões Intravenosas , New York , Padrões de Prática Médica/ética , Acidente Vascular Cerebral/diagnóstico , Fatores de Tempo , Tempo para o Tratamento , Resultado do TratamentoRESUMO
Severe combined immune deficiency (SCID) is a group of genetically heterogeneous diseases caused by an early block in T cell differentiation and present with life threatening infections, often within the first year of life. Janus kinase (JAK)3 gene mutations have been found to cause autosomal recessive T-B+ SCID phenotype. In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes. We present the cases and discuss the current literature.
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Linfócitos B/imunologia , Íntrons/genética , Janus Quinase 3/genética , Células Matadoras Naturais/imunologia , Splicing de RNA/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T/imunologia , Consanguinidade , Feminino , Humanos , Lactente , Janus Quinase 3/imunologia , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/imunologiaRESUMO
Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis.
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Adenosina Desaminase/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Adenosina Desaminase/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , FenótipoRESUMO
OBJECTIVES: Evaluate a potential association between Wilms' tumour (WT) and renal cystic lesions. METHODS: Digital records and imaging files of consecutive patients diagnosed with WT between 2004 and 2014 were retrospectively reviewed under an Institutional Review Board waiver of informed consent. The locations of renal cysts seen on US, CT, and/or MRI were recorded and compared with the locations of newly developed WT. RESULTS: A total of 48 patients (mean age 3 years 9 months) presented with newly diagnosed WT in the study period. Mean follow-up was 4.5 (range 1-10) years. WT was unilateral in 40 children, bilateral in 8. Renal cysts were identified in only one of the forty patients (2.5 %) with unilateral disease - in the contralateral kidney. In contrast, renal cysts were found in seven of eight patients with bilateral WT (87.5 %), in two of whom, new tumours developed in the same location where cysts had been seen on previous imaging studies. CONCLUSIONS: Renal cystic lesions in patients with Wilms' tumour should be regarded as potential tumour precursors, and followed with frequent imaging. KEY POINTS: ⢠Cortical renal cystic lesions have a high association with bilateral Wilms' tumour. ⢠In children with Wilms' tumour renal cysts are possible tumour precursors. ⢠MRI appears to be the best modality in depicting the cortical cysts.
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Cistos/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Nefropatias/diagnóstico por imagem , Tumor de Wilms/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Estudos RetrospectivosRESUMO
PURPOSE: To evaluate radiological findings in a cohort of 22 patients with infantile malignant osteopetrosis in order to establish the correlation between radiological findings and different genetic backgrounds. MATERIALS AND METHODS: Clinical files, genetic analysis results, and radiological examinations of children treated for osteopetrosis with bone marrow transplantation in a referral center in the last 5 years were retrospectively evaluated. The study received institutional review board (IRB) approval. RESULTS: Twenty-two patients were included in the study: 18 males, four females, ages 1 month-9 years 10 months, and the median age was 11 months (mean 23 months). There were 12 patients with different mutations in the TCIRG1 gene, five with mutations in the SNX10 gene, four children harbored RANK mutations, and one patient had a CLCN7 mutation. We noted more severe radiological findings in patients with TCIRG1 and RANK mutations, including fractures, osteopetrorickets, hydrocephalus, and hepatomegaly. Varus deformity of the femoral neck was seen exclusively in patients with a TCIRG1 mutation. CONCLUSIONS: The variable genetic spectrum of osteopetrosis is associated with a variable radiological presentation. These correlations may be helpful for priorities in genetic analysis.
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Colo do Fêmur/diagnóstico por imagem , Mutação , Osteopetrose/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Osteopetrose/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Nexinas de Classificação/genética , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for infantile malignant osteopetrosis (IMO), but is associated with a high incidence of adverse outcomes. In this study, we present our experience with HSCT for IMO patients comparing different types of conditioning regimens. METHODS: Thirty-eight patients with IMO (aged from 1 month to 6 years, median 0.66 years) who underwent allogeneic HSCT from 1983 in our hospital were included in this retrospective study. Fludarabine-based conditioning regimens were used in 26 patients and 12 patients were transplanted using other conditioning regimens. RESULTS: The overall survival after conditioning with fludarabine was 96% (25/26) versus 58% (7/12) for the alternative regimens (P = 0.004), with significantly fewer adverse effects including hypercalcemia and veno-occlusive disease of liver. All patients who survive are clinically well. CONCLUSIONS: We conclude that fludarabine-based conditioning regimens are safe and effective in patients with IMO, improving morbidity and mortality related to HSCT.