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1.
Front Immunol ; 10: 2007, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507604

RESUMO

Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.

2.
Liver Int ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454466

RESUMO

BACKGROUNDS AND AIMS: In Indonesia 1.9 million people are chronically infected with hepatitis C virus (HCV), but a national strategic plan for elimination has not yet been developed, despite the availability of low-cost treatments which could save many lives. We used epidemiological- and cost-modelling to estimate targets and resource requirements of a national elimination program and explore the potential impact and cost-effectiveness. METHODS: To model the HCV epidemic, we used a dynamic model, parameterised with Indonesia-specific data, accounting for disease progression, injecting drug use, and demographics. Future scale-up scenarios were designed for 2018-2050 to capture possible policy choices. Costs of an initial five-year national strategy and of long-term elimination were estimated for the most feasible scenario, as agreed with government and local partners. Cost savings from reduced drug and diagnostics prices were also estimated. The cost-effectiveness of baseline predictions and those with drug price reductions were compared to the no-treatment scenario. RESULTS: Elimination by 2045, considered the most feasible path to scale-up, would prevent 739,000 new infections and avert 158,000 HCV-related deaths. The costs would be $5.6 billion (USD) using baseline prices but could fall to $2.7 billion if price reductions for HCV drugs and diagnostics are secured. With these price reductions, the incremental cost-effectiveness ratio for a 2045 elimination program would be cost-effective at $300 (USD) per year of life saved versus the no-treatment scenario. CONCLUSIONS: This study has underpinned advocacy efforts to secure Indonesian government commitment to HCV elimination, and provides further inputs for HCV strategic planning efforts. This article is protected by copyright. All rights reserved.

3.
South Med J ; 112(6): 320-324, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31158886

RESUMO

OBJECTIVE: To determine whether physician spirituality, religion, and sense of calling toward medicine are predictors of self-reported empathic compassion. METHODS: We sampled 2000 practicing US physicians from all specialties and used self-reported measures of general and clinical empathic compassion taken from previous studies. Independent variables were single-item measures of calling, spirituality, and religiosity (importance of religion). RESULTS: The survey response rate was 64.5% (1289/2000). Physicians with a strong sense of calling were more likely to report higher general empathic compassion (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.26-3.15) and higher clinical empathic compassion (OR 3.33, 95% CI 2.07-5.36). Similarly, physicians who considered themselves spiritual were more likely to report higher general empathic compassion (OR 2.76, 95% CI 1.69-4.50) and higher clinical empathic compassion (OR 2.32, 95% CI 1.38-3.90). We did not find an association between religiosity and measures of physicians' empathic compassion. CONCLUSIONS: This national study of practicing US physicians from various specialties found that spirituality (not religiousness) and the identification of medicine as a calling are associated with physicians' empathic compassion. Further study is needed to understand how spirituality and calling are linked to prosocial behaviors among physicians that may be enhancing their clinical empathy and promoting compassionate patient care.

4.
Clin Immunol ; 202: 33-39, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30946917

RESUMO

PURPOSE: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility. METHODS: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study. RESULTS: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group. CONCLUSIONS: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.

5.
Blood ; 134(1): 9-21, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-30940614

RESUMO

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

6.
Am J Med Genet A ; 179(6): 993-1000, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30888095

RESUMO

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.

7.
J Med Syst ; 42(12): 255, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30406430

RESUMO

Virtual rehabilitation yields outcomes that are at least as good as traditional care for improving upper limb function and the capacity to carry out activities of daily living. Due to the advent of low-cost gaming systems and patient preference for game-based therapies, video game technology will likely be increasingly utilized in physical therapy practice in the coming years. Gaming systems that incorporate low-cost motion capture technology often generate large datasets of therapeutic movements performed over the course of rehabilitation. An infrastructure has yet to be established, however, to enable efficient processing of large quantities of movement data that are collected outside of a controlled laboratory setting. In this paper, a methodology is presented for extracting and evaluating therapeutic movements from game-based rehabilitation that occurs in uncontrolled and unmonitored settings. By overcoming these challenges, meaningful kinematic analysis of rehabilitation trajectory within an individual becomes feasible. Moreover, this methodological approach provides a vehicle for analyzing large datasets generated in uncontrolled clinical settings to enable better predictions of rehabilitation potential and dose-response relationships for personalized medicine.

8.
Br J Haematol ; 183(4): 608-617, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30421536

RESUMO

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV 600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV 600E mutation was present compared to 2·9% if it was absent (P = 0·002).

9.
PLoS One ; 13(11): e0206743, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30395636

RESUMO

Dendrites function as the primary sites for synaptic input and integration with impairments in dendritic arborization being associated with dysfunctional neuronal circuitry. Post-mitotic neurons require high levels of basal autophagy to clear cytotoxic materials and autophagic dysfunction under native or cellular stress conditions has been linked to neuronal cell death as well as axo-dendritic degeneration. However, relatively little is known regarding the developmental role of basal autophagy in directing aspects of dendritic arborization or the mechanisms by which the autophagic machinery may be transcriptionally regulated to promote dendritic diversification. We demonstrate that autophagy-related (Atg) genes are positively regulated by the homeodomain transcription factor Cut, and that basal autophagy functions as a downstream effector pathway for Cut-mediated dendritic terminal branching in Drosophila multidendritic (md) sensory neurons. Further, loss of function analyses implicate Atg genes in promoting cell type-specific dendritic arborization and terminal branching, while gain of function studies suggest that excessive autophagy leads to dramatic reductions in dendritic complexity. We demonstrate that the Atg1 initiator kinase interacts with the dual leucine zipper kinase (DLK) pathway by negatively regulating the E3 ubiquitin ligase Highwire and positively regulating the MAPKKK Wallenda. Finally, autophagic induction partially rescues dendritic atrophy defects observed in a model of polyglutamine toxicity. Collectively, these studies implicate transcriptional control of basal autophagy in directing dendritic terminal branching and demonstrate the importance of homeostatic control of autophagic levels for dendritic arbor complexity under native or cellular stress conditions.

10.
J Clin Immunol ; 38(7): 778-786, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30251145

RESUMO

Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high-throughput SCID screening. Clinical Trials: NCT02244450.

11.
Proc Natl Acad Sci U S A ; 115(34): E8007-E8016, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072435

RESUMO

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.


Assuntos
Éxons , Síndromes de Imunodeficiência/genética , Mutação , Penetrância , Biossíntese de Proteínas/genética , Processamento de RNA/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Regiões 5' não Traduzidas , Feminino , Efeito Fundador , Heterozigoto , Humanos , Síndromes de Imunodeficiência/metabolismo , Masculino , Receptores de Laminina/biossíntese , Proteínas Ribossômicas/biossíntese , Baço/metabolismo
12.
J Pediatr ; 202: 311-314.e2, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29980289

RESUMO

Severe combined immunodeficiency screening by measuring T-receptor excision circles at birth allows evaluation of the impact of various maternal conditions on newborn immunity. The slight decrease observed in a French cohort of newborns to HIV-infected mothers can be explained by the confounding factors of prematurity and African descent.

13.
Haematologica ; 103(7): 1143-1149, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29599204

RESUMO

In this retrospective study, we evaluate long-term complications in nearly all ß-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.

14.
J Pediatr ; 194: 211-217.e5, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29198545

RESUMO

OBJECTIVE: To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life. STUDY DESIGN: The French Reference Center for PIDs conducted a prospective multicenter cohort that enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms. RESULTS: Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions. CONCLUSIONS: Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35.

15.
J Adv Nurs ; 74(3): 579-590, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28910496

RESUMO

AIMS: To explore the lived-experiences of stroke survivors as expressed in blogs and to discover the role the blogs play in the writers' lives. BACKGROUND: Stroke can be a devastating, life changing event. Previous qualitative studies tend to examine one aspect of life after stroke. As stroke often has multiple effects, it is necessary to look widely at its lived-experience. New resources which can enable researchers to explore the lived-experience of stroke are blogs. DESIGN: Phenomenological exploration using an interpretive thematic analysis. METHODS: The Internet was searched for stroke survivors' blogs (January-March 2016) using pre-set criteria, seeking blogs with entries over an extended time (>1 year). Suitable blogs were identified and codes of meaning were identified and developed into categories, subthemes and themes. FINDINGS: Eight blogs were identified for analysis. Of the 40 categories, eight subthemes were assimilated; internal dialogue, emotions, transition, stroke effects, health care, "in the world", relationships, rehabilitation. Two main themes were identified related to perspectives of lived-experience; Internal relationship with "self" and External relationship with "the world". Participants expressed loss and initially strove to regain their "old" lives, their focus being recovery and independence. CONCLUSION: Stroke survivors must transition from their previous life to a new and initially unwelcome way of being. Rehabilitation should respect this process and support stroke survivors as they undertake this individual journey.


Assuntos
Blogging , Acontecimentos que Mudam a Vida , Acidente Vascular Cerebral/psicologia , Adaptação Psicológica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Reabilitação do Acidente Vascular Cerebral , Sobreviventes
16.
J Crohns Colitis ; 12(2): 258-261, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-28961694

RESUMO

Azathioprine is commonly used in Crohn's disease. It has been administered to many pregnant women over many years without significant side effects. However, pancytopenia and severe combined immune deficiency-like disease have been reported in infants whose mothers received azathioprine throughout pregnancy. Moreover, myelotoxicity has been described in patients being treated with azathioprine and having a low or absent thiopurine S-methyl transferase [TPMT] activity.Here, we describe the case of a newborn girl found to be highly lymphopenic [< 300 CD3+ T cells] after a positive newborn screening for severe combined immuno deficiency. The clinical examination was normal. The mother was treated with azathioprine throughout her pregnancy, without any reduction of the dose. It was shown that the mother was heterozygous for the 3A [TPMT] activity mutation and that the baby was homozygous for the same mutation; 6-thioguanine nucleotides were high (744 pmol/8.108 red blood cells [RBC]) in the mother and detectable in the infant [177 pmol/8.108 RBC].Although rare, this case illustrates the potential grave consequences of unsuspected TPMT homozygosity in a newborn of a mother receiving thiopurines during pregnancy. Because of the severity of the risk for the newborn, consideration should be given to performing maternal genetic testing and newborn routine blood count in cases of thiopurine treatment during pregnancy.


Assuntos
Azatioprina/efeitos adversos , Doença de Crohn/tratamento farmacológico , Imunossupressores/efeitos adversos , Linfopenia/induzido quimicamente , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Doença de Crohn/genética , Feminino , Homozigoto , Humanos , Recém-Nascido , Linfopenia/genética , Metiltransferases/genética , Mutação , Gravidez
17.
Cancer Res Treat ; 50(1): 148-155, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28324923

RESUMO

PURPOSE: Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([123I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. MATERIALS AND METHODS: Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m2/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m2, and doxorubicin, 45 mg/m2. RESULTS: Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). CONCLUSION: TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/tratamento farmacológico , Adulto , Idoso , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neuroblastoma/patologia , Fatores de Risco , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Vincristina/administração & dosagem
18.
JAMA ; 318(15): 1450-1459, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-28973065

RESUMO

Importance: The high mortality rate in critically ill elderly patients has led to questioning of the beneficial effect of intensive care unit (ICU) admission and to a variable ICU use among this population. Objective: To determine whether a recommendation for systematic ICU admission in critically ill elderly patients reduces 6-month mortality compared with usual practice. Design, Setting, and Participants: Multicenter, cluster-randomized clinical trial of 3037 critically ill patients aged 75 years or older, free of cancer, with preserved functional status (Index of Independence in Activities of Daily Living ≥4) and nutritional status (absence of cachexia) who arrived at the emergency department of one of 24 hospitals in France between January 2012 and April 2015 and were followed up until November 2015. Interventions: Centers were randomly assigned either to use a program to promote systematic ICU admission of patients (n=1519 participants) or to follow standard practice (n=1518 participants). Main Outcomes and Measures: The primary outcome was death at 6 months. Secondary outcomes included ICU admission rate, in-hospital death, functional status, and quality of life (12-Item Short Form Health Survey, ranging from 0 to 100, with higher score representing better self-reported health) at 6 months. Results: One patient withdrew consent, leaving 3036 patients included in the trial (median age, 85 [interquartile range, 81-89] years; 1361 [45%] men). Patients in the systematic strategy group had an increased risk of death at 6 months (45% vs 39%; relative risk [RR], 1.16; 95% CI, 1.07-1.26) despite an increased ICU admission rate (61% vs 34%; RR, 1.80; 95% CI, 1.66-1.95). After adjustments for baseline characteristics, patients in the systematic strategy group were more likely to be admitted to an ICU (RR, 1.68; 95% CI, 1.54-1.82) and had a higher risk of in-hospital death (RR, 1.18; 95% CI, 1.03-1.33) but had no significant increase in risk of death at 6 months (RR, 1.05; 95% CI, 0.96-1.14). Functional status and physical quality of life at 6 months were not significantly different between groups. Conclusions and Relevance: Among critically ill elderly patients in France, a program to promote systematic ICU admission increased ICU use but did not reduce 6-month mortality. Additional research is needed to understand the decision to admit elderly patients to the ICU. Trial Registration: clinicaltrials.gov Identifier: NCT01508819.


Assuntos
Resultados de Cuidados Críticos , Estado Terminal/mortalidade , Unidades de Terapia Intensiva/estatística & dados numéricos , Admissão do Paciente/estatística & dados numéricos , Triagem , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Cuidados Críticos/normas , Feminino , França/epidemiologia , Nível de Saúde , Mortalidade Hospitalar , Humanos , Masculino , Avaliação de Resultados (Cuidados de Saúde) , Avaliação de Programas e Projetos de Saúde , Qualidade de Vida , Fatores de Tempo
20.
Mol Cancer ; 16(1): 115, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28679432

RESUMO

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with constitutive activation of the MAPKinase RAS-RAF-MEK-ERK cell signaling pathway. We analyzed 9 LCH cases without BRAF V600 and MAP2K1 mutations by whole exome sequencing. We identified a new somatic BRAF splicing mutation in 2 cases. Both cases were childhood single system (SS) LCH cases, with self-healing outcome of the bone lesions. This mutant consisted in a 9 base pair duplication (c.1511_1517 + 2 duplication), encoding for a predicted mutant protein with insertion of 3 amino acids (p.Arg506_Lys507insLeuLeuArg) in the N-terminal lobe of the kinase domain of BRAF. Transient expression of the c.1511_1517 + 2dup BRAF mutant in HEK293 cells enhanced MAPKinase pathway activation, and was not inhibited by vemurafenib but was inhibited by PLX8394, a second-generation BRAF inhibitor able to inhibit signaling of BRAF monomers and dimers. Future LCH molecular screening panel should include this new mutation to better define its prevalence in LCH and its restriction to autoregressive bone SS LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Processamento de RNA/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Éxons/genética , Feminino , Duplicação Gênica , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Lactente , Masculino , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
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