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Child and adolescent mental health systems are facing limited resources of available psychosocial interventions, often leading to long waiting lists for acceptance to treatment. We describe the feasibility of a short-term (8-10 sessions) psychological crisis intervention (CI) protocol for children and adolescents aged 8-17 years (n = 30, mean ± standard deviation 12.9 ± 2.4 years) who were referred to an outpatient mental health clinic due to suicidal ideation, aggression, severe anxiety, or extreme family conflict. The participants were assessed before and after the CI, and at a 3-6-months follow-up visit. The psychiatric assessments included clinical evaluation by a senior psychiatrist, and the completion of self-report questionnaires by both the participants and their parents. Following the establishment of the CI unit, the waiting lists for urgent cases were reduced from a median of 84 days in the two preceding years to 23 days in the following 3 years (H[2] = 18.5, p < 0.0001) for patients of the CI unit. A 1-year psychiatric follow-up after the end of the CI revealed that 72% did not require additional psychotherapy. The overall clinical evaluation measures (clinical evaluation, parents-report and child report) improved and had been preserved at the 3-6-months follow-up. Our results demonstrate the feasibility of a short-term CI protocol for expediting admission to treatment for urgent psychiatric cases.
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Intervenção em Crise , Psicoterapia , Humanos , Criança , Adolescente , Estudos de Viabilidade , Psicoterapia/métodos , Assistência Ambulatorial , Serviço Hospitalar de EmergênciaRESUMO
BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Testes Genéticos , Nefropatias , Criança , Humanos , Nefropatias/genética , Fenótipo , Encaminhamento e Consulta , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic resulted in repeated surges of patients, sometimes challenging triage protocols and appropriate control of patient flow. Available models, such as the National Early Warning Score (NEWS), have shown significant limitations. Still, they are used by some centers to triage COVID-19 patients due to the lack of better tools. OBJECTIVES: To establish a practical and automated triage tool based on readily available clinical data to rapidly determine a distinction between patients who are prone to respiratory failure. METHODS: The electronic medical records of COVID-19 patients admitted to the Sheba Medical Center March-April 2020 were analyzed. Population data extraction and exploration were conducted using a MDClone (Israel) big data platform. Patients were divided into three groups: non-intubated, intubated within 24 hours, and intubated after 24 hours. The NEWS and our model where applied to all three groups and a best fit prediction model for the prediction of respiratory failure was established. RESULTS: The cohort included 385 patients, 42 of whom were eventually intubated, 15 within 24 hours or less. The NEWS score was significantly lower for the non-intubated patients compared to the two other groups. Our improved model, which included NEWS elements combined with other clinical data elements, showed significantly better performance. The model's receiver operating characteristic curve had area under curve (AUC) of 0.92 with of sensitivity 0.81, specificity 0.89, and negative predictive value (NPV) 98.4% compared to AUC of 0.63 with NEWS. As patients deteriorate and require further support with supplemental O2, the need for re-triage emerges. Our model was able to identify those patients on supplementary O2 prone to respiratory failure with an AUC of 0.86 sensitivity 0.95, and specificity 0.7 NPV 98.9%, whereas NEWS had an AUC of 0.76. For both groups positive predictive value was approximately 35. CONCLUSIONS: Our model, based on readily available and simple clinical parameters, showed an excellent ability to predict negative outcome among patients with COVID-19 and therefore might be used as an initial screening tool for patient triage in emergency departments and other COVID-19 specific areas of the hospital.
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COVID-19 , Insuficiência Respiratória , COVID-19/complicações , COVID-19/diagnóstico , Humanos , Pandemias , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Estudos Retrospectivos , TriagemRESUMO
BACKGROUND: Healthcare workers (HCW) treating coronavirus disease 2019 (COVID-19) patients face high levels of psychological stress. We aimed to compare mental health outcomes, risk and protective factors for posttraumatic stress symptoms (PTSS), probable depression, and anxiety between HCW working in COVID-19 and non-COVID-19 wards. METHODS: A self-report survey, administered in a large tertiary hospital in Israel during the peak of the COVID-19 outbreak was completed by 828 HCW (42.2% physicians, 57.8% nurses. Patient-Reported Outcomes Measurement Information System; the Patient Health Questionnaire-9; the Primary Care-Post Traumatic Stress Disorder Screen for DSM-5 (PC-PTSD-5) were used for assessing anxiety, depression, and PTSS, respectively. Pandemic-related stress factors, negative experiences, and potential protective factors were also assessed. RESULTS: Median PC-PTSD scores differed significantly between study teams (χ2 [5] = 17.24; p = .004). Prevalence of probable depression and anxiety were similar in both groups. Risk factors for mental health outcomes included mental exhaustion, anxiety about being infected and infecting family. Overall, higher proportion of the COVID-19 team witnessed patient deaths as compared to the non-COVID-19 team (50.2% vs. 24.7%). Witnessing patient death at the COVID-19 wards was associated with a four-fold increased likelihood of PTSS (odds ratio [OR] = 3.97; 95% confidence interval [CI], 1.58-9.99; p = .0007), compared with the non-COVID-19 wards (OR 0.91; 95% CI, 0.51-1.61; p = .43). CONCLUSIONS: Witnessing patient death appears to be a risk factor for PTSS unique to HCW directly engaged in treating patients with COVID-19. Our findings suggest that helping HCW cope with COVID-19 related deaths might reduce their risk of posttraumatic stress.
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COVID-19 , Ansiedade , Estudos Transversais , Depressão/epidemiologia , Pessoal de Saúde , Humanos , Israel/epidemiologia , Avaliação de Resultados em Cuidados de Saúde , SARS-CoV-2RESUMO
BACKGROUND: Physicians play a crucial frontline role in the COVID-19 pandemic, which may involve high levels of anxiety. We aimed to investigate the association between pandemic-related stress factors (PRSF) and anxiety and to evaluate the potential effect of resilience on anxiety among physicians. METHODS: A self-report digital survey was completed by 1106 Israeli physicians (564 males and 542 females) during the COVID-19 outbreak. Anxiety was measured by the 8-item version of the Patient-Reported Outcomes Measurement Information System. Resilience was evaluated by the 10-item Connor-Davidson Resilience Scale. Stress was assessed using a PRSF inventory. RESULTS: Physicians reported high levels of anxiety with a mean score of 59.20 ± 7.95. We found an inverse association between resilience and anxiety. Four salient PRSF (mental exhaustion, anxiety about being infected, anxiety infecting family members, and sleep difficulties) positively associated with anxiety scores. CONCLUSIONS: Our study identified specific PRSF including workload burden and fear of infection that are associated with increased anxiety and resilience that is associated with reduced anxiety among physicians.
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Betacoronavirus , COVID-19 , Infecções por Coronavirus , Médicos , Pneumonia Viral , Resiliência Psicológica , Ansiedade/epidemiologia , Infecções por Coronavirus/epidemiologia , Depressão , Feminino , Pessoal de Saúde , Humanos , Masculino , Pandemias , Pneumonia Viral/epidemiologia , SARS-CoV-2RESUMO
OBJECTIVES: Stenotrophomonas maltophilia is a gram-negative opportunistic bacterium that may cause a myriad of clinical diseases in immunocompromised individuals. We aimed to describe the clinical characteristics, risk factors, mortality, and treatment of S. maltophilia bacteremia in critically ill children, a topic on which data are sparse. DESIGN: A multicenter observational retrospective study in which medical charts of critically ill children with S. maltophilia bacteremia were reviewed between 2012 and 2017. SETTING: Data were collected from each of the four largest PICUs nationwide, allocated in tertiary medical centers to which children with complex conditions are referred regularly. PATIENTS: A total of 68 suitable cases of S. maltophilia bacteremia were retrieved and reviewed. MEASUREMENTS AND MAIN RESULTS: The total occurrence rate of S. maltophilia isolation had increased significantly during the study period (r = 0.65; p = 0.02). The crude mortality was 42%, and the attributed mortality was 18%. Significant risk factors for mortality were a longer length of hospital stay prior to infection (33 d in nonsurvivors vs 28 in survivors; p = 0.03), a nosocomial source of infection (p = 0.02), presentation with septic shock (p < 0.001), and treatment with chemotherapy (p = 0.007) or carbapenem antibiotics (p = 0.05) prior to culture retrieval. On multivariate analysis, septic shock (odds ratio, 14.6; 95% CI, 1.45-147.05; p = 0.023) and being treated with chemotherapy prior to infection (odds ratio, 5.2; 95% CI, 1.59-17.19; p = 0.006)] were associated with mortality. The combination of ciprofloxacin, trimethoprim-sulfamethoxazole, and minocycline resulted in the longest survival time (p < 0.01). CONCLUSIONS: The significant attributed mortality associated with S. maltophilia bacteremia in critically ill children calls for an aggressive therapeutic approach. The findings of this investigation favor a combination of trimethoprim-sulfamethoxazole, ciprofloxacin, and minocycline.
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Antibacterianos/administração & dosagem , Ciprofloxacina/administração & dosagem , Infecções por Bactérias Gram-Negativas , Minociclina/administração & dosagem , Stenotrophomonas maltophilia/imunologia , Sulfadoxina/administração & dosagem , Trimetoprima/administração & dosagem , Criança , Pré-Escolar , Comorbidade , Estado Terminal , Combinação de Medicamentos , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/mortalidade , Humanos , Hospedeiro Imunocomprometido , Lactente , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
Primary immunodeficiency diseases comprise a group of heterogeneous genetic defects that affect immune system development and/or function. Here we use in vitro differentiation of human induced pluripotent stem cells (iPSCs) generated from patients with different recombination-activating gene 1 (RAG1) mutations to assess T-cell development and T-cell receptor (TCR) V(D)J recombination. RAG1-mutants from severe combined immunodeficient (SCID) patient cells showed a failure to sustain progression beyond the CD3(--)CD4(-)CD8(-)CD7(+)CD5(+)CD38(-)CD31(-/lo)CD45RA(+) stage of T-cell development to reach the CD3(-/+)CD4(+)CD8(+)CD7(+)CD5(+)CD38(+)CD31(+)CD45RA(-) stage. Despite residual mutant RAG1 recombination activity from an Omenn syndrome (OS) patient, similar impaired T-cell differentiation was observed, due to increased single-strand DNA breaks that likely occur due to heterodimers consisting of both an N-terminal truncated and a catalytically dead RAG1. Furthermore, deep-sequencing analysis of TCR-ß (TRB) and TCR-α (TRA) rearrangements of CD3(-)CD4(+)CD8(-) immature single-positive and CD3(+)CD4(+)CD8(+) double-positive cells showed severe restriction of repertoire diversity with preferential usage of few Variable, Diversity, and Joining genes, and skewed length distribution of the TRB and TRA complementary determining region 3 sequences from SCID and OS iPSC-derived cells, whereas control iPSCs yielded T-cell progenitors with a broadly diversified repertoire. Finally, no TRA/δ excision circles (TRECs), a marker of TRA/δ locus rearrangements, were detected in SCID and OS-derived T-lineage cells, consistent with a pre-TCR block in T-cell development. This study compares human T-cell development of SCID vs OS patients, and elucidates important differences that help to explain the wide range of immunologic phenotypes that result from different mutations within the same gene of various patients.
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Proteínas de Homeodomínio/genética , Células-Tronco Pluripotentes Induzidas/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Linfócitos T/patologia , Células Cultivadas , Quebras de DNA , Genes RAG-1 , Humanos , Lactente , Mutação , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Recombinação V(D)JRESUMO
In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-ß (IFN-ß) and/or IFN-λ1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-ß and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-α or IFN-ß ( IFN-α/ß) but not IFN-λ1. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/ß intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.
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Sistema Nervoso Central/patologia , Herpesvirus Humano 1/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Receptor 3 Toll-Like/deficiência , Astrócitos/imunologia , Astrócitos/virologia , Biomarcadores , Diferenciação Celular , Linhagem da Célula , Separação Celular , Células Cultivadas , Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Criança , Suscetibilidade a Doenças , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/metabolismo , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade Inata , Células-Tronco Pluripotentes Induzidas/virologia , Interferons/imunologia , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/genética , Células-Tronco Neurais/imunologia , Células-Tronco Neurais/virologia , Neurônios/imunologia , Neurônios/patologia , Neurônios/virologia , Oligodendroglia/imunologia , Oligodendroglia/patologia , Oligodendroglia/virologia , Receptor 3 Toll-Like/genéticaRESUMO
BACKGROUND: Ataxia telangiectasia (AT) is a rare, multi-systemic, genetic disorder. Mutations in the ATM gene cause dysfunction in cell-cycle, apoptosis and V (D) J recombination leading to neurodegeneration, cellular, humoral immunodeficiencies and predisposition to malignancies. Previous studies have suggested that a sub-group of AT patients with elevated IgM levels have a distinct and more severe phenotype. In the current study we aimed to better characterize this group of patients. METHODS: We performed a retrospective review of 46 patient records, followed from January 1986 to January 2015 at the Israeli National AT Center. Demographic, clinical, radiological, laboratory data was reviewed and compared between AT patients with elevated IgM levels (EIgM) and patients with normal IgM levels (NIgM). RESULTS: 15/46(32.6%) patients had significantly elevated IgM levels. This group had a unique phenotype characterized mainly by increased risk of infection and early mortality. Colonization of lower respiratory tract with Mycobacterium gordonae and Pseudomonas aeruginosa as well as viral skin infections were more frequent in EIgM patients. Patients with NIgM had a significantly longer survival as compared to patients with EIgM but had an increased incidence of fatty liver or cirrhosis. T-cell recombination excision circles and kappa-deleting element recombination circle levels were significantly lower in the EIgM group, suggesting an abnormal class switching in this group. CONCLUSIONS: EIgM in AT patients are indicative of a more severe phenotype that probably results from a specific immune dysfunction. EIgM in AT should be considered a unique AT phenotype that may require different management.
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Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/imunologia , Imunoglobulina M/sangue , Adolescente , Ataxia Telangiectasia/mortalidade , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Infecções/etiologia , Hepatopatias/etiologia , Pneumopatias/etiologia , Masculino , Neoplasias/etiologia , Fenótipo , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS) is a congenital multisystem anomaly characterized by typical facial features, palatal anomalies, congenital heart defects, hypocalcemia, immunodeficiency, and cognitive and neuropsychiatric symptoms. The aim of our study was to investigate T- and B-lymphocyte characteristics associated with 22q11.2DS. METHODS: Seventy-five individuals with 22q11.2DS were tested for T and B lymphocytes by examination of T-cell receptor rearrangement excision circles (TRECs) and B-cell κ-deleting recombination excision circles (KRECs), respectively. RESULTS: The 22q11.2DS individuals displayed low levels of TRECs, while exhibiting normal levels of KRECs. There was a significant positive correlation between TREC and KREC in the 22q11.2DS group, but not in controls. Both TREC and KREC levels showed a significant decrease with age and only TREC was low in 22q11.2DS individuals with recurrent infections. No difference in TREC levels was found between 22q11.2DS individuals who underwent heart surgery (with or without thymectomy) and those who did not. CONCLUSION: T-cell immunodeficiency in 22q11.2DS includes low TREC levels, which may contribute to recurrent infections in individuals with this syndrome. A correlation between T- and B-cell abnormalities in 22q11.2DS was identified. The B-cell abnormalities could account for part of the immunological deficiency seen in 22q11.2DS.
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Medula Óssea/patologia , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Timo/patologia , Adolescente , Adulto , Linfócitos B/citologia , Estudos de Casos e Controles , Criança , Síndrome de DiGeorge/imunologia , Feminino , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Humanos , Masculino , Recombinação Genética , Linfócitos T/citologia , Adulto JovemRESUMO
OBJECTIVE: Traditionally, pediatric tracheostomy has been viewed as a technically demanding procedure with a high complication rate, requiring the routine use of a formal operating room. Pediatric bedside tracheostomy in an intensive care unit (ICU) setting has not been widely reported, in contrast to the widespread adult bedside ICU tracheostomy. Transport of these critically ill, multiple life support systems dependent patients can be technically difficult, labor intensive, and potentially risky for these patients. Our study aimed to demonstrate the safety and efficacy of bedside tracheostomy in the pediatric ICU. MATERIALS AND METHODS: A retrospective analysis of all pediatric patients undergoing tracheostomy at a tertiary care center, between 1st of January 2013 and 31st of December 2019. RESULTS: During the study period, 117 pediatric patients underwent tracheostomy, 57 (48.7%) were performed bedside while 60 (51.3%) were performed in the operating room. Patients' ages ranged from 2 weeks to 17 years of age, with a median age of 16 months. No case of bedside tracheostomy necessitated a shift to the operating room. There was no difference in 30-day morbidity and mortality between the 2 groups. CONCLUSIONS: Our results suggest that pediatric open bedside tracheostomy in an ICU setting is a safe procedure, with similar complications and outcomes compared to tracheostomy performed in the operating room.
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Unidades de Terapia Intensiva Pediátrica , Traqueostomia , Humanos , Traqueostomia/métodos , Traqueostomia/efeitos adversos , Estudos Retrospectivos , Criança , Feminino , Masculino , Pré-Escolar , Lactente , Adolescente , Recém-Nascido , Segurança do Paciente , Complicações Pós-Operatórias/epidemiologia , Salas CirúrgicasRESUMO
BACKGROUND: The decision to allocate hospitals for the initial reception of hostages abducted on the October 7th Hamas attack introduced an array of unprecedented challenges. These challenges stemmed from a paucity of existing literature and protocols, lack of information regarding captivity conditions, and variability in hostage characteristics and circumstances. OBJECTIVE: To describe the rapid development, implementation and evaluation of the Hostage-ReSPOND protocol, a comprehensive trauma-informed procedure for the care of hostages, including young children, their caregivers and families, immediately following their release from prolonged captivity. METHODS: A multidisciplinary expert focus group conducted a comprehensive literature review to develop the ReSPOND protocol, consisting of: Readiness of teams via multifaceted trainings, utilizing live simulations and video debriefings; Specialized professional teams experienced in providing holistic trauma-informed care; Personalized care tailored to individualized and developmentally-informed needs; Optimal safety rooted in creating a secure environment and trauma-informed response to young children, adolescents, caregivers and families; and Navigating Discharge, through coordination with community-based care systems. RESULTS: A designated facility at the Children's hospital was carefully prepared for receiving 29 hostages, aged 3.9-80 years, 28% under the age of 18. Implementation of the ReSPOND protocol, which prioritized holistic psychosocial interventions above urgent medical care, proved feasible and effective in managing the diverse and complex needs of returnees as per provider report. Finally, systemic assessment of returnee's immediate and long-term mental health needs proved highly challenging. CONCLUSIONS: There is currently no literature addressing the response to released hostages, especially those involving infants, young children and families within a children's hospital facility. This study has the potential to fill a crucial gap in knowledge by introducing a novel protocol which could offer valuable insights for public health organizations tasked with providing acute care to diverse individuals and families experiencing extreme, multi-layered mass traumatization.
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Prevention and treatment of complications are the backbone of medical care, particularly in critical care settings. Early detection and prompt intervention can potentially prevent complications from occurring and improve outcomes. In this study, we use four longitudinal vital signs variables of intensive care unit patients, focusing on predicting acute hypertensive episodes (AHEs). These episodes represent elevations in blood pressure and may result in clinical damage or indicate a change in a patient's clinical situation, such as an elevation in intracranial pressure or kidney failure. Prediction of AHEs may allow clinicians to anticipate changes in the patient's condition and respond early on to prevent these from occurring. Temporal abstraction was employed to transform the multivariate temporal data into a uniform representation of symbolic time intervals, from which frequent time-intervals-related patterns (TIRPs) are mined and used as features for AHE prediction. A novel TIRP metric for classification, called coverage, is introduced that measures the coverage of a TIRP's instances in a time window. For comparison, several baseline models were applied on the raw time series data, including logistic regression and sequential deep learning models, are used. Our results show that using frequent TIRPs as features outperforms the baseline models, and the use of the coverage, metric outperforms other TIRP metrics. Two approaches to predicting AHEs in real-life application conditions are evaluated: using a sliding window to continuously predict whether a patient would experience an AHE within a specific prediction time period ahead, our models produced an AUC-ROC of 82%, but with low AUPRC. Alternatively, predicting whether an AHE would generally occur during the entire admission resulted in an AUC-ROC of 74%.
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Hipertensão , Unidades de Terapia Intensiva , Humanos , Estado Terminal , Pressão Sanguínea , Cuidados Críticos , Hipertensão/diagnósticoRESUMO
BACKGROUND: Machine learning (ML)-derived notifications for impending episodes of hemodynamic instability and respiratory failure events are interesting because they can alert physicians in time to intervene before these complications occur. RESEARCH QUESTION: Do ML alerts, telemedicine system (TS)-generated alerts, or biomedical monitors (BMs) have superior performance for predicting episodes of intubation or administration of vasopressors? STUDY DESIGN AND METHODS: An ML algorithm was trained to predict intubation and vasopressor initiation events among critically ill adults. Its performance was compared with BM alarms and TS alerts. RESULTS: ML notifications were substantially more accurate and precise, with 50-fold lower alarm burden than TS alerts for predicting vasopressor initiation and intubation events. ML notifications of internal validation cohorts demonstrated similar performance for independent academic medical center external validation and COVID-19 cohorts. Characteristics were also measured for a control group of recent patients that validated event detection methods and compared TS alert and BM alarm performance. The TS test characteristics were substantially better, with 10-fold less alarm burden than BM alarms. The accuracy of ML alerts (0.87-0.94) was in the range of other clinically actionable tests; the accuracy of TS (0.28-0.53) and BM (0.019-0.028) alerts were not. Overall test performance (F scores) for ML notifications were more than fivefold higher than for TS alerts, which were higher than those of BM alarms. INTERPRETATION: ML-derived notifications for clinically actioned hemodynamic instability and respiratory failure events represent an advance because the magnitude of the differences of accuracy, precision, misclassification rate, and pre-event lead time is large enough to allow more proactive care and has markedly lower frequency and interruption of bedside physician work flows.
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BACKGROUND: COVID-19 is an ongoing global crisis, with a multitude of factors that affect mental health worldwide. We explored potential predictors for the emergence and maintenance of depression, anxiety, and posttraumatic stress symptoms (PTSS) in the general population in Israel. METHODS: Across the span of 16 months, 2478 people completed a repeated self-report survey which inquired psychiatric symptoms and pandemic related stress factors (PRSF). We applied mixed-effects models to assess how each stressor contributes to depression, anxiety and PTSS at each time point, and longitudinally assessed participants who completed at least two consecutive surveys (n = 400). We weighted our sample to increase representativeness of the population. RESULTS: Fatigue was the strongest predictor for depression, anxiety and PTSS at all time points, and predicted deterioration overtime. Financial concerns associated with depression and anxiety at all time points, and with their deterioration overtime. Health related concerns were uniquely associated with anxiety and PTSS at all time points and their deterioration, but not with depression. Improvement in sense of protection overtime associated with decrease in depression and anxiety. Hesitancy towards vaccination was associated to higher financial concerns and lower sense of protection by the authorities. CONCLUSIONS: Our findings accentuate the multitude of risk factors for psychiatric morbidity during COVID-19, and the centrality of fatigue in determining mental health outcomes.
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COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Israel/epidemiologia , Fatores de Proteção , Depressão/epidemiologia , Depressão/psicologia , Controle de Doenças Transmissíveis , Ansiedade/epidemiologia , Ansiedade/psicologia , Fadiga/epidemiologia , Fadiga/etiologia , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Allogeneic hematopoietic stem cell transplantation is the treatment of choice for severe primary immunodeficiencies (PIDs). For patients lacking an HLA-identical donor, gene therapy is an attractive therapeutic option. Approaches based on insertion of a functional gene by using viral vectors have provided proof of concept for the ability of gene therapy to cure PIDs. However, leukemic transformation as a result of insertional mutagenesis has been observed, prompting development of novel approaches based on introduction of DNA double-strand breaks into the endogenous locus to achieve gene correction, or into a safe genomic location ("safe harbor"). Homing endonucleases and zinc finger nucleases are target-specific endonucleases that induce site-specific DNA double-strand breaks, facilitating homologous recombination around their target sites to achieve gene correction or gene insertion into safe harbors. An alternative approach to achieve site-specific insertion of functional genes is based on transposons, DNA elements that spontaneously translocate from a specific chromosomal location to another. These novel tools may lead to efficient and safer strategies to achieve gene therapy for PIDs and other disorders.
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Terapia Genética/tendências , Síndromes de Imunodeficiência/terapia , Elementos de DNA Transponíveis/genética , Endonucleases/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Modelos Genéticos , Reparo Gênico Alvo-Dirigido/métodos , Reparo Gênico Alvo-Dirigido/tendências , Transposases/genética , Vírus/genética , Dedos de Zinco/genéticaRESUMO
BACKGROUND: Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control. OBJECTIVES: We aimed to define thymic output and characterize immune function in a cohort of patients with molecularly defined CHH with and without associated clinical immunodeficiency. METHODS: We studied the distribution of B and T lymphocytes (including recent thymic emigrants), in vitro lymphocyte proliferation, cell cycle, and apoptosis in 18 patients with CHH compared with controls. RESULTS: Patients with CHH have a markedly reduced number of recent thymic emigrants, and their peripheral T cells show defects in cell cycle control and display increased apoptosis, resulting in poor proliferation on activation. CONCLUSION: These data confirm that RMRP mutations result in significant defects of cell-mediated immunity and provide a link between the cellular phenotype and the immunodeficiency in CHH.
Assuntos
Apoptose/imunologia , Ciclo Celular/imunologia , Doença de Hirschsprung/imunologia , Síndromes de Imunodeficiência/imunologia , Osteocondrodisplasias/congênito , Linfócitos T/imunologia , Timo/imunologia , Adolescente , Separação Celular , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Genótipo , Cabelo/anormalidades , Cabelo/imunologia , Cabelo/patologia , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Masculino , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/imunologia , Osteocondrodisplasias/patologia , Fenótipo , Reação em Cadeia da Polimerase , Doenças da Imunodeficiência Primária , RNA Longo não Codificante , RNA não Traduzido/genética , Adulto JovemRESUMO
BACKGROUND: The novel ability to epigenetically reprogram somatic cells into induced pluripotent stem cells (iPSCs) through the exogenous expression of transcription promises to revolutionize the study of human diseases. OBJECTIVE: Here we report on the generation of 25 iPSC lines from 6 patients with various forms of primary immunodeficiencies (PIDs) affecting adaptive immunity, innate immunity, or both. METHODS: Patients' dermal fibroblasts were reprogrammed by expression of 4 transcription factors, octamer-binding transcription factor 4 (OCT4), sex determining region Y-box 2 (SOX2), Krueppel-like factor 4 (KLF4), and cellular myelomonocytosis proto-oncogene (cMYC), by using a single excisable polycistronic lentiviral vector. RESULTS: iPSCs derived from patients with PIDs show a stemness profile that is comparable with that observed in human embryonic stem cells. After in vitro differentiation into embryoid bodies, pluripotency of the patient-derived iPSC lines was demonstrated by expression of genes characteristic of each of the 3 embryonic layers. We have confirmed the patient-specific origin of the iPSC lines and ascertained maintenance of karyotypic integrity. CONCLUSION: By providing a limitless source of diseased stem cells that can be differentiated into various cell types in vitro, the repository of iPSC lines from patients with PIDs represents a unique resource to investigate the pathophysiology of hematopoietic and extrahematopoietic manifestations of these diseases and might assist in the development of novel therapeutic approaches based on gene correction.
Assuntos
Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/fisiopatologia , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Imunidade Adaptativa , Desdiferenciação Celular , Diferenciação Celular , Linhagem Celular , Transdiferenciação Celular , DNA/genética , Expressão Gênica , Genes myc , Humanos , Imunidade Inata , Síndromes de Imunodeficiência/genética , Cariotipagem , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fator 3 de Transcrição de Octâmero/genética , Proto-Oncogene Mas , Fatores de Transcrição SOXB1/genéticaRESUMO
Burn injuries are a significant cause of morbidity among children. Ultra-Orthodox Jewish children are at higher risk for burn injuries. The goal of this study was to examine the clinical characteristics of moderate to severe burns in this population in comparison to the general population in Israel. This retrospective cohort study included all pediatric patients 0 to 18 years of age admitted with burn injuries from January 1, 2015 through December 31, 2018. Data were collected regarding demography, etiology, and clinical characteristics. Of 778 burns injuries presented to our tertiary center, 385 (49.5%) were hospitalized. Of those 212 (55%) were non-ultra-Orthodox Jews, 135 (35%) were ultra-Orthodox Jews, and 38 (10%) were non-Jewish patients. The total body surface area percentage (TBSA%) of scald-type burns was larger in ultra-Orthodox compared to non-ultra-Orthodox children (median TBSA% of 7% vs 5%, respectively, P < .05). Among the ultra-Orthodox group, the median TBSA% during weekdays was 6%, and for weekends, the TBSA% was 7.5% (P < .05). Females demonstrated the greatest diversity between subgroups. On weekends, ultra-Orthodox female's median TBSA% was 10%, and non-ultra-Orthodox female's TBSA% was 4.5% (P < .05). Ultra-Orthodox children and especially girls had a significantly higher median TBSA% than non-ultra-Orthodox children for burns occurring during weekends. This may be the result of the unique cultural norms of the ultra-Orthodox Jewish community, in particular, their lifestyle and observation of the Sabbath. These findings provide a focus for better intervention and prevention of pediatric burns among this unique population.