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Extreme precipitation is a considerable contributor to meteorological disasters and there is a great need to mitigate its socioeconomic effects through skilful nowcasting that has high resolution, long lead times and local details1-3. Current methods are subject to blur, dissipation, intensity or location errors, with physics-based numerical methods struggling to capture pivotal chaotic dynamics such as convective initiation4 and data-driven learning methods failing to obey intrinsic physical laws such as advective conservation5. We present NowcastNet, a nonlinear nowcasting model for extreme precipitation that unifies physical-evolution schemes and conditional-learning methods into a neural-network framework with end-to-end forecast error optimization. On the basis of radar observations from the USA and China, our model produces physically plausible precipitation nowcasts with sharp multiscale patterns over regions of 2,048 km × 2,048 km and with lead times of up to 3 h. In a systematic evaluation by 62 professional meteorologists from across China, our model ranks first in 71% of cases against the leading methods. NowcastNet provides skilful forecasts at light-to-heavy rain rates, particularly for extreme-precipitation events accompanied by advective or convective processes that were previously considered intractable.
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Hemophagocytic lymphohistiocytosis (HLH) is a disorder that has been recognized since the middle of the last century. In recent decades, increasing understanding of the genetic roots and pathophysiology of HLH has led to improved diagnosis and treatment of this once universally fatal disorder. HLH is best conceptualized as a maladaptive state of excessive T cell activation driving life-threatening myeloid cell activation, largely via interferon-gamma (IFN-γ). In familial forms of HLH (F-HLH), inherited defects of lymphocyte cytotoxic biology underlie excessive T cell activation, demonstrating the importance of the perforin/granzyme pathway as a negative feedback loop limiting acute T cell activation in response to environmental factors. HLH occurring in other contexts and without apparent inherited genetic predisposition remains poorly understood, though it may share some downstream aspects of pathophysiology including excessive IFN-γ action and activation of innate immune effectors. Iatrogenic forms of HLH occurring after immune-activating therapies for cancer are providing new insights into the potential toxicities of inadequately controlled T cell activation. Diagnosing HLH increasingly relies on context-specific measures of T cell activation, IFN-γ activity, and inflammation. Treatment of HLH largely relies on cytotoxic chemotherapy, though targeted therapies against T cells, IFN-γ, and other cytokines are increasingly utilized.
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Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Linfócitos T/metabolismo , Citocinas , Interferon gama/metabolismo , InflamaçãoRESUMO
Jointly profiling the transcriptome, chromatin accessibility and other molecular properties of single cells offers a powerful way to study cellular diversity. Here we present MultiVI, a probabilistic model to analyze such multiomic data and leverage it to enhance single-modality datasets. MultiVI creates a joint representation that allows an analysis of all modalities included in the multiomic input data, even for cells for which one or more modalities are missing. It is available at scvi-tools.org .
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Modelos Estatísticos , TranscriptomaRESUMO
Current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here we performed a case-control study to test and possibly improve these clinical criteria. We also developed two complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (n=366) were children <16 years with verified familial and/or genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (n=25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329+361 children in two cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on the number of diagnostic criteria fulfilled from 17 variables studied, reveled almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without NK-cell function was also studied which showed accuracy 99.0% (sensitivity 96.2%; specificity 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.
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ABSTRACT: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
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Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Transtornos Linfoproliferativos , Recém-Nascido , Humanos , Etoposídeo/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/métodos , Transtornos Linfoproliferativos/etiologiaRESUMO
Detecting differentially expressed genes is important for characterizing subpopulations of cells. In scRNA-seq data, however, nuisance variation due to technical factors like sequencing depth and RNA capture efficiency obscures the underlying biological signal. Deep generative models have been extensively applied to scRNA-seq data, with a special focus on embedding cells into a low-dimensional latent space and correcting for batch effects. However, little attention has been paid to the problem of utilizing the uncertainty from the deep generative model for differential expression (DE). Furthermore, the existing approaches do not allow for controlling for effect size or the false discovery rate (FDR). Here, we present lvm-DE, a generic Bayesian approach for performing DE predictions from a fitted deep generative model, while controlling the FDR. We apply the lvm-DE framework to scVI and scSphere, two deep generative models. The resulting approaches outperform state-of-the-art methods at estimating the log fold change in gene expression levels as well as detecting differentially expressed genes between subpopulations of cells.
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RNA , Análise de Célula Única , Teorema de Bayes , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Perfilação da Expressão Gênica/métodosRESUMO
Many applications of machine-learning methods involve an iterative protocol in which data are collected, a model is trained, and then outputs of that model are used to choose what data to consider next. For example, a data-driven approach for designing proteins is to train a regression model to predict the fitness of protein sequences and then use it to propose new sequences believed to exhibit greater fitness than observed in the training data. Since validating designed sequences in the wet laboratory is typically costly, it is important to quantify the uncertainty in the model's predictions. This is challenging because of a characteristic type of distribution shift between the training and test data that arises in the design setting-one in which the training and test data are statistically dependent, as the latter is chosen based on the former. Consequently, the model's error on the test data-that is, the designed sequences-has an unknown and possibly complex relationship with its error on the training data. We introduce a method to construct confidence sets for predictions in such settings, which account for the dependence between the training and test data. The confidence sets we construct have finite-sample guarantees that hold for any regression model, even when it is used to choose the test-time input distribution. As a motivating use case, we use real datasets to demonstrate how our method quantifies uncertainty for the predicted fitness of designed proteins and can therefore be used to select design algorithms that achieve acceptable tradeoffs between high predicted fitness and low predictive uncertainty.
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Algoritmos , Aprendizado de Máquina , Retroalimentação , Incerteza , Conformação MolecularRESUMO
XIAP (X-linked inhibitor of apoptosis) deficiency is a rare inborn error of immunity. XIAP deficiency causes hyperinflammatory disease manifestations due to dysregulated TNF (tumor necrosis factor)-receptor signaling and NLRP3 (NOD- [nucleotide-binding oligomerization domain], LRR- [leucine-rich repeat] and pyrin domain-containing protein 3) inflammasome function. Safe and effective long-term treatments are needed and are especially important to help prevent the need for high-risk allogeneic hematopoietic cell transplantation. Here we evaluated inflammasome inhibitors as potential therapeutics with a focus on the natural flavonoid antioxidant quercetin. Bone marrow (BM)-derived macrophages were derived from XIAP-deficient or wild-type (WT) mice. Human monocytes were obtained from control or XIAP-deficient patients. Cells were stimulated with TLR (Toll-like receptor) agonists or TNF-α ± inhibitors or quercetin. For in vivo lipopolysaccharide (LPS) challenge experiments, XIAP-deficient or WT mice were fed mouse chow ± supplemental quercetin (50 mg/kg per day exposure) for 7 days followed by a challenge with 10 ng/kg LPS. IL-1ß (interleukin-1ß) and IL-18 were measured by ELISA (enzyme-linked immunosorbent assay). In murine studies, quercetin prevented IL-1ß secretion from XIAP knockout cells following TLR agonists or TNF-α stimulation (P < .05) and strongly reduced constitutive production of IL-18 by both WT and XIAP-deficient cells (P < .05). At 4 hours after in vivo LPS challenge, blood levels of IL-1ß and IL-18 were significantly decreased in mice that had received quercetin-supplemented chow (P < .05). In experiments using human cells, quercetin greatly reduced IL-1ß secretion by monocytes following TNF-α stimulation (P < .05). Our data suggest that quercetin may be an effective natural therapeutic for the prevention of XIAP deficiency-associated hyperinflammation. Clinical trials, including careful pharmacokinetic and pharmacodynamic studies to ensure that effective levels of quercetin can be obtained, are warranted.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Proteínas Inibidoras de Apoptose , Interleucina-18 , Interleucina-1beta , Lipopolissacarídeos/farmacologia , Transtornos Linfoproliferativos , Camundongos , Quercetina/farmacologia , Quercetina/uso terapêutico , Fator de Necrose Tumoral alfa , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.
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Biomarcadores Tumorais/sangue , Ferritinas/sangue , Neoplasias Hematológicas/complicações , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/mortalidade , Idoso , Feminino , Seguimentos , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.
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Histiocitose de Células de Langerhans , Piridonas , Pirimidinonas , Criança , Humanos , Histiocitose de Células de Langerhans/tratamento farmacológico , Imidazóis/uso terapêutico , Oximas/efeitos adversos , Mutação , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Primary hemophagocytic lymphohistiocytosis (pHLH) is an immune-mediated, hyperinflammatory disorder. Interferon-γ (IFNγ) plays a key role in the pathophysiology of pHLH. Emapalumab, a fully human, anti-IFNγ monoclonal antibody neutralizes both free and receptor-bound IFNγ. However, inhibiting IFNγ-mediated signaling could result in immune dysfunction and immunosuppression. This exploratory exposure-safety analysis investigated the relationship between emapalumab and the incidence of adverse events in patients with pHLH. Increased exposure to emapalumab was not associated with an increased predicted risk of severe adverse events, infection, or infusion-related reactions. Emapalumab was associated with a favorable and manageable safety profile across all assessed doses and treatment durations.
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Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/complicações , Anticorpos Monoclonais/efeitos adversos , Anticorpos Neutralizantes/uso terapêutico , Interferon gamaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) has been described for decades in association with malignancies (M-HLH). While its mechanism is unknown, M-HLH has a poor prognosis, ranging from 10% to 30% overall survival. Mature T-cell lymphomas, diffuse large B-cell lymphoma, and Hodgkin lymphoma, with or without viral co-triggers such as Epstein-Barr virus, are among the most frequent underlying entities. Most M-HLH cases occur at the presentation of malignancy, but they may also occur during therapy as a result of immune compromise from chemotherapy (HLH in the context of immune compromise, IC-HLH) and (typically) disordered response to infection or after immune-activating therapies (Rx-HLH, also known as cytokine release syndrome, CRS). IC-HLH typically occurs months after diagnosis in the context of fungal, bacterial, or viral infection, though it may occur without an apparent trigger. Rx-HLH can be associated with checkpoint blockade, chimeric antigen receptor T-cell therapy, or bispecific T-cell engaging therapy. Until recently, M-HLH diagnosis and treatment strategies were extrapolated from familial HLH (F-HLH), though optimized diagnostic and therapeutic treatment strategies are emerging.
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Neoplasias Hematológicas , Linfo-Histiocitose Hemofagocítica , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/terapia , Humanos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Neoplasias/imunologia , Neoplasias/terapia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/etiologia , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
⢠Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. ⢠HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. ⢠Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. ⢠Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. ⢠In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. ⢠Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Filogenia , HIV-1/genética , Farmacorresistência Viral/genética , Antirretrovirais/uso terapêutico , Mutação , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêuticoRESUMO
BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).
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Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Interferon gama/antagonistas & inibidores , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Adolescente , Idade de Início , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Neutralizantes/efeitos adversos , Quimiocina CXCL9/sangue , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Infecções/etiologia , Estimativa de Kaplan-Meier , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
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Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Reumatologia , Criança , Adulto , Humanos , Estados Unidos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/etiologia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/terapia , ConsensoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory disorder in which numerous cytokines are elevated, though interferon-γ (IFN-γ) is central to disease pathogenesis and a key therapeutic target. Experimental and early clinical reports have shown that ruxolitinib, a small molecule inhibitor of Janus kinases (JAKs), which are essential for cytokine signaling, may be therapeutic in HLH. In contrast, we found that intermittently administered ruxolitinib at various dose levels failed to prevent HLH development or treat established murine HLH. High doses of ruxolitinib blocked IFN-γ signaling only transiently after administration, consistent with human pharmacokinetics, and only continuously administered drug could prevent HLH development or treat established HLH. Continuously administered ruxolitinib was therapeutic in only a narrow dose range and intermittently dosed ruxolitinib worsened survival and decreased bone marrow cellularity of animals concurrently treated with anti-IFN-γ antibody, indicating a narrow therapeutic window and potential toxicity. Because JAK2 is essential for hematopoietic cytokine signaling, we also tested a JAK1-selective inhibitor and observed therapeutic benefit without apparent toxicity, though it did not improve survival when combined with anti-IFN-γ. We conclude that continuous blockade of IFN-γ signaling is necessary for optimal control of HLH and that JAK2 inhibition may be toxic in this disorder.
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Interferon gama/imunologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/imunologia , Linfo-Histiocitose Hemofagocítica , Nitrilas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Janus Quinase 2/genética , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Camundongos , Transdução de Sinais/imunologiaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation that has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. Although clinical similarities between these syndromes suggest similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T-cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T-cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38high/HLA-DR+ effector cells, with activation of CD8+ T cells being most pronounced. Activated T cells were type 1 polarized, proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue-infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38high/HLA-DR+ cells among CD8+ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T-cell activation whereas early sepsis is not, and that these 2 syndromes can be readily distinguished by T-cell phenotypes.
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ADP-Ribosil Ciclase 1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Síndrome da Liberação de Citocina/diagnóstico , Antígenos HLA-DR/metabolismo , Ativação Linfocitária/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Glicoproteínas de Membrana/metabolismo , Sepse/diagnóstico , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Sepse/imunologia , Sepse/patologia , Adulto JovemRESUMO
AIM: To describe positive and negative spiritual responses to providing COVID-related nursing care among nurses working in hospitals. BACKGROUND: The COVID pandemic has intensified and publicised the threats to nurse well-being. Absent from the recommendations for promoting nurse well-being is recognition of how nurses' spirituality and/or religiosity is affected by the strain of COVID caring or how it may be affecting their well-being. DESIGN: Cross-sectional, descriptive observational, mixed methods study. METHODS: Data were collected from 523 registered nurses employed in three Southern California hospitals during March-May, 2022 when these hospitals' COVID case counts were <15%. Using Online survey methods, data were obtained using the Religious/Spiritual Struggles Scale-Short Form, Moral Injury Symptom Scale-Healthcare Professionals, Post-traumatic Growth Inventory and demographic and work-related items. STROBE guidelines for cross-sectional observational studies were observed. RESULTS: The mean for religious/spiritual struggles was 1.98 (range of 1-5, comparable to a little bit). Although roughly half of the sample reported the struggles were not experienced/did not apply, 23%-36.5% reported experiencing these struggles at least somewhat. The most frequent struggle was to find ultimate meaning. The mean observed for moral injury was 6.5 (range of 1-10); applying established criteria indicated it was troubling for at least 50%. The mean for post-traumatic growth was 4 (on a scale of 0-6); using established criteria, 41% experienced PTG. Quantitative findings were illustrated by the qualitative responses that occasionally expressed spiritual tragedy and transformation concurrently. CONCLUSION: The professional work of nursing impacts nurses in invisible, spiritual ways that can be tragic and/or transformative. RELEVANCE TO CLINICAL PRACTICE: Interventions to address nurses' mental health challenges must include attention to these invisible struggles. Nurses' mental health challenges must be met in part by addressing how they can surmount spiritual tragedy-and allow spiritual transformation.
Assuntos
COVID-19 , Espiritualidade , Humanos , COVID-19/epidemiologia , Estudos Transversais , Pandemias , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Evidence-based practice (EBP) is increasingly being adopted in healthcare organizations to improve patient care and outcomes. Yet, barriers remain that prevent consistent implementation of EBP in clinical settings. AIMS: To increase EBP competencies and promote practice change, a regional academic-community hospital in Los Angeles, California, jointly with a university school of nursing, developed and implemented an EBP scholar program. METHODS: A multistep EBP process was delivered during monthly didactic workshops to ensure optimal delivery and acquisition of EBP core competencies. The Iowa Model of Evidence-Based Practice to Promote Quality Care was integrated into the curriculum to assist program scholar's efforts to systematically direct EBP implementation at the organizational level. Additional strategies were incorporated including one-to-one mentoring, institutional recognition, and protected time. The 13-item EBP Competency Scale for practicing registered professional nurses was used to measure EBP competency at baseline and post-program completion. RESULTS: Five recruited scholars completed the baseline survey and three completed the postsurvey. EBP competency increased from 52.9% to 62.75%. Scholars submitted abstracts for conference poster presentation, podium presentations, and conference poster awards. One article was submitted and accepted for journal publication. LINKING EVIDENCE TO ACTION: A multistep EBP process can enhance EBP delivery, improve EBP competency, and facilitate dissemination.
Assuntos
Prática Clínica Baseada em Evidências , Tutoria , Humanos , Qualidade da Assistência à Saúde , Inquéritos e Questionários , Mentores , Enfermagem Baseada em EvidênciasRESUMO
X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p = 0.01) and 8.2 (CI 2.1-32.7, p < 0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.