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Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Mesilato de Imatinib/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVES: COVID-19 pandemic seems to be under control. However, despite the vaccines, 5 to 10% of the patients with mild disease develop moderate to critical forms with potential lethal evolution. In addition to assess lung infection spread, chest CT helps to detect complications. Developing a prediction model to identify at-risk patients of worsening from mild COVID-19 combining simple clinical and biological parameters with qualitative or quantitative data using CT would be relevant to organizing optimal patient management. METHODS: Four French hospitals were used for model training and internal validation. External validation was conducted in two independent hospitals. We used easy-to-obtain clinical (age, gender, smoking, symptoms' onset, cardiovascular comorbidities, diabetes, chronic respiratory diseases, immunosuppression) and biological parameters (lymphocytes, CRP) with qualitative or quantitative data (including radiomics) from the initial CT in mild COVID-19 patients. RESULTS: Qualitative CT scan with clinical and biological parameters can predict which patients with an initial mild presentation would develop a moderate to critical form of COVID-19, with a c-index of 0.70 (95% CI 0.63; 0.77). CT scan quantification improved the performance of the prediction up to 0.73 (95% CI 0.67; 0.79) and radiomics up to 0.77 (95% CI 0.71; 0.83). Results were similar in both validation cohorts, considering CT scans with or without injection. CONCLUSION: Adding CT scan quantification or radiomics to simple clinical and biological parameters can better predict which patients with an initial mild COVID-19 would worsen than qualitative analyses alone. This tool could help to the fair use of healthcare resources and to screen patients for potential new drugs to prevent a pejorative evolution of COVID-19. CLINICAL TRIAL REGISTRATION: NCT04481620. CLINICAL RELEVANCE STATEMENT: CT scan quantification or radiomics analysis is superior to qualitative analysis, when used with simple clinical and biological parameters, to determine which patients with an initial mild presentation of COVID-19 would worsen to a moderate to critical form. KEY POINTS: ⢠Qualitative CT scan analyses with simple clinical and biological parameters can predict which patients with an initial mild COVID-19 and respiratory symptoms would worsen with a c-index of 0.70. ⢠Adding CT scan quantification improves the performance of the clinical prediction model to an AUC of 0.73. ⢠Radiomics analyses slightly improve the performance of the model to a c-index of 0.77.
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COVID-19 , Humanos , SARS-CoV-2 , Pandemias , Modelos Estatísticos , Prognóstico , Estudos RetrospectivosRESUMO
As ectotherms with moist, permeable skins, amphibians continually seek a physiological balance between maintaining hydration and optimizing body temperature. Laboratory studies have suggested that dehydrated and starved amphibians should select cooler temperatures to slow the rate of water loss and reduce metabolism. However, much less is known about amphibian thermoregulatory behaviour in the wild, where environmental conditions and constraints may be more variable. In seasonally cold environments, where animals must maximize growth, gamete production and/or fat storage for winter dormancy over a short active season, maintaining a high metabolic rate may be primary. We investigated the thermoregulatory behaviour of the Fowler's Toads, Anaxyrus fowleri, in the wild at their northern range limit at Long Point, Ontario. We outfitted adult toads with small temperature loggers and radio-tracked them for periods of 24 hours. Simultaneously, we also recorded air and subsurface temperatures to a depth of 18.6 cm. When active at night, toads rapidly equilibrated with ambient air temperatures. However, during the day, resting toads selected and maintained body temperatures around 30 °C during the heat of the day by adjusting the depth to which they were buried. This strongly suggests that they behaviourally thermoregulate during their resting hours to maintain a high metabolic rate without regard to the dryness of their immediate surroundings.
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Comportamento Animal , Regulação da Temperatura Corporal , Bufonidae/fisiologia , Microclima , Animais , Feminino , Masculino , TelemetriaRESUMO
Early molecular response has been associated with clinical outcome in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The BCR-ABL1 transcript rate decline from baseline to 3 months has been demonstrated to be more predictive than a single BCR-ABL1 level at 3 months (M3). However, it cannot be used routinely because ABL1, as an internal gene control, is not reliable for BCR-ABL1 quantification above 10%. This study aimed to compare clinical outcome and molecular response of chronic phase CML patients, depending on the percentage of BCR-ABL1 transcript decrease from month 3 to month 6 using ABL1 as an internal control gene. Two hundred sixteen chronic phase CML patients treated with imatinib 400 mg for whom M3 and month 6 molecular data were available were included in the study. Associations with event-free (EFS), failure-free (FFS), progression-free (PFS), and overall survivals (OS) molecular response 4 log and 4.5 log were assessed. The percentage of BCR-ABL1 decline from month 3 to month 6 was significantly linked to the EFS and the FFS (p < 0.001). A common cut-off of 67% of decline predicted the better risk of event. Patients with a decrease below 67% have worse EFS and FFS as compared to those having a higher decrease (p < 0.001). The impact was confirmed by multivariate analysis. Since the slope between diagnosis and 3 months cannot be reliable using ABL1 as an internal gene control, the second decline rate of BCR-ABL1 transcript between month 3 and month 6 could efficiently identify patients at higher risk of event.
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Proteínas de Fusão bcr-abl , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva , RNA Mensageiro , RNA Neoplásico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Taxa de SobrevidaAssuntos
Variações do Número de Cópias de DNA , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Proto-Oncogênicas c-myc/genética , Cariótipo Anormal , Idoso de 80 Anos ou mais , Suscetibilidade a Doenças , Feminino , Humanos , Hibridização in Situ FluorescenteRESUMO
Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1+AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1+AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50-91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1+AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1+AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1+AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.
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Mesilato de Imatinib , Leucemia Mieloide Aguda , Sistema de Registros , Translocação Genética , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Mesilato de Imatinib/uso terapêutico , Mesilato de Imatinib/administração & dosagem , Idoso , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Cromossomos Humanos Par 22/genética , Proteínas de Fusão bcr-abl/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos Par 9/genética , Adulto Jovem , NucleofosminaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) with myelodysplasia-related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate- or adverse-risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy. METHODS: A large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63-year-old) with what was called at the time AML-MRC has been explored, and data are reported here. RESULTS: Patient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1-5.6) with a mean 1-year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA. CONCLUSIONS: These data, reporting about an ill-explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , RecidivaRESUMO
Myeloproliferative neoplasms, mastocytosis, myeloid/lymphoid neoplasms with hypereosinophilia and tyrosine kinase gene fusions, and myelodysplastic/myeloproliferative neoplasms are clonal hematopoietic cancers that, with the exception of certain entities, have an indolent course. In addition to their increasingly important role in the diagnosis of these entities, as shown by the recent classification of hematolymphoid tumors in the 5th edition of the World Health Organization and the International Consensus Classification of myeloid neoplasms and acute leukemias, identification of the profile of acquired genetic abnormalities is essential for adapting patient management and early detection of patients at high risk of progression. Alongside molecular abnormalities, cytogenetic abnormalities play an important role in the diagnosis, prognosis and follow-up of these diseases. Here, we review the recent literature on the impact of chromosomal abnormalities in these different entities and provide updated cytogenetic recommendations and guidelines for their management.
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Hematologia , Mastocitose , Transtornos Mieloproliferativos , Humanos , Aberrações Cromossômicas , Análise Citogenética , Mastocitose/diagnóstico , Mastocitose/genética , Mastocitose/terapia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapiaRESUMO
We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best supportive care (BSC). Complete response was obtained in 37/19/0% (p = .0008). Allogeneic stem-cell transplantation (alloSCT) was performed in 39.3/10.3/0%. Median overall survival (OS) and 5-year OS were 8.2/9.6/2.2 months and 16/6/2% (p < .0001). Predictive factors of worse OS were post-myelodysplastic/chronic myelomonocytic leukemia, bone marrow blasts ≥20%, adverse cytogenetics, AZA cycle ≥2 and no alloSCT at R/R for AZA and age, performance status, white blood cell count and myelodysplasia-related changes for IC. The impact of treatment was time-dependent: adjusted hazard ratio for OS was in favor of AZA up to 1 month, was not different between 1 and 7 months, then was in favor of IC after 7 months. While AZA represents a therapeutic option for the oldest patients, it does not lead to long-term survivors.
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Azacitidina , Leucemia Mieloide Aguda , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Doença Crônica , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Sistema de Registros , Resultado do TratamentoRESUMO
Large earthquakes often lead to transient deformation and enhanced seismic activity, with their fastest evolution occurring at the early, ephemeral post-rupture period. Here, we investigate this elusive phase using geophysical observations from the 2004 moment magnitude 6.0 Parkfield, California, earthquake. We image continuously evolving afterslip, along with aftershocks, on the San Andreas fault over a minutes-to-days postseismic time span. Our results reveal a multistage scenario, including immediate onset of afterslip following tens-of-seconds-long coseismic shaking, short-lived slip reversals within minutes, expanding afterslip within hours, and slip migration between subparallel fault strands within days. The early afterslip and associated stress changes appear synchronized with local aftershock rates, with increasing afterslip often preceding larger aftershocks, suggesting the control of afterslip on fine-scale aftershock behavior. We interpret complex shallow processes as dynamic signatures of a three-dimensional fault-zone structure. These findings highlight important roles of aseismic source processes and structural factors in seismicity evolution, offering potential prospects for improving aftershock forecasts.
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BACKGROUND: Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP-CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment-free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence-free survival (MRFS) after stop according to recommendations. METHODS: Over a 10-year period, newly diagnosed CP-CML patients and treated with first-line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first-line treatments. RESULTS: From January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41-62.19] at 2 years and 43.8% [31.45-56.15] at 5 years. Patients receiving frontline second-generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others. CONCLUSION: One third of CP-CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second-generation TKI frontline were associated with the highest MRFS.
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Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Seleção de Pacientes , Inibidores de Proteínas Quinases/uso terapêutico , Suspensão de Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Proteínas de Fusão bcr-abl/análise , Guias como Assunto , Humanos , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Recidiva , Indução de Remissão , Suspensão de Tratamento/estatística & dados numéricos , Adulto JovemRESUMO
Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.
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Postremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P < .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Atenção à Saúde , Intervalo Livre de Doença , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2-3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2-3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2-3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.
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A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse-Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0-32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27-45), 24.7% (95%CI: 1-33) and 19.7% (95%CI: 1-28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.
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Histiocitose/etiologia , Malária Falciparum/sangue , Antimaláricos , Citofagocitose , Infecções por HIV/complicações , Hepatite C/complicações , Humanos , Malária Falciparum/complicações , Malária Falciparum/tratamento farmacológico , Malária Falciparum/fisiopatologia , Masculino , Pessoa de Meia-Idade , Quinina/uso terapêutico , Trombocitopenia/etiologia , Resultado do TratamentoRESUMO
Our understanding of plate boundary deformation has been enhanced by transient signals observed against the backdrop of time-independent secular motions. We make use of a new analysis of displacement time series from about 1,000 continuous Global Positioning System (GPS) stations in California from 1999 to 2018 to distinguish tectonic and nontectonic transients from secular motion. A primary objective is to define a high-resolution three-dimensional reference frame (datum) for California that can be rapidly maintained with geodetic data to accommodate both secular and time-dependent motions. To this end, we compare the displacements to those predicted by a horizontal secular fault slip model for the region and construct displacement and strain rate fields. Over the past 19 years, California has experienced 19 geodetically detectable earthquakes and widespread postseismic deformation. We observe postseismic strain rate variations as large as 1,000 nstrain/year with moment releases equivalent up to an Mw6.8 earthquake. We find significant secular differences up to 10 mm/year with the fault slip model, from the Mendocino Triple Junction to the southern Cascadia subduction zone, the northern Basin and Range, and the Santa Barbara channel. Secular vertical uplift is observed across the Transverse Ranges, Coastal Ranges, Sierra Nevada, as well as large-scale postseismic uplift after the 1999 Mw7.1 Hector Mine and 2010 Mw7.2 El Mayor-Cucapah earthquakes. We also identify areas of vertical land motions due to anthropogenic, natural, and magmatic processes. Finally, we demonstrate the utility of the kinematic datum by improving the accuracy of high-spatial-resolution 12-day repeat-cycle Sentinel-1 Interferometric Synthetic Aperture Radar displacement and velocity maps.