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Active-case finding (ACF) using chest X-ray is an essential method of finding and diagnosing Tuberculosis (TB) cases that may be missed in Indonesia's routine TB case finding. This study compares active and passive TB case-finding strategies. A retrospective study of TB case notification was conducted. Data between 1 January and 31 December 2021, was used. The population in this study were TB cases notified from Kulon Progo District health facilities, including those found through routine activities or active-case findings. A total of 249 TB cases were diagnosed in Kulon Progo in 2021, and 102 (41%) were bacteriologically confirmed. The TB patients' ages ranged from 0 to 85 years (median 52, IQR 31-61). The majority of cases were male (59%, 147/249) and mostly among people aged 15-59 (61.4%, 153/249). The proportion of clinical TB diagnoses among cases found from active-case findings was 74.7% (68/91) while the proportion among passive-case findings was 50% (79/158). Active-case finding contributed 91 (36.5%) TB cases to the total cases detected in Kulon Progo in 2021. The use of chest X-rays in active-case findings likely contributed to the detection of a higher proportion of clinical TB than in passive-case findings.
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Multiparameter flow cytometry is widely used for acute myeloid leukemia minimal residual disease testing (AML MRD) but is time consuming and demands substantial expertise. Machine learning offers potential advancements in accuracy and efficiency, but has yet to be widely adopted for this application. To explore this, we trained single cell XGBoost classifiers from 98 diagnostic AML cell populations and 30 MRD negative samples. Performance was assessed by cross-validation. Predictions were integrated with UMAP as a heatmap parameter for an augmented/interactive AML MRD analysis framework, which was benchmarked against traditional MRD analysis for 25 test cases. The results showed that XGBoost achieved a median AUC of 0.97, effectively distinguishing diverse AML cell populations from normal cells. When integrated with UMAP, the classifiers highlighted MRD populations against the background of normal events. Our pipeline, MAGIC-DR, incorporated classifier predictions and UMAP into flow cytometry standard (FCS) files. This enabled a human-in-the-loop machine learning guided MRD workflow. Validation against conventional analysis for 25 MRD samples showed 100% concordance in myeloid blast detection, with MAGIC-DR also identifying several immature monocytic populations not readily found by conventional analysis. In conclusion, Integrating a supervised classifier with unsupervised dimension reduction offers a robust method for AML MRD analysis that can be seamlessly integrated into conventional workflows. Our approach can support and augment human analysis by highlighting abnormal populations that can be gated on for quantification and further assessment. This has the potential to speed up MRD analysis, and potentially improve detection sensitivity for certain AML immunophenotypes.
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Citometría de Flujo , Leucemia Mieloide Aguda , Aprendizaje Automático , Neoplasia Residual , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Neoplasia Residual/diagnóstico , Neoplasia Residual/patología , Citometría de Flujo/métodos , Inmunofenotipificación/métodosRESUMEN
In Indonesia, the implementation of tuberculosis (TB) contact investigation is limited, with low detection rates. We report the yield of and risk factors for TB disease and infection for household contacts (HHCs) investigated using chest X-ray (CXR) screening. We identified HHCs aged five years and above of bacteriologically confirmed index cases from 2018 to 2022 in Yogyakarta City and Kulon Progo. All HHCs were offered screening for TB symptoms; TB infection testing with either tuberculin skin testing or interferon gamma release assay; and referral for CXR. Sputum from those with symptoms or CXR suggestive of TB was tested with Xpert MTB/RIF. Risk factors for active TB disease and latent TB infection (LTBI) were identified by logistic regression models. We screened 2857 HHCs for TB between June 2020 and December 2022, with 68 (2.4%) diagnosed with active TB. Of 2621 HHCs eligible for LTBI investigation, 1083 (45.7%) were diagnosed with LTBI. The factors associated with active TB were age, being underweight, diabetes mellitus, urban living, and sleeping in the same house as an index case. Factors associated with LTBI were increasing age and male gender. Conclusions: Screening for HHC including CXR and TST/IGRA yielded a moderate prevalence of TB disease and infection.
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Coverage of tuberculosis preventive treatment (TPT) in Indonesia is inadequate, and persons who start TPT often do not complete treatment. In 2020, Zero TB Yogyakarta implemented person-centered contact investigation and shorter TPT regimen provision in collaboration with primary health care centers. Between 1 January 2020 and 31 August 2022, we assessed eligibility for TPT among household contacts of persons with bacteriologically confirmed TB (index cases) and offered them a 3-month TPT regimen (3RH or 3HP). A dedicated nurse monitored contacts on TPT for treatment adherence and side effects every week in the first month and every two weeks in the next months. Contacts were also able to contact a nurse by phone or ask for home visits at any point if they had any concerns. A total of 1016 contacts were eligible for TPT: 772 (78.8%) started short regimen TPT with 706 (91.5%) completing their TPT. Side effects were reported in 26 (39%) of the non-completion group. We conclude that high rates of TPT uptake and completion among contacts assessed as eligible for TPT can be achieved through person-centered care and the use of shorter regimens. Side-effect monitoring and management while on TPT is vital for improving TPT completion.
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A novel case of neurotrophic keratitis and severe corneal melt requiring surgical management is presented 1 month following trans-scleral cyclodiode for Coats disease and neovascular glaucoma. Risk factors contributing to the complication include previous extracapsular cataract surgery, perioperative use of topical non-steroidal anti-inflammatories and dexamethasone/neomycin, as well as other topical drops containing preservatives such as benzalkonium chloride. Meticulous consideration of preoptimization of the ocular surface and rationalization of perioperative eye drop regimes is discussed.
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This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.
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Anemia , Leucemia Mieloide Aguda , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Daunorrubicina , Citarabina , Azacitidina/uso terapéutico , Anemia/tratamiento farmacológico , Náusea/tratamiento farmacológicoRESUMEN
OBJECTIVES: To evaluate the effect of miosis and laser peripheral iridotomy (LPI) on intraocular lens (IOL) power prediction and ocular biometry in eyes with primary angle closure disease (PACD). METHODS: In this prospective observational study, primary angle closure suspects (PACS), and subjects classified with primary angle closure (PAC)/primary angle-closure glaucoma (PACG) undergoing LPI were enrolled. Ocular biometric parameters were measured with IOLMaster700 at baseline (T0), one week after pilocarpine instillation (T1), and another week post LPI (T2). Biometric changes and the IOL power predicted for emmetropia using Barrett Universal II, Haigis, Holladay2, Hoffer Q and SRK/T formulae were analysed and compared among different time points. RESULTS: 100 eyes of 50 PACS and 50 PAC/PACG patients were enrolled. Following pilocarpine-induced miosis, lens thickness (LT) increased and anterior chamber depth (ACD) decreased (all groups p < 0.01), while white-to-white diameter decreased and central corneal thickness increased significantly only in the PACS cohort (both p < 0.01). Compared to baseline, LPI induced an increase of ACD and a slight decrease of LT in PACS (both p < 0.01), whereas only axial length changed significantly (p = 0.012) in the PAC/PACG cohort. Regardless of the formula used, no significant difference to the predicted IOL power for emmetropia existed among the three time points in each group (all p > 0.1). CONCLUSION: We report the changes of anterior segment parameters induced by miosis and LPI in PACD. These interventions do not significantly affect the IOL power calculation predicted for emmetropia in Chinese eyes when common third-, fourth-and new generation IOL formulae are used.
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Glaucoma de Ángulo Cerrado , Rayos Láser , Lentes Intraoculares , Humanos , Glaucoma de Ángulo Cerrado/cirugía , Miosis/inducido químicamente , Estudios Prospectivos , Pilocarpina/farmacología , Mióticos/farmacología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Presión IntraocularRESUMEN
Background: In the clinical laboratory, middleware is a software application that sits between the analyzer and the laboratory information system (LIS). One of the more common uses of middleware is to perform more efficient result autoverification than can be achieved by the LIS or analyzer alone. In addition to autoverification, middleware can support highly customized rules to handle samples and results from specific patient locations. The objective of this study was to review the impact of customized middleware rules that were designed and implemented in the hematology laboratory of a 1000-bed tertiary care adult academic center hospital. Methods: Three novel initiatives using middleware rules to achieve workflow efficiencies were retrospectively reviewed over different audit periods: preliminary neutrophil resulting for oncology patients, microcytosis interpretive comments, and 1 white blood cell differential (WBCD) reported per day. In addition, autoverification rates for complete blood count and differential (CBCD) and coagulation tests were calculated. Results: A preliminary neutrophil count was released from middleware on average 64â¯min before the final CBCD for Leukemia/Bone Marrow Transplant (L/BMT) outpatients, and on average 59â¯min earlier for oncology patients. Reflexing interpretive comments for select instances of microcytosis removed on average 500 slides per month from technologist review with an estimated cost savings of approximately $3383.33 CAD per month. The 1 WBCD per day rule resulted in a 5.1% cancelation rate, resulting in an estimated monthly cost savings of $943.46 CAD in reagents and technologist time. Finally, middleware rules achieved very high autoverification rates of 97.2% and 88.3% for CBC and CBCD results, respectively. Conclusions: Implementation of customized middleware hematology rules in our institution resulted in multiple positive impacts on workflow, achieving high autoverification rates, reduced slide reviews, cost savings, and improved standardization.
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This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Azacitidina/efectos adversos , Bencimidazoles/efectos adversos , Quimioterapia Combinada/efectos adversos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Compuestos de Fenilurea/efectos adversos , Medición de Riesgo , Resultado del TratamientoRESUMEN
Type 2 idiopathic macular telangiectasia (MacTel-2) is a progressive adult-onset macular disease associated with bilateral perifoveal vascular changes, Muller cell degeneration and increased blood-retinal barrier permeability. The pathophysiological mechanisms of MacTel-2 remain unclear, however it was previously reported that anti-retinal antibodies in MacTel-2 patients are a significant feature of the disease. In this study, we aimed to compare the prevalence of anti-retinal antibodies in patients MacTel-2, healthy controls and patients with other retinal diseases. MacTel-2 patients diagnosed with multimodal imaging were enrolled and their disease severities were graded using spectral-domain optical coherence tomography. For comparison, patients with age-related macular degeneration (AMD), inherited retinal diseases (IRDs) or no retinal disease (healthy controls) were recruited as controls. Blood serum samples were screened for immunoglobulin G anti-retinal antibodies by western blotting, followed by densitometry analysis. Odds ratios (OR) with 95% confidence intervals (CI) were calculated and p < 0.05 considered statistically significant. Overall, anti-retinal antibody-positive cases were older (64 ± 15 vs 53 ± 17 years, p < 0.001) and females were more likely to develop anti-retinal antibodies (OR: 2.41, CI: 1.12-5.18). The frequency of anti-retinal antibody detection in MacTel-2 patients (n = 42, 36%) was not significantly different from healthy controls (n = 52, 25%) or IRD patients (n = 18, 25%) and the majority of MacTel-2 patients had no anti-retinal antibodies. In contrast, the frequency of anti-retinal antibody detection was significantly higher in patients with AMD (n = 15, 73%, p < 0.001). The lack of a greater anti-retinal antibody frequency or specificity in the MacTel-2 cohort suggests that antibody mediated immunological mechanisms may play a less significant role in MacTel-2 disease pathogenesis.
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Retinopatía Diabética , Degeneración Macular , Telangiectasia Retiniana , Adulto , Retinopatía Diabética/patología , Femenino , Humanos , Inmunoglobulina G , Degeneración Macular/patología , Retina/patología , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/patología , Tomografía de Coherencia Óptica/métodosRESUMEN
This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
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Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Citarabina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Citarabina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Background: Two combination therapies recently approved and recommended for use in combination with low-dose cytarabine (LDAC) in acute myeloid leukemia patients unfit for intensive chemotherapy are glasdegib+LDAC and venetoclax+LDAC. Materials & methods: An indirect treatment comparison used median overall survival, overall survival hazard ratios, complete remission (CR), CR+CR with incomplete blood count recovery and transfusion independence to assess comparative effectiveness, and a simulated treatment comparison accounted for differences in patient characteristics between trials. Results: Differences in efficacy between glasdegib+LDAC and venetoclax+LDAC were suggestive and not statistically significant. Conclusion: With no significant differences in comparative effectiveness, considerations such as safety profiles, burden of administration and patient preference are likely to guide treatment decisions.
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Citarabina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles , Compuestos Bicíclicos Heterocíclicos con Puentes , Citarabina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea , SulfonamidasRESUMEN
PURPOSE: Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed. METHODS: Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis. RESULTS: All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142-295%) and 137% (97-193%) in the moderate group, and 202% (146-281%) and 120% (77-188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related. CONCLUSION: The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).
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Antineoplásicos/farmacocinética , Bencimidazoles/farmacocinética , Compuestos de Fenilurea/farmacocinética , Insuficiencia Renal/fisiopatología , Administración Oral , Anciano , Antineoplásicos/efectos adversos , Área Bajo la Curva , Bencimidazoles/efectos adversos , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: We implemented front-line loop-mediated isothermal amplification (LAMP)-based malaria screening in our nonendemic multicenter health region to reduce reliance on microscopy without sacrificing diagnostic efficiency. We aimed to evaluate changes in test volumes, positivity rates, turnaround times, and approximate labor time savings resulting from implementation of LAMP-based malaria testing to assess the efficacy of the novel testing algorithm in our regional hub-and-spoke testing model. METHODS: We reviewed data generated from institutional malaria testing between 2016 and 2019, having implemented LAMP in October 2018 as a front-line screening test for all malaria investigations from our hub facility and investigations from satellite facilities with negative rapid diagnostic tests (RDTs) and microscopy. RESULTS: Blood film microscopy and RDT workloads decreased substantially in the year following LAMP implementation (by 90% and 46%, respectively,) despite similar numbers of patients tested and positivity rates for malaria compared with historical data. LAMP turnaround times (TATs) were comparable to historical TATs for RDTs, and TATs for RDTs and thick films did not increase with the change in workflow. CONCLUSIONS: LAMP was successfully implemented in our multicenter health region malaria diagnostic algorithm, significantly reducing reliance on microscopic evaluations and RDT and providing substantial labor time savings without compromising TATs.
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Malaria/diagnóstico , Malaria/patología , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico , Pruebas Diagnósticas de Rutina , Humanos , Masculino , Tamizaje Masivo , Microscopía/métodos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificación de Ácido Nucleico/métodos , Sensibilidad y EspecificidadRESUMEN
Glasdegib is approved for treating acute myeloid leukemia in elderly patients at 100 mg once daily in combination with low-dose cytarabine. Exposure-efficacy analysis showed that the survival benefit of glasdegib was not glasdegib exposure-dependent. The relationship between glasdegib exposure and adverse event (AE) cluster terms of clinical concern was explored in this analysis. The incidence and severity of dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged was modeled using ordinal logistic regression. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Estimated pharmacokinetic parameters were used to derive glasdegib exposure metrics. Demographic characteristics, disease factors, and other variables of interest as potential moderators of safety signals were evaluated. Clinical trial data from patients who received single-agent glasdegib (N = 70; 5-640 mg once daily); or glasdegib (N = 202, 100-200 mg once daily) with low-dose cytarabine, decitabine, or daunorubicin and cytarabine were analyzed. Glasdegib exposure was statistically significantly associated with the cluster term safety end points dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged. The impact of age on muscle spasms and baseline body weight and creatinine clearance on renal toxicity helped explain the AE grade distribution. At the 100 mg once daily clinical dose, the predicted probabilities of the highest AE grade were 11.3%, 6.7%, 7.7%, and 2.5% for dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged, respectively. Overall, the predicted probability of developing an AE of any severity for these safety end points was low. Therefore, no starting dose adjustments are recommended for glasdegib based on the observed safety profile.
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Antineoplásicos/administración & dosificación , Bencimidazoles/administración & dosificación , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Tasa de SupervivenciaRESUMEN
PURPOSE: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS). METHODS: Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment-response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure-response (glasdegib + LDAC, n = 75) analyses. RESULTS: The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28-0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS. CONCLUSION: Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD. CLINICAL TRIAL NUMBER: NCT01546038.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bencimidazoles/administración & dosificación , Citarabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Bencimidazoles/farmacocinética , Citarabina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Hedgehog/metabolismo , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/farmacocinética , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Social, behavioural and community engagement (SBCE) interventions are essential for global maternal, newborn and child health (MNCH) strategies. Past efforts to synthesise research on SBCE interventions identified a need for clear priorities to guide future research. WHO led an exercise to identify global research priorities for SBCE interventions to improve MNCH. METHODS: We adapted the Child Health and Nutrition Research Initiative method and combined quantitative and qualitative methods to determine MNCH SBCE intervention research priorities applicable across different contexts. Using online surveys and meetings, researchers and programme experts proposed up to three research priorities and scored the compiled priorities against four criteria - health and social impact, equity, feasibility, and overall importance. Priorities were then ranked by score. A group of 29 experts finalised the top 10 research priorities for each of maternal, newborn or child health and a cross-cutting area. RESULTS: A total of 310 experts proposed 867 research priorities, which were consolidated into 444 priorities and scored by 280 experts. Top maternal and newborn health priorities focused on research to improve the delivery of SBCE interventions that strengthen self-care/family care practices and care-seeking behaviour. Child health priorities focused on the delivery of SBCE interventions, emphasising determinants of service utilisation and breastfeeding and nutrition practices. Cross-cutting MNCH priorities highlighted the need for better integration of SBCE into facility-based and community-based health services. CONCLUSIONS: Achieving global targets for MNCH requires increased investment in SBCE interventions that build capacities of individuals, families and communities as agents of their own health. Findings from this exercise provide guidance to prioritise investments and ensure that they are best directed to achieve global objectives. Stakeholders are encouraged to use these priorities to guide future research investments and to adapt them for country programmes by engaging with national level stakeholders.
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Salud Infantil , Servicios de Salud Materna , Niño , Femenino , Salud Global , Prioridades en Salud , Humanos , Salud del Lactante , Recién Nacido , Salud Materna , Embarazo , InvestigaciónRESUMEN
Astrocytes are critical for the maintenance of retinal ganglion cell (RGC) axonal function and viability, and form a key component of the functional neurovascular unit. Recently, we described the quantitative properties of astrocytes in relation to the capillary distributions in optic nerve laminar regions. Here, we provide a quantitative analysis of astrocytes and RGC axons in longitudinal sections of optic nerve tissue. Histological and immunocytochemical techniques are used to demonstrate the density of astrocytes, RGC axons and glia-neuron ratios across the pre laminar, lamina cribrosa and post laminar compartments of the optic nerve head (ONH). A study of human, pig, horse and rat optic nerves was performed and comparisons are made between species. This study demonstrates that the distribution of astrocytes correlates closely with the density of axonal processes, in accordance with the functional requirement of different regions of the ganglion cell axon. There was a consistency of glia-neuron ratios in the majority of laminar compartments, except for the human and rat prelaminar regions, which demonstrated lower ratios of astrocyte to axonal processes. The distribution of astrocytes may reflect a functional susceptibility to development of disease in the prelaminar region of the optic nerve. Interspecies comparison at the lamina cribrosa showed strikingly consistent glia-neuron ratios. Collectively, our findings suggest there may be a critical ratio of glia to neuron needed to maintain healthy cellular physiology across different laminar compartments of the optic nerve, with particular importance for the health of the lamina cribrosa region. It is possible that, in disease processes, the glia-neuron relationships across the different laminar compartments may be perturbed and this may be relevant for the development of glaucoma. Emerging technologies may further aid our understanding in how the physiology of optic nerve tissue cellular structure may be affected by changes to ONH characteristics and elevated intraocular pressure induced damage. Such findings may also permit the early identification of RGC axonal injury by identifying quantifiable changes in structural tissue architecture when pathophysiological pathways predominate.