Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase ...inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.
We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD high and ITD low, respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.
A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.
The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34(+) blood cells to pre-empt relapse in patients with CD34(+) ...myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34(+) donor chimerism to <80% and received four azacitidine cycles (75 mg/m(2)/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34(+) donor chimerism to ≥80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34(+) donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1-11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56-558) after initial decrease of CD34(+) donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.
Changes in fertility patterns are hypothesized to be among the many second-order consequences of armed conflict, but expectations about the direction of such effects are theoretically ambiguous. ...Prior research, from a range of contexts, has also yielded inconsistent results. We contribute to this debate by using harmonized data and methods to examine the effects of exposure to conflict on preferred and observed fertility outcomes across a spatially and temporally extensive population. We use high-resolution georeferenced data from 25 sub-Saharan African countries, combining records of violent events from the Armed Conflict Location and Event Data Project (ACLED) with data on fertility goals and outcomes from the Demographic and Health Surveys (n = 368,765 women aged 15–49 years). We estimate a series of linear and logistic regression models to assess the effects of exposure to conflict events on ideal family size and the probability of childbearing within the 12 months prior to the interview. We find that, on average, exposure to armed conflict leads to modest reductions in both respondents’ preferred family size and their probability of recent childbearing. Many of these effects are heterogeneous between demographic groups and across contexts, which suggests systematic differences in women’s vulnerability or preferred responses to armed conflict. Additional analyses suggest that conflict-related fertility declines may be driven by delays or reductions in marriage. These results contribute new evidence about the demographic effects of conflict and their underlying mechanisms, and broadly underline the importance of studying the second-order effects of organized violence on vulnerable populations.
Owing to the more recent positive results with the anti-CD33 immunotoxin gemtuzumab ozogamicin, therapy against acute myeloid leukemias (AMLs) targeting CD33 holds many promises. Here, CD33 and CD123 ...expression on AML blasts was studied by flow cytometry in a cohort of 319 patients with detailed information on French-American-British/World Health Organization (FAB/WHO) classification, cytogenetics and molecular aberrations. AMLs of 87.8% express CD33 and would therefore be targetable with anti-CD33 therapies. Additionally, 9.4% of AMLs express CD123 without concomitant CD33 expression. Thus, nearly all AMLs could be either targeted via CD33 or CD123. Simultaneous presence of both antigens was observed in 69.5% of patients. Most importantly, even AMLs with adverse cytogenetics express CD33 and CD123 levels comparable to those with favorable and intermediate subtypes. Some patient groups with unfavorable alterations, such as FMS-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations, high FLT3-ITD mutant/wild-type ratios and monosomy 5 are even characterized by high expression of CD33 and CD123. In addition, blasts of patients with mutant nucleophosmin (NPM1) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of minimal residual disease-guided interventions in mutated NPM1-positive AMLs. These results stimulate the development of novel concepts to redirect immune effector cells toward CD33- and CD123-expressing blasts using bi-specific antibodies or engineered T cells expressing chimeric antigen receptors.
Racial Diversity and Segregation LICHTER, DANIEL T.; THIEDE, BRIAN C.; BROOKS, MATTHEW M.
RSF : Russell Sage Foundation journal of the social sciences,
02/2023, Letnik:
9, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This article uses 2020 Census data to document recent trends in suburbanization, ethnoracial diversity, and residential segregation in the United States. It considers variation across inner-ring ...suburbs, outlying suburbs, and exurban areas at the metropolitan (metro) fringe. Suburbanization has recently continued, albeit more slowly than the 1990s and 2000s. Nearly two-thirds of all metro residents now live in the suburbs, fueled by change among ethnoracial minorities. For the first time, a majority of metro Blacks reside in suburbs. America’s suburbs, especially inner-ring suburbs, have experienced extraordinary increases in racial diversity. Declines continue in metro segregation, and segregation remains lower in the suburbs than principal cities, especially in outlying and fringe areas. For suburban Asians and Hispanics, however, exposure to Whites has declined since 1990. The suburban fringe remains the least diverse component of metro America. The fringe is less segregated than other metro areas, but has experienced patterns (such as growing Black-White segregation) contrary to national trends.
In the last decade growing interest has emerged in quantifying the spatial and temporal variations in mountain building. Until recently, insufficient data have been available to attempt such a task ...at the scale of large orogens such as the Himalaya. The Himalaya accommodates ongoing convergence between India and Eurasia and is a focal point for studying orogen evolution and hypothesized interactions between tectonics and climate. Here we integrate 1126 published bedrock mineral cooling ages with a transient 1D Monte-Carlo thermal–kinematic erosion model to quantify the denudation histories along ~2700km of the Himalaya. The model free parameter is a temporally variable denudation rate from 50Ma to present. Thermophysical material properties and boundary conditions were tuned to individual study areas. Monte-Carlo simulations were conducted to identify the range of denudation histories that can reproduce the observed cooling ages. Results indicate large temporal and spatial variations in denudation and these are resolvable across different tectonic units of the Himalaya. More specifically, across >1000km of the southern Greater Himalaya denudation rates were highest (~1.5–3mm/yr) between ~10 and 2Ma and lower (0.5–2.6mm/yr) over the last 2My. These differences are best determined in the NW-Himalaya. In contrast to this, across the ~2500km length of the northern Greater Himalaya denudation rates vary over length scales of ~300–1700km. Slower denudation (<1mm/yr) occurred between 10 and 4Ma followed by a large increase (1.2–2.6mm/yr) in the last ~4Ma. We find that only the southern Greater Himalayan Sequence clearly supports a continuous co-evolution of tectonics, climate and denudation. Results from the higher elevation northern Greater Himalaya suggest either tectonic driven variations in denudation due to a ramp-flat geometry in the main décollement and/or recent glacially enhanced denudation.
•First systematic orogenwide quantification of erosion and denudation rates in the Himalaya.•Large spatio-temporal along-strike and orogen-perpendicular variations in denudation found.•First systematic variation in denudation between GHS-N and GHS-S discovered.•Punctuated periods of GHS-N denudation over spatio-temporal scales of ~300–1700km and 2–4Myr.•Over the last 10Ma >1000km stretch of GHS-S where sustained and high denudation rates were present.
•Climate variability may influence nutrition through multiple pathways.•High temperatures and low precipitation reduce child weight.•High temperatures also increase the risk of wasting.•Climate ...effects are generally consistent across sub-populations.
Climatic variability affects many underlying determinants of child malnutrition, including food availability, access, and utilization. Evidence of the effects of changing temperatures and precipitation on children’s nutritional status nonetheless remains limited. Research addressing this knowledge gap is merited given the short- and long-run consequences of malnutrition. We address this issue by estimating the effects of temperature and precipitation anomalies on the weight and wasting status of children ages 0–59 months across 18 countries in sub-Saharan Africa. Linear regression models show that high temperatures and low precipitation are associated with reductions in child weight, and that high temperatures also lead to increased risk of wasting. We find little evidence of substantively meaningful differences in these effects across sub-populations of interest. Our results underscore the vulnerability of young children to climatic variability and its second-order economic and epidemiological effects. The study also highlights the corresponding need to design and assess interventions to effectively mitigate these impacts.
Along the Southern Himalayan Front (SHF), areas with concentrated precipitation coincide with rapid exhumation, as indicated by young mineral cooling ages. Twenty new, young (<1–5 Ma) apatite fission ...track (AFT) ages have been obtained from the Himalayan Crystalline Core along the Sutlej Valley, NW India. The AFT ages correlate with elevation, but show no spatial relationship to tectonic structures, such as the Main Central Thrust or the Southern Tibetan Fault System. Monsoonal precipitation in this region exerts a strong influence on erosional surface processes. Fluvial erosional unloading along the SHF is focused on high mountainous areas, where the orographic barrier forces out >80% of the annual precipitation. AFT cooling ages reveal a coincidence between rapid erosion and exhumation that is focused in a ∼50–70-km-wide sector of the Himalaya, rather than encompassing the entire orogen. Assuming simplified constant exhumation rates, the rocks of two age vs. elevation transects were exhumed at ∼1.4±0.2 and ∼1.1±0.4 mm/a with an average cooling rate of ∼40–50 °C/Ma during Pliocene–Quarternary time. Following other recently published hypotheses regarding the relation between tectonics and climate in the Himalaya, we suggest that this concentrated loss of material was accommodated by motion along a back-stepping thrust to the south and a normal fault zone to the north as part of an extruding wedge. Climatically controlled erosional processes focus on this wedge and suggest that climatically controlled surface processes determine tectonic deformation in the internal part of the Himalaya.
Currently 18FFDDNP is the only PET imaging probe with the ability to visualize hyperphosphorylated tau fibrillar aggregates in living subjects. In this work, we evaluate in vivo 18FFDDNP labeling of ...brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking amyloid-β deposits.
Fifteen patients with PSP received 18FFDDNP PET scanning. 18FFDDNP distribution volume ratios, in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson's disease with short disease duration, and age-matched control subjects without neurodegenerative disorders.
18FFDDNP binding was present in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain, and cerebellar white matter) regardless of disease severity, with progressive subcortical and cortical involvement as disease severity increased. Brain patterns of 18FFDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region 18FFDDNP binding was distinctive for PSP subjects and separated them from controls and patients with Parkinson's disease.
These results provide evidence that 18FFDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, 18FFDDNP PET may provide a tool to detect changes in tau pathology distribution either associated with disease progression or as a treatment biomarker for future tau-specific therapies. Patterns of 18FFDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult.
Climate change is expected to undermine population health and well-being in low- and middle-income countries, but relatively few analyses have directly examined these effects using individual-level ...data at global scales, particularly for reproductive-age women. To address this lacuna, we harmonize nationally representative data from the Demographic and Health Surveys on reproductive health, body mass index (BMI), and temporary migration from 2.5 million adult women (ages 15 to 49) in approximately 109,000 sites across 59 low- and middle-income countries, which we link to high-resolution climate data. We use this linked dataset to estimate fixed-effect logistic regression models of demographic and health outcomes as a function of climate exposures, woman-level and site-level characteristics, seasonality, and regional time trends, allowing us to plausibly isolate climate effects from other influences on health and migration. Specifically, we measure the effects of recent exposures to temperature and precipitation anomalies on the likelihood of having a live birth in the past year, desire for another child, use of modern contraception, underweight (BMI < 18.5), and temporary migration, and subsequently allow for nonlinearity as well as heterogeneity across education, rural/urban residence, and baseline climate. This analysis reveals that exposures to high temperatures increase live births, reduce desire for another child, increase underweight, and increase temporary migration, particularly in rural areas. The findings represent clear evidence that anthropogenic temperature increases contribute to temporary migration and are a significant threat to women's health and reproductive autonomy in low- and middle-income countries.
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