Evolving patterns and clinical outcome of genetic studies performed at diagnosis in acute myeloid leukemia patients: Real life data from the PETHEMA Registry.

BACKGROUND: There are no studies assessing the evolution and patterns of genetic studies performed at diagnosis in acute myeloid leukemia (AML) patients. Such studies could help to identify potential gaps in our present diagnostic practices, especially in the context of increasingly complex procedures and classifications. METHODS: The REALMOL study (NCT05541224) evaluated the evolution, patterns, and clinical impact of performing main genetic and molecular studies performed at diagnosis in 7285 adult AML patients included in the PETHEMA AML registry (NCT02607059) between 2000 and 2021. RESULTS: Screening rates increased for all tests across different time periods (2000-2007, 2008-2016, and 2017-2021) and was the most influential factor for NPM1, FLT3-ITD, and next-generation sequencing (NGS) determinations: NPM1 testing increased from 28.9% to 72.8% and 95.2% (p < .001), whereas FLT3-ITD testing increased from 38.1% to 74.1% and 95.9% (p < .0001). NGS testing was not performed between 2000-2007 and only reached 3.5% in 2008-2016, but significantly increased to 72% in 2017-2021 (p < .001). Treatment decision was the most influential factor to perform karyotype (odds ratio [OR], 6.057; 95% confidence interval [CI], 4.702-7.802), and fluorescence in situ hybridation (OR, 2.273; 95% CI, 1.901-2.719) studies. Patients ≥70 years old or with an Eastern Cooperative Oncology Group ≥2 were less likely to undergo these diagnostic procedures. Performing genetic studies were associated with a favorable impact on overall survival, especially in patients who received intensive chemotherapy. CONCLUSIONS: This unique study provides relevant information about the evolving landscape of genetic and molecular diagnosis for adult AML patients in real-world setting, highlighting the increased complexity of genetic diagnosis over the past 2 decades.

Boarding in the emergency department: challenges and mitigation strategies.

PURPOSE OF REVIEW: Herein, we conducted a review of the literature to better understand the issue of prolonged emergency department (ED) boarding by providing an overview of the current evidence on the available causes, consequences, and mitigation strategies. RECENT FINDINGS: Severely ill patients awaiting transfer to intensive care units (ICU) imposes additional burdens on the emergency care team from both a clinical and management perspective. The reasons for prolonged ED boarding are multifactorial. ED boarding compromises patients' safety and outcomes, and is associated with increased team burnout and dissatisfaction. Mitigation strategies include the optimization of patients' flow, the establishment of resuscitative care units, deployment of mobile critical care teams, and improvements in training. Staffing adjustments, changes in hospital operations, and quality improvement initiatives are required to improve this situation, while active bed management and implementation of capacity command centers may also help. SUMMARY: Considering the characteristics of healthcare systems, such as funding mechanisms, organizational structures, delivery models, access and quality of care, the challenge of ED boarding of critically ill patients requires a nuanced and adaptable approach. Solutions are complex but must involve the entirety of the hospital system, emergency department, staff adjustment, and education.

Nature-based solutions are critical for putting Brazil on track towards net-zero emissions by 2050.

Most of the world's nations (around 130) have committed to reaching net-zero carbon dioxide or greenhouse gas (GHG) emissions by 2050, yet robust policies rarely underpin these ambitions. To investigate whether existing and expected national policies will allow Brazil to meet its net-zero GHG emissions pledge by 2050, we applied a detailed regional integrated assessment modelling approach. This included quantifying the role of nature-based solutions, such as the protection and restoration of ecosystems, and engineered solutions, such as bioenergy with carbon capture and storage. Our results highlight ecosystem protection as the most critical cost-effective climate mitigation measure for Brazil, whereas relying heavily on costly and not-mature-yet engineered solutions will jeopardise Brazil's chances of achieving its net-zero pledge by mid-century. We show that the full implementation of Brazil's Forest Code (FC), a key policy for emission reduction in Brazil, would be enough for the country to achieve its short-term climate targets up to 2030. However, it would reduce the gap to net-zero GHG emissions by 38% by 2050. The FC, combined with zero legal deforestation and additional large-scale ecosystem restoration, would reduce this gap by 62% by mid-century, keeping Brazil on a clear path towards net-zero GHG emissions by around 2040. While some level of deployment of negative emissions technologies will be needed for Brazil to achieve and sustain its net-zero pledge, we show that the more mitigation measures from the land-use sector, the less costly engineered solutions from the energy sector will be required. Our analysis underlines the urgent need for Brazil to go beyond existing policies to help fight climate emergency, to align its short- and long-term climate targets, and to build climate resilience while curbing biodiversity loss.

Food supplement vitamins, minerals, amino-acids, fatty acids, phenolic and alkaloid-based substances: An overview of their interaction with drugs.

Food supplements are a widespread group of products ingested as a diet complement, whose consumption has recently skyrocketed due to the consumers' concern with their well-being. Among food supplements, vitamin- and mineral-based ones are the top sellers, and the demand of others, such as those containing polyphenols, is increasing. Owing to their alleged natural characteristics, consumers take the safety of food supplements for granted, and use them even when taking medicines. Thus, their potential interactions with drugs have been sparsely evaluated. This manuscript aims to bring forth an up-to-date overview of the most important knowledge involving the interactions between food supplements and drugs, relevant to be aware by nutritionists and other healthcare professionals. To this end, an extensive bibliographic review was conducted focusing on peer reviewed data from experimental in vivo evidence and clinical studies whenever major clinical interactions have been reported. Elder people and polymedicated or chronic patients are especially vulnerable to the therapeutic ineffectiveness and toxicity caused by these types of interactions. Drugs used to treat cardiovascular, autoimmune, nervous, and oncological diseases are commonly involved in important clinical interactions with food supplements, many with a narrow therapeutic margin.

Halophytes as source of bioactive phenolic compounds and their potential applications.

Halophytes are salt-tolerant plants that inhabit environments in which they are exposed to extreme stress, wherefore they exhibit conserved and divergent metabolic responses different from those of conventional plants. Thus, the synthesis and accumulation of metabolites, especially of those oxidative stress-related such as phenolic compounds, should be investigated. The potential of halophytes as a source of phenolics and their prospective industrial applications are evaluated based on a comprehensive review of the scientific literature on the phenolic compounds of more than forty halophytes and their biological activities. Additionally, an overview of the analytical methodologies adopted for phenolics determination in halophytes is provided. Finally, the prospective uses and beneficial effects of the phenolic preparations from these plants are discussed. Halophytes are complex matrices, exhibiting a wide variety of phenolics in their composition, wherefore the results can be greatly affected depending on the organ plant under analysis and the extraction methodology, especially the extraction solvent used. High-performance liquid chromatography, coupled with diode array detection (HPLC-DAD) or mass spectrometry (HPLC-MS), are the most used technique. Halophytes biosynthesize phenolics in concentrations that justify the remarkable antioxidant and antimicrobial activities shown, making them ideal sources of bioactive molecules to be employed in a multitude of sectors.

The role of endocrine disruptors in female infertility.

INTRODUCTION:  According to the World Health Organization, infertility is a public health problem that affects around 48 million couples and 186 million individuals worldwide. Endocrine disruptors are one of the causes that raise more concern, given that it is a problem that has evolved with the progress of society. Many chemicals are used by food industry, entering food chain, and directly affecting human health. Endocrine disruptors have the capacity of interfering with the normal hormonal action, metabolism, and biosynthesis, which can lead to a variation of the normal hormonal homeostasis. Some of these endocrine disruptors are highly associated with diseases that are positively correlated with female infertility, such as polycystic ovary syndrome, endometriosis, irregular menstrual cycle and also disturbances on processes as steroidogenesis and development of the ovarian follicles. RESULTS: The present literature review covers various aspects of the possible relationship between endocrine disruptors and female infertility. Bisphenol A and its metabolites, phthalates, dioxins, organochlorine, and organophosphate compounds are groups of chemicals considered to have the capacity to disrupt endocrine activity and herein addressed. The results reported in in vivo studies and in clinical trials addressing endocrine disruptors and female infertility were discussed as well as their possible mechanism of action. CONCLUSIONS: Large, double-blind, placebo-controlled randomized clinical trials are needed to better understand the mechanisms of action of endocrine disruptors in female infertility, as well as the doses and frequency of exposure responsible for it.

Stabilizing Effect of a 4c/6e Hypervalent Bond in Dinitrodiphenyl Disulfides and Their Thermochemical Properties: Experimental and Computational Approach.

Thermochemical properties and intramolecular interactions of 2,2'-dinitrodiphenyl disulfide (2DNDPDS) and 4,4'-dinitrodiphenyl disulfide (4DNDPDS) were determined and analyzed. Their standard molar formation enthalpies in the gas phase (ΔfHm°(g)'s) were experimentally determined; theoretically, they were computed using the G4 composite method and atomization reactions. Specifically, ΔfHm°(g)'s were obtained by combining formation enthalpies in the condensed phase and enthalpies of phase change. Formation enthalpies in the condensed phase were determined experimentally through combustion energies, which in turn were found by means of a rotatory bomb combustion calorimeter. Sublimation enthalpies were derived from thermogravimetric experiments, measuring the rate of mass loss and using Langmuir and Clausius-Clapeyron equations. Fusion enthalpies and heat capacities of the solid and liquid phases were measured as functions of temperature by differential scanning calorimetry, and the heat capacities of the gas phase were calculated via molecular orbital calculations. Theoretical and experimental ΔfHm°(g)'s differed by <5.5kJ·mol-1, and isomerization enthalpies are discussed. In addition, using theoretical tools [natural bond orbitals (NBO) and quantum theory of atoms in molecules (QTAIM)], intramolecular interactions were analyzed. An uncommon hypervalent four-center six-electron interaction of type O···S-S···O was found in 2DNDPDS. This hypervalent interaction, in addition to the extent of conjugation between the aryl and NO2 moieties and the formation of intramolecular C-H···S hydrogen bonds, counteracts the repulsion caused by steric repulsions. Hydrogen bonding was confirmed through geometric parameters as well as QTAIM.

How emotions are metaphorically embodied: measuring hand and head action strengths of typical emotional states.

This study measured hand and head action strengths of eight typical emotional states using an authentic but implicit emotion elicitation task. Participants listened to and then retold five stories in which eight typical emotional states were experienced by the narrators. The number of hand and head gestures that occur naturally while experiencing an emotional state was used as an index to determine the hand and head action strength of that emotional state. Results showed a larger number of head gestures than hand gestures, suggesting that head action strengths of the eight emotional states are stronger than their hand action strengths. These findings are consistent with the data extracted from Lancaster Sensorimotor Norms (LSN), although the two sets of data were gathered in two completely different experimental conditions and in two different languages. Furthermore, our data showed a prototypical directionality effect for the typical emotional states, specifically, happiness, anger and pride were primarily accompanied by upward gestures but downward gestures for sadness and shame; surprise was primarily accompanied by forward gestures but backward gestures for fear and disgust.

Pterospartum tridentatum Liqueur Using Spirits Aged with Almond Shells: Chemical Characterization and Phenolic Profile.

With great cultural significance, spirits and distillate beverages constitute an important niche market in Europe. The development of new food products, particularly for the functionalization of these beverages, is increasing exponentially. The present work aimed to develop a new wine spirit beverage aged with almond shells and flowers of P. tridentatum for further characterization of bioactive and phenolic compounds, coupled with a sensorial study to evaluate the acceptance of this new product by the market. Twenty-one phenolic compounds were identified, mainly isoflavonoids and O- and C-glycosylated flavonoids, especially in P. tridentatum flowers, indicating that it is a highly aromatizing agent. The developed liqueur and wine spirits (almonds and flowers) showed distinct physicochemical properties, with the last two samples showing greater appreciation and purchase intention by consumers due to their sweetness and smoothness. The most promising results were found for the carqueja flower, which should be further investigated in an industrial context to contribute to its valorization in its regions of origin, such as Beira Interior and Trás-os-Montes (Portugal).

Towards the Sustainable Exploitation of Salt-Tolerant Plants: Nutritional Characterisation, Phenolics Composition, and Potential Contaminants Analysis of Salicornia ramosissima and Sarcocornia perennis alpini.

Increasing soil salinisation represents a serious threat to food security, and therefore the exploitation of high-yielding halophytes, such as Salicornia and Sarcocornia, needs to be considered not merely in arid regions but worldwide. In this study, Salicornia ramosissima and Sarcocornia perennis alpini were evaluated for nutrients, bioactive compounds, antioxidant capacity, and contaminants. Both were shown to be nutritionally relevant, exhibiting notable levels of crude fibre and ash, i.e., 11.26-15.34 and 39.46-40.41% dry weight (dw), respectively, and the major minerals were Na, K, and Mg. Total phenolics thereof were 67.05 and 38.20 mg of gallic acid equivalents/g extract dw, respectively, mainly p-coumaric acid and quercetin. Both species displayed antioxidant capacity, but S. ramossima was prominent in both the DPPH and ß-carotene bleaching assays. Aflatoxin B1 was detected in S. ramosissima, at 5.21 µg/Kg dw, which may pose a health threat. The Cd and Pb levels in both were low, but the 0.01 mg/Kg Hg in S. perennis alpini met the maximum legal limit established for marine species including algae. Both species exhibit high potential for use in the agro-food, cosmetics, and pharmaceutical sectors, but specific regulations and careful cultivation strategies need to be implemented, in order to minimise contamination risks by mycotoxins and heavy metals.

Identification of seasonal variation in the diagnosis of acute myeloid leukaemia: a population-based study.

Until now, the role that seasonal factors play in the aetiology of acute myeloid leukaemia (AML) has been unclear. Demonstration of seasonality in AML diagnosis would provide supportive evidence of an underlying seasonal aetiology. To investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age, we used population-based data from a Spanish hospital discharge registry. We conducted a larger study than any to date of 26 472 cases of AML diagnosed in Spain between 2004 and 2015. Using multivariable Poisson generalized linear autoregressive moving average modelling, we found an upward long-term trend, with monthly incidence rates of AML annually increasing by 0.4% [95% confidence interval (CI), 0.2%-0.6%; p = 0.0011]. January displayed the highest incidence rate of AML, with a minimum average difference of 7% when compared to February (95% CI, 2%-12%; p = 0.0143) and a maximum average difference of 16% compared to November (95% CI, 11%-21%; p < 0.0001) and August (95% CI, 10%-21%; p < 0.0001). Such seasonal effect was consistent among subgroups according to sex and age. Our finding that AML diagnosis is seasonal strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development and/or proliferation of disease, pointing to prevention opportunities.

Lupin (Lupinus albus L.) Seeds: Balancing the Good and the Bad and Addressing Future Challenges.

Lupinus albus L. (lupine) is a legume whose grain/seed has gained increasing interest. Its recognized nutritional properties, namely a high content of protein, dietary fiber and its low fat content, make lupine a suitable alternative not only for animal protein, but also as a substitute for more processed and less balanced flours from a nutritional point of view, used in the preparation of bread, cakes and cookies, among others. In addition, its nutritional and bioactive compounds have potential benefits for human health in the prevention and treatment of some diseases. However, the existence of some anti-nutritional compounds and contaminants reveal some concern, requiring effective methods for their detection and eventual removal. This review intends to address the potential of lupine (L. albus) in food and human health and to balance the pros and cons. Nutritional and anti-nutritional components of L. albus seeds and possible contaminants of lupine seeds are examined. The potential health benefits of lupine (seeds), including energy metabolism, cardiovascular diseases, hypertension, glucose and insulin metabolism, bower function and anticonvulsant action, are discussed based on scientific evidence (both clinical trials and studies performed with animal models).

Thermochemical Study of 1-Methylhydantoin.

Using static bomb combustion calorimetry, the combustion energy of 1-methylhydantoin was obtained, from which the standard molar enthalpy of formation of the crystalline phase at T = 298.15 K of the compound studied was calculated. Through thermogravimetry, mass loss rates were measured as a function of temperature, from which the enthalpy of vaporization was calculated. Additionally, some properties of fusion were determined by differential scanning calorimetry, such as enthalpy and temperature. Adding the enthalpy of fusion to the enthalpy of vaporization, the enthalpy of sublimation of the compound was obtained at T = 298.15 K. By combining the enthalpy of formation of the compound in crystalline phase with its enthalpy of sublimation, the respective standard molar enthalpy of formation in the gas phase was calculated. On the other hand, the results obtained in the present work were compared with those of other derivatives of hydantoin, with which the effect of the change of some substituents in the base heterocyclic ring was evaluated.

A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia.

BACKGROUND: Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). METHODS: Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. RESULTS: The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). CONCLUSIONS: FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.

Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia.

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. To elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly-acquired (NRAS and FLT3) mutations. Moreover, we observed cooperation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML.

Clinical, biological, and prognostic implications of SF3B1 co-occurrence mutations in very low/low- and intermediate-risk MDS patients.

SF3B1 is a highly mutated gene in myelodysplastic syndrome (MDS) patients, related to a specific subtype and parameters of good prognosis in MDS without excess blasts. More than 40% of MDS patients carry at least two myeloid-related gene mutations but little is known about the impact of concurrent mutations on the outcome of MDS patients. In applying next-generation sequencing (NGS) with a 117 myeloid gene custom panel, we analyzed the co-occurrence of SF3B1 with other mutations to reveal their clinical, biological, and prognostic implications in very low/low- and intermediate-risk MDS patients. Mutations in addition to those of SF3B1 were present in 80.4% of patients (median of 2 additional mutations/patient, range 0-5). The most frequently mutated genes were as follows: TET2 (39.2%), DNMT3A (25.5%), SRSF2 (10.8%), CDH23 (5.9%), and ASXL1, CUX1, and KMT2D (4.9% each). The presence of at least two mutations concomitant with that of SF3B1 had an adverse impact on survival compared with those with the SF3B1 mutation and fewer than two additional mutations (median of 54 vs. 87 months, respectively: p = 0.007). The co-occurrence of SF3B1 mutations with specific genes is also linked to a dismal prognosis: SRSF2 mutations were associated with shorter overall survival (OS) than SRSF2wt (median, 27 vs. 75 months, respectively; p = 0.001), concomitant IDH2 mutations (median OS, 11 [mut] vs. 75 [wt] months; p = 0.001), BCOR mutations (median OS, 11 [mut] vs. 71 [wt] months; p = 0.036), and NUP98 and STAG2 mutations (median OS, 27 and 11 vs. 71 months, respectively; p = 0.008 and p = 0.002). Mutations in CHIP genes (TET2, DNMT3A) did not significantly affect the clinical features or outcome. Our results suggest that a more comprehensive NGS study in low-risk MDS SF3B1mut patients is essential for a better prognostic evaluation.

Sepsis in patients hospitalized with coronavirus disease 2019: how often and how severe?

PURPOSE OF REVIEW: To discuss why severe COVID-19 should be considered sepsis and how co-infection and secondary infection can aggravate this condition and perpetuate organ dysfunction leading to high mortality rates. RECENT FINDINGS: In severe COVID-19, there is both direct viral toxicity and dysregulated host response to infection. Although both coinfection and/or secondary infection are present, the latest is of greater concern mainly in resource-poor settings. Patients with severe COVID-19 present a phenotype of multiorgan dysfunction that leads to death in an unacceptable high percentage of the patients, with wide variability around the world. Similarly to endemic sepsis, the mortality of COVID-19 critically ill patients is higher in low-income and middle-income countries as compared with high-income countries. Disparities, including hospital strain, resources limitations, higher incidence of healthcare-associated infections (HAI), and staffing issues could in part explain this variability. SUMMARY: The high mortality rates of critically ill patients with severe COVID-19 disease are not only related to the severity of patient disease but also to modifiable factors, such as the ICU strain, HAI incidence, and organizational aspects. Therefore, HAI prevention and the delivery of best evidence-based care for these patients to avoid additional damage is important. Quality improvement interventions might help in improving outcomes mainly in resource-limited settings.

Investigating salience strategies to counteract obesity.

The investigation of the characteristics and attributes that make a brand prominent for shoppers is known as salience research. This line of study concentrates on influencing buying behaviors via the manipulation of shopping environments and food products. Such promotional strategies successfully attract massive food sales and therefore have been associated with changes in dietary patterns and the epidemic expansion of non-communicable diseases, like obesity. Marketers have empirically proven that global buying patterns are influenced by their salience strategies and techniques. However, despite the significance of such methods, empirical salience investigations have rarely been extended beyond their primary business focus to the field of health promotion. Therefore, this study is presenting a way of transferring the salience knowledge to the health promotion field in order to track dietary choices and possibly gain information to identify buying and eating behaviors connected to obesity. The salience literature from various disciplines permits to hypothesize that consumers are more likely to have unhealthy diets when food-choices and conditions are saliently manipulated. A quasi-experimental method (combining salience measures with Bayesian analysis) was used to test this proposition. The results support the hypothesis and endorse the introduced research tool. As predicted, data reflect the latest national overweight and obesity statistics and suggest that habitual unhealthy diets are more likely when salience strategies link food products to taste, social and emotional attributes. These preliminary findings encourage further investigation to enhance the method as a possible epidemiological tool.

Permutation tests are robust and powerful at 0.5% and 5% significance levels.

Recent replication crisis has led to a number of ad hoc suggestions to decrease the chance of making false positive findings. Among them, Johnson (Proceedings of the National Academy of Sciences, 110, 19313-19317, 2013) and Benjamin et al. (Nature Human Behaviour, 2, 6-10 2018) recommend using the significance level of α = 0.005 (0.5%) as opposed to the conventional 0.05 (5%) level. Even though their suggestion is easy to implement, it is unclear whether or not the commonly used statistical tests are robust and/or powerful at such a small significance level. Therefore, the main aim of our study is to investigate the robustness and power curve behaviors of independent (unpaired) two-sample tests for metric and ordinal data at nominal significance levels of α = 0.005 and α = 0.05. Through an extensive simulation study, it is found that the permutation versions of the Welch t-test and the Brunner-Munzel test are particularly robust and powerful while the commonly used two-sample tests which utilize t-distribution tend to be either liberal or conservative, and have peculiar power curve behaviors under skewed distributions with variance heterogeneity.

Identification of relapse-associated gene mutations by next-generation sequencing in low-risk acute myeloid leukaemia patients.

Recommended genetic categorization of acute myeloid leukaemias (AML) includes a favourable-risk category, but not all these patients have good prognosis. Here, we used next-generation sequencing to evaluate the mutational profile of 166 low-risk AML patients: 30 core-binding factor (CBF)-AMLs, 33 nucleophosmin (NPM1)-AMLs, 4 biCEBPα-AMLs and 101 acute promyelocytic leukaemias (APLs). Functional categories of mutated genes differed among subgroups. NPM1-AMLs showed frequent variations in DNA-methylation genes (DNMT3A, TET2, IDH1/2) (79%), although without prognostic impact. Within this group, splicing-gene mutations were an independent factor for relapse-free (RFS) and overall survival (OS). In CBF-AML, poor independent factors for RFS and OS were mutations in RAS pathway and cohesin genes, respectively. In APL, the mutational profile differed according to the risk groups. High-risk APLs showed a high mutation rate in cell-signalling genes (P = 0·002), highlighting an increased incidence of FLT3 internal tandem duplication (ITD) (65%, P < 0·0001). Remarkably, in low-risk APLs (n = 28), NRAS mutations were strongly correlated with a shorter five-year RFS (25% vs. 100%, P < 0·0001). Overall, a high number of mutations (≥3) was the worst prognostic factor RFS (HR = 2·6, P = 0·003). These results suggest that gene mutations may identify conventional low-risk AML patients with poor prognosis and might be useful for better risk stratification and treatment decisions.