Search

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug–target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+and IgA+plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new ‘gland-associated immune niche’ has implications for respiratory health.

Over the past decade, fatty liver disease has become a forefront health issue. The clinical implication of this silent disease extends well beyond just the liver and is linked to a variety of health concerns, including cardiovascular disease, diabetes, and cancer. The prevalence of fatty liver disease in the United States is estimated to be 25% and increasing. This article reviews the pathophysiology of fatty liver disease, how clinicians can recognize contributing factors, and appropriate interventions based on the American Association for the Study of Liver Disease's guidelines.

This article reports on general developments affecting cross-border international investments, as well as a regional review of the most recent developments in this area. We begin with one of the [...]

Health disparities disproportionately affect patients in racial and ethnic minority groups, and these disparities are linked to economic, environmental, and social disadvantage. It is widely known that health disparities impact patients with allergic and immunologic conditions, yet universal and comprehensive training in health disparities is lacking. More robust educational opportunities are needed to fully equip trainees with tools to recognize and develop effective strategies to reduce the burden of health disparities. Also, there are no universal standards or requirements for professional medical boards in their respective maintenance of certification programs that will ensure ongoing training for practicing providers that will help them identify and manage individual or societal issues such as social determinants that contribute to health disparities. Further, the long-term impact of systematic discrimination, implicit and overt bias, and medical mistrust among populations most often affected by disparities compounds the complexity of the methods and types of training that is desperately needed to overcome health disparities. We provide a commentary on important topics that should be addressed during allergy and immunology training and beyond. We further highlight strategies and tools that should be used to tackle this important issue affecting millions of patients under our specialty care. It is past time for us to go beyond the bedside and comprehensively integrate health disparities training in our fellowship programs and in our practices.

Abstract. Snoring in college students may be the earliest presentation of adult sleep-disordered breathing, yet the literature contains few studies that demonstrate its effects on learning or whether early diagnosis [...]

IntroductionLittle is known on whether cigarette filter-related knowledge or beliefs are associated with support for policies to reduce their environmental impact.MethodsA cross-sectional, population-based sample of US adults aged 18–64 years (n=2979) was used to evaluate filter-related knowledge and beliefs by smoking status using data collected between 24 October 2018 and 17 December 2018. Multivariate logistic regression models explored whether these knowledge and belief items were associated with support for two policies, a US$0.75 litter fee and a ban on sales of filtered cigarettes, controlling for demographic characteristics and smoking status.ResultsRegardless of smoking status, 71% did not know plastic was a cigarette filter component and 20% believed filters were biodegradable. Overall, 23% believed filters reduce health harms and 60% believed filters make it easier to smoke; 90% believed cigarette butts are harmful to the environment. Individuals believing cigarette butts harmed the environment were more likely to support a litter fee (adjusted OR (aOR)=2.33, 95% CI: 1.71 to 3.17). Individuals believing that filters are not biodegradable had higher odds of supporting a litter fee (OR=1.47, 95% CI: 1.15 to 1.88). Respondents believing that filters do not make cigarettes less harmful were more likely to support a litter fee (aOR=1.50, 95% CI: 1.20 to 1.88) and filter ban (aOR=2.03, 95% CI: 1.64 to 2.50). Belief that filters make it easier to smoke was associated with decreased support for a filter ban (aOR=0.69, 95% CI: 0.58 to 0.83).ConclusionsComprehensive efforts are needed to educate the public about the impact of cigarette filters in order to build support for effective tobacco product waste policy.

Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination.

The wide range of IoT devices and wireless devices used in healthcare, hospitals and enterprises generates a large volume of digital data that must be processed, analysed and stored. Owing to the small processing capacity of these devices, the data generated cannot be processed on-board. Therefore, we suggest offloading this data to an efficient server. Time-critical applications cannot rely on the availability of cloud servers since they are in a remote location. The paper examines algorithms such as Deep Reinforcement Learning for Online Computation Offloading (DROO), coordinate descent, adaptive boosting, and then implements the K-nearest neighbour time critical optimisation algorithm as a fog offloading network topology. The offloading decision is based on the cost function, which includes latency, memory consumption and model accuracy. The topology implementing K-NN can be trained quickly and offers almost 99% accuracy when it comes to data offloading. Based on the comparative analysis, it excels over other machine learning approaches.

BackgroundLittle is known regarding how oral nicotine products (eg, nicotine pouches, lozenges) are marketed to consumers, including whether potential implicit reduced harm claims are used. In the current study, we explored the marketing claims present in a sample of direct-mail oral nicotine advertisements sent to US consumers (March 2018–August 2020).MethodsDirect-mail ads (n=50) were acquired from Mintel and dual-coded for the following claims: alternative to other tobacco products, ability to use anywhere, spit-free, smoke-free and product does not contain tobacco leaf. We merged the coded data with Mintel’s volume estimate (number of mail pieces sent to consumers) and calculated the proportion of oral nicotine advertisements containing claims by category.ResultsOf the 38 million pieces of oral nicotine direct-mail sent to US consumers, most featured claims that the product could be used anywhere (84%, 31.8 million pieces); was an alternative to other tobacco products (69%, 26.1 million pieces); and did not contain tobacco leaf (eg, ‘tobacco leaf-free’, ‘simple’ approach of extracting nicotine from tobacco; 55%, 20.7 million pieces). A slightly smaller proportion contained claims that oral nicotine was ‘spit-free’ (52%, 19.8 million pieces) or ‘smoke-free’ (31%, 11.7 million pieces).ConclusionOur results provide an early indication of marketing claims used to promote oral nicotine. The strategies documented, particularly the use of language to highlight oral nicotine is tobacco-free, may covey these products as lower-risk to consumers despite the lack of evidence or proper federal authorisation that oral nicotine products are a modified-risk tobacco product. Future research is needed to examine consumer perceptions of such claims.

Purpose: Estimate public support for prohibiting multiunit housing (MUH) e-cigarette and cigarette use.Design: Cross-sectional study.Setting: Data from an online panel survey.Sample: A Fall 2018 nationally representative sample of 3,415 (99.3% response rate) United States (US) adults 18-64 years old.Measures: Policy support for prohibiting MUH smoking and e-cigarette use, sociodemographics, and tobacco perceptions and behaviors.Analysis: Weighted multivariate logistic regression examined predictors of support for prohibiting 1) cigarette use and 2) e-cigarette use in MUH.Results: Most respondents expressed support for prohibiting smoking (76.9%) and e-cigarette use (74.0%) in MUH. About 17% (n = 588) of the sample lived in MUH, and living in MUH was not predictive of support for either policy. For both cigarette and e-cigarette policies, current smokers (n = 630; OR = 0.44, p < 0.001; OR = 0.59, p < 0.01) and current e-cigarette users (n = 305; OR = 0.42, p < 0.001; OR = 0.22, p < 0.001) had lower odds of support. Notably, while most smokers supported prohibiting cigarette (51.4%) and e-cigarette use in MUH (51.1%), there was less support among current e-cigarette users for prohibiting cigarette (48.1%) and e-cigarette use in MUH (34.5%).Conclusion: Majority support for prohibiting smoking and e-cigarette use in MUH is promising for policy adoption; however, lower support of both policies among e-cigarette users needs to be examined, as increasing use of e-cigarettes may be shifting social norms away from support for smoke free housing policies.

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

Background: Southeast Michigan is home to the second largest Middle Eastern and North African (MENA) US population. There is increasing interest in understanding correlates of psychosocial outcomes and health behaviors in this growing population. One potentially important health correlate is ethnic identity (EI). This paper reports the development, validity, and initial correlates of a new measure of MENA identity named the MENA-IM. Methods: We used convenience sampling at locations frequented by individuals of MENA descent in southeast Michigan. We also measured EI centrality, religiosity, cultural mistrust, substance use, and health status to assess convergent and divergent validity. Exloratory and Confirmatory Factor Analysis identified three subscales, which were valid for both Arab and Chaldean respondents and were named (1) MENA cultural affiliation, (2) MENA media use, and (3) multicultural affiliation. We also created and tested a 20-item, single-factor version. Results: We obtained data from 378 adults, 73% of whom identified as Arab and 27% as Chaldean. MENA-IM scores were higher among older, lower-educated, lower-income, non-US born, and Arabic-speaking respondents. Arab respondents reported significantly higher scores than Chaldeans. MENA-IM scores were positively associated with EI centrality and religiosity. Higher MENA-IM scores were found among those not reporting use of marijuana, alcohol, and opiates. Higher MENA-IM scores were also found among those without a self-reported history of heart disease and among those with better mental health status. Discussion: The MENA-IM has strong psychometric properties and demonstrated initial evidence of convergent and discriminant validity. In general, values on the measure were associated with better psychosocial and health status. How the measure performs with MENA populations outside of Michigan and how it may relate to other health outcomes merit investigation.

Byline: Deepak. Saxena, Deepika. Singhal, Minal. Patel Dear Editor, We read with interest the article written by Bandhu and Raje, [sup][1] We would like to draw the attention of the [...]

To propose a metric evaluating the quality of comprehensive medication reviews (CMRs), and to discuss the optimal setting for CMR delivery.

Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon–producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in ∼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.

Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype–Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.

Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later1–3. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.

The article discusses the accomplishments by the World Health Assembly (WHA) in its goal to eradicate measles in five of six World Health Organization (WHO) regions by 2020. Also cited are the estimated number of measles deaths and averted deaths in 2000-2019, and the coverage of the first dose of measles-containing vaccine (MCV1) and MCV2 in one-year-old children.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.

The acquisition of mutations in hematologic stem cells (clonal hematopoiesis) is common with normal aging and can be identified as an incidental finding through clinical genetic testing. Clonal hematopoiesis is associated with a heightened risk of developing hematologic neoplasms (especially myeloid) and accelerated atherosclerotic cardiovascular disease. This article discusses a multidisciplinary clinical approach to the management of patients with clonal hematopoiesis. Key areas of research needed to establish evidence-based clinical care guidelines and intervention strategies for individuals with clonal hematopoiesis are discussed.

In this article, the researchers have provided a discussion on computation offloading and the importance of docker-based containers, known as light weight virtualization, to improve the performance of edge computing systems. At the end, they have also proposed techniques and a case study for computation offloading and light weight virtualization.

The article describes the progress towards the World Health Assembly milestones and regional measles elimination during 2000 to 2018. Highlights include an increase in estimated measles-containing vaccine (MCV1) coverage during the time period, estimation of MCV1 and second dose coverage through routine immunization services, and the estimated number of 346 million people who received measles vaccination in 2018 during 45 supplementary immunization activities in 37 countries.

Introduction

Introduction:Genomic profiling in myeloid cancers is vital for disease classification, risk stratification, and treatment decisions. Whole genome sequencing (WGS) captures a complete range of biomarkers, overcoming conventional diagnostic constraints of multiple assays (Duncavage et al, 2021). Duncavage et al's seminal work demonstrated WGS as an alternative and sensitive approach to cytogenetics. Due to emerging evidence, NCCN integrated WGS in their AML testing guidelines (v2.2023). Given the importance of WGS in myeloid cancers, we developed Isabl GxT Heme, an analytical platform, that uses unmatched WGS data as input, assesses all mutation types across the entire genome (structural variants (SVs) and copy number variations (CNVs), small mutations) and delivers an automated report of clinically relevant findings in accordance to latest clinical guidelines. Here we use the Duncavage dataset to analytically validate this WGS approach for the Isabl platform.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are a promising new class of targeted therapy used in a variety of solid tumors with homologous recombination deficiencies (HRD). Data from clinical trials and observational studies have linked PARPi and platinum-based agents to therapy-related myeloid neoplasia (tMN). However, interpretation of these findings is limited by confounding variables including germline mutation status and prior therapeutic exposure. We and others have shown that the oncologic therapies known to confer an elevated risk of leukemia also promote the expansion of clonal hematopoiesis (CH) due to mutations of genes in the DNA damage response (DDR) pathway, including TP53, PPM1Dand CHEK2. However, the extent to which CH is associated with targeted therapies such as PARPi is not clear. We hypothesized that exposure to PARPi confers a competitive advantage to hematopoietic stem/progenitor cells (HSPCs) containing mutations in DDR pathway genes. Moreover, we hypothesized that in patients with germline mutations in HRD genes, such as BRCA1/BRCA2genotoxic stress induced by PARPi or cytotoxic agents is increased, further enhancing the fitness of HSPCs carrying DDR gene mutations .

Supplemental Digital Content is available in the text.

BackgroundThe electronic nicotine delivery system (ENDS) JUUL has quickly captured the ENDS market, representing 74.6% of the total dollar share for this category as of November 2018. Although JUUL is marketed as an alternative to cigarettes intended for current adult smokers, evidence suggests that a majority of ENDS users are concurrently current cigarette smokers. Little is known about the dual use of JUUL and cigarettes, as well as the reasons for trying JUUL among adult tobacco users.MethodsA survey fielded via web and phone of 1332 current cigarette, cigar, little cigar or cigarillo (CLCC), and ENDS users aged 18–54 years was conducted from March to May 2018. Weighted descriptive and bivariate analyses examined JUUL use and reasons for trying JUUL by demographics, combustible tobacco use, ENDS use and intention to quit.ResultsApproximately 81% of our sample reported current use of two or more tobacco products, including cigarettes, CLCCs or ENDS. Among current tobacco users, 15% ever used JUUL and 12% used JUUL in the past 30 days. Most individuals (74%) reporting ever JUUL use indicated using it for 5 days or fewer in the past 30 days. The most common reason for trying JUUL was trying to quit smoking cigarettes (37%), followed by family, friends or colleagues using the product (32%).ConclusionAlthough some tobacco users may be initiating JUUL to decrease combustible use, most were using the product infrequently and concurrently with other products. Findings have significant implications for cessation intervention efforts and policy development to help smokers quit.

The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring BCR-ABL1and MLLtranslocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified PHF6and DNMT3Amutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and BCR-ABL1/MLLtranslocations. PHF6- and DNMT3A-mutated MPAL showed marked predilection for T-lineage differentiation (5/6 PHF6mutated, 6/6 DNMT3Amutated). PHF6-mutated MPAL occurred in a younger patient cohort compared with DNMT3A-mutated cases (median age, 27 years vs 61 years, P< .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored PHF6mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, P= .001) and a higher relapse incidence (78% vs 22%, P= .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry–sorted populations demonstrated that PHF6mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating PHF6as an early mutation in MPAL pathogenesis. In conclusion, PHF6and DNMT3Amutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.

The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring BCR-ABL1 and MLL translocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified PHF6 and DNMT3A mutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and BCR-ABL1/MLL translocations. PHF6- and DNMT3A-mutated MPAL showed marked predilection for T-lineage differentiation (5/6 PHF6 mutated, 6/6 DNMT3A mutated). PHF6-mutated MPAL occurred in a younger patient cohort compared with DNMT3A-mutated cases (median age, 27 years vs 61 years, P < .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored PHF6 mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, P = .001) and a higher relapse incidence (78% vs 22%, P = .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry–sorted populations demonstrated that PHF6 mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating PHF6 as an early mutation in MPAL pathogenesis. In conclusion, PHF6 and DNMT3A mutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.

Behavior change research to promote health and prevent disease increasingly relies on a complex set of interacting characteristics across levels of influence such as biological, psychological, behavioral, interpersonal, and environmental. How to best develop health-related interventions that incorporate the individual, the macro-environment, and their interactions remains a challenge. This article considers a set of key dimensions that constitute what we refer to as the ecology of research across a broad context of multilevel research (MLR), spanning fundamental multilevel research (FMLR), multilevel intervention research (MLIR), and multilevel implementation science (MIS). With the goal of promoting improvements in MLIR, we describe the inherent interdependencies among aspects of research and consider how the growth and development of evidence and resources influence the cross-talk among researchers from different perspectives (e.g., disciplines and domains). We propose a framework that highlights opportunities to reduce barriers and address gaps in areas critical to generating an evidence base through MLR, MLIR, and MIS. Overall, we aim to support strategic decisions that can accelerate our understanding of ML health outcomes and interactions among factors within and across levels, with the goal of strengthening the effectiveness of ML interventions across health-related outcomes.Development of strategies to support healthy lifestyle choices benefits from research that considers influences from the individual to the environment and includes many different perspectives.

BackgroundElectronic cigarettes (e-cigarettes) are a common tobacco product in the US. Despite lacking Food and Drug Administration (FDA) approval for cessation, e-cigarettes, including JUUL, a popular device, have been viewed by some as a potential tool for tobacco users seeking to quit combustible tobacco use. It is unknown how current and former smokers report using these products for cigarette smoking cessation.MethodsOnline surveys were collected from a probability-based panel of US adults aged 18–64, with an oversample of past 12-month JUUL users (n=3415). Weighted past 12-month and past 30-day use of popular e-cigarette brands were measured. Former smokers with a quit attempt in the past 4 years and current smokers with a quit attempt in the past 12 months were asked about methods for smoking cessation, including e-cigarettes and nicotine replacement therapies (NRTs) use.ResultsAmong former smokers (n=157), 21.2% used e-cigarettes and/or NRTs to help them quit. Specifically, 2.2% used JUUL only, compared with 10.3% who used NRTs only, and 6.9% used other e-cigarettes only to quit. Among current smokers with a quit attempt (n=308), 24.0% used any product (NRT or e-cigarettes) to quit, and only 1.1% used JUUL only. Current smokers reported relatively low use of NRTs only (10.1%), other e-cigarettes only (5.6%) and other e-cigarettes and NRTs (5.1%).ConclusionsData suggest that few smokers in the US use e-cigarettes, and JUUL specifically, for cessation, and NRTs use is relatively low. All e-cigarettes should undergo FDA review to minimise recreational use and understand their cessation efficacy.

BEST MAN: Twice is just as nice for Usher as he returns to No. 1 on the Hot R&B/Hip-Hop Singles & Tracks chart with 'U Got It Bad.' In July, [...]

MORE THAN POP: At first glance, the sight of pop group 'N Sync on the Hot R&B/Hip-Hop Singles & Tracks chart may seem a little strange. Its current single, 'Gone' [...]

More than five years after it tied with WEA and Sony as the distribution company with the most charted titles in the top 10 of the Hot R&B/Hip-Hop Singles & [...]

On Top R&B/Hip-Hop Albums, P. Diddy & the Bad Boy Family make a premature debut at No. 83 with The Saga Continues...(Bad Boy/Arista). The album, which was released July 10, [...]

The first charting single for Alicia Keys maybe titled 'Fallin'' (J), but it earns Greatest Gainer/Airplay honors this issue as it moves up nine notches to No. 16. The single [...]

After a five-week ride at the top of Hot R&B/Hip-Hop Singles & Tracks by R. Kelly's 'Fiesta' (Jive), the retail release of Usher's 'U Remind Me' (Arista) prompts it to [...]

This issue's Greatest Gainer/Airplay on Singles & Tracks is 'I'm Real' (Epic) by Jennifer Lopez Featuring Ja Rule, which moves 61-88, following its debut last issue--Lopez's highest debut to date. [...]

Ginuwine earns the Hot Shot Debut on Hot R&B/Hip-Hop Singles & Tracks, bowing at No. 55 with 'Differences' (Epic), his second single from The Life. 'Differences,' which was No. 6 [...]

TRACKS OF LIFE: This issue marks the first chart appearance of this young century by the Isley Brothers, with 'Contagious.' The title enters Hot R&B/Hip-Hop Singles & Tracks at No. [...]

ST. LOUIS NEWS: Hailing from St. Louis, Nelly exploded on the scene last year with his debut single '(Hot S**t) Country Grammar' (Fo' Reel/Universal), which peaked at No. 5 on [...]

Despite increasing its audience by 2.4 million and retaining its bullet, 'Wait a Minute' by Ray-J Featuring Lil' Kim is surpassed by 'Music' by Erick Sermon Featuring Marvin Gaye and [...]

'Fiesta' (Jive) by R. Kelly Featuring Jay-Z holds on to No. 1 on the Hot R&B/Hip-Hop Singles & Tracks chart for the third consecutive week. It increases in audience by [...]