Risk of Sleep Apnea Is Associated with Abdominal Obesity Among Asian Americans: Comparing Waist-to-Hip Ratio and Body Mass Index.

OBJECTIVE: This study examines associations between the risk of sleep apnea and abdominal obesity (assessed by waist-to-hip ratio (WHR)) and general obesity (assessed by body mass index (BMI)) in a sample of Chinese and Korean American immigrants. METHODS: The dataset included Chinese and Korean participants aged 50-75 who were recruited from primary care physicians' clinics from April 2018 to June 2020 in the Baltimore-Washington D.C. Metropolitan area (n = 394). Abdominal obesity was determined if WHR ≥ 0.9 in men and WHR ≥ 0.85 in women. General obesity was determined if BMI ≥ 30. The risk of sleep apnea was determined by using the Berlin questionnaire. Poisson regression models examined associations between sleep apnea risk and obesity. Models controlled for socio-demographic risk factors. RESULTS: Twelve percent of the study participants were classified as a high risk for sleep apnea, and 75% had abdominal obesity whereas 6.4% had general obesity. High risk of sleep apnea was positively associated with abdominal obesity (PR = 1.31, 95% CI: 1.17-1.47) and general obesity (PR = 2.19, 95% CI: 0.90-5.32), marginally significant at p < 0.1). CONCLUSIONS: Chinese and Korean immigrants living in the USA who are at high risk of sleep apnea have higher abdominal obesity, even after accounting for sociodemographic characteristics. Abdominal obesity may be a better indicator than general obesity when examining the risk of sleep apnea among Asian Americans. INFORMATION ON CLINICAL TRIAL: Name: Screening To Prevent ColoRectal Cancer (STOP CRC) among At-Risk Asian American Primary Care Patients NCT Number: NCT03481296; Date of registration: March 29, 2018 URL: https://clinicaltrials.gov/ct2/show/NCT03481296?term=Sunmin+Lee&draw=2&rank=1.

Estimating personal exposures to household air pollution and plastic garbage burning among adolescent girls in Jalapa, Guatemala.

Waste collection services are uncommon in rural areas of low-resource countries, causing waste accumulation and subsequent dumping and burning of garbage. Air pollution from household garbage burning, including plastics, has been observed in Jalapa, Guatemala in addition to household air pollution (HAP) from cooking. Adolescent girls often help with these cooking and household tasks, but little is known about their exposures. We characterized 24-h exposures to HAP and household garbage burning in adolescent girls by measuring fine particulate matter (PM2.5), black carbon (BC), urinary biomarkers of polycyclic aromatic hydrocarbons (PAHs), bisphenol A (BPA), and phthalates. We recruited 60 girls between 13 and 17 years of age who helped with cooking activities and lived with participants of the Household Air Pollution Intervention Network (HAPIN) trial. We recruited n = 30 girls each from the control (wood-burning stove) and intervention (liquefied petroleum gas stove) arms. We also measured real-time kitchen concentrations of BC in 20 homes (33%). PM2.5 and BC were measured in n = 21 control and n = 20 intervention participants. Median concentrations of personal PM2.5 and BC and kitchen BC were lower (p < 0.05) in the intervention arm by 87%, 80%, and 85%, respectively. PAH metabolite concentrations were lower (p < 0.001) for all nine metabolites in intervention (n = 26) compared to control participants (n = 29). Urinary BPA concentrations were 66% higher in participants who reported using cosmetics (p = 0.02), and phthalate concentrations were 63% higher in participants who had reported using hair products during the sample period (p = 0.05). Our results suggest that gas stoves can reduce HAP exposures among adolescents who are not primary cooks at home. Biomarkers of plastic exposure were not associated with intervention status, but some were elevated compared to age- and sex-matched participants of the National Health and Nutrition Examination Survey (NHANES).

Ethanol inhibits pancreatic acinar cell autophagy through upregulation of ATG4B, mediating pathological responses of alcoholic pancreatitis.

Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy drives nonalcoholic pancreatitis, but the effects of ethanol (EtOH) and alcoholic pancreatitis on autophagy are poorly understood. Here, we find that ethanol reduces autophagosome formation in pancreatic acinar cells, both in a mouse model of alcoholic pancreatitis induced by a combination of EtOH diet and cerulein (a CCK ortholog) and in EtOH+CCK-treated acinar cells (ex vivo model). Ethanol treatments decreased pancreatic level of LC3-II, a key mediator of autophagosome formation. This was caused by ethanol-induced upregulation of ATG4B, a cysteine protease that, cell dependently, regulates the balance between cytosolic LC3-I and membrane-bound LC3-II. We show that ATG4B negatively regulates LC3-II in acinar cells subjected to EtOH treatments. Ethanol raised ATG4B level by inhibiting its degradation, enhanced ATG4B enzymatic activity, and strengthened its interaction with LC3-II. We also found an increase in ATG4B and impaired autophagy in a dissimilar, nonsecretagogue model of alcoholic pancreatitis induced by EtOH plus palmitoleic acid. Adenoviral ATG4B overexpression in acinar cells greatly reduced LC3-II and inhibited autophagy. Furthermore, it aggravated trypsinogen activation and necrosis, mimicking key responses of ex vivo alcoholic pancreatitis. Conversely, shRNA Atg4B knockdown enhanced autophagosome formation and alleviated ethanol-induced acinar cell damage. The results reveal a novel mechanism, whereby ethanol inhibits autophagosome formation and thus sensitizes pancreatitis, and a key role of ATG4B in ethanol's effects on autophagy. Enhancing pancreatic autophagy, particularly by downregulating ATG4B, could be beneficial in mitigating the severity of alcoholic pancreatitis.NEW & NOTEWORTHY Ethanol sensitizes mice and humans to pancreatitis, but the underlying mechanisms remain obscure. Autophagy is important for maintaining pancreatic acinar cell homeostasis, and its impairment drives pancreatitis. This study reveals a novel mechanism, whereby ethanol inhibits autophagosome formation through upregulating ATG4B, a key cysteine protease. ATG4B upregulation inhibits autophagy in acinar cells and aggravates pathological responses of experimental alcoholic pancreatitis. Enhancing pancreatic autophagy, particularly by down-regulating ATG4B, could be beneficial for treatment of alcoholic pancreatitis.

Single-cell transcriptomics of human-skin-equivalent organoids.

Several methods for generating human-skin-equivalent (HSE) organoid cultures are in use to study skin biology; however, few studies thoroughly characterize these systems. To fill this gap, we use single-cell transcriptomics to compare in vitro HSEs, xenograft HSEs, and in vivo epidermis. By combining differential gene expression, pseudotime analyses, and spatial localization, we reconstruct HSE keratinocyte differentiation trajectories that recapitulate known in vivo epidermal differentiation pathways and show that HSEs contain major in vivo cellular states. However, HSEs also develop unique keratinocyte states, an expanded basal stem cell program, and disrupted terminal differentiation. Cell-cell communication modeling shows aberrant epithelial-to-mesenchymal transition (EMT)-associated signaling pathways that alter upon epidermal growth factor (EGF) supplementation. Last, xenograft HSEs at early time points post transplantation significantly rescue many in vitro deficits while undergoing a hypoxic response that drives an alternative differentiation lineage. This study highlights the strengths and limitations of organoid cultures and identifies areas for potential innovation.

Prenatal exposure to persistent and non-persistent chemical mixtures and associations with adverse birth outcomes in the Atlanta African American Maternal-Child Cohort.

BACKGROUND: African Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. OBJECTIVE: We examined the individual and mixture effects of non-persistent chemicals and persistent organic pollutants (POPs) on gestational age at birth and birthweight for gestational age z-scores within a prospective cohort of pregnant AAs. METHODS: First-trimester serum and urine samples obtained from participants within the Atlanta African American Maternal-Child cohort were analyzed for 43 environmental chemicals, including per-and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides, pyrethroid insecticides, phthalates, bisphenol A, nicotine, and the primary metabolite of delta-9-tetrahydrocannabinol. Linear regression was used to estimate individual associations between chemicals and gestational age and birthweight z-scores (N ranging from 107 to 523). Mixture associations were estimated using quantile g-computation, principal component (PC) analyses, and hierarchical Bayesian kernel machine regression among complete cases (N = 86). RESULTS: Using quantile g-computation, increasing all chemical exposures by one quantile was modestly associated with a reduction in gestational age (mean change per quartile increase = -0.47, 95% CI = -1.56, 0.61) and birthweight z-scores (mean change per quartile increase = -0.49, 95% CI = -1.14, 0.15). All PCs were associated with a reduction in birthweight z-scores; associations were greatest in magnitude for the two PCs reflecting exposure to combined tobacco, insecticides, PBDEs, and phthalates. In single pollutant models, we observed inconsistent and largely non-significant associations. SIGNIFANCE: We conducted multiple targeted exposure assessment methods to quantify levels of environmental chemicals and leveraged mixture methods to quantify their joint effects on gestational age and birthweight z-scores. Our findings suggest that prenatal exposure to multiple classes of persistent and non-persistent chemicals is associated with reduced gestational age and birthweight z-scores in AAs. IMPACT: African Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. In the present study, we analyzed serum and urine samples for levels of 43 environmental chemicals. We used quantile g-computation, principal component analysis, and BKMR to assess associations between chemical exposure mixtures and adverse birth outcomes. Our findings suggest that prenatal exposure to multiple classes of chemicals is associated with reduced birthweight z-scores, a proxy for fetal growth, in AAs.

The Cross-Sectional Association of Sleep Disturbance and Sleep Apnea With Complex Multimorbidity Among Chinese and Korean Americans.

A new concept called complex multimorbidity provides a more reliable measure of disease burden than multimorbidity based on a simple count of diseases, by categorizing diseases according to the body system they affect. This study examined associations between sleep measures and complex multimorbidity among Chinese and Korean Americans in the Baltimore-Washington DC Metropolitan Area, using cross-sectional data (n = 400) from the Screening to Prevent Colorectal Cancer study (2018-2020). Sleep disturbance was measured using the 8-item Patient Reported Outcomes Measurement Information System Sleep Disturbance scale and sleep apnea risk was assessed using the Berlin questionnaire. Complex multimorbidity was defined as the coexistence of 3 or more of body system disorders assessed by self-report of physician-diagnosed diseases. Poisson regression models with adjustments indicated that individuals with sleep disturbance had 2.15 times the prevalence of having complex multimorbidity (95% confidence interval (CI): 1.07, 4.29). Individuals with a high risk of sleep apnea had 1.19 times the prevalence of having complex multimorbidity (95% CI: 0.47, 3.01). These findings suggest a need for interventions to increase awareness of the importance of sleep among health-care providers and the public and to educate them about causes, signs, and treatment of sleep disturbance and sleep apnea.

Associations between microbial communities and key chemical constituents in U.S. domestic moist snuff.

BACKGROUND: Smokeless tobacco (ST) products are widely used throughout the world and contribute to morbidity and mortality in users through an increased risk of cancers and oral diseases. Bacterial populations in ST contribute to taste, but their presence can also create carcinogenic, Tobacco-Specific N-nitrosamines (TSNAs). Previous studies of microbial communities in tobacco products lacked chemistry data (e.g. nicotine, TSNAs) to characterize the products and identify associations between carcinogen levels and taxonomic groups. This study uses statistical analysis to identify potential associations between microbial and chemical constituents in moist snuff products. METHODS: We quantitatively analyzed 38 smokeless tobacco products for TSNAs using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nicotine using gas chromatography with mass spectrometry (GC-MS). Moisture content determinations (by weight loss on drying), and pH measurements were also performed. We used 16S rRNA gene sequencing to characterize the microbial composition, and additionally measured total 16S bacterial counts using a quantitative PCR assay. RESULTS: Our findings link chemical constituents to their associated bacterial populations. We found core taxonomic groups often varied between manufacturers. When manufacturer and flavor were controlled for as confounding variables, the genus Lactobacillus was found to be positively associated with TSNAs. while the genera Enteractinococcus and Brevibacterium were negatively associated. Three genera (Corynebacterium, Brachybacterium, and Xanthomonas) were found to be negatively associated with nicotine concentrations. Associations were also investigated separately for products from each manufacturer. Products from one manufacturer had a positive association between TSNAs and bacteria in the genus Marinilactibacillus. Additionally, we found that TSNA levels in many products were lower compared with previously published chemical surveys. Finally, we observed consistent results when either relative or absolute abundance data were analyzed, while results from analyses of log-ratio-transformed abundances were divergent.

The association of acculturative stress with self-reported sleep disturbance and sleep duration among Asian Americans.

STUDY OBJECTIVES: This study aims to examine associations between acculturative stress-defined as the psychological impact, or stress reaction, of adapting to a new cultural context-and self-reported sleep outcomes among Chinese and Korean immigrants in the United States. METHODS: In this cross-sectional study, acculturative stress was assessed using a 9-item scale, and sleep disturbance was measured using the 8-item scale. Sleep duration was self-reported. Poisson and linear regression analyses were conducted to examine the associations between acculturative stress, sleep disturbance, and sleep duration. RESULTS: Our sample consists of 400 participants (females: 52%, Chinese: 50%, Koreans: 50%, the mean of age = 58.4). 81.8% of them were classified as having no sleep disturbance, whereas 18.2% were classified as having sleep disturbance. Poisson models revealed that greater acculturative stress was associated with a higher prevalence of sleep disturbance (Prevalence Ratio (PR): 1.18, 95% confidence interval (CI): 1.06% to 1.31%). In linear models, a one-unit increase in acculturative stress was associated with 0.08 hr less sleep (p < .05). Interaction tests indicated effect modification for sleep disturbance by sex and ethnic identity: only women had a significant association between acculturative stress and sleep disturbance (PR: 1.30; 95% CI: 1.13 to 1.49), while the association was significant for individuals identifying as "very Asian" (PR: 1.21; 95% CI: 1.08 to 1.35), but not for those identifying as "mostly Asian" or "bicultural/western". CONCLUSIONS: If findings are replicated, we suggest developing intervention programs for Asian immigrants to minimize acculturative stress and bolster protective factors that decrease the risk for poor sleep outcomes.Information on Clinical Trial: Name: Screening To Prevent ColoRectal Cancer (STOP CRC) among At-Risk Asian American Primary Care Patients NCT Number: NCT03481296 URL: https://clinicaltrials.gov/ct2/show/NCT03481296?term=Sunmin+Lee&draw=2&rank=1.

Testimony and meaning: A qualitative study of Black women with cancer diagnoses.

OBJECTIVE: Research has established religion and spirituality as important resources for Black people in the U.S. coping with adversity. Most research has been from an etic perspective, examining religious variables that are valid across multiple religions. In the present study, we asked what emic aspects of the Black church's practices and theological emphases women with cancer drew on in constructing meaning-making narratives from their cancer experience. METHOD: In this consensual qualitative research study, we interviewed 30 Black women with cancer histories with an average age of 64.5. RESULTS: The religious practice of testimony emerged as the predominant theme. Testimony (a) provided a meaningful purpose to the cancer experience; (b) had a specific content of describing what God had done in their lives as well as some common theological emphases; (c) had dual desired outcomes of helping others and bringing glory to God; and (d) had an associated practice of giving testimony. CONCLUSION: We discuss testimony as a narrative structure and highlight its importance in informing culturally sensitive interventions aimed at supporting Black women with cancer. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Chemical analysis of snus products from the United States and northern Europe.

INTRODUCTION: Snus is an oral tobacco product that originated in Sweden. Snus products are available as fine-cut loose tobacco or in pre-portioned porous "pouches." Some snus products undergo tobacco pasteurization during manufacturing, a process that removes or reduces nitrite-forming microbes, resulting in less tobacco-specific nitrosamine content in the product. Some tobacco companies and researchers have suggested that snus is potentially less harmful than traditional tobacco and thus a potential smoking cessation aid or an alternative to continued cigarette consumption. Although snus is available in various countries, limited information exists on snus variants from different manufacturers. METHODS: Moisture, pH, nicotine, and tobacco-specific N'-nitrosamines (TSNAs) were quantified in 64 snus products made by 10 manufacturers in the United States and Northern Europe (NE). Reported means, standard errors, and differences are least-square (LS) estimates from bootstrapped mixed effects models, which accounted for correlation among repeated measurements. Minor alkaloids and select flavors were also measured. RESULTS: Among all product types, moisture (27.4%-59.5%), pH (pH 5.87-9.10), total nicotine (6.81-20.6 mg/g, wet), unprotonated nicotine (0.083-15.7 mg/g), and total TSNAs (390-4,910 ng/g) varied widely. The LS-mean unprotonated nicotine concentration of NE portion (7.72 mg/g, SE = 0.963) and NE loose (5.06 mg/g, SE = 1.26) snus were each significantly higher than US portion snus (1.00 mg/g, SE = 1.56). Concentrations of minor alkaloids varied most among products with the highest total nicotine levels. The LS-mean NNN+NNK were higher in snus sold in the US (1360 ng/g, SE = 207) than in NE (836 ng/g, SE = 132) countries. The most abundant flavor compounds detected were pulegone, eucalyptol, and menthol. CONCLUSION: Physical and chemical characteristics of US and NE products labeled as snus can vary considerably and should not be considered "equivalent". Our findings could inform public health and policy decisions pertaining to snus exposure and potential adverse health effects associated with snus.

Development of a Cigarette Tobacco Filler Standard Reference Material.

A new tobacco filler Standard Reference Material (SRM) has been issued by the National Institute of Standards and Technology (NIST) in September 2016 with certified and reference mass fraction values for nicotine, N-nitrosonornicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and volatiles. The constituents have been determined by multiple analytical methods with measurements at NIST and at the Centers for Disease Control and Prevention, and with confirmatory measurements by commercial laboratories. This effort highlights the development of the first SRM for reduced nicotine and reduced tobacco-specific nitrosamines with certified values for composition.

Caffeine Concentrations in Coffee, Tea, Chocolate, and Energy Drink Flavored E-liquids.

INTRODUCTION: Most electronic cigarettes (e-cigarettes) contain a solution of propylene glycol/glycerin and nicotine, as well as flavors. E-cigarettes and their associated e-liquids are available in numerous flavor varieties. A subset of the flavor varieties include coffee, tea, chocolate, and energy drink, which, in beverage form, are commonly recognized sources of caffeine. Recently, some manufacturers have begun marketing e-liquid products as energy enhancers that contain caffeine as an additive. METHODS: A Gas Chromatography-Mass Spectrometry (GC-MS) method for the quantitation of caffeine in e-liquids was developed, optimized and validated. The method was then applied to assess caffeine concentrations in 44 flavored e-liquids from cartridges, disposables, and refill solutions. Products chosen were flavors traditionally associated with caffeine (ie, coffee, tea, chocolate, and energy drink), marketed as energy boosters, or labeled as caffeine-containing by the manufacturer. RESULTS: Caffeine was detected in 42% of coffee-flavored products, 66% of tea-flavored products, and 50% of chocolate-flavored e-liquids (limit of detection [LOD] - 0.04 µg/g). Detectable caffeine concentrations ranged from 3.3 µg/g to 703 µg/g. Energy drink-flavored products did not contain detectable concentrations of caffeine. Eleven of 12 products marketed as energy enhancers contained caffeine, though in widely varying concentrations (31.7 µg/g to 9290 µg/g). CONCLUSIONS: E-liquid flavors commonly associated with caffeine content like coffee, tea, chocolate, and energy drink often contained caffeine, but at concentrations significantly lower than their dietary counterparts. Estimated daily exposures from all e-cigarette products containing caffeine were much less than ingestion of traditional caffeinated beverages like coffee. IMPLICATIONS: This study presents an optimized and validated method for the measurement of caffeine in e-liquids. The method is applicable to all e-liquid matrices and could potentially be used to ensure regulatory compliance for those geographic regions that forbid caffeine in e-cigarette products. The application of the method shows that caffeine concentrations and estimated total caffeine exposure from e-cigarette products is significantly lower than oral intake from beverages. However, because very little is known about the effects of caffeine inhalation, e-cigarette users should proceed with caution when using caffeine containing e-cigarette products. Further research is necessary to determine associated effects from inhaling caffeine.

Predictors of Serum Polybrominated Diphenyl Ether (PBDE) Concentrations among Children Aged 1-5 Years.

Serum concentrations of PBDEs were measured using gas chromatography-tandem mass spectrometry in 80 children aged 15-71 months. Demographic and behavioral data were collected on parental questionnaires; a research nurse recorded anthropometric measures and insurance status. For a subset of children (n = 17), PBDEs were measured in house dust and child handwipes sampled during a home visit. In linear and Tobit regression, log-transformed PBDE congeners were modeled as a function of child characteristics, including neighborhood-level socioeconomic indicators. BDE congeners 47, 99, and 100 were highly correlated and summed for analysis; BDE-153 was examined individually. PBDE serum concentrations were associated with socioeconomic factors; for example, a $20,000 increase in median household income in a child's ZIP code was associated with a 34% decrease (95%CI = 14-49%) in BDE-153 and a 26% decrease (95%CI = 6-42%) in ∑BDE-47,-99,-100. Lower body-mass index (BMI) z-score and household smoking were strong predictors of higher BDE-153 levels. Among children who participated in a home visit, serum PBDE was positively correlated with handwipe PBDE (Spearman r ∑BDE-47, -99, -100 = 0.48, p = 0.09), but not dust PBDE. Results indicate socioeconomic factors and BMI are strong predictors of serum PBDE levels among young children. PBDEs measured on handwipes are more predictive of serum PBDE levels than vacuum-collected dust.

Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome.

The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed "X-SPINK1". Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3+/- mice rescued perinatal lethality, but the resulting Spink3-/-;XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3-/-;XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis.

Characterization of SPECTRUM Variable Nicotine Research Cigarettes.

OBJECTIVE: To provide researchers an extensive characterization of the SPECTRUM variable nicotine research cigarettes. METHODS: Data on cigarette physical properties, nicotine content, harmful and potentially harmful constituents in the tobacco filler was compiled. RESULTS: Data on physical properties, concentrations of menthol, nicotine and minor alkaloids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, ammonia, and toxic metals in the filler tobacco for all available varieties of Spectrum research cigarettes are provided. The similarity in the chemistry and physical properties of SPECTRUM cigarettes to commercial cigarettes renders them acceptable for use in behavioral studies. Baseline information on harmful and potentially harmful constituents in research tobacco products, particularly constituent levels such as minor alkaloids that fall outside typical ranges reported for commercial, provide researchers with the opportunity to monitor smoking behavior and to identify biomarkers that will inform efforts to understand the role of nicotine in creating and sustaining addiction. CONCLUSIONS: Well characterized research cigarettes suitable for human consumption are an important tool in clinical studies for investigating the physiological impacts of cigarettes delivering various levels of nicotine, the impact of reduced nicotine cigarettes on nicotine addiction, and the relationship between nicotine dose and smoking behavior.

Burden of Influenza-Related Hospitalizations and Attributable Mortality in Pediatric Acute Lymphoblastic Leukemia.

BACKGROUND: Influenza can be severe in patients with underlying malignancy; however, the rate of influenza hospitalizations and attributable mortality in children with cancer is unknown. METHODS: We performed a retrospective cohort study among 10 698 children with new-onset acute lymphoblastic leukemia (ALL) from 41 US children's hospitals between January 1999 and September 2011. Influenza-related hospitalizations were identified using ICD-9 discharge diagnosis codes, excluding hospitalizations during low-prevalence influenza periods. Follow-up was censored at the earliest of 5 events: end of study period, expected end of chemotherapy, last known hospitalization, hematopoietic stem cell transplant, or death. Data were collected on hospitalization characteristics and resource utilization. Hospitalization rates were calculated using season-adjusted person-time. Crude attributable in-hospital mortality was calculated using baseline mortality for noninfluenza hospitalizations during the same period. Subgroup analysis was performed by time from ALL diagnosis and by age category. RESULTS: The rate of influenza-related hospitalizations was 618.3 per 100 000 person-months. Rates were similar by time from ALL diagnosis and across age categories. Overall attributable in-hospital mortality was 1.0% (95% confidence interval [CI], 0.3%-2.3%) and was highest for children <6 months from diagnosis (1.6%; 95% CI, 0.4%-4.5%) and children <2 years of age (6.7%; 95% CI, 1.3%-22.7%). Total length of stay, days of broad-spectrum antibiotic exposure, and duration of intensive care were significantly greater for influenza-related hospitalizations compared with noninfluenza hospitalizations. CONCLUSIONS: The burden of influenza-related hospitalizations in children with ALL is high and associated with significantly increased resource utilization and attributable mortality.

Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States.

BACKGROUND: Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients. METHODS: The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression, and Poisson regression, respectively. RESULTS: A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 (P = .0023). The case fatality rate was 9.0% in the intensively timed DCTER (dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin [daunomycin]/idarubicin) induction and 3.8% for ADE (cytarabine, daunomycin, and etoposide) induction (adjusted odds ratio = 2.2, 95% confidence interval = 1.1-4.5). Patients treated with intensively timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials. CONCLUSIONS: Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens.

Phosphatase and tensin homolog regulates the pluripotent state and lineage fate choice in human embryonic stem cells.

Understanding the intrinsic and extrinsic signals that regulate the molecular basis of the pluripotent state may improve our understanding of mammalian embryogenesis, different states of pluripotency, and our ability to tailor lineage differentiation. Although the role of the PI3K/Akt pathway in the self-renewal and maintenance of mESCs is well-established, the specific contribution of the pathway or of its negative regulator, PTEN, in the maintenance of the human pluripotent state is less understood. To explore the PI3K/AKT pathway in human embryonic stem cell (hESC) pluripotency and differentiation, we generated stable PTEN knockdown (KD) hESCs using short hairpin RNA. Similar to mESCs, we found that PTEN KD hESCs have increased self-renewal, cell survival, and proliferation over multiple passages compared to control cells. However, in contrast to mESCs, in vitro, PTEN KD hESCs differentiated inefficiently in directed differentiation assays, in part due to the continued maintenance of OCT4 and NANOG expression. In teratoma assays, PTEN KD hESCs generated tissues from the three germ layers, although with a bias toward neuroectoderm differentiation. These results demonstrate that PTEN is a key regulator of hESC growth and differentiation, and manipulation of this pathway may improve our ability to regulate and understand the pluripotent state.

Reconstitution of herpes simplex virus microtubule-dependent trafficking in vitro.

Microtubule-mediated anterograde transport of herpes simplex virus (HSV) from the neuronal cell body to the axon terminal is crucial for the spread and transmission of the virus. It is therefore of central importance to identify the cellular and viral factors responsible for this trafficking event. In previous studies, we isolated HSV-containing cytoplasmic organelles from infected cells and showed that they represent the first and only destination for HSV capsids after they emerge from the nucleus. In the present study, we tested whether these cytoplasmic compartments were capable of microtubule-dependent traffic. Organelles containing green fluorescent protein-labeled HSV capsids were isolated and found to be able to bind rhodamine-labeled microtubules polymerized in vitro. Following the addition of ATP, the HSV-associated organelles trafficked along the microtubules, as visualized by time lapse microscopy in an imaging microchamber. The velocity and processivity of trafficking resembled those seen for neurotropic herpesvirus traffic in living axons. The use of motor-specific inhibitors indicated that traffic was predominantly kinesin mediated, consistent with the reconstitution of anterograde traffic. Immunocytochemical studies revealed that the majority of HSV-containing organelles attached to the microtubules contained the trans-Golgi network marker TGN46. This simple, minimal reconstitution of microtubule-mediated anterograde traffic should facilitate and complement molecular analysis of HSV egress in vivo.