Correlates of susceptibility to waterpipe tobacco smoking in young adults.

INTRODUCTION: Many US young adults are susceptible to waterpipe (i.e., hookah) tobacco smoking (WTS) initiation, but research on factors associated with WTS susceptibility is limited. We examined sociodemographic, other tobacco and substance use, and attitudes and perceptions correlates of WTS susceptibility among young adults. METHODS: Baseline data from a randomized trial testing WTS risk messages was collected in US young adults aged 18 to 30 years who never used waterpipe tobacco but were susceptible to WTS (n = 294). Extent of susceptibility to WTS was defined using the average score of a valid scale with higher scores indicating higher susceptibility. Correlates were sociodemographics, other tobacco and substance use, and attitudes and perceptions. Multiple linear regression models identified correlates of greater WTS susceptibility. RESULTS: Participants averaged 25 (SD 3.2) years of age, 60% were male, 22% were Black non-Hispanic, 47% completed some college education, and 66% were employed. Our models consistently showed that more positive attitudes toward WTS (ß = -0.08, p<0.01), lower perceived addictiveness relative to cigarettes (ß = -0.09, p = 0.04), and greater perceived social acceptability of WTS (ß = 0.05, p<0.01) were positively correlated with WTS susceptibility. Additionally, young adults who smoked cigarillos (ß = 0.53, p<0.01), used cannabis (ß = 0.14, p = 0.02), and Black non-Hispanic versus White non-Hispanic young adults (ß = 0.18, p = 0.03) also had higher WTS susceptibility. CONCLUSIONS: Findings suggest that WTS prevention efforts require multicomponent interventions including targeting subpopulations at greater risk based on race/ethnicity and other tobacco and substance use. These interventions should consider attitudes and social acceptability of WTS as modifiable targets to maximize public health benefits.

Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study.

BACKGROUND AND AIMS: Oral nicotine pouches (ONPs) probably offer reduced harm compared with cigarettes, but independent data concerning their misuse liability are lacking. We compared nicotine delivery and craving relief from ONPs with different nicotine concentrations to cigarettes. DESIGN: This was a single-blind, three-visit (≥ 48-hour washout), randomized-cross-over study. Participants were encouraged to complete all study visits in less than 1 month. SETTING: The study took place in Rural/Appalachian Ohio. PARTICIPANTS: Participants comprised 30 adults who smoke cigarettes. Participants (meanage = 34.5) were 60% men and 90% White. INTERVENTION: Participants who were ≥ 12-hour tobacco-abstinent used: (1) a 3-mg nicotine concentration ONP, (2) a 6-mg nicotine concentration ONP and (3) usual brand cigarette in separate visits. ONPs (wintergreen Zyn) were used for 30 minutes; cigarettes were puffed every 30 sec for 5 minutes. MEASUREMENTS: Plasma nicotine and self-reported craving were assessed at t = 0, 5, 15, 30, 60 and 90 minutes. The primary outcome was plasma nicotine concentration at t = 30 minutes. A secondary outcome was craving relief at t = 5 minutes. FINDINGS: At t = 30, mean [95% confidence interval (CI)] plasma nicotine was 9.5 ng/ml (95% CI = 7.1, 11.9 ng/ml) for the 3 mg nicotine ONP, 17.5 ng/ml (95% CI = 13.7, 21.3) for the 6 mg nicotine ONP and 11.4 ng/ml (95% CI = 9.2, 13.6 ng/ml) for the cigarette. Mean plasma nicotine at t = 30 minutes differed between the 3- and 6-mg nicotine ONPs (P = 0.001) and between the 6-mg nicotine ONP and cigarette (P = 0.002). Mean (95% CI) craving at t = 5 minutes was lower for the cigarette (mean = 1.00, 95% CI = 0.61, 1.39) than either the 3 mg (mean = 2.25, 95% CI = 1.68, 2.82; P < 0.0001) or 6 mg nicotine (mean = 2.19, 95% CI = 1.60, 2.79; P < 0.0001) ONP. CONCLUSIONS: Among adult smokers, using 6-mg nicotine concentration oral nicotine pouches (ONPs) was associated with greater plasma nicotine delivery at 30 minutes than 3-mg ONPs or cigarettes, but neither ONP relieved craving symptoms at 5 minutes as strongly as a cigarette. Accelerating the speed of nicotine delivery in ONPs might increase their misuse liability relative to cigarettes.

Perceptions of oral nicotine pouches & their marketing among Ohio Appalachia smokers and smokeless tobacco users.

BACKGROUND: Oral nicotine pouches (ONPs) are novel products, gaining popularity and marketed as "tobacco-free" alternatives to cigarettes and smokeless tobacco (SLT), but their public health impact is unknown. This study qualitatively examined ONP appeal and perceptions among cigarette smokers and SLT users from Ohio Appalachia. METHODS: In 2022, we conducted 10 virtual focus groups with smokers (n = 19) and smokeless tobacco users (n = 18) from Appalachia Ohio aged ≥21 to examine perceptions of risks and benefits, substitutability for cigarettes and SLT, and ONP marketing. We transcribed focus groups verbatim, thematically coded transcripts, and analyzed coded data for prominent themes. RESULTS: Participants perceived ONPs to have similar or less risk than cigarettes/SLT but prominently discussed gastrointestinal and cardiovascular risks. Addiction risk was thought to be comparable to cigarettes/SLT, citing "nicotine is nicotine." Participants viewed ONPs to be situational rather than complete substitutes for cigarettes/SLT, viewing them as "cleaner," more socially acceptable, and discrete. Despite appealing features of ONP marketing, participants surmised ads would appeal to youth, new users, tobacco users seeking to cut down/quit, or to "high class," "white-collar" demographics. CONCLUSIONS: Participants' perceptions of ONPs and their marketing suggest ONPs are more likely to be used as situational versus complete substitutes for cigarettes and SLT. While situational substitution could exacerbate disparities in Appalachia by facilitating more frequent tobacco/nicotine use, complete substitution could reduce disparities. Research is needed to understand how perceptions, the appeal of ONP marketing, and novel product features translate to patterns of use to understand ONPs' potential impact.

Awareness of alcohol as a breast cancer risk factor and intentions to reduce alcohol consumption among U.S. young adult women.

Alcohol consumption is prevalent in young adult women and linked with breast cancer risk. Research to inform interventions targeting alcohol consumption as a breast cancer prevention strategy is limited. We examined young women's awareness of alcohol use as a breast cancer risk factor, identified correlates of awareness, and determined how awareness and conceptual predictors relate to intentions to reduce drinking. Women aged 18-25 years who drank alcohol in the past month (N = 493) completed a cross-sectional survey. Measures captured sociodemographics, breast cancer risk factors, awareness of alcohol use as a breast cancer risk factor, intentions to reduce drinking, and conceptual predictors. Analyses examined correlates of awareness and associations between awareness, conceptual predictors, and intentions to reduce drinking. Awareness was low (28%) and intentions to reduce drinking were moderate (M = 2.60, SD = 0.73, range 1-4). In multivariable analyses, awareness was associated with greater worry about cancer, beliefs that there's not much one can do to reduce cancer risk and everything causes cancer, higher perceived breast cancer risk, and stronger beliefs that reducing drinking reduces breast cancer risk. Awareness was not associated with intentions to reduce drinking. Younger age, older age of alcohol initiation, negative attitudes towards alcohol, fewer friends consuming alcohol, and stronger self-efficacy were associated with intentions to reduce drinking. Few young women recognize alcohol consumption as a breast cancer risk factor. Researchers and policymakers can apply our findings to design new or refine existing interventions to optimize their impact on awareness and alcohol consumption in young women.

Alcohol use is common among young adult women and is linked to an increased risk of breast cancer later in life. This study aimed to identify factors linked to young women's awareness of alcohol as a breast cancer risk factor and factors linked to intentions to reduce drinking. We surveyed 493 women aged 18­25 who resided in Ohio and reported drinking alcohol in the past month. Only 28% of the women were aware that alcohol use increases breast cancer risk, and intentions to reduce drinking were moderate. Factors associated with awareness of alcohol use as a breast cancer risk factor included cancer worry, believing there's not much you can do to lower your risk of cancer, believing everything causes cancer, higher perceived risk of breast cancer, and stronger beliefs that drinking less reduces breast cancer risk. Factors linked to intentions to reduce drinking included younger age, older age at first drinking, more negative attitudes about alcohol, believing fewer friends drink, and higher confidence to reduce drinking. The findings can help researchers and policymakers create new interventions to educate young women about the link between alcohol consumption and breast cancer risk and reduce alcohol use as a breast cancer prevention strategy.

Correlates of motivation to quit waterpipe tobacco smoking among US young adults: implications for cessation interventions.

Waterpipe tobacco smoking is a public health concern that poses many of the same health risks as cigarette smoking, especially among young adults-a subpopulation characterized by the highest prevalence of waterpipe tobacco smoking. Nevertheless, it remains understudied relative to other forms of tobacco use. We examined sociodemographic, behavioral and cognitive factors associated with young adults' motivation to quit waterpipe smoking using a theory-informed approach. We completed a secondary analysis of baseline data on waterpipe tobacco smoking beliefs and behavior collected from 349 US young adults aged 18-30 years. We analyzed sociodemographics, tobacco use and cessation behaviors and perceptions, and theory-related constructs associated with motivation to quit waterpipe tobacco smoking using linear regression. Overall, participants reported low motivation (mean = 2.68, SD = 1.56, scale range 1-7) and high self-efficacy (mean = 5.12, SD = 1.79) to quit waterpipe tobacco smoking. In multivariable analysis, prior quit attempts (ß = 1.10, P < 0.01), greater perceived risks of waterpipe tobacco smoking (ß = 0.42, P < 0.01) and increasingly negative attitudes toward waterpipe tobacco smoking (ß = 0.29, P < 0.01) were associated with higher motivation to quit. These findings highlight the importance of those factors as potential cessation determinants. These findings can help guide the development and refinement of interventions targeting young adult waterpipe tobacco smoking.

The Effects of Oral Nicotine Pouch Packaging Features on Adult Tobacco Users' and Non-Users' Product Perceptions.

BACKGROUND: Oral nicotine pouches (ONPs) are novel products that are marketed as "tobacco-free" alternatives to cigarettes and smokeless tobacco (ST). This study examined the effects of ONP packaging features on adult tobacco users' and non-users' product perceptions. MATERIALS AND METHODS: Adult tobacco users (cigarettes, ST, and dual cigarette/ST) and non-users (total N = 301) viewed ONP pack images in a 4 × 3 × 2 between-subject experiment testing the effects of the displayed flavor (cool mint, coffee, dark frost, and smooth), nicotine concentration (none displayed on the package, 3 mg, and 6 mg), and addiction warning label (yes or no). The outcomes were perceived substitutability of ONPs for cigarettes and ST and perceived risks. We modeled the effects of tobacco user status and the experimental factors on these outcomes. RESULTS: All tobacco user groups perceived ONPs to be significantly less harmful and less addictive than non-users. There were significant effects of nicotine concentration on perceived risks. Compared to packages that did not display nicotine concentration, packages displaying 6 mg nicotine concentration produced significantly lower perceived harm (ß = -0.23, 95% CI -0.44, -0.02), perceived addictiveness (ß = -0.28, 95% CI -0.51, -0.05), risk appraisals of harm (ß = -0.50, 95% CI -0.88, -0.12) and risk appraisals of addictiveness (ß = -0.53, 95% CI -0.95, -0.11). CONCLUSIONS: The study findings demonstrate that the nicotine concentration displayed on ONP packaging can affect adults' perceptions of ONPs. Further research on the effects of ONP packaging features emphasizing nicotine (e.g., "tobacco free" nicotine claims) on tobacco users and non-users is needed to assess their potential public health impact.

Correlates of U.S. Young adults' awareness of alcohol use as a behavioral risk factor for cancer.

Although alcohol increases the risk of cancer, awareness of alcohol-related cancer risks is low. Alcohol use is prevalent among young adults, and understanding factors associated with awareness and perceptions of alcohol-related cancer risks in this group is critical for cancer prevention efforts. We examined the demographic, tobacco, and alcohol related correlates of young adults' awareness and perceptions of alcohol as a behavioral risk factor for cancer. We completed a secondary analysis of data collected in February 2020 in the U.S. from 1,328 young adults (ages 18-30) who completed a cross-sectional online survey. Participants reported (1) awareness of alcohol as a risk factor for cancer and (2) perceived risks of serious disease such as cancer. We analyzed demographic characteristics, alcohol use, and tobacco use associated with these outcome variables using multivariable regression. Overall, 18.5% of participants believed that alcohol does not increase cancer risk. Perceived cancer risk associated with alcohol use was moderate (M 3.2, SD 1.6, 1-7 scale). In multivariable analysis, awareness of risk was significantly higher among those with higher socioeconomic status. Perceived risk was significantly greater among those with higher socioeconomic status, higher alcohol consumption, and a history of tobacco use. These findings indicate research is warranted to better understand awareness of alcohol as a behavioral risk factor for cancer and associated beliefs in subgroups of young adults to help guide the development of interventions to raise awareness of the risks of cancer associated with alcohol use.

Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations.

BACKGROUND: The etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain's susceptibility is not known. OBJECTIVE: We aimed to determine the mechanism underlying the unique susceptibility to anaphylaxis in C3H/HeJ mice. We tested the role of deleterious Toll-like receptor 4 (Tlr4) or dedicator of cytokinesis 8 (Dock8) mutations in this strain because both genes have been associated with food allergy. METHODS: We generated C3H/HeJ mice with corrected Dock8 or Tlr4 alleles and sensitized and challenged them with peanut. We then characterized the antibody response to sensitization, anaphylaxis response to both oral and systemic peanut challenge, gut microbiome, and biomarkers of gut permeability. RESULTS: In contrast to C3H/HeJ mice, C57BL/6 mice were resistant to anaphylaxis after oral peanut challenge; however, both strains undergo anaphylaxis with intraperitoneal challenge. Restoring Tlr4 or Dock8 function in C3H/HeJ mice did not protect from anaphylaxis. Instead, we discovered enhanced gut permeability resulting in ingested allergens in the bloodstream in C3H/HeJ mice compared to C57BL/6 mice, which correlated with an increased number of goblet cells in the small intestine. CONCLUSIONS: Our work highlights the potential importance of gut permeability in driving anaphylaxis to ingested food allergens; it also indicates that genetic loci outside of Tlr4 and Dock8 are responsible for the oral anaphylactic susceptibility of C3H/HeJ mice.

Shared and distinctive features of the gut microbiome of C57BL/6 mice from different vendors and production sites, and in response to a new vivarium.

Animal models play a critical role in establishing causal relationships between gut microbiota and disease. The laboratory mouse is widely used to study the role of microbes in various disorders; however, differences between mouse vendors, genetic lineages and husbandry protocols have been shown to contribute to variation in phenotypes and to non-reproducibility of experimental results. We sought to understand how gut microbiome profiles of mice vary by vendor, vendor production facility and health status upon receipt into an academic facility and how they change over 12 weeks in the new environment. C57BL/6 mice were sourced from two different production sites for each of three different vendors. Mice were shipped to an academic research vivarium, and fresh-catch stool samples were collected from mice immediately from the shipping box upon receipt, and again after 2, 6 and 12 weeks in the new facility. Substantial variation in bacterial proportional abundance was observed among mice from each vendor at the time of receipt, but shared microbes accounted for most sequence reads. Vendor-specific microbes were generally of low abundance. Microbial profiles of mice from all vendors exhibited shifts over time, highlighting the importance of environmental conditions on microbial dynamics. Our results emphasize the need for continued efforts to account for sources of variation in animal models and understand how they contribute to experimental reproducibility.

'Somebody that looks like me' matters: a qualitative study of black women's preferences for receiving sexual health services in the USA.

Research dedicated to understanding the sexual experiences of Black women has historically been framed around adverse outcomes. There are limited data that can be used to understand the lived experiences of Black women related to sexual health care. Twenty-five Black women aged 18- 35 from across nine US states were interviewed to gain insight into their experiences and preferences for receiving sexual health services. Three themes were developed from their accounts: individual and structural barriers affect access to and perceived quality of care; service provider race and gender impact sexual health care experiences; and personalised care improves engagement. Findings suggest the need for culturally informed training for sexual health practitioners working with Black women.

Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and MEIS1 Expression.

PURPOSE: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. PATIENTS AND METHODS: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II. RESULTS: Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed. CONCLUSIONS: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.

A mutation in mouse Krüppel-like factor 15 alters the gut microbiome and response to obesogenic diet.

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high fat diets. HLB444 shares similar phenotypic traits with engineered full- and adipose-specific Klf15 knockout strains; however, some phenotypic differences between this mutant and the other models suggest that the Klf15 mutation in HLB444 is a hypomorphic variant. The HLB444 model will inform further annotation of transcriptional functions of KLF15, especially with respect to the role of the first zinc-finger domain.

Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.

BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB). RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor ß (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sjögren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low. CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term. IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sjögren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.

Whole-Exome Sequencing of Adult and Pediatric Cohorts of the Rare Vascular Disorder Systemic Capillary Leak Syndrome.

OBJECTIVE: Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole-exome sequencing (WES) may be conducted by critical care providers. DESIGN: Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives. SETTING: Tertiary children's hospitals and referral research laboratory. PATIENTS: Children and adults with SCLS. INTERVENTIONS: None. MEASUREMENTS: Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, biallelic, de novo, and heterozygous variants with allelic enrichment and metabolic pathway analyses. MAIN RESULTS: Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or biallelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants. CONCLUSIONS: The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.

Adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (Clarkson disease).

BACKGROUND: Systemic Capillary Leak Syndrome (SCLS) is an extremely rare and life-threatening vascular disorder of unknown etiology. SCLS is characterized by abrupt and transient episodes of hypotensive shock and edema due to plasma leakage into peripheral tissues. The disorder has garnered attention recently because its initial presentation resembles more common vascular disorders including systemic anaphylaxis, sepsis, and acute infections with the Ebola/Marburg family of filoviruses. Although approximately 70-85% of patients with SCLS have a concurrent monoclonal gammopathy of unknown significance (MGUS), any contribution of the paraprotein to acute flares is unknown. PROCEDURE: To identify circulating factors that might trigger acute SCLS crises, we profiled transcriptomes of paired peripheral blood mononuclear cell fractions obtained from patients during acute attacks and convalescent intervals by microarray. RESULTS: This study uncovered 61 genes that were significantly up- or downregulated more than 2.5-fold in acute samples relative to respective baselines. One of the most upregulated genes was ADM, which encodes the vasoactive peptide adrenomedullin. A stable ADM protein surrogate (pro-ADM) was markedly elevated in SCLS acute sera compared to remission samples or sera from healthy controls. Monocytes and endothelial cells (ECs) from SCLS subjects expressed significantly more ADM in response to proinflammatory stimuli compared to healthy control cells. Application of ADM to ECs elicited protective effects on vascular barrier function, suggesting a feedback protective mechanism in SCLS. CONCLUSIONS: Since ADM has established hypotensive effects, differentiating between these dual actions of ADM is crucial for therapeutic applications aimed at more common diseases associated with increased ADM levels.

Effects of chronic ketamine on hippocampal cross-frequency coupling: implications for schizophrenia pathophysiology.

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross-frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14-day consecutive administration of ketamine (30 mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low-frequency (0-30 Hz) phase and high-frequency (30-115 Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre- and post-injection while the animals performed a foraging task on a four-arm rectangular maze. Permutation analysis of frequency band-specific change in amplitudes revealed between-group differences in theta (6-12 Hz) and slow gamma (25-50 Hz) but not fast gamma (65-100 Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low-frequency phase and high-frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.

Factors associated with using opiates while under extended-release naltrexone blockade: A descriptive pilot study.

BACKGROUND AND AIM: Extended-release naltrexone (XR-NTX) blocks the effects of opioids for 4weeks, yet many patients continue to use them. To learn more about why this occurs, we collected self-reports on subjective effects and drug use factors from participants' most recent heroin/opiate use while under XR-NTX blockade. METHODS: Participants (n=38) were unemployed, heroin-dependent adults enrolled in a randomized controlled trial evaluating employment-based incentives to promote adherence to XR-NTX. A subset of participants (n=18) were asked to complete a survey about their most recent use of heroin/opiates when they provided an opiate-positive urine sample while under XR-NTX blockade. Surveys were administered weekly, and participants could complete multiple surveys throughout the trial. Participants reported how high they were (11-point scale; 0=not at all, 10=extremely), how much heroin/opiates they took (less, more, or about the same as usual before starting naltrexone), whether they used cocaine at the same time, and the routes of administration for heroin/opiates and cocaine (if used). All analyses were descriptive. RESULTS: Of the 107 surveys, 75.7% indicated being "not at all" high the last time heroin/opiates were used. 75.5% of surveys reported opiate amounts that were less than usual, and only 7.5% reported amounts larger than usual. Cocaine was used at the same time as heroin for 57.9% of surveys but typically through a different route (74.2%). DISCUSSION: Using heroin/opiates while under XR-NTX blockade is not strongly associated with self-reports of high, taking larger than normal amounts of opiates, or taking opiates and cocaine simultaneously via the same route. Future research should incorporate measures of naltrexone concentration and more comprehensive and frequent assessments using ecological momentary assessment.

A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis.

BACKGROUND: Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). OBJECTIVE: We sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. METHODS: We prospectively enrolled patients with IA (≥3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after FcεRI aggregation. RESULTS: Clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. CONCLUSION: Patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy.

SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND: Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. METHODS: We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). RESULTS: 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. CONCLUSIONS: This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.

A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript.

PURPOSE: In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma. PATIENTS AND METHODS: Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis. RESULTS: The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS-FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment. CONCLUSIONS: Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS-FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure.