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Nontuberculous mycobacteria (NTM) are ubiquitous environmental opportunistic pathogens that can cause chronic lung disease. Within the United States, Hawai'i has the highest incidence of NTM lung disease, though the precise reasons are yet to be fully elucidated. One possibility is the high prevalence of NTM in the Hawai'i environment acting as a potential reservoir for opportunistic NTM infections. Through our previous initiatives to collect and characterize NTM in Hawai'i, community scientists of Hawai'i have collected thousands of environmental samples for sequencing. Here, these community scientists were invited for the first time into a high school lab in O'ahu for a genomic sequencing workshop, where participants sequenced four of the collected isolate genomic samples using the Oxford Nanopore Technologies MinION sequencer. Participants generated high quality long read data that when combined with short read Illumina data yielded complete bacterial genomic assemblies suitable for in-depth analysis. The gene annotation analysis identified a suite of genes that might help NTM thrive in the Hawai'i environment. Further, we found evidence of co-occurring methylobacteria, revealed from the sequencing data, suggesting that in some cases methylobacteria and NTM may coexist in the same niche, challenging previously accepted paradigms. The sequencing efforts presented here generated novel insights regarding the potential survival strategies and microbial interactions of NTM in the geographic hot spot of Hawai'i. We highlight the contributions of community scientists and present an activity that can be reimplemented as a workshop or classroom activity by other research groups to engage their local communities. [ABSTRACT FROM AUTHOR]

Objective: Growing evidence suggests increasing frequencies of autoimmunity and autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25‐year span in the US. Methods: Serum ANA were measured by standard indirect immunofluorescence assays on HEp‐2 cells in 13,519 participants age ≥12 years from the National Health and Nutrition Examination Survey, with approximately one‐third from each of 3 time periods: 1988–1991, 1999–2004, and 2011–2012. We used logistic regression adjusted for sex, age, race/ethnicity, and survey design variables to estimate changes in ANA prevalence across the time periods. Results: The prevalence of ANA was 11.0% (95% confidence interval [95% CI] 9.7–12.6%) in 1988–1991, 11.4% (95% CI 10.2–12.8%) in 1999–2004, and 16.1% (95% CI 14.4–18.0%) in 2011–2012 (P for trend <0.0001), corresponding to ~22.3 million, ~26.6 million, and ~41.5 million affected individuals, respectively. Among adolescents age 12–19 years, ANA prevalence increased substantially, with odds ratios of 2.07 (95% CI 1.18–3.64) and 2.77 (95% CI 1.56–4.91) in the second and third time periods relative to the first (P for trend = 0.0004). ANA prevalence increased in both sexes (especially in men), older adults (age ≥50 years), and non‐Hispanic white individuals. These increases in ANA prevalence were not explained by concurrent trends in weight (obesity/overweight), smoking exposure, or alcohol consumption. Conclusion: The prevalence of ANA in the US has increased considerably in recent years. Additional studies to determine factors underlying these increases in ANA prevalence could elucidate causes of autoimmunity and enable the development of preventative measures. [ABSTRACT FROM AUTHOR]

Objective: Growing evidence suggests increasing frequencies of autoimmunity and certain autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25‐year span in the US. Methods: Serum ANA were measured by standard indirect immunofluorescence assays on HEp‐2 cells in 14,211 participants age ≥12 years from the National Health and Nutrition Examination Survey, with approximately one‐third from each of 3 time periods: 1988–1991, 1999–2004, and 2011–2012. We used logistic regression adjusted for sex, age, race/ethnicity, and survey design variables to estimate changes in ANA prevalence across the time periods. Results: The prevalence of ANA was 11.0% (95% confidence interval [95% CI] 9.7–12.6%) in 1988–1991, 11.5% (95% CI 10.3–12.8%) in 1999–2004, and 15.9% (95% CI 14.3–17.6%) in 2011–2012 (P for trend < 0.0001), which corresponds to ~22 million, ~27 million, and ~41 million affected individuals, respectively. Among adolescents age 12–19 years, ANA prevalence increased substantially, with odds ratios (ORs) of 2.02 (95% CI 1.16–3.53) and 2.88 (95% CI 1.64–5.04) in the second and third time periods relative to the first (P for trend < 0.0001). ANA prevalence increased in both sexes (especially in men), older adults (age ≥50 years), and non‐Hispanic whites. These increases in ANA prevalence were not explained by concurrent trends in weight (obesity/overweight), smoking exposure, or alcohol consumption. Conclusion: The prevalence of ANA in the US has increased considerably in recent years. Additional studies to determine factors underlying these increases in ANA prevalence could elucidate causes of autoimmunity and enable the development of preventative measures. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses several articles published within issue on topics including racial perspective for American future, Aryanism in Germany; and communal experiments in America.

Objective: Recent studies suggest antinuclear antibodies (ANA) may be related to mortality risk, but evidence is sparse and inconclusive. Thus, we investigated ANA associations with all-cause and cause-specific mortality in U.S. adults. Methods: Our sample included 3357 adults (ages ≥20 years) from the 1999–2004 National Health and Nutrition Examination Survey with ANA measurements (1:80 dilution) and mortality data through 2011 (median follow-up: 9.4 years). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) via weighted Cox regression to assess ANA associations with mortality from all causes, cardiovascular disease (CVD), and cancer. Models adjusted for age, sex, race/ethnicity, education, and obesity. Analyses examined mortality in the full sample and in subgroups based on self-reported histories of CVD and cancer, both overall and stratified by sex and age at enrollment. Results: Overall, ANA were not strongly associated with death from all causes (HR: 1.13; CI: 0.79, 1.60), from CVD (HR: 1.60; CI: 0.80, 3.20), or from cancer (HR: 1.58; CI: 0.75, 3.33), though all three HR estimates exceeded 1. In the subgroup with a history of cancer, ANA were associated with elevated all-cause mortality in men (HR: 2.28; CI: 1.01, 5.14) and in participants who enrolled at age ≥75 years (HR: 1.99; CI: 1.04, 3.80). Conclusion: These findings suggest that ANA are not strongly associated with mortality in the general population. Longitudinal studies with repeated assessments are needed to understand the temporal relationship between ANA, aging-associated diseases, and mortality. [ABSTRACT FROM AUTHOR]

The authors discuss the rise in nontuberculous mycobacteria (NTM) lung disease in the U.S. They discuss the ways by which natural disasters complicate the recovery process of patients with infectious diseases and the geographic overlap between NTM infections and disaster frequencies in the country. They also call for more environmental studies and NTM infection surveillance before and after natural disasters to minimize the occurrence of NTM infections.

Purpose: Autoantibodies to cytoplasmic structures called rods and rings (RR) are primarily specific to patients with hepatitis C virus (HCV) infection treated with pegylated interferon-alpha/ribavirin (IFN/R). Our aim is to examine anti-RR antibodies specificity and correlation with the response to IFN/R therapy in two independent cohorts (US and Italy) of HCV patients. Methods: Sera from the US cohort ( n = 47) and the Italian cohort ( n = 46) pre-selected for anti-RR antibodies were analyzed by immunofluorescence and radioimmunoprecipitation. The prevalence and titers of anti-RR were analyzed for correlation with the response to IFN/R therapy. Results: In the US cohort, anti-RR antibodies were more frequently non-responders to IFN/R (71 % vs 29 % responders). Titers in responder patients ( n = 11) were ≤1:3200, whereas titers in non-responder patients ( n = 27) reached 1:819,200 ( p = 0.0016). In the Italian cohort, anti-RR titers ranged from 1:200 to >1:819,200 and only relapsers had the highest anti-RR titers. Radioimmunoprecipitation demonstrated that anti-RR autoantibodies were mainly anti-inosine monophosphate dehydrogenase 2 (IMPDH2) - 96 % in the Italian cohort vs. 53 % in the US cohort. Conclusions: In the two cohorts analyzed, the anti-IMPDH2 response as a component of the anti-RR response is much more prominent in the Italian cohort. The reason for the difference between the US and Italian cohorts is unclear but it possibly illustrates the heterogeneity in response and the overall negative correlation between the production of these autoantibodies and response to IFN/R therapy. Patients with high titer anti-RR antibodies are either relapsers (Italian) or non-responders/relapsers (US). [ABSTRACT FROM AUTHOR]

Objective To estimate the prevalence, types, and sociodemographic and biobehavioral correlates of antinuclear antibodies (ANAs) in the US. Methods We conducted a cross-sectional analysis of 4,754 individuals from the National Health and Nutrition Examination Survey 1999-2004. ANAs were assessed by indirect immunofluorescence. In ANA-positive individuals, cellular staining patterns were determined, and specific autoantibody reactivities were assessed by immunoprecipitation. Results The ANA prevalence in the US population of individuals ages 12 years and older was 13.8% (95% confidence interval [95% CI] 12.2-15.5%). ANA prevalence increased with age ( P = 0.01), and ANAs were more prevalent among females than males (17.8% versus 9.6%; P < 0.001), with the female-to-male ratio peaking at 40-49 years of age. ANA prevalence was modestly higher in African Americans compared with whites (age-adjusted prevalence odds ratio [POR] 1.30, 95% CI 1.00-1.70). Remarkably, ANAs were less common in overweight and obese individuals (age-adjusted POR 0.74) than in persons of normal weight. No significant associations of ANA with education, family income, alcohol use, smoking history, serum levels of cotinine, or C-reactive protein were observed. In ANA-positive individuals, nuclear patterns were seen in 84.6%, cytoplasmic patterns were seen in 21.8%, and nucleolar patterns were seen in 6.1%; the most common specific autoantibodies were anti-Ro (3.9%) and anti-Su (2.4%). Conclusion These findings suggest that more than 32 million persons in the US have ANAs, and that the prevalence is higher among females, older individuals, African Americans, and those with a normal body weight. These data will serve as a useful baseline for future investigations of predictors and changes in ANA prevalence over time. [ABSTRACT FROM AUTHOR]

Abstract: The Autoantibody Standardization Committee was established in the early 1980s based on the recognized needs for reference human autoimmune sera that were critical for academic, clinical, and industrial laboratories. To date, 14 reference reagents are available without charge from the Biological Reference Reagents distribution center at the Centers for Disease Control and Prevention. A web site has been developed under “AutoAbSC.Org” to communicate to the wider stakeholder community and to facilitate ongoing activities in continuing the mission in autoantibody standardization. [Copyright &y& Elsevier]

The purpose of this study was to investigate the relationship between alcohol dependence and health-related quality of life (HRQoL) in people with and without other selected psychiatric disorders. A sample of 127,308 Veterans Health Administration enrollees completed a survey that included questions about alcohol use and the Veterans SF-36, a well-validated measure of HRQoL. In addition, a Veterans Administration database was used to obtain respondents' past-year history of alcohol dependence and other psychiatric disorders. Comorbid psychiatric disorders significantly moderated or attenuated the relationship between alcohol dependence and HRQoL. Respondents with a history of alcohol dependence plus one or more other psychiatric disorders had significantly lower HRQoL in domains pertaining to psychological and social functioning than respondents with alcohol dependence only. Effect size differences (mean differences of clinical groups/pooled standard deviation) were large (greater than 0.80 of one standard deviation). Respondents with a history of alcohol dependence only vs. no history of alcohol dependence had poorer HRQoL. Effect size differences were small to moderate (between 0.20 and 0.50 of one standard deviation). Findings highlight the important moderating influence of comorbid psychiatric disorders in the relationship between alcohol dependence and HRQoL. As comorbid psychiatric disorders are often associated with poorer treatment outcome, findings also provide strong corroboration for the importance of treating other psychiatric disorders concurrently with alcohol dependence. [ABSTRACT FROM AUTHOR]

The prevalence of autoimmunity in the U.S. has increased recently for undetermined reasons. Little is known about associations between autoimmunity and environmental causes. In a large representative sample of the U.S. population, we expanded our prior exploratory study of how exposures to selected xenobiotics and dioxin-like (DL) mixtures relate to antinuclear antibodies (ANA), the most common biomarker of autoimmunity. We analyzed cross-sectional data on 12,058 participants aged ≥ 12 years from three time periods of the National Health and Nutrition Examination Survey between 1988 and 2012, of whom 14% were ANA-positive. We used lognormal regression models and censored-data methods to estimate ANA associations with xenobiotic concentrations overall and in sex, age, and race/ethnicity subgroups. Our analyses adjusted for potential confounders and appropriately handled concentrations below detection limits. Observed ANA associations were positive for most DL compounds and nonDL polychlorinated biphenyls (PCBs), negative for most phthalates, and mixed for other xenobiotic classes. After correcting for multiple comparisons, some associations remained statistically significant. In subgroup analyses, the most significant finding was a positive ANA association with N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (MHB2) in males, followed by positive associations with 2,2′,3,5′-tetrachlorobiphenyl (PCB 44), 2,2′,4,5′-tetrachlorobiphenyl (PCB 49), and 2,2′,3,4′,5′,6-hexachlorobiphenyl (PCB 149) in 12–19 year-olds, and with 3,4,4′,5-tetrachlorobiphenyl (PCB 81), 2,2′,3,3′,4,4′,5,5′,6-nonachlorobiphenyl (PCB 206), and N-acetyl-S-(phenyl)-L-cysteine (PMA) in Mexican Americans. Negative associations were found with mono-benzyl phthalate (MBzP) in 20–49 year-olds and mono-n-butyl phthalate (MnBP) in 12–19 year-olds. In overall analyses, combining stratum-specific results across race/ethnicity strata revealed a positive ANA association with PCB 81 and a negative ANA association with N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA). This study identified potential associations between ANA and various xenobiotics. Further investigation to confirm these observations and elucidate effects of certain xenobiotics on immune regulation could have important mechanistic, preventive, and treatment implications for a variety of immune-mediated disorders. [ABSTRACT FROM AUTHOR]

Objective: Recent studies report high-titer anti-dense fine speckled 70 (DFS70) autoantibodies in persons with inflammatory conditions, but the clinical significance remains unclear. Our goals were to estimate anti-DFS70 autoantibody prevalence, identify correlates, and assess time trends., Methods: Serum antinuclear antibodies (ANA) were measured by indirect immunofluorescence assay on HEp-2 cells in 13,519 participants ≥12 years old from three time periods (1988-1991, 1999-2004, 2011-2012) of the National Health and Nutrition Examination Survey. ANA-positive participants with dense fine speckled staining were evaluated for anti-DFS70 antibodies by enzyme-linked immunosorbent assay. We used logistic models adjusted for survey-design variables to estimate period-specific anti-DFS70 antibody prevalence in the US, and we further adjusted for sex, age, and race/ethnicity to identify correlates and assess time trends., Results: Women were more likely than men (odds ratio (OR)=2.97), black persons were less likely than white persons (OR=0.60), and active smokers were less likely than nonsmokers (OR=0.28) to have anti-DFS70 antibodies. The prevalence of anti-DFS70 antibodies increased from 1.6% in 1988-1991 to 2.5% in 1999-2004 to 4.0% in 2011-2012, which corresponds to 3.2 million, 5.8 million, and 10.4 million seropositive individuals, respectively. This increasing time trend in the US population (P<0.0001) was modified in some subgroups and was not explained by concurrent changes in tobacco smoke exposure. Some, but not all, anti-DFS70 antibody correlates and time trends resembled those reported for total ANA., Conclusion: More research is needed to elucidate anti-DFS70 antibody triggers, their pathologic or potentially protective influences on disease, and their possible clinical implications., Competing Interests: Authors GD and CC were employed by the company Social and Scientific Systems, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dinse, Zheng, Co, Parks, Weinberg, Miller and Chan.)

Nontuberculous mycobacteria (NTM) are opportunistic pathogens that cause chronic pulmonary disease (PD). NTM infections are thought to be acquired from the environment; however, the basal environmental factors that drive and sustain NTM prevalence are not well understood. The highest prevalence of NTM PD cases in the United States is reported from Hawai'i, which is unique in its climate and soil composition, providing an opportunity to investigate the environmental drivers of NTM prevalence. We used microbiological sampling and spatial logistic regression complemented with fine-scale soil mineralogy to model the probability of NTM presence across the natural landscape of Hawai'i. Over 7 years, we collected and microbiologically cultured 771 samples from 422 geographic sites in natural areas across the Hawaiian Islands for the presence of NTM. NTM were detected in 210 of these samples (27%), with Mycobacterium abscessus being the most frequently isolated species. The probability of NTM presence was highest in expansive soils (those that swell with water) with a high water balance (>1-m difference between rainfall and evapotranspiration) and rich in Fe-oxides/hydroxides. We observed a positive association between NTM presence and iron in wet soils, supporting past studies, but no such association in dry soils. High soil-water balance may facilitate underground movement of NTM into the aquifer system, potentially compounded by expansive capabilities allowing crack formation under drought conditions, representing further possible avenues for aquifer infiltration. These results suggest both precipitation and soil properties are mechanisms by which surface NTM may reach the human water supply. IMPORTANCE Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, being found commonly in soils and natural bodies of freshwater. However, little is known about the environmental niches of NTM and how they relate to NTM prevalence in homes and other human-dominated areas. To characterize NTM environmental associations, we collected and cultured 771 samples from 422 geographic sites in natural areas across Hawai'i, the U.S. state with the highest prevalence of NTM pulmonary disease. We show that the environmental niches of NTM are most associated with highly expansive, moist soils containing high levels of iron oxides/hydroxides. Understanding the factors associated with NTM presence in the natural environment will be crucial for identifying potential mechanisms and risk factors associated with NTM infiltration into water supplies, which are ultimately piped into homes where most exposure risk is thought to occur.

Background: Physical activity and exercise improve function, symptom control, and health-related quality of life (QoL) for many cancer survivors; however, the evidence is limited and inconsistent in lung cancer. We examined the relationship between leisure-time physical activity (LTPA) and health-related QoL in a national sample of US lung cancer survivors., Methods: We conducted a cross-sectional study using the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System. We defined LTPA as a self-report of engaging in any physical activity or exercise such as running, calisthenics, golf, gardening, or walking for exercise in the past 30 days, health-related QoL as the number of days of having poor physical or mental health in the past 30 days, and general health status. We analyzed using multivariable logistic regressions with 95% confidence intervals (CIs)., Results: Among 614 lung cancer survivors, 316 (51.5%) reported engaging in LTPA. The counts (and proportions) of participants who engaged in LTPA vs no LTPA were, respectively, 135 (42.7%) vs 63 (21.1%) for 0 days of poor physical health, 222 (70.3%) vs 174 (58.4%) for 0 days of poor mental health, and 158 (50.0%) vs 77 (25.8%) for good to excellent general health. In multivariable analyses, participating in LTPA was associated with odds ratios of 2.64 (95% CI = 1.76 to 3.96) and 1.43 (95% CI = 0.97 to 2.10) for 0 days of poor physical and mental health, respectively, and 2.61 (95% CI = 1.74 to 3.91) for good to excellent general health., Conclusions: Participating in LTPA was associated with improved health-related QoL. Interventions to promote LTPA and/or exercise-based rehabilitation may improve QoL among lung cancer survivors., (Published by Oxford University Press 2021.)

Background: The prevalence of nontuberculous mycobacterial lung disease (NTMLD) in the US has increased; however, data characterizing the associated healthcare utilization and expenditure at the national level are limited. Objective: To examine associations between economic outcomes and the use of anti- Mycobacterium avium complex (MAC) guidelines-based treatment (GBT) for newly-diagnosed NTMLD in a US national managed care claims database (Optum ® Clinformatics ® Data Mart). Methods: NTMLD was defined as having ≥2 claims for NTMLD (ICD-9 031.0; ICD-10 A31.0) on separate occasions ≥30 days apart (between 2007 and 2016). The cohort included patients insured continuously over a period of at least 36 months (12 months before initial NTMLD diagnostic claim and for the subsequent 24 months). Treatment was classified as GBT (consistent with American Thoracic Society/Infectious Diseases Society of America guidelines), non-GBT, or untreated. All-cause hospitalization rates and total healthcare expenditures at Year 2 were assessed as outcomes of the treatment prescribed in Year 1 after NTMLD diagnosis. Results: A total of 1,039 patients met study criteria for NTMLD (GBT, n  = 294; non-GBT, n  = 298; untreated, n  = 447). After adjustment for baseline characteristics, GBT was associated with a significantly lower all-cause hospitalization risk vs non-GBT (odds ratio [OR] = 0.53; 95% CI = 0.33-0.85, p  = 0.008), and vs being untreated (OR = 0.57; 95% CI = 0.35-0.91, p  = 0.020). Adjusted total healthcare expenditure in Year 2 with GBT ($69,691) was lower than that with non-GBT ($77,624) with a difference of -$7,933 (95% CI = -$14,968 to -$899; p  = 0.03). Conclusions: Patients with NTMLD in a US managed care claims database who were prescribed GBT had lower hospitalization risk than those who were prescribed non-GBT or were untreated. GBT was associated with lower total healthcare expenditure compared with non-GBT.

Bacteria within the genus Mycobacterium can be abundant in showerheads, and the inhalation of aerosolized mycobacteria while showering has been implicated as a mode of transmission in nontuberculous mycobacterial (NTM) lung infections. Despite their importance, the diversity, distributions, and environmental predictors of showerhead-associated mycobacteria remain largely unresolved. To address these knowledge gaps, we worked with citizen scientists to collect showerhead biofilm samples and associated water chemistry data from 656 households located across the United States and Europe. Our cultivation-independent analyses revealed that the genus Mycobacterium was consistently the most abundant genus of bacteria detected in residential showerheads, and yet mycobacterial diversity and abundances were highly variable. Mycobacteria were far more abundant, on average, in showerheads receiving municipal water than in those receiving well water and in U.S. households than in European households, patterns that are likely driven by differences in the use of chlorine disinfectants. Moreover, we found that water source, water chemistry, and household location also influenced the prevalence of specific mycobacterial lineages detected in showerheads. We identified geographic regions within the United States where showerheads have particularly high abundances of potentially pathogenic lineages of mycobacteria, and these "hot spots" generally overlapped those regions where NTM lung disease is most prevalent. Together, these results emphasize the public health relevance of mycobacteria in showerhead biofilms. They further demonstrate that mycobacterial distributions in showerhead biofilms are often predictable from household location and water chemistry, knowledge that advances our understanding of NTM transmission dynamics and the development of strategies to reduce exposures to these emerging pathogens. IMPORTANCE Bacteria thrive in showerheads and throughout household water distribution systems. While most of these bacteria are innocuous, some are potential pathogens, including members of the genus Mycobacterium that can cause nontuberculous mycobacterial (NTM) lung infection, an increasing threat to public health. We found that showerheads in households across the United States and Europe often harbor abundant mycobacterial communities that vary in composition depending on geographic location, water chemistry, and water source, with households receiving water treated with chlorine disinfectants having particularly high abundances of certain mycobacteria. The regions in the United States where NTM lung infections are most common were the same regions where pathogenic mycobacteria were most prevalent in showerheads, highlighting the important role of showerheads in the transmission of NTM infections., (Copyright © 2018 Gebert et al.)

Background: Clinical reports link specific medications with the development of antinuclear antibodies (ANA), but population-based evidence is limited., Objective: The present study investigated associations between prescription medication use and ANA in a representative sample of the adult noninstitutionalized US population, first focusing on medications previously related to ANA and then considering all medications reported in the National Health and Nutrition Examination Survey (NHANES)., Methods: Based on NHANES data (1999-2004) for 3608 adults (ages ≥18 years), we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess associations between recent medication use and ANA (overall and in sex and age subgroups), adjusted for potential confounders and the survey sampling design., Results: We found no evidence that most medications previously associated with ANA in specific individuals were risk factors for ANA in the general population, although statistical power was limited for some medications. Overall, ANA were less prevalent in adults who recently used any prescription medications compared with those who did not (OR = 0.73; CI = 0.57,0.93), and likewise several classes of medications were inversely associated with ANA, including hormones (OR = 0.73; CI = 0.55,0.98), thiazide diuretics (OR = 0.43; CI = 0.24,0.79), sulfonylureas (OR = 0.41; CI = 0.19,0.89), and selective serotonin reuptake inhibitor antidepressants (OR = 0.65; CI = 0.42,0.98). Positive associations with ANA were seen for loop diuretics (OR = 1.72; CI = 1.03,2.88) in all adults, and for benzodiazepines (OR = 2.11; CI = 1.09,4.10) and bronchodilators (OR = 1.83; CI = 1.00,3.38) in older (ages ≥60) adults. Estrogens were positively associated with ANA in older women (OR = 1.80; CI = 1.00,3.23) but inversely associated with ANA in younger (ages 18-59) women (OR = 0.43; CI = 0.20,0.93). Regarding individual medications, ANA were positively associated with ciprofloxacin (OR = 4.23; CI = 1.21,14.8), furosemide (OR = 1.79; CI = 1.09,2.93), and omeprazole (OR = 2.05; CI = 1.03,4.10) in all adults, and with salmeterol (OR = 3.76; CI = 1.66,8.52), tolterodine (OR = 6.64; CI = 1.45,30.5), and triamterene (OR = 3.10; CI = 1.08,8.88) in older adults. Also, in younger adults, hydrochlorothiazide was inversely associated with ANA (OR = 0.44; CI = 0.20,0.98)., Conclusions: Our findings in the general population do not confirm most clinically reported positive associations between specific medications and ANA in some individuals. However, novel positive ANA associations with other medications, as well as unexplained inverse associations with certain classes of medications and overall medication use, deserve further research to clarify the possible roles of medications as risk and protective factors in the development of autoantibodies and autoimmune disease., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Notch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009., Methods: Dose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity., Results: Thirty-five patients received LY900009 at dose levels ranging from 2-60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1-4 h post-dose. LY900009 inhibited plasma levels of amyloid-β peptide in a dose-dependent manner with 80-90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway., Conclusions: The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Autoantibodies are of growing interest in cancer research as potential biomarkers; yet, the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population and are more prevalent in women and older adults. Here, we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women., Methods: We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 years and older from the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence ORs (POR) and 95% confidence intervals (CI) were adjusted for age, race, and poverty-income ratio, and models were stratified by menopause status., Results: In premenopausal women ages 20 years and older, ANA prevalence was associated with parity (P < 0.001; parous vs. nulliparous POR = 2.0; 95% CI, 1.2-3.4), but in parous women, ANA did not vary by number of births, age at first birth, years since last birth, or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (P = 0.019; age 16-20 vs. 10-12 years POR = 3.0; 95% CI, 1.6-5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence., Conclusions: Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women., Impact: These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women., (©2014 American Association for Cancer Research.)

Emergency managers are often charged with prioritizing the relative importance of key issues and tasks associated with disaster response. However, little work has been done to identify specific ways that the decision-making process can be improved. This exercise was conducted with 220 employees of the US Department of Veterans Affairs, who were asked to assign priority rankings to a list of possible options of the most important issues to address after a hypothetical disaster scenario impacting a Veterans Affairs Medical Center. We found that groups that were assigned to represent perspectives farther from the impacted site had less agreement in their identification of the top priorities than those assigned to the impacted facility. These findings suggest that greater geographic and administrative proximity to the impacted site may generate greater clarity and certainty about priority setting. Given the complex structure of many organizations, and the multiple levels of group decision making and coordination likely to be needed during disasters, research to better understand training needs with respect to decision making is essential to improve preparedness. Relatively simple modifications to exercises, as outlined here, could provide valuable information to better understand emergency management decision making across multiple organizational levels.

Lung disease due to Mycobacterium avium complex (MAC) organisms is increasing. A greater understanding of the host immune response to MAC organisms will provide a foundation to develop novel therapies for these recalcitrant infections. IL-32 is a newly described pro-inflammatory cytokine that enhances host immunity against various microbial pathogens. Cytokines that induce IL-32 such as interferon-gamma, IL-18, IL-12 and tumor necrosis factor-alpha are of considerable importance to mycobacterial immunity. We performed immunohistochemistry and morphometric analysis to quantify IL-32 expression in the lungs of 11 patients with MAC lung disease and 10 controls with normal lung tissues. After normalizing for basement membrane length, there was a profound increase in IL-32 expression in the airway epithelial cells of the MAC-infected lungs compared with controls. Following normalization for alveolar surface area, there was a trend toward increased IL-32 expression in type II alveolar cells and alveolar macrophages in the lungs of MAC patients. Human airway epithelial cells (BEAS-2B) infected with M. avium produced IL-32 by a nuclear factor-kappa B-dependent mechanism. In both BEAS-2B cells and human monocyte-derived macrophages, exogenous IL-32γ significantly reduced the growth of intracellular M. avium. This finding was corroborated by an increase in the number of intracellular M. avium recovered from THP-1 monocytes silenced for endogenous IL-32 expression. The anti-mycobacterial effect of IL-32 may be due, in part, to increased apoptosis of infected cells. These findings indicate that IL-32 facilitates host defense against MAC organisms but may also contribute to the airway inflammation associated with MAC pulmonary disease.

The lack of frequent real-world opportunities to study preparedness for large-scale public health emergencies has hindered the development of an evidence base to support best practices, performance measures, standards, and other tools needed to assess and improve the nation's multibillion dollar investment in public health preparedness. In this article, we argue that initial funding priorities for public health systems research on preparedness should focus on using engineering-style methods to identify core preparedness processes, developing novel data sources and measures based on smaller-scale proxy events, and developing performance improvement approaches to support the translation of research into practice within the wide variety of public health systems found in the nation.

Purpose and Experimental Design: Cancer sera contain antibodies which react with a unique group of autologous cellular antigens called tumor-associated antigens (TAAs), but the low frequency of positive reactions against any individual antigen has precluded use of autoantibodies as useful diagnostic markers. With enzyme immunoassay, we examined antibody frequencies to a panel of seven TAAs, c-myc, cyclin B1, IMP1, Koc, p53, p62, and survivin, in 527 cancer patients (64 breast cancer patients, 45 colorectal cancers, 91 gastric cancers, 65 hepatocellular carcinomas, 56 lung cancers, and 206 prostate cancers), and 346 normals. We used recursive partitioning to assess whether we could accurately classify individuals as either cancer patients or normals on the basis of the profile of antibody reactivity to the seven TAAs for each individual., Results: Recursive partitioning resulted in the selection of subsets of the seven-panel TAA, which differentiated between tumors and controls, and these subsets were unique to each cancer cohort. The classification trees had sensitivities ranging from 0.77 to 0.92 and specificities ranging from 0.85 to 0.91 in the cancer cohorts when normal means +2 SDs were used as standard cutoffs for immunoassay positivity. Antibody to cyclin B1 was the initial discriminating node for gastric and lung cancers, and for hepatocellular carcinoma, and was a subsequent discriminating node in all of the other cancer cohorts. c-myc was the initial discriminating node in breast cancer, p62 in prostate cancer, and IMP1 in colon cancer. Recursive partitioning demonstrated that no more than three of the seven TAAs were needed for any cancer cohort to arrive at these levels of sensitivity and specificity., Conclusions: This initial study shows that multiple antigen miniarrays can provide accurate and valuable tools for cancer detection and diagnosis. Performance of the miniarrays might be enhanced by other combinations of TAAs appropriately selected for different cancer cohorts.

Cancer sera contain antibodies which react with a unique group of autologous cellular antigens called tumor-associated antigens (TAAs). This study determines whether a mini-array of multiple TAAs would enhance antibody detection and be a useful approach to cancer detection and diagnosis. The mini-array of TAAs comprised full-length recombinant proteins expressed from cDNAs encoding c-myc, p53, cyclin B1, p62, Koc, IMP1, and survivin. Enzyme immunoassay was used to detect antibodies in 527 sera from six different types of cancer. Antibody frequency to any individual TAA was variable but rarely exceeded 15-20%. With the successive addition of TAAs to a final total of seven antigens, there was a stepwise increase of positive antibody reactions up to a range of 44-68%. Breast, lung, and prostate cancer patients showed separate and distinct profiles of reactivity, suggesting that uniquely constituted antigen mini-arrays might be developed to distinguish between some types of cancer. Distinct antibody profiles were not observed in gastric, colorectal, and hepatocellular carcinomas with this set of seven TAAs. Detection of autoantibodies in cancer can be enhanced by using a mini-array of several TAAs as target antigens. Additional studies in early cancer patients and high-risk individuals and the design of unique antigen panels for different cancers would help to determine whether multiple antigen mini-arrays for the detection of autoantibodies might contribute a clinically useful noninvasive approach to cancer detection and diagnosis.