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ZongYao Wang,1 John S Sundy,1 Catherine M Foss,1 Huiman X Barnhart,2 Scott M Palmer,1 Sallie D Allgood,3 Evan Trudeau,1 Katie M Alexander,3 Marc C Levesque31Division of Pulmonary, Allergy and Critical Care Medicine, 2Duke Clinical Research Institute, 3Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USABackground: The CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects.Methods: A total of 291 participants, 18–40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects.Results: We found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans.Conclusion: These results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.Keywords: total serum immunoglobulin E, IgE, skin prick test, SPT, CD14-159T, single nucleotide polymorphism, SNP, lipopolysaccharide, LPS, endotoxin

In 2014, a fire at an open cut coalmine in regional Victoria, Australia burned for 6 weeks. Residents of the nearby town of Morwell were exposed to smoke, which included high levels of fine particulate matter (PM 2.5 ). We investigated whether the long-term effects of PM 2.5 on respiratory health were moderated by diet quality. A cross-sectional analysis was conducted of data collected 8.5 years after the mine fire from 282 residents of Morwell and 166 residents from the nearby unexposed town of Sale. Primary outcomes were respiratory symptoms. Exposure was coalmine fire-related PM 2.5 and diet quality was assessed as Australian Recommended Food Score (ARFS) derived using the Australian Eating Survey (AES). The moderating effect of diet quality on respiratory outcomes associated with PM 2.5 was assessed using logistic regression models, adjusting for potential confounders. Diet quality was poor in this sample, with 60% in the lowest category of overall diet quality. Overall diet quality and fruit and vegetable quality significantly attenuated the association between PM 2.5 and prevalence of chronic cough and phlegm. Sauce/condiment intake was associated with a greater effect of PM 2.5 on COPD prevalence. No other moderating effects were significant. The moderating effects of overall diet quality and vegetable and fruit intake aligned with a priori hypotheses, suggesting potential protective benefits. While more evidence is needed to confirm these findings, improving diets, especially fruit and vegetable intake, may provide some protection against the effects of smoke exposure from fire events., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Thara Govindaraju, Matthew Carroll, Brigitte M. Borg, Catherine L. Smith, Caroline X. Gao, David Brown, David Poland, Shantelle Allgood, Jillian F. Skin, Michael J. Abrasion, Tyler J. Lane reports financial support was provided by Victoria Department of Health. Michael J. Abramson reports a relationship with Pfizer, Boehringer-Ingelheim, Sanofi, GSK that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic, low-intensity air pollution exposure has been consistently associated with increased atherosclerosis in adults. However, there was limited research regarding the implications of acute, high-intensity air pollution exposure during childhood. We aimed to determine whether there were any associations between early-life exposure to such an episode and early-life vascular function changes., Methods: We conducted a prospective cohort study of children (<9 years old) who lived in the vicinity of the Hazelwood coal mine fire (n = 206). Vascular function was measured using noninvasive diagnostic methods including carotid intima-media thickness and pulse wave velocity (PWV). Exposure estimates were calculated from prognostic models and location diaries during the exposure period completed by each participant's parent. Linear mixed-effects models were used to determine whether there were any associations between exposure and changes in vascular outcomes at the 3- and 7-year follow-ups and over time., Results: At the 7-year follow-up, each 10 μg/m 3 increase in daily PM 2.5 in utero was associated with increased PWV ( β = 0.13 m/s; 95% confidence interval [CI] = 0.02, 0.24; P = 0.02). The association between in utero exposure to daily PM 2.5 was not altered by adjustment for covariates, body mass index, and maternal fire stress. Each 1 µg/m 3 increase in background PM 2.5 was associated with increased PWV ( β = 0.68 m/s; 95% CI = 0.10, 1.26; P = 0.025), in children from the in utero exposure group. There was a trend toward smaller PWV ( β = -0.17 m/s; 95% CI = -0.366, 0.02) from the 3- to 7-year follow-up clinic suggesting that the deficits observed previously in children exposed postnatally did not persist., Conclusion: There was a moderate improvement in vascular stiffness of children exposed to PM 2.5 from a local coal mine fire in infancy. There was a mild increase in vascular stiffness in children exposed to PM 2.5 from a local coal mine fire while their mothers were pregnant., Competing Interests: E.J.H., A.B., S.A., A.J.W., M.D., G.J.W., C.X.G., K.N., F.H.J., and G.R.Z. declare that they have no conflicts of interest with regard to the content of this report. M.J.A. reports a relationship with Pfizer Global Research and Development that includes funding grants. M.J.A. reports a relationship with Boehringer Ingelheim GmbH that includes funding grants. M.J.A. reports a relationship with Sanofi Australia that includes consulting or advisory, and funding grants. M.J.A. reports a relationship with GlaxoSmithKline that includes funding grants and speaking and lecture fees., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Background: In 2014, the Hazelwood coalmine fire shrouded the regional Australian town of Morwell in smoke and ash for 6 weeks. One of the fire's by-products, PM 2.5 , is associated with an increased risk of COVID-19 and severe disease. However, it is unclear whether the effect persisted for years after exposure. In this study, we surveyed a cohort established prior to the pandemic to determine whether PM 2.5 from the coalmine fire increased long-term vulnerability to COVID-19 and severe disease., Methods: From August to December 2022, 612 members of the Hazelwood Health Study's adult cohort, established in 2016/17, participated in a follow-up survey that included standardized items to capture COVID-19 cases, as well as questions about hospitalization and vaccinations. Associations were evaluated in crude and adjusted logistic regression models., Results: A total of 268 (44%) participants self-reported or met symptom criteria for having had COVID-19 at least once. All models found a positive association, with odds of COVID-19 increasing by between 4% and 30% for a 10 μg/m 3 increase in coalmine fire-related PM 2.5 exposure. However, the association was significant in only 2 of the 18 models. There were insufficient hospitalizations to examine severity (n = 7; 1%)., Conclusion: The findings are inconclusive on the effect of coalmine fire-related PM 2.5 exposure on long-term vulnerability to COVID-19. Given the positive association that was robust to modelling variations as well as evidence for a causal mechanism, it would be prudent to treat PM 2.5 from fire events as a long-term risk factor until more evidence accumulates., (© 2023 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: An intersectional approach to health research provides an analytical foundation to explain the multidimensionality of health status, resource accessibility, privilege, oppression, and current and historical context. The use of intersectionality in health research has known limitations. Its use in health-related fields too often focuses on outcomes, such as health disparities, rather than processes, such as power structures and social determinants., Objective: This scoping review serves to examine how intersectionality has been implemented by nurses in the peer-reviewed literature. We offer insight into how it may be incorporated to inform future nursing research and healthcare provision., Design & Methods: Systematic searches of PubMed ( n = 257), SCOPUS ( n = 807), EMBASE ( n = 396), CINAHL ( n = 224), and Health Source: Nursing and Academics ( n = 491), published since the seminal publication on intersectionality (1989 - 2023), identified 131 research articles that met inclusion and exclusion criteria. Data extraction and synthesis were used to describe the breadth and depth of the literature specific to the application of intersectionality in nursing research., Results: The included studies used intersectionality to examine the intersections of numerous identities, such as race, gender, and immigration status. However, most studies were descriptive/observational in nature, underreported their methods, and conducted deficit-based research instead of strength-based inquiries. Of note, the vast majority of included articles were published within the last five years., Conclusions: Future researchers using intersectionality as a framework can improve their approach by reporting clear definitions and operationalization of intersectionality. Observational science dominated the included studies; future research should focus on intervention development and evaluation using an intersectional lens. Lastly, caution should be placed on research that focuses solely on deficits among marginalized communities, which places scientists at risk of perpetuating stereotypes or enhancing already-existing stigmas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objectives: Despite decades of communication training, studies repeatedly demonstrate that clinicians fail to elicit patients' agendas. Our goal was to provide clinicians with actionable guidance about the effectiveness of agenda-soliciting questions., Methods: We coded clinician agenda-soliciting questions and patient responses in audio-recorded ambulatory encounters at an urban academic hospital. To evaluate the association between question type and odds of the patient raising a concern, we performed mixed-effects logistic regression., Results: We identified 346 agenda-soliciting questions within 138 visits (mean 2.51/visit; range 0-9). Agenda-soliciting questions were categorized as personal state inquiries (37%, "How are you?"), feeling-focused (5% "How're you feeling?"), problem-focused (12%; "Are you having any problems"), direct solicitations (3%; "Anything you want to discuss today?"), "what else" (3%), "anything else" (14%), leading (16%; "Nothing else today?"), and space-reducing (11% "Anything else? Smoking?"). Patients raised a concern in response to 107 clinician questions (27%). Patients were more likely to raise a concern to direct solicitation (OR 22.95, 95% CI 2.62-200.70) or "what else" (OR 4.68, 95% CI 1.05-20.77) questions., Conclusions: The most effective agenda-soliciting questions are used least frequently by clinicians., Practice Implications: Clinicians should elicit patient agendas by using direct language, and solicit additional concerns using "what else" vs. "anything else" questions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator that has led to large benefits in lung function, pulmonary exacerbation rates, and respiratory symptoms. Less is known about the effect of ETI on non-pulmonary symptoms. The objective of this study was to examine the changes in patient reported outcomes after starting ETI in multiple non-pulmonary symptoms., Methods: This was a prospective cohort study of adults with CF. Participants completed questionnaires prior to starting ETI and then at weeks 2, 4, 6, 8, 10, 12, and 14 after starting ETI. They completed the following validated instruments: PROMIS Pain Intensity, PROMIS Pain Interference, FACIT Fatigue, SNOT22, PAC-SYM, PHQ8, GAD7 and Pittsburgh Sleep Quality Index. Longitudinal changes for outcomes were modelled using linear regression based on general estimating equations., Results: 22 participants enrolled who answered questionnaires before and after starting ETI. The median age was 35.3 years (IQR 11.1) and 13 (59.1%) were male. In models adjusted for age, sex, and baseline value there were significant improvements in pain interference (β = -2.57; 95% CI -4.92, -0.23), sinus symptoms (β = -4.50; 95% CI -7.59, -1.41), and sleep disturbance (β = -1.90; 95% CI -2.71, -1.09) over 14 weeks after starting ETI. No symptom areas worsened over the study period., Conclusions: In this prospective study we found statistically significant improvements in three different non-pulmonary symptom areas in people with CF started on ETI. While this was a small, uncontrolled study it suggests that use of highly effective CFTR modulators can result in benefits for patients beyond pulmonary symptoms., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Dr. Lechtzin has served as a site principal investigator for Vertex Pharmaceuticals clinical trials. Dr. Allgood received research support from the Blaustein Pain Fund., (© 2023 The Authors.)

Due to climate change, catastrophic events such as landscape fires are increasing in frequency and severity. However, relatively little is known about the longer-term mental health outcomes of such events. Follow-up was conducted of 709 adults exposed to smoke from the 2014 Hazelwood mine fire in Morwell, Victoria, Australia. Participants completed two surveys evaluating posttraumatic distress, measured using the Impact of Events Scale-Revised (IES-R), three and six years after the mine fire. Mixed-effects regression models were used to evaluate longitudinal changes in distress. IES-R total scores increased on average by 2.6 points (95%CI: 1.2 to 3.9 points) between the two survey rounds, with increases across all three posttraumatic distress symptom clusters, particularly intrusive symptoms. This increase in distress was evident across all levels of fine particulate matter (PM 2.5 ) exposure to the mine fire smoke. Age was an effect modifier between mine fire PM 2.5 exposure and posttraumatic distress, with younger adults impacted more by exposure to the mine fire. Greater exposure to PM 2.5 from the mine fire was still associated with increased psychological distress some six years later, with the overall level of distress increasing between the two survey rounds. The follow-up survey coincided with the Black Summer bushfire season in south-eastern Australia and exposure to this new smoke event may have triggered distress sensitivities stemming from exposure to the earlier mine fire. Public health responses to disaster events should take into consideration prior exposures and vulnerable groups, particularly younger adults., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: As nurses, we identify our profession as a caring one, but how does this identity translate from a conceptual definition, to real-world practice for the Clinical Research Nurse?, Aim: To offer a novel, four-point conceptual model that encapsulates the Clinical Research Nurse's intrinsic value, active leadership, and direct contribution to high quality, person-centered, safe care, addressing current misperceptions of research nursing., Methods: This paper describes the provision of 'care', safely delivered by the Clinical Research Nurse through a four-point conceptual model and case-driven example., Discussion: Clinical research nursing is conceptualized within the domains of Care and Trust, Role, Impact, and Integration. The case example demonstrates real-world application of these domains and the expertise required to balance the complexities of clinical needs and research demands in a healthcare environment., Conclusions: This paper offers a mechanism for understanding the importance of the Clinical Research Nurse and their role in maintaining safety and a high-level view of the care arena. These reflections are considered with an international application for the role., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Black transgender women are disproportionately affected by violence and poor care-delivery, contributing to poor mental health. Little is known regarding the effect of transgender and gender diverse (TGD) community connection (TCC) on health. This analysis (a) explores relationships between TCC, polyvictimization, and mental health and (b) analyzes how TCC influenced help-seeking following violent experiences among Black transgender women. Mixed-methods data from 19 Black transgender women were analyzed using correlational and thematic content analyses. Findings suggest that TCC is associated with improved help-seeking and mental health among Black transgender women, highlighting a need for longitudinal research to identify approaches for leveraging TCC.

Background: Chronic pain is common among people living with cystic fibrosis (CF) and associated with worse clinical outcomes. Despite this, little is known about how pain is managed and how opioids are used to treat pain. The purpose of this convergent mixed methods study was to examine self-reported satisfaction and effectiveness of pain management strategies among a sample of adults with CF who are prescribed opioids., Methods: We developed an online survey querying 4 domains - demographics, pain characteristics, pain communication, and management strategies. This was distributed nationally to adults with CF (n=48) via various online platforms. We obtained quantitative and qualitative responses regarding satisfaction and effectiveness of pain management. Emerged themes from qualitative data were compared with responses from quantitative survey domains., Results: Participants reported high levels of satisfaction and effectiveness with their opioid pain management plans. However, qualitative themes emerged regarding fears of addiction, experiences of feeling stigmatized by the healthcare system and ineffectiveness and inefficiency of alternative therapies for adequate pain relief., Conclusions: Adults with CF reported opioids as an important component of their current pain management plans despite risks associated with opioid use. CF-specific pain management guideline development is warranted as is further research exploring pain development., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose, (Copyright © 2021. Published by Elsevier B.V.)

Background: Females with cystic fibrosis (CF) have been shown to have worse pulmonary exacerbation (PEx) related outcomes compared to males. However, it is unknown if sex differences in treatment patterns are contributing to these outcomes. Thus, we sought to explore sex differences in treatment patterns in the Standardized Treatment of Pulmonary Exacerbations (STOP) cohort., Methods: Data for 220 participants from the STOP cohort were analyzed. Multivariable regression models were used to assess if female sex was associated with duration of treatment with IV antibiotics and inpatient length of stay. Secondary outcomes included antibiotic selection, adjunctive therapies, mean FEV1pp and CFRSD-CRISS respiratory symptom scores at the four study assessments., Results: In our adjusted model, the average number of IV antibiotic treatment days was 13% higher in females compared to males (IRR 1.13, 95% CI=1.02,1.25; p=0.02). We found no sex differences in inpatient length of stay, number of IV antibiotics, antibiotic selection or initiation of adjunctive therapies. Overall, females had higher CFRSD-CRISS scores at the end of IV therapy indicating worse symptom severity (23.6 for females vs. 18.5 for males, p=0.03)., Conclusions: Despite females having a longer treatment duration, our findings demonstrate that males and females are receiving similar treatments which suggest that the outcome disparities in females with CF may not be due to failure to provide the same level of care. Further research dedicated to sex differences in CF is necessary to understand why clinical outcomes differ between males and females., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Stable epigenetic changes appear uncommon, suggesting that changes typically dissipate or are repaired. Changes that stably alter gene expression across generations presumably require particular conditions that are currently unknown. Here we report that a minimal combination of cis-regulatory sequences can support permanent RNA silencing of a single-copy transgene and its derivatives in C. elegans simply upon mating. Mating disrupts competing RNA-based mechanisms to initiate silencing that can last for >300 generations. This stable silencing requires components of the small RNA pathway and can silence homologous sequences in trans. While animals do not recover from mating-induced silencing, they often recover from and become resistant to trans silencing. Recovery is also observed in most cases when double-stranded RNA is used to silence the same coding sequence in different regulatory contexts that drive germline expression. Therefore, we propose that regulatory features can evolve to oppose permanent and potentially maladaptive responses to transient change., (© 2021. The Author(s).)

Background: The U.S. Centers for Disease Control and Prevention (CDC) develops tools to support implementation of evidence-based interventions for school health. To advance understanding of factors influencing the use of these implementation tools, we conducted an evaluation of state, school district, and local school staffs' use of four CDC tools to support implementation of physical activity, nutrition, health education, and parent engagement. Two frameworks guided the evaluation: Interactive Systems Framework (ISF) for Dissemination and Implementation and Consolidated Framework for Implementation Research (CFIR)., Methods: The evaluation applied a mixed methods, cross-sectional design that included online surveys (n = 69 state staff from 43 states), phone interviews (n = 13 state staff from 6 states), and in-person interviews (n = 90 district and school staff from 8 districts in 5 states). Descriptive analyses were applied to surveys and content analysis to interviews., Results: The survey found that the majority of state staff surveyed was aware of three of the CDC tools but most were knowledgeable and confident in their ability to use only two. These same two tools were the ones for which states were most likely to have provided training and technical assistance in the past year. Interviews provided insight into how tools were used and why use varied, with themes organized within the ISF domain "support strategies" (e.g., training, technical assistance) and four CFIR domains: (1) characteristics of tools, (2) inner setting, (3) outer setting, and (4) individuals. Overall, tools were valued for the credibility of their source (CDC) and evidence strength and quality. Respondents reported that tools were too complex for use by school staff. However, if tools were adaptable and compatible with inner and outer setting factors, state and district staff were willing and able to adapt tools for school use., Conclusions: Implementation tools are essential to supporting broad-scale implementation of evidence-based interventions. This study illustrates how CFIR and ISF might be applied to evaluate factors influencing tools' use and provides recommendations for designing tools to fit within the multi-tiered systems involved in promoting, supporting, and implementing evidence-based interventions in schools. Findings have relevance for the design of implementation tools for use by other multi-tiered systems.

Rationale: Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life., Objectives: The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects., Methods: We conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms., Measurements and Main Results: The primary outcome was the 52-week change in FEV 1 . Secondary outcomes included time to first exacerbation and subsequent exacerbation, quality of life, and change in weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference between study arms in 52-week mean change in FEV 1 slope (mean slope difference, 0.00 L, 95% confidence interval, -0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms., Conclusions: An intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).

The prevalence of fungi in the respiratory tracts of cystic fibrosis (CF) patients has risen. However, fungal surveillance is not routinely performed in most clinical centers in the United States, which may lead to an underestimation of the true prevalence of the problem. We conducted a prospective study comparing the rates of detection for clinically important fungi (CIF), defined as Aspergillus , Scedosporium , and Trichosporon species and Exophiala dermatitidis , in CF sputa using standard bacterial and selective fungal culture media, including Sabouraud dextrose agar with gentamicin (SDA), inhibitory mold agar (IMA), and brain heart infusion (BHI) agar with chloramphenicol and gentamicin. We described the prevalence of these fungi in an adult CF population. A total of 487 CF respiratory samples were collected from 211 unique participants. CIF were detected in 184 (37.8%) samples. Only 26.1% of CIF-positive samples were detected in bacterial culture medium, whereas greater rates of detection for fungi were found in IMA (65.8%; P < 0.001), in SDA (at 30°C, 64.7%; P = 0.005), and in BHI agar (63.0%; P = 0.001). The prevalences of Aspergillus and Scedosporium species were 40.8% and 5.2%, respectively, which are greater than the nationally reported prevalence numbers of 20.4% and 1.9%. Selective fungal culture media and longer incubation periods yielded higher rates of detection for CIF in CF sputum samples compared with that detected in bacterial culture medium, resulting in an underdetection of fungi by bacterial culture alone. The prevalence of fungi in CF may be better estimated by using selective fungal culture media, and this may translate to important clinical decisions., (Copyright © 2017 American Society for Microbiology.)

Although precise numbers are difficult to obtain, the population of patients receiving long-term ventilation has increased over the last 20 years, and includes patients with chronic lung diseases, neuromuscular diseases, spinal cord injury, and children with complex disorders. This article reviews the equipment and logistics involved with ventilation outside of the hospital. Discussed are common locations for long-term ventilation, airway and secretion management, and many of the potential challenges faced by individuals on long-term ventilation., (Published by Elsevier Inc.)

Context: Pain is a common problem in patients with cystic fibrosis (CF) and in adults is associated with lower quality of life and more pulmonary complications. Less is known about the impact of pain in adolescents with CF., Objectives: This study aimed to describe pain in an adolescent CF population and to determine if pain at baseline is associated with lower health-related quality of life (HRQoL) and worse pulmonary outcomes at six-month follow-up., Methods: We administered surveys at baseline and at six months to CF patients aged 12 to 20 years. Analyses included Wilcoxon log-rank tests, Spearman correlations, and linear and logistic regressions., Results: Seventy-three patients (86.9%) completed the baseline questionnaire and 53 patients (63.1%) completed the six-month follow-up questionnaire. Mean age was 15.6 ± 2.5 and mean FEV 1 was 79 ± 26% predicted; 89% of patients reported pain in the three months before the survey, but in most it was short lived and mild to moderate in severity. Abdominal pain was the most common location. Pain was associated with increased pulmonary exacerbations (odds ratios = 1.99 for every one-point increase on a composite pain scale, P = 0.03) and with lower HRQoL., Conclusions: Pain in adolescents with CF is associated with lower HRQoL and more pulmonary exacerbations. Greater efforts are needed to manage pain in this population and to determine if treatment of pain improves other outcomes., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Chronic lymphocytic leukemia (CLL) -like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotype and cytogenetic abnormalities with CLL, from which it is discriminated by a cutoff value of 5 × 10(9)/L circulating clonal B cells. However, the clonal size in MBL is extremely variable and allows discrimination of two distinct entities (high-count [HC] and low-count [LC]-MBL) based on a cutoff value of 0.5 × 10(9)/L clonal B cells. HC-MBL is associated with lymphocytosis and progresses to CLL requiring treatment at a rate of 1.1% per year, whereas LC-MBL is found in the general population only through high-sensitivity techniques and carries limited, if any, risk of progression. We performed an immunogenetic profiling of 333 cases with CLL-like MBL supplemented by detailed comparisons with CLL, focusing especially on CLL Rai stage 0 (CLL-0). LC- and HC-MBL had similar somatic hypermutation status, yet different IGHV gene repertoires and frequencies of B-cell receptor (BcR) stereotypy. In particular, stereotyped BcRs were infrequent in LC-MBL and were often not CLL specific. In contrast, HC-MBL exhibited clear immunogenetic similarities to CLL-0. These findings indicate that LC-MBL may not represent a true preleukemic condition, thus differing from HC-MBL/CLL-0 in which the identification of factors endowing malignant potential is strongly warranted.

Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.

Background: The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+) T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells., Methods and Findings: In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis., Conclusions: Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.

Background: Exhaled breath condensate (EBC) pH and exhaled nitric oxide (FeNO) have been proposed as markers of asthma severity. EBC pH values below 6.5 have been associated with asthma exacerbations. Protonation of airway nitrite occurs at low pH and may contribute to FeNO., Objective: To establish normative EBC pH values and to determine the contribution of EBC pH to FeNO in healthy African Americans., Methods: Two hundred seventy healthy African American subjects without asthma between 18 and 40 years old were evaluated. Subjects had simultaneous measurement of EBC pH, EBC nitrite, nitrate, and FeNO., Results: The median EBC pH was 8.14 (interquartile range, 7.83-8.28). Of subjects, 11.9% had an EBC pH < or = 6.5. In subjects with EBC pH values below 6.5, there was an inverse correlation between EBC pH and FeNO (r(2) = 0.158; P = .0245; n = 32). In the entire cohort, there was a direct correlation between EBC pH and EBC nitrite (r(2) = 0.163; P < .0001), but there was no correlation between EBC nitrite and FeNO. In multivariate analyses, EBC pH and nitrite did not contribute significantly to FeNO variation while controlling for other confounders of FeNO., Conclusion: There was an increased prevalence (11.9%) of low EBC pH (less than 6.5) in healthy African American subjects compared with white subjects (<5%). EBC pH and nitrite were directly correlated, but there was no correlation between EBC nitrite and FeNO. FeNO correlated with EBC pH at pH values less than 6.5 in univariate but not multivariate analyses. This suggests that EBC pH and nitrite are not significant determinants of FeNO in healthy subjects.

Background: Asthma is a significant cause of morbidity and mortality for African Americans. Fraction of exhaled nitric oxide (FeNO) levels are increased in patients with asthma, and airway levels of nitric oxide metabolites regulate airway inflammation and airway diameter. More needs to be known about the factors that regulate FeNO. There is a need for FeNO reference values for African Americans., Objective: We sought to establish reference values and identify factors associated with FeNO levels in healthy African American adults., Methods: FeNO levels were measured in 895 healthy, nonsmoking African Americans between the ages of 18 and 40 years. FeNO measurements were repeated in 84 subjects. Factors potentially associated with FeNO were measured, including blood pressure, height, weight, and serum total IgE, eosinophil cationic protein, C-reactive protein, and nitrate levels. Data on respiratory symptoms, including upper respiratory tract infection (URI) symptoms, were collected. Univariate and multivariate analyses of the relationship between these variables and FeNO levels were performed., Results: In healthy, nonsmoking African Americans FeNO levels were stable during repeated measurements (intraclass correlation coefficient, 0.81). Sex (P < .0001), serum total IgE levels (P < .0001), and current URI symptoms (P = .0002) contributed significantly to FeNO variability but together accounted for less than 50% of the variation in FeNO levels., Conclusion: The high correlation between repeated measurements of FeNO and the low correlation coefficients of known factors associated with FeNO suggest that other factors might contribute substantially to variability of FeNO levels in African Americans.