Airway Hyperresponsiveness To Mannitol As A Theragnostic Marker Of Response To Daily Treatment With Inhaled Corticosteroids

Airway inflammation and airway hyperresponsiveness (AHR) are the key pathophysiological features of asthma. AHR measured using an indirect stimulus such as mannitol, reflects the presence of airway inflammation, disease severity and activity, and may be a useful marker of response to daily treatment with inhaled corticosteroids (ICS). This thesis explores the utility of the mannitol bronchial provocation test (BPT) as a theragnostic marker of ICS treatment in asthma. All studies were performed on clinical patients that attended a pulmonary function laboratory (PFL) and had AHR to mannitol. The first study was a retrospective analysis in a large cohort of military and police recruits. We investigated responsiveness to mannitol in recruits that had a positive BPT and repeated the test after using daily treatment with ICS for 4 months. AHR persisted in only a small proportion of recruits. Lung function parameters and other clinical features in these recruits were assessed to determine what characteristics predicted persistent AHR. The second study was a prospective pilot randomised parallel group trial of two forms of monitoring facilitated by the PFL. We recruited asthmatics referred to the PFL for assessment, who had AHR to mannitol and symptoms indicating their asthma was not well-controlled, and who subsequently commenced daily treatment with ICS. The mannitol group attended the PFL for serial monitoring of AHR to mannitol. The comparator group had spirometry measured, in accordance with asthma management guidelines, which recommend the inclusion of an objective marker such as spirometry to complement symptoms in monitoring asthma. Along with feedback of each marker, the goal of either resolving AHR or improving spirometry was reinforced at each visit and the importance of ongoing adherence to therapy to achieve this goal. We aimed to determine if serial monitoring and providing feedback of AHR to mannitol improved asthma control when compared to using spirometry and symptoms alone. The third study using the same dataset of the second study explored the time-course of improvement in objective and subjective markers of asthma with the introduction of ICS. Symptoms and spirometry results improve rapidly with the introduction of ICS therapy. However, there are few data regarding the time-course of improvements that occur in AHR to mannitol over the initial months of daily treatment with ICS. We assessed the change in symptoms, spirometry, fraction of exhaled nitric oxide (FeNO) and AHR to mannitol over an 18-week period, following daily ICS therapy. This thesis found; with 4-5 months of daily treatment with ICS, AHR to mannitol is attenuated and can be resolved. More severe AHR and lower spirometry before starting daily therapy increases the likelihood of persistent AHR. Feedback and goal setting using response to mannitol appear to result in greater improvement in AHR, in those with moderate to severe AHR prior to treatment compared to using symptoms and spirometry alone. AHR to mannitol takes longer to improve compared to symptoms, spirometry, and exhaled nitric oxide

The Precarious State of Family Balance Sheets

This report seeks to develop a clear picture of the current state of household financial security. It begins by exploring three components of family balance sheets -- income, expenditures, and wealth -- and how they have changed over the past several decades, and concludes with an examination of how these pieces interrelate and why understanding family finances requires that they be examined holistically. The data tell a powerful story about the state of household economic security and opportunity: Despite the national recovery, most families feel vulnerable and stressed, and could not withstand a serious financial emergency. This reality must begin to change if the American Dream is to remain alive and well for future generations

Neighborhood Poverty and Household Financial Security

In a previous study, The Pew Charitable Trusts examined the effects of neighborhood context on American families' economic mobility. That analysis found that neighborhood poverty is associated with downward mobility, reinforcing other research that has shown a link between high-poverty neighborhoods and unemployment, poorer performing schools, and increased violence, all of which pose risks to residents' economic security.This chartbook draws on data from the Survey of American Family Finances, commissioned by Pew in November 2014, to illustrate the health of family balance sheets in high- and low-poverty communities across the United States and to examine how neighborhood context influences people's attitudes toward the economy

Coupled spin-lattice fluctuations in a compound with orbital degrees of freedom: the Cr based dimer system Sr3Cr2O8

We report on an extended fluctuation regime in the spin dimer system Sr3Cr2O8 based on anomalies in Raman active phonons and magnetic scattering. The compound has two characteristic temperatures, TS = 275 K, related to a Jahn-Teller transition with structural distortions and orbital ordering and a second, T*= 150 K, which is due to further changes in the orbital sector. Below TS quasielastic scattering marks strong fluctuations and in addition phonon anomalies are observed. For temperatures below T* we observe an exponential decrease of one phonon linewidth and determine a gap of the orbital excitations. At low temperatures the observation of two- and three-magnon scattering allows the determination of the spin excitation gap.Comment: 7 pages, 4 figures, 1 tabl

Urinary eicosanoid metabolites in HIV-infected women with central obesity switching to raltegravir: an analysis from the women, integrase, and fat accumulation trial.

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m(2) completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus -0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥ 50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study

The Complex Story of American Debt

This report explores a key element of wealth: household debt. Debt is sometimes acquired for mobility-enhancing purposes, such as to pay for college or purchase a home. But debt can also serve as a stopgap for families to cover regular expenses or deal with financial emergencies, especially if their savings are not sufficient. The type and amount of debt that households carry contribute to their wealth and their overall financial health

Recommendations for dealing with waste contaminated with Ebola virus: a Hazard Analysis of Critical Control Points approach

Objective To assess, within communities experiencing Ebola virus outbreaks, the risks associated with the disposal of human waste and to generate recommendations for mitigating such risks. Methods A team with expertise in the Hazard Analysis of Critical Control Points framework identified waste products from the care of individuals with Ebola virus disease and constructed, tested and confirmed flow diagrams showing the creation of such products. After listing potential hazards associated with each step in each flow diagram, the team conducted a hazard analysis, determined critical control points and made recommendations to mitigate the transmission risks at each control point. Findings The collection, transportation, cleaning and shared use of blood-soiled fomites and the shared use of latrines contaminated with blood or bloodied faeces appeared to be associated with particularly high levels of risk of Ebola virus transmission. More moderate levels of risk were associated with the collection and transportation of material contaminated with bodily fluids other than blood, shared use of latrines soiled with such fluids, the cleaning and shared use of fomites soiled with such fluids, and the contamination of the environment during the collection and transportation of blood-contaminated waste. Conclusion The risk of the waste-related transmission of Ebola virus could be reduced by the use of full personal protective equipment, appropriate hand hygiene and an appropriate disinfectant after careful cleaning. Use of the Hazard Analysis of Critical Control Points framework could facilitate rapid responses to outbreaks of emerging infectious disease

Urinary Eicosanoid Metabolites in HIV-Infected Women with Central Obesity Switching to Raltegravir: An Analysis from the Women, Integrase, and Fat Accumulation Trial

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m2 completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus −0.02; P=0.06). Baseline PGI-M was lower in the RAL arm (P=0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho=0.45; P=0.04) and TxB2 (rho=0.44; P=0.005) changes, with a trend seen for PGE-M (rho=0.41; P=0.07). In an adjusted model, age ≥ 50 years (N=8) was associated with increased PGE-M (P=0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study

Daily Factors Driving Daily Substance Use and Chronic Pain Among Older Adults with HIV: A Study Using Ecological Momentary Assessment

Background: Adults 50 and older make up approximately 50% of persons living with HIV. Multiple co-morbidities are common among this group, including chronic pain and substance abuse, yet little is known about the daily factors that either enhance or inhibit these experiences or behaviors. This study explored daily drivers of substance use, pain, and relief from pain among older adults living with HIV utilizing ecological momentary assessment (EMA). Method: Participants (N=55), ages 49–71, completed seven consecutive days of daily EMA online surveys prior to treatment initiation within a randomized controlled trial. Multilevel modeling tested predictors of pain, substance use, and relief from pain by examining within- and between-person relationships. Results: Results revealed an associational, reciprocal relationship between daily worst pain and daily drinking, where greater worst pain ratings predicted heavier drinking and heavier drinking predicted greater daily and overall pain. Greater happiness and poorer quality of sleep predicted greater daily worst pain. Exercising and overall confidence to cope with pain without medication were associated with lower levels of daily worst pain. Finally, spending less time with a loved one over time and reporting any coping behavior were associated with relief from pain. Conclusion: Investigation of daily factors that drive pain and substance use behaviors among this unique population help inform which daily factors are most risky to their health and well-being. Alcohol use emerged as the only substance associated with both driving pain and responding to pain. Findings suggest key points for prevention and intervention

Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance)

PURPOSE: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned. RESULTS: From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%). CONCLUSION: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting