Leukotriene antagonists as first-line or add-on asthma controller therapy

Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score =6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score =1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group

The effectiveness of a sustained nurse home visiting intervention for Aboriginal infants compared with non-Aboriginal infants and with Aboriginal infants receiving usual child health care : a quasi-experimental trial : the Bulundidi Gudaga study

Background: In Australia there is commitment to developing interventions that will 'Close the Gap' between the health and welfare of Indigenous and non-Indigenous Australians and recognition that early childhood interventions offer the greatest potential for long term change. Nurse led sustained home visiting programs are considered an effective way to deliver a health and parenting service, however there is little international or Australian evidence that demonstrates the effectiveness of these programs for Aboriginal infants. This protocol describes the Bulundidi Gudaga Study, a quasi-experimental design, comparing three cohorts of families from the Macarthur region in south western Sydney to explore the effectiveness of the Maternal Early Childhood Sustained Home-visiting (MECSH) program for Aboriginal families. Methods: Mothers were recruited when booking into the local hospital for perinatal care and families are followed up until child is age 4 years. Participants are from three distinct cohorts: Aboriginal MECSH intervention cohort (Group A), Non-Aboriginal MECSH intervention cohort (Group B) and Aboriginal non-intervention cohort (Group C). Eligible mothers were those identified as at risk during the Safe Start assessment conducted by antenatal clinic midwives. Mothers in Group A were eligible if they were pregnant with an Aboriginal infant. Mothers in Group B were eligible if they were pregnant with a non-Aboriginal infant. Mothers in Group C are part of the Gudaga descriptive cohort study and were recruited between October 2005 and May 2007. The difference in duration of breastfeeding, child body mass index, and child development outcomes at 18 months and 4 years of age will be measured as primary outcomes. We will also evaluate the intervention effect on secondary measures including: child dental health; the way the program is received; patterns of child health and illness; patterns of maternal health, health knowledge and behaviours; family and environmental conditions; and service usage for mothers and families. Discussion: Involving local Aboriginal research and intervention staff and investing in established relationships between the research team and the local Aboriginal community is enabling this study to generate evidence regarding the effectiveness of interventions that are feasible to implement and sustainable in the context of Aboriginal communities and local service systems. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12616001721493 Registered 14 Dec 2016. Retrospectively registered

Wounding with a Microneedling Device Corrects the Inappropriate Ultraviolet B Radiation Response in Geriatric Ski

Non-melanoma skin cancer primarily affects geriatric patients as evidenced by the fact that only 20% of these cancers are diagnosed in patients under the age of 60 years. Of importance, geriatric skin responds to procarcinogenic ultraviolet B radiation (UVB) in a manner that permits the establishment of tumor cells. Recent studies have indicated that wounding of geriatric skin with fractionated resurfacing lasers and dermabrasion upregulates fibroblast production of insulin-like growth factor-1 (IGF-1) and normalizes the procarcinogenic acute UVB response consisting of basal keratinocytes proliferating while still harboring unrepaired DNA damage. The present studies tested the ability of wounding with a commercially available microneedling device to upregulate IGF-1 levels and normalize the geriatric UVB response. Geriatric volunteers were treated with a microneedling device on buttock skin and 3 months later the IGF-1 levels and UVB responses tested in wounded vs control skin. Wounding via microneedling upregulated IGF-1 and resulted in lower levels of basal keratinocytes proliferating with unrepaired DNA damage. The ability of microneedling to protect against the formation of UVB-damaged proliferating keratinocytes indicates the potential of this wounding modality to reduce aging-associated non-melanoma skin cancer

Carbon budget of tidal wetlands, estuaries, and shelf waters of eastern North America

Author Posting. © American Geophysical Union, 2018. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 32 (2018): 389-416, doi:10.1002/2017GB005790.Carbon cycling in the coastal zone affects global carbon budgets and is critical for understanding the urgent issues of hypoxia, acidification, and tidal wetland loss. However, there are no regional carbon budgets spanning the three main ecosystems in coastal waters: tidal wetlands, estuaries, and shelf waters. Here we construct such a budget for eastern North America using historical data, empirical models, remote sensing algorithms, and process‐based models. Considering the net fluxes of total carbon at the domain boundaries, 59 ± 12% (± 2 standard errors) of the carbon entering is from rivers and 41 ± 12% is from the atmosphere, while 80 ± 9% of the carbon leaving is exported to the open ocean and 20 ± 9% is buried. Net lateral carbon transfers between the three main ecosystem types are comparable to fluxes at the domain boundaries. Each ecosystem type contributes substantially to exchange with the atmosphere, with CO2 uptake split evenly between tidal wetlands and shelf waters, and estuarine CO2 outgassing offsetting half of the uptake. Similarly, burial is about equal in tidal wetlands and shelf waters, while estuaries play a smaller but still substantial role. The importance of tidal wetlands and estuaries in the overall budget is remarkable given that they, respectively, make up only 2.4 and 8.9% of the study domain area. This study shows that coastal carbon budgets should explicitly include tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.NASA Interdisciplinary Science program Grant Number: NNX14AF93G; NASA Carbon Cycle Science Program Grant Number: NNX14AM37G; NASA Ocean Biology and Biogeochemistry Program Grant Number: NNX11AD47G; National Science Foundation's Chemical Oceanography Program Grant Number: OCE‐12605742018-10-0

Common fragile sites are characterized by histone hypoacetylation

Common fragile sites (CFSs) represent large, highly unstable regions of the human genome. CFS sequences are sensitive to perturbation of replication; however, the molecular basis for the instability at CFSs is poorly understood. We hypothesized that a unique epigenetic pattern may underlie the unusual sensitivity of CFSs to replication interference. To examine this hypothesis, we analyzed chromatin modification patterns within the six human CFSs with the highest levels of breakage, and their surrounding non-fragile regions (NCFSs). Chromatin at most of the CFSs analyzed has significantly less histone acetylation than that of their surrounding NCFSs. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Furthermore, chromatin at the most commonly expressed CFS, the FRA3B, is more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. These results demonstrate that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs might be relatively more compact than that of the NCFSs, indicating a role for chromatin conformation in genomic instability at CFSs. Moreover, lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of this regions

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion

Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity

We are grateful to members of the D.S. laboratory and Dr. E. Fernández-Malavé for discussions and critical reading of the manuscript. We appreciate the support of A. Tomás-Loba, G. Sabio, P. Martín, A. Tsilingiri, A.R. Ramiro, C.L. Abram, C.A. Lowell, J.M. García-Lobo, M. Molina, and M.C. Rodríguez for providing reagents and support. We thank the staff at the Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) facilities for technical support. M.M.-L. received a Formación de Personal Universitario (FPU) fellowship (AP2010-5935) from the Spanish Ministerio de Educación. S.I. is funded by grant SAF2015-74561-JIN from the Spanish Ministerio de Ciencia, Innovación, y Universidades (MCIU) and Fondos Europeos de Desarrollo Regional (FEDER). G.D.B and D.M.R. are supported by the Wellcome Trust and the MRC Centre for Medical Mycology at the University of Aberdeen. S.L.L. is supported by the Swiss National Science Foundation (PP00P3_150758). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, the Agencia Estatal de Investigación, and FEDER; B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MCIU, and FEDER; the Acteria Foundation; the Constantes y Vitales prize (Atresmedia); La Marató de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020), and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).Peer reviewedPublisher PD

Miller Early Childhood Sustained Home-visiting (MECSH) trial: design, method and sample description

<p>Abstract</p> <p>Background</p> <p>Home visiting programs comprising intensive and sustained visits by professionals (usually nurses) over the first two years of life show promise in promoting child health and family functioning, and ameliorating disadvantage. Australian evidence of the effectiveness of sustained nurse home visiting in early childhood is limited. This paper describes the method and cohort characteristics of the first Australian study of sustained home visiting commencing antenatally and continuing to child-age two years for at-risk mothers in a disadvantaged community (the Miller Early Childhood Sustained Home-visiting trial).</p> <p>Methods and design</p> <p>Mothers reporting risks for poorer parenting outcomes residing in an area of socioeconomic disadvantage were recruited between February 2003 and March 2005. Mothers randomised to the intervention group received a standardised program of nurse home visiting. Interviews and observations covering child, maternal, family and environmental issues were undertaken with mothers antenatally and at 1, 12 and 24 months postpartum. Standardised tests of child development and maternal-child interaction were undertaken at 18 and 30 months postpartum. Information from hospital and community heath records was also obtained.</p> <p>Discussion</p> <p>A total of 338 women were identified and invited to participate, and 208 were recruited to the study. Rates of active follow-up were 86% at 12 months, 74% at 24 months and 63% at 30 months postpartum. Participation in particular data points ranged from 66% at 1 month to 51% at 24 months postpartum. Rates of active follow-up and data point participation were not significantly different for the intervention or comparison group at any data point. Mothers who presented for antenatal care prior to 20 weeks pregnant, those with household income from full-time employment and those who reported being abused themselves as a child were more likely to be retained in the study. The Miller Early Childhood Sustained Home-visiting trial will provide Australian evidence of the effectiveness of sustained nurse home visiting for children at risk of poorer health and developmental outcomes.</p> <p>Trial registration</p> <p>ACTRN12608000473369</p

Quantifying resilience of humans and other animals

All life requires the capacity to recover from challenges that are as inevitable as they are unpredictable. Understanding this resilience is essential for managing the health of humans and their livestock. It has long been difficult to quantify resilience directly, forcing practitioners to rely on indirect static indicators of health. However, measurements from wearable electronics and other sources now allow us to analyze the dynamics of physiology and behavior with unsurpassed resolution. The resulting flood of data coincides with the emergence of novel analytical tools for estimating resilience from the pattern of micro-recoveries observed in natural time series. Such dynamic indicators of resilience (DIORs) may be used to monitor the risk of systemic failure across systems ranging from organs to entire organisms. These tools invite a fundamental rethink of our approach to the adaptive management of health and resilience