Dynamic regulation of airway surface liquid pH by TMEM16A and SLC26A4 in cystic fibrosis nasal epithelia with rare mutations

Copyright \ua9 2023 the Author(s). Published by PNAS. In cystic fibrosis (CF), defects in the CF transmembrane conductance regulator (CFTR) channel lead to an acidic airway surface liquid (ASL), which compromises innate defence mechanisms, predisposing to pulmonary failure. Restoring ASL pH is a potential therapy for people with CF, particularly for those who cannot benefit from current highly effective modulator therapy. However, we lack a comprehensive understanding of the complex mechanisms underlying ASL pH regulation. The calcium-activated chloride channel, TMEM16A, and the anion exchanger, SLC26A4, have been proposed as targets for restoring ASL pH, but current results are contradictory and often utilise nonphysiological conditions. To provide better evidence for a role of these two proteins in ASL pH homeostasis, we developed an efficient CRISPR-Cas9-based approach to knock-out (KO) relevant transporters in primary airway basal cells lacking CFTR and then measured dynamic changes in ASL pH under thin-film conditions in fully differentiated airway cultures, which better simulate the in vivo situation. Unexpectantly, we found that both proteins regulated steady-state as well as agonist-stimulated ASL pH, but only under inflammatory conditions. Furthermore, we identified two Food and Drug Administration (FDA)-approved drugs which raised ASL pH by activating SLC26A4. While we identified a role for SLC26A4 in fluid absorption, KO had no effect on cyclic adenosine monophosphate (cAMP)-stimulated fluid secretion in airway organoids. Overall, we have identified a role of TMEM16A in ASL pH homeostasis and shown that both TMEM16A and SLC26A4 could be important alternative targets for ASL pH therapy in CF, particularly for those people who do not produce any functional CFTR

Development and usability evaluation of a nutrition and lifestyle guidance application for people living with and beyond cancer

There is a need to provide accessible information for health care professionals and for people living beyond treatment. Mobile and digital health technologies provide an ideal platform to access diet and nutrition guidance that is both trusted and evidence-based and so that people know how to alter and monitor eating patterns and behaviours to improve the quality of life. Participatory design and usability evaluation approaches have been utilised to develop a nutrition and lifestyle guidance smartphone application for both people living with and beyond cancer, and for health care professionals involved in advising such patients. The challenges centred on the design, development and evaluation of the first version of a new mobile application named ‘Life Beyond’ are presented. This proof of concept application aims to centralise evidence-based nutrition and lifestyle guidance for those living beyond cancer. It enables users to obtain guidance and information, create and track nutrition and activity related goals and track their progress in the completion of these goals. Consistent feedback from participatory design and usability evaluations drove this research and helped to create an initial solution that met the user expectations. The System Usability Scale (SUS) score of 67.69 denotes an ‘average’ usability and hence further development. More research of extensive end user engagement is needed before an optimal solution is disseminated

Chumnguh Thleum: Understanding Liver Illness and Hepatitis B Among Cambodian Immigrants

Cambodian immigrants are over 25 times more likely to have evidence of chronic hepatitis B infection than the general US population. Carriers of HBV are over 100 times more likely to develop liver cancer than non-carriers. Liver cancer incidence is the second leading cancer for Cambodian men and the sixth for Cambodian women. Despite this, this underserved population has received very little attention from health disparities researchers. Culturally and linguistically appropriate interventions are necessary to increase hepatitis B knowledge, serologic testing, and vaccination among Cambodian Americans. Eight group interviews were held with Cambodian American men (48) and women (49). Focus group discussion revealed unanticipated information about sociocultural influences on participants’ understanding about hepatitis B transmission, disease course, and prevention and treatment informed by humoral theories underlying Khmer medicine, by biomedicine, and by migration experiences. Our findings reveal the value of qualitative exploration to providing cultural context to biomedical information—a formula for effective health promotion and practice

Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review.

© 2015 Owiti et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Hepatitis B and C (HBV, HCV) infections are associated with high morbidity and mortality. Many countries with traditionally low prevalence (such as UK) are now planning interventions (screening, vaccination, and treatment) of high-risk immigrants from countries with high prevalence. This review aimed to synthesise the evidence on immigrants' knowledge of HBV and HCV that might influence the uptake of clinical interventions. The review was also used to inform the design and successful delivery of a randomised controlled trial of targeted screening and treatment. METHODS: Five databases (PubMed, CINHAL, SOCIOFILE, PsycINFO & Web of Science) were systematically searched, supplemented by reference tracking, searches of selected journals, and of relevant websites. We aimed to identify qualitative and quantitative studies that investigated knowledge of HBV and HCV among immigrants from high endemic areas to low endemic areas. Evidence, extracted according to a conceptual framework of Kleinman's explanatory model, was subjected to narrative synthesis. We adapted the PEN-3 model to categorise and analyse themes, and recommend strategies for interventions to influence help-seeking behaviour. RESULTS: We identified 51 publications including quantitative (n = 39), qualitative (n = 11), and mixed methods (n = 1) designs. Most of the quantitative studies included small samples and had heterogeneous methods and outcomes. The studies mainly concentrated on hepatitis B and ethnic groups of South East Asian immigrants residing in USA, Canada, and Australia. Many immigrants lacked adequate knowledge of aetiology, symptoms, transmission risk factors, prevention strategies, and treatment, of hepatitis HBV and HCV. Ethnicity, gender, better education, higher income, and English proficiency influenced variations in levels and forms of knowledge. CONCLUSION: Immigrants are vulnerable to HBV and HCV, and risk life-threatening complications from these infections because of poor knowledge and help-seeking behaviour. Primary studies in this area are extremely diverse and of variable quality precluding meta-analysis. Further research is needed outside North America and Australia

Gravitational Radiation from Post-Newtonian Sources and Inspiralling Compact Binaries

The article reviews the current status of a theoretical approach to the problem of the emission of gravitational waves by isolated systems in the context of general relativity. Part A of the article deals with general post-Newtonian sources. The exterior field of the source is investigated by means of a combination of analytic post-Minkowskian and multipolar approximations. The physical observables in the far-zone of the source are described by a specific set of radiative multipole moments. By matching the exterior solution to the metric of the post-Newtonian source in the near-zone we obtain the explicit expressions of the source multipole moments. The relationships between the radiative and source moments involve many non-linear multipole interactions, among them those associated with the tails (and tails-of-tails) of gravitational waves. Part B of the article is devoted to the application to compact binary systems. We present the equations of binary motion, and the associated Lagrangian and Hamiltonian, at the third post-Newtonian (3PN) order beyond the Newtonian acceleration. The gravitational-wave energy flux, taking consistently into account the relativistic corrections in the binary moments as well as the various tail effects, is derived through 3.5PN order with respect to the quadrupole formalism. The binary's orbital phase, whose prior knowledge is crucial for searching and analyzing the signals from inspiralling compact binaries, is deduced from an energy balance argument.Comment: 109 pages, 1 figure; this version is an update of the Living Review article originally published in 2002; available on-line at http://www.livingreviews.org

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

The ethics of digital well-being: a multidisciplinary perspective

This chapter serves as an introduction to the edited collection of the same name, which includes chapters that explore digital well-being from a range of disciplinary perspectives, including philosophy, psychology, economics, health care, and education. The purpose of this introductory chapter is to provide a short primer on the different disciplinary approaches to the study of well-being. To supplement this primer, we also invited key experts from several disciplines—philosophy, psychology, public policy, and health care—to share their thoughts on what they believe are the most important open questions and ethical issues for the multi-disciplinary study of digital well-being. We also introduce and discuss several themes that we believe will be fundamental to the ongoing study of digital well-being: digital gratitude, automated interventions, and sustainable co-well-being

Neural network involving medial orbitofrontal cortex and dorsal periaqueductal gray regulation in human alcohol abuse.

Prompted by recent evidence of neural circuitry in rodent models, functional magnetic resonance imaging and functional connectivity analyses were conducted for a large adolescent population at two ages, together with alcohol abuse measures, to characterize a neural network that may underlie the onset of alcoholism. A network centered on the medial orbitofrontal cortex (mOFC), as well as including the dorsal periaqueductal gray (dPAG), central nucleus of the amygdala, and nucleus accumbens, was identified, consistent with the rodent models, with evidence of both inhibitory and excitatory coregulation by the mOFC over the dPAG. Furthermore, significant relationships were detected between raised baseline excitatory coregulation in this network and impulsivity measures, supporting a role for negative urgency in alcohol dependence

Logging Affects Fledgling Sex Ratios and Baseline Corticosterone in a Forest Songbird

Silviculture (logging) creates a disturbance to forested environments. The degree to which forests are modified depends on the logging prescription and forest stand characteristics. In this study we compared the effects of two methods of group-selection (“moderate” and “heavy”) silviculture (GSS) and undisturbed reference stands on stress and offspring sex ratios of a forest interior species, the Ovenbird (Seiurus aurocapilla), in Algonquin Provincial Park, Canada. Blood samples were taken from nestlings for corticosterone and molecular sexing. We found that logging creates a disturbance that is stressful for nestling Ovenbirds, as illustrated by elevated baseline corticosterone in cut sites. Ovenbirds nesting in undisturbed reference forest produce fewer male offspring per brood (proportion male = 30%) while logging with progressively greater forest disturbance, shifted the offspring sex ratio towards males (proportion male: moderate = 50%, heavy = 70%). If Ovenbirds in undisturbed forests usually produce female-biased broods, then the production of males as a result of logging may disrupt population viability. We recommend a broad examination of nestling sex ratios in response to anthropogenic disturbance to determine the generality of our findings