Novel capsaicin cough endpoints effectively discriminate between healthy controls and patients with refractory chronic cough

Rationale Chronic cough is a common problem, substantially affecting quality of life. Effective treatments and diagnostic clinical tools for refractory chronic cough are lacking which remains a diagnosis of exclusion. Objectives To investigate capsaicin evoked cough responses in healthy volunteers and refractory chronic cough patients and assess the discriminatory ability of novel endpoints. Methods Dose-response capsaicin cough challenges were performed, and receiver operating characteristic curves constructed to evaluate the discriminatory value of novel endpoints; Emax (maximum number of coughs evoked by any capsaicin concentration) and ED50 (capsaicin concentration evoking at least half of Emax). Measurements and main results Ninety-three healthy volunteers (median age 39yrs(IQR; 29–52), 47 females) and 51 refractory chronic cough patients (59yrs(53–67), 31 females) were studied. Emax was significantly higher in the patient group compared to healthy volunteers (p < 0.001) and ED50 was significantly lower (p = 0.001). Both parameters were influenced by gender; females had a higher Emax (p = 0.009) and more sensitive ED50 (p < 0.001) but there were no correlations with other patient demographics. There was a significant relationship between Emax and cough frequency in the patient group (p < 0.001). Emax effectively discriminated between the groups (AUC = 0.83, 95% CI; 0.75–0.90, p < 0.001) independently of ED50 which was less favourable (AUC = 0.66, 95% CI; 0.57–0.76, p = 0.002). Emax and ED50 were shown to be repeatable, and the dose-response method well tolerated. Conclusion Novel capsaicin dose-response endpoints effectively discriminate between healthy controls and refractory chronic cough patients, which may better represent pathophysiological mechanisms and show promise for development as a tool to identify patients with cough hyper-excitability

Dosing practices made mundane: Enacting HIV pre-exposure prophylaxis adherence in domestic routines

Maintaining routines of medication dosing requires effort amidst the variabilities of everyday life. This article offers a sociomaterial analysis of how the oral HIV prevention regimen, pre-exposure prophylaxis (PrEP), is put to use and made to work, including in situations which disrupt or complicate dosing regimes. Other than a daily pill, PrEP can be taken less frequently based on anticipated sexual activity and HIV risk, including 'on-demand' and 'periodic' dosing. Drawing on 40 interviews with PrEP users in Australia in 2022, we explore PrEP and its dosing as features of assemblages in which bodies, routines, desires, material objects and the home environment interact. Dosing emerges as a practice of coordination involving dosette boxes, blister packs, alarms, partners, pets, planning sex, routines and domestic space, and as an effect of experimentations with timing to suit life circumstances and manage side effects. Dosing is materialised in the mundane; a practice that is made to work, as well as domesticated, in its situations. Although there are no 'simple' solutions to adherence, our analysis offers practical insights into how routine, planning and experimentation come together to capacitate PrEP to work in people's lives, in sometimes unexpected ways, including through adaptations of PrEP dosing

Variations in HIV Prevention Coverage in Subpopulations of Australian Gay and Bisexual Men, 2017–2021: Implications for Reducing Inequities in the Combination Prevention Era

Using repeated behavioural surveillance data collected from gay and bisexual men (GBM) across Australia, we assessed trends in HIV prevention coverage (the level of ‘safe sex’ achieved in the population by the use of effective prevention methods, including condoms, pre-exposure prophylaxis [PrEP] and having an undetectable viral load). We stratified these trends by age, country of birth/recency of arrival, sexual identity, and the proportion of gay residents in the participant’s suburb. Among 25,865 participants with casual male partners, HIV prevention coverage increased from 69.8% in 2017 to 75.2% in 2021, lower than the UNAIDS target of 95%. Higher levels of coverage were achieved among older GBM (≥ 45 years), non-recently-arrived migrants, and in suburbs with ≥ 10% gay residents. The lowest levels of prevention coverage (and highest levels of HIV risk) were recorded among younger GBM (&lt; 25 years) and bisexual and other-identified participants. Younger, recently-arrived, and bisexual GBM were the most likely to use condoms, while PrEP use was concentrated among gay men, 25–44-year-olds, and in suburbs with more gay residents. The use of undetectable viral load was most common among participants aged ≥ 45 years. Our analysis shows that high HIV prevention coverage can be achieved through a mixture of condom use, PrEP use, and undetectable viral load, or by emphasising PrEP use. In the Australian context, younger, bisexual and other-identified GBM should be prioritised for enhanced access to effective HIV prevention methods. We encourage other jurisdictions to assess the level of coverage achieved by combination prevention, and variations in uptake

'It felt like it was night all the time' : listening to the experiences of birth mothers whose children have been taken into care or adopted

The child care literature consistently reports a lack of support for birth mothers following their child being taken into care or adopted. This is despite consistent evidence of the long-term consequences of the removal of children on their mental health. The aim of this study is to explore the effects of separation, the subsequent sense of identity and the experience of contact and support throughout the process. Semi-structured interviews were conducted with seven mothers recruited from birth mother support groups and the transcripts analysed using Interpretative Phenomenological Analysis (IPA). Four themes emerged: ‘no one in my corner’; disconnecting from emotion; renegotiating identity; and the children are gone but still here. The findings contribute to our understanding of the experiences of birth mothers whose children are removed from their care and are discussed within a range of psychological theories.Peer reviewedFinal Accepted Versio

Mimicking microbial 'education' of the immune system: a strategy to revert the epidemic trend of atopy and allergic asthma?

Deficient microbial stimulation of the immune system, caused by hygiene, may underly the atopy and allergic asthma epidemic we are currently experiencing. Consistent with this 'hygiene hypothesis', research on immunotherapy of allergic diseases also centres on bacteria-derived molecules (eg DNA immunostimulatory sequences) as adjuvants for allergen-specific type 1 immune responses. If we understood how certain microbes physiologically 'educate' our immune system to interact safely with environmental nonmicrobial antigens, we might be able to learn to mimic their beneficial actions. Programmed 'immunoeducation' would consist of safe administration, by the correct route, dose and timing, of those microbial stimuli that are necessary to 'train' the developing mucosal immune system and to maintain an appropriate homeostatic equilibrium between its components. Overall, this would result in a prevention of atopy that is not limited to certain specific allergens. Although such a strategy is far beyond our present potential, it may in principle revert the epidemic trend of atopy and allergic asthma without jeopardizing the fight against infectious diseases

Spatial heterogeneity of habitat suitability for Rift Valley fever occurrence in Tanzania: an ecological niche modelling approach

Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics

Biodiversity Loss and the Taxonomic Bottleneck: Emerging Biodiversity Science

Human domination of the Earth has resulted in dramatic changes to global and local patterns of biodiversity. Biodiversity is critical to human sustainability because it drives the ecosystem services that provide the core of our life-support system. As we, the human species, are the primary factor leading to the decline in biodiversity, we need detailed information about the biodiversity and species composition of specific locations in order to understand how different species contribute to ecosystem services and how humans can sustainably conserve and manage biodiversity. Taxonomy and ecology, two fundamental sciences that generate the knowledge about biodiversity, are associated with a number of limitations that prevent them from providing the information needed to fully understand the relevance of biodiversity in its entirety for human sustainability: (1) biodiversity conservation strategies that tend to be overly focused on research and policy on a global scale with little impact on local biodiversity; (2) the small knowledge base of extant global biodiversity; (3) a lack of much-needed site-specific data on the species composition of communities in human-dominated landscapes, which hinders ecosystem management and biodiversity conservation; (4) biodiversity studies with a lack of taxonomic precision; (5) a lack of taxonomic expertise and trained taxonomists; (6) a taxonomic bottleneck in biodiversity inventory and assessment; and (7) neglect of taxonomic resources and a lack of taxonomic service infrastructure for biodiversity science. These limitations are directly related to contemporary trends in research, conservation strategies, environmental stewardship, environmental education, sustainable development, and local site-specific conservation. Today’s biological knowledge is built on the known global biodiversity, which represents barely 20% of what is currently extant (commonly accepted estimate of 10 million species) on planet Earth. Much remains unexplored and unknown, particularly in hotspots regions of Africa, South Eastern Asia, and South and Central America, including many developing or underdeveloped countries, where localized biodiversity is scarcely studied or described. ‘‘Backyard biodiversity’’, defined as local biodiversity near human habitation, refers to the natural resources and capital for ecosystem services at the grassroots level, which urgently needs to be explored, documented, and conserved as it is the backbone of sustainable economic development in these countries. Beginning with early identification and documentation of local flora and fauna, taxonomy has documented global biodiversity and natural history based on the collection of ‘‘backyard biodiversity’’ specimens worldwide. However, this branch of science suffered a continuous decline in the latter half of the twentieth century, and has now reached a point of potential demise. At present there are very few professional taxonomists and trained local parataxonomists worldwide, while the need for, and demands on, taxonomic services by conservation and resource management communities are rapidly increasing. Systematic collections, the material basis of biodiversity information, have been neglected and abandoned, particularly at institutions of higher learning. Considering the rapid increase in the human population and urbanization, human sustainability requires new conceptual and practical approaches to refocusing and energizing the study of the biodiversity that is the core of natural resources for sustainable development and biotic capital for sustaining our life-support system. In this paper we aim to document and extrapolate the essence of biodiversity, discuss the state and nature of taxonomic demise, the trends of recent biodiversity studies, and suggest reasonable approaches to a biodiversity science to facilitate the expansion of global biodiversity knowledge and to create useful data on backyard biodiversity worldwide towards human sustainability

Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes

Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement