Lichen biomonitoring to assess spatial variability, potential sources and human health risks of polycyclic aromatic hydrocarbons (PAHs) and airborne metal concentrations in Manchester (UK).

Airborne metals and organic pollutants are linked to severe human health impacts, i.e. affecting the nervous system and being associated with cancer. Airborne metals and polycyclic aromatic hydrocarbons (PAHs) in urban environments are derived from diverse sources, including combustion and industrial and vehicular emissions, posing a threat to air quality and subsequently human health. A lichen biomonitoring approach was used to assess spatial variability of airborne metals and PAHs, identify potential pollution sources and assess human health risks across the City of Manchester (UK). Metal concentrations recorded in lichen samples were highest within the city centre area and along the major road network, and lichen PAH profiles were dominated by 4-ring PAHs (189.82 ng g-1 in Xanthoria parietina), with 5- and 6-ring PAHs also contributing to the overall PAH profile. Cluster analysis and pollution index factor (PIF) calculations for lichen-derived metal concentrations suggested deteriorated air quality being primarily linked to vehicular emissions. Comparably, PAH diagnostic ratios identified vehicular sources as a primary cause of PAH pollution across Manchester. However, local more complex sources (e.g. industrial emissions) were further identified. Human health risk assessment found a "moderate" risk for adults and children by airborne potential harmful element (PHEs) concentrations, whereas PAH exposure in Manchester is potentially linked to 1455 (ILCR = 1.45 × 10-3) cancer cases (in 1,000,000). Findings of this study indicate that an easy-to-use lichen biomonitoring approach can aid to identify hotspots of impaired air quality and potential human health impacts by airborne metals and PAHs across an urban environment, particularly at locations that are not continuously covered by (non-)automated air quality measurement programmes.

The Metabolism of Lufotrelvir, a Prodrug Investigated for the Treatment of SARS-COV2 in Humans Following Intravenous Administration.

The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19. On administration of [14C]lufotrelvir, only 63% of the dose was obtained in excreta over 10 days and total drug-related material demonstrated a prolonged terminal phase half-life in plasma. A considerable portion of the labeled material was unextractable from fecal homogenate and plasma. The position of the carbon-14 atom in the labeled material was at a leucine carbonyl, and pronase digestion of the pellet derived from extraction of the fecal homogenate showed that [14C]leucine was released. SIGNIFICANCE STATEMENT: Lufotrelvir is an experimental phosphate prodrug intravenous therapy investigated for the potential treatment of COVID-19 in a hospital setting. The overall metabolism of lufotrelvir was determined in human healthy volunteers and clinical trial participants with COVID-19. Conversion of the phosphate prodrug to the active drug PF-00835231 was complete and the subsequent metabolic clearance of the active drug was largely via amide bond hydrolysis. Substantial drug-related material was not recovered due to loss of the carbon-14 label to endogenous metabolism.

Developing and validating a prediction model of adolescent major depressive disorder in the offspring of depressed parents.

BACKGROUND: Parental depression is common and is a major risk factor for depression in adolescents. Early identification of adolescents at elevated risk of developing major depressive disorder (MDD) in this group could improve early access to preventive interventions. METHODS: Using longitudinal data from 337 adolescents at high familial risk of depression, we developed a risk prediction model for adolescent MDD. The model was externally validated in an independent cohort of 1,384 adolescents at high familial risk. We assessed predictors at baseline and MDD at follow-up (a median of 2-3 years later). We compared the risk prediction model to a simple comparison model based on screening for depressive symptoms. Decision curve analysis was used to identify which model-predicted risk score thresholds were associated with the greatest clinical benefit. RESULTS: The MDD risk prediction model discriminated between those adolescents who did and did not develop MDD in the development (C-statistic = .783, IQR (interquartile range) = .779, .778) and the validation samples (C-statistic = .722, IQR = -.694, .741). Calibration in the validation sample was good to excellent (calibration intercept = .011, C-slope = .851). The MDD risk prediction model was superior to the simple comparison model where discrimination was no better than chance (C-statistic = .544, IQR = .536, .572). Decision curve analysis found that the highest clinical utility was at the lowest risk score thresholds (0.01-0.05). CONCLUSIONS: The developed risk prediction model successfully discriminated adolescents who developed MDD from those who did not. In practice, this model could be further developed with user involvement into a tool to target individuals for low-intensity, selective preventive intervention.

Quantitative Evaluation of Dendritic Nanoparticles in Mice: Biodistribution Dynamics and Downstream Tumor Efficacy Outcomes.

A physiologically based pharmacokinetic model was developed to describe the tissue distribution kinetics of a dendritic nanoparticle and its conjugated active pharmaceutical ingredient (API) in plasma, liver, spleen, and tumors. Tumor growth data from MV-4-11 tumor-bearing mice were incorporated to investigate the exposure/efficacy relationship. The nanoparticle demonstrated improved antitumor activity compared to the conventional API formulation, owing to the extended released API concentrations at the site of action. Model simulations further enabled the identification of critical parameters that influence API exposure in tumors and downstream efficacy outcomes upon nanoparticle administration. The model was utilized to explore a range of dosing schedules and their effect on tumor growth kinetics, demonstrating the improved antitumor activity of nanoparticles with less frequent dosing compared to the same dose of naked APIs in conventional formulations.

Exploration of factors associated with spatial-temporal veterinary surveillance diagnoses of rumen fluke (Calicophoron daubneyi) infections in ruminants using zero-inflated mixed modelling.

Rumen fluke (Calicophoron daubneyi) has emerged as a prominent parasite of ruminants in Europe over the past decades. Epidemiological questions remain regarding this observed increase in prevalence as well as the prospect for future paramphistomosis risk. This study aimed to identify factors associated with the temporal−spatial prevalence of rumen fluke as measured by veterinary surveillance in a temperate region using zero-inflated negative binomial mixed modelling. Modelling revealed that summer rainfall, raindays and sunshine hours and mean winter temperature as significant positively associated climate variables for rumen fluke prevalence over space and time (P < 0.05). Rumen fluke prevalence was also higher in counties with higher cattle/sheep densities and was positively associated with rumen fluke case rates in the previous years (P < 0.05). Equivalent models for fasciolosis prevalence revealed no significant association with winter temperature and sunshine hours, (P > 0.05). These results confirm a strong association between rainfall and the prevalence of both fluke species in a temperate environment, likely due to the role of Galba truncatula as their intermediate snail host. It also highlights the potential added importance of winter temperature and sunshine hours in rumen fluke epidemiology when compared to liver fluke.

Oropharyngeal swallowing physiology and safety in patients with Idiopathic Pulmonary Fibrosis: a consecutive descriptive case series.

INTRODUCTION: Dysphagia occurs in multiple respiratory pathophysiologies, increasing the risk of pulmonary complications secondary to aspiration. Reflux associated aspiration and a dysregulated lung microbiome is implicated in Idiopathic Pulmonary Fibrosis (IPF), but swallowing dysfunction has not been described. We aimed to explore oropharyngeal swallowing in IPF patients, without known swallowing dysfunction. METHODS: Fourteen consecutive outpatients with a secure diagnosis of IPF were recruited and the 10-item Eating Assessment Tool (Eat 10) used to assess patient perception of swallowing difficulty. Oropharyngeal swallowing was assessed in ten patients using Videofluoroscopy Swallow Studies (VFSS). The studies were rated using validated scales: Penetration-Aspiration Scale (PAS); standardised Modified Barium Swallow Impairment Profile (MBSImP). RESULTS: EAT-10 scores indicated frank swallowing difficulty in 4/14 patients. Videofluoroscopy Studies showed that 3/10 patients had airway penetration, and one aspirated liquid without a cough response. Median MBSImp for oral impairment was 5, range [3-7] and pharyngeal impairment 4, range [1-14] indicating, overall mild alteration to swallowing physiology. CONCLUSION: We conclude that people with IPF can show a range of swallowing dysfunction, including aspiration into an unprotected airway. To our knowledge, this is the first report on swallowing physiology and safety in IPF. We believe a proportion of this group may be at risk of aspiration. Further work is indicated to fully explore swallowing in this vulnerable group.

The effect of walking and stationary work on the acute back pain, muscle activation, posture and postural control of older women.

Back pain is associated with activity such as walking or assembly line work that involves upper-body movement. However, no single study has explored the effect of these tasks on back pain, spinal angles and balance in an older adult female population. This study investigated changes in back pain, postural sway, upper-, lower- and full-spine angle and EMG activation of trunk muscles following 30 minutes of walking and a modified quiet standing task. Fourteen older adult females (62 ± 11yrs) with low to moderate chronic back pain were recruited as participants. Findings demonstrated that following these activities, increased acute back pain and upper-spine flexion occur although acute back pain was not clinically significant; postural control and muscle activation remained unchanged. This suggests that walking and modified quiet standing can lead to subtle acute back pain in older females that could be due to an increased upper spinal flexion rather than muscle fatigue. Practitioner summary: Back pain and postural problems are common in older adults. Older adult female participants experienced increased back pain and greater upper-spine flexion following 30-minute walking and standing with trunk rotation, but the practical importance was less clear. However, balance was unaffected, suggesting no increase in fall risk. Abbreviations: CBP: chronic back pain; MQS: modified quiet standing; QS: quiet standing; RPE: rating of perceived exertion; TD: trapezius descendens; TT: trapezius transversalis; TA: trapezius ascendens; ESL: erector spinae longissimus; C7: seventh cervical vertebrae; T7: seventh thoracic vertebrae; T10: tenth thoracic vertebrae; T12: twelfth thoracic vertebrae; L2: second lumbar vertebrae; S2: second sacral vertebrae; AP: anterior-posterior; ML: medial-lateral; SWAYtot: total postural sway; M: mean.

Evolution of Esophagectomy for Cancer Over 30 Years: Changes in Presentation, Management and Outcomes.

BACKGROUND: Esophageal cancer has seen a considerable change in management and outcomes over the last 30 years. Historically, the overall prognosis has been regarded as poor; however, the use of multimodal treatment and the integration of enhanced recovery pathways have improved short- and long-term outcomes. OBJECTIVE: The aim of this study was to evaluate the changing trends in presentation, management, and outcomes for patients undergoing surgical treatment for esophageal cancer over 30 years from a single-center, high-volume unit in the UK. PATIENTS AND METHODS: Data from consecutive patients undergoing esophagectomy for cancer (adenocarcinoma or squamous cell carcinoma) between 1989 and 2018 from a single-center, high-volume unit were reviewed. Presentation method, management strategies, and outcomes were evaluated. Patients were grouped into successive 5-year cohorts for comparison and evaluation of changing trends. RESULTS: Between 1989 and 2018, 1486 patients underwent esophagectomy for cancer. Median age was 65 years (interquartile range [IQR] 59-71) and 1105 (75%) patients were male. Adenocarcinoma constituted 1105 (75%) patients, and overall median survival was 29 months (IQR 15-68). Patient presentation changed, with epigastric discomfort now the most common presentation (70%). An improvement in mortality from 5 to 2% (p < 0.001) was seen over the time period, and overall survival improved from 22 to 56 months (p < 0.001); however, morbidity increased from 54 to 68% (p = 0.004). CONCLUSIONS: Long-term outcomes have significantly improved over the 30-year study period. In addition, mortality and length of stay have improved despite an increase in complications. The reasons for this are multifactorial and include the use of perioperative chemo(radio)therapy, the introduction of an enhanced recovery pathway, and improved patient selection.

Coherence function-encoded optical palpation.

Optical palpation maps stress at the surface of biological tissue into 2D images. It relies on measuring surface deformation of a compliant layer, which to date has been performed with optical coherence tomography (OCT). OCT-based optical palpation holds promise for improved clinical diagnostics; however, the complexity and cost hinder broad adoption. In this Letter, we introduce coherence function-encoded optical palpation (CFE-OP) using a novel optical profilometry technique that exploits the envelope of the coherence function rather than its peak position, which is typically used to retrieve depth information. CFE-OP utilizes a Fabry-Perot laser diode (bandwidth, 2.2 nm) and a single photodiode in a Michelson interferometer to detect the position along the coherence envelope as a function of path length. This technique greatly reduces complexity and cost in comparison to the OCT-based approach. We perform CFE-OP on phantom and excised human breast tissue, demonstrating comparable mechanical contrast to OCT-based optical palpation and the capability to distinguish stiff tumor from soft benign tissue.

Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7.

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

Temporal dynamics of trematode intermediate snail host environmental DNA in small water body habitats.

Environmental DNA (eDNA) surveying has potential to become a powerful tool for sustainable parasite control. As trematode parasites require an intermediate snail host that is often aquatic or amphibious to fulfil their lifecycle, water-based eDNA analyses can be used to screen habitats for the presence of snail hosts and identify trematode infection risk areas. The aim of this study was to identify climatic and environmental factors associated with the detection of Galba truncatula eDNA. Fourteen potential G. truncatula habitats on two farms were surveyed over a 9-month period, with eDNA detected using a filter capture, extraction and PCR protocol with data analysed using a generalized estimation equation. The probability of detecting G. truncatula eDNA increased in habitats where snails were visually detected, as temperature increased, and as water pH decreased (P < 0.05). Rainfall was positively associated with eDNA detection in watercourse habitats on farm A, but negatively associated with eDNA detection in watercourse habitats on farm B (P < 0.001), which may be explained by differences in watercourse gradient. This study is the first to identify factors associated with trematode intermediate snail host eDNA detection. These factors should be considered in standardized protocols to evaluate the results of future eDNA surveys.

Fatigue crack growth in epoxy polymer nanocomposites.

The present paper describes detailed analyses of experimental data for the cyclic-fatigue behaviour of epoxy nanocomposite polymers. It has been shown that the data may be interpreted using the Hartman-Schijve relationship to yield a unique, 'master', linear relationship for each epoxy nanocomposite polymer. By fitting the experimental data to the Hartman-Schijve relationship, two key materials parameters may be deduced: (i) the term A, which may be thought of as the fatigue equivalent to the quasi-static value of the fracture energy, Gc, and (ii) the fatigue threshold value, [Formula: see text], below which no significant fatigue crack growth (FCG) occurs. It has then been established that the values of these parameters, together with the slope, n, and intercept, D, of the Hartman-Schijve master relationship, may be used (i) to compute the experimental results measured for the fatigue behaviour of the epoxy nanocomposite polymers, (ii) to understand the observed fracture and fatigue behaviour of these materials with respect to the structure of the epoxy nanocomposite polymers, and (iii) to deduce the 'upper-bound', i.e. 'worst-case', FCG rate curve which may be used by industry as a material development, material selection, design and service-life prediction tool when these epoxy nanocomposite polymers are used in engineering applications such as structural adhesives and/or as matrices in fibre-reinforced composites. This article is part of a discussion meeting issue 'A cracking approach to inventing new tough materials: fracture stranger than friction'.

Practitioner review: Co-design of digital mental health technologies with children and young people.

BACKGROUND: There is increasing interest in digital technologies to help improve children and young people's mental health, and the evidence for the effectiveness for these approaches is rising. However, there is concern regarding levels of user engagement, uptake and adherence. Key guidance regarding digital health interventions stress the importance of early user input in the development, evaluation and implementation of technologies to help ensure they are engaging, feasible, acceptable and potentially effective. Co-design is a process of active involvement of stakeholders, requiring a change from the traditional approaches to intervention development. However, there is a lack of literature to inform the co-design of digital technologies to help child and adolescent mental health. METHODS: We reviewed the literature and practice in the co-design of digital mental health technologies with children and young people. We searched Medline, PsycInfo and Web of Science databases, guidelines, reviews and reference lists, contacted key authors for relevant studies, and extracted key themes on aspects of co-design relevant to practice. We supplemented this with case studies and methods reported by researchers working in the field. RESULTS: We identified 25 original articles and 30 digital mental health technologies that were designed/developed with children and young people. The themes identified were as follows: principles of co-design (including potential stakeholders and stages of involvement), methods of involving and engaging the range of users, co-designing the prototype and the challenges of co-design. CONCLUSIONS: Co-design involves all relevant stakeholders throughout the life and research cycle of the programme. This review helps to inform practitioners and researchers interested in the development of digital health technologies for children and young people. Future work in this field will need to consider the changing face of technology, methods of engaging with the diversity in the user group, and the evaluation of the co-design process and its impact on the technology.

Ethnicity classification systems for public health surveys: experiences from HIV behavioural surveillance among men who have sex with men.

BACKGROUND: Race and ethnicity classification systems have considerable implications for public health, including the potential to reveal or mask inequities. Given increasing "super-diversity" and multiple racial/ethnic identities in many global settings, especially among younger generations, different ethnicity classification systems can underrepresent population heterogeneity and can misallocate and render invisible Indigenous people and ethnic minorities. We investigated three ethnicity classification methods and their relationship to sample size, socio-demographics and sexual health indicators. METHODS: We examined data from New Zealand's HIV behavioural surveillance programme for men who have sex with men (MSM) in 2006, 2008, 2011, and 2014. Participation was voluntary, anonymous and self-completed; recruitment was via community venues and online. Ethnicity allowed for multiple responses; we investigated three methods of dealing with these: Prioritisation, Single/Combination, and Total Response. Major ethnic groups included Asian, European, indigenous Maori, and Pacific. For each classification method, statistically significant associations with ethnicity for demographic and eight sexual health indicators were assessed using multivariable logistic regression. RESULTS: Overall, 10,525 MSM provided ethnicity data. Classification methods produced different sample sizes, and there were ethnic disparities for every sexual health indicator. In multivariable analysis, when compared with European MSM, ethnic differences were inconsistent across classification systems for two of the eight sexual health outcomes: Maori MSM were less likely to report regular partner condomless anal intercourse using Prioritisation or Total Response but not Single/Combination, and Pacific MSM were more likely to report an STI diagnosis when using Total Response but not Prioritisation or Single/Combination. CONCLUSIONS: Different classification approaches alter sample sizes and identification of health inequities. Future research should strive for equal explanatory power of Indigenous and ethnic minority groups and examine additional measures such as socially-assigned ethnicity and experiences of discrimination and racism. These findings have broad implications for surveillance and research that is used to inform public health responses.

Indigenous perspectives on education for sustainable healthcare.

A range of global environmental changes are contributing to an increasing global burden of disease. Since human health and well-being are intimately associated with the health of our planet, healthcare providers will not only be charged with caring for this expanding disease burden but will also need to become more environmentally sustainable in their professional practice. There is thus an urgent need in the health professions education community to prioritize environmentally sustainable healthcare practice, which must include and prioritize Indigenous voices and Indigenous knowledge systems. Critical global dialogue on the significance of Indigenous knowledge systems in educating health professionals for a sustainable future will be required if we are ready to ensure the generations that follow us are able to live healthy lives. Indigenous ways of 'being' in the world, which emphasize the importance of interconnection and reciprocal stewardship with everything in the natural world, are essential for advancing education for sustainable healthcare and overall well-being. Given the colonial legacy however, Indigenous people, despite their essential knowledge systems and abilities, still face many barriers accessing safe decolonizing spaces and presence in health professions education, which needs to be addressed.

Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis.

BACKGROUND: Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough. METHODS: Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency. RESULTS: Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole. CONCLUSIONS: A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Dynamic changes in intrathymic ILC populations during murine neonatal development.

Members of the innate lymphoid cell (ILC) family have been implicated in the development of thymic microenvironments and the recovery of this architecture after damage. However, a detailed characterization of this family in the thymus is lacking. To better understand the thymic ILC compartment, we have utilized multiple in vivo models including the fate mapping of inhibitor of DNA binding-2 (Id2) expression and the use of Id2 reporter mice. Our data demonstrate that ILCs are more prominent immediately after birth, but were rapidly diluted as the T-cell development program increased. As observed in the embryonic thymus, CCR6+ NKp46- lymphoid tissue inducer (LTi) cells were the main ILC3 population present, but numbers of these cells swiftly declined in the neonate and ILC3 were barely detectable in adult thymus. This loss of ILC3 means ILC2 are the dominant ILC population in the thymus. Thymic ILC2 were able to produce IL-5 and IL-13, were located within the medulla, and did not result from ILC3 plasticity. Furthermore, in WT mice, thymic ILC2 express little RANKL (receptor activator of nuclear factor kappa-B ligand) arguing that functionally, these cells provide different signals to LTi cells in the thymus. Collectively, these data reveal a dynamic switch in the ILC populations of the thymus during neonatal development.

Why cultural safety rather than cultural competency is required to achieve health equity: a literature review and recommended definition.

BACKGROUND: Eliminating indigenous and ethnic health inequities requires addressing the determinants of health inequities which includes institutionalised racism, and ensuring a health care system that delivers appropriate and equitable care. There is growing recognition of the importance of cultural competency and cultural safety at both individual health practitioner and organisational levels to achieve equitable health care. Some jurisdictions have included cultural competency in health professional licensing legislation, health professional accreditation standards, and pre-service and in-service training programmes. However, there are mixed definitions and understandings of cultural competency and cultural safety, and how best to achieve them. METHODS: A literature review of 59 international articles on the definitions of cultural competency and cultural safety was undertaken. Findings were contextualised to the cultural competency legislation, statements and initiatives present within Aotearoa New Zealand, a national Symposium on Cultural Competence and Maori Health, convened by the Medical Council of New Zealand and Te Ohu Rata o Aotearoa - Maori Medical Practitioners Association (Te ORA) and consultation with Maori medical practitioners via Te ORA. RESULTS: Health practitioners, healthcare organisations and health systems need to be engaged in working towards cultural safety and critical consciousness. To do this, they must be prepared to critique the 'taken for granted' power structures and be prepared to challenge their own culture and cultural systems rather than prioritise becoming 'competent' in the cultures of others. The objective of cultural safety activities also needs to be clearly linked to achieving health equity. Healthcare organisations and authorities need to be held accountable for providing culturally safe care, as defined by patients and their communities, and as measured through progress towards achieving health equity. CONCLUSIONS: A move to cultural safety rather than cultural competency is recommended. We propose a definition for cultural safety that we believe to be more fit for purpose in achieving health equity, and clarify the essential principles and practical steps to operationalise this approach in healthcare organisations and workforce development. The unintended consequences of a narrow or limited understanding of cultural competency are discussed, along with recommendations for how a broader conceptualisation of these terms is important.