Neoblast-like stem cells of Fasciola hepatica.

The common liver fluke (Fasciola hepatica) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces. Here, we investigate and characterise the proliferating cells that underpin development in F. hepatica. We provide evidence that these cells are capable of self-renewal, differentiation, and are sensitive to ionising radiation- all attributes of neoblasts in other flatworms. Changes in cell proliferation were also noted during the early stages of in vitro juvenile growth/development (around four to seven days post excystment), which coincided with a marked reduction in the nuclear area of proliferating cells. Furthermore, we generated transcriptomes from worms following irradiation-based ablation of neoblasts, identifying 124 significantly downregulated transcripts, including known stem cell markers such as fgfrA and plk1. Sixty-eight of these had homologues associated with neoblast-like cells in Schistosoma mansoni. Finally, RNA interference mediated knockdown of histone h2b (a marker of proliferating cells), ablated neoblast-like cells and impaired worm development in vitro. In summary, this work demonstrates that the proliferating cells of F. hepatica are equivalent to neoblasts of other flatworm species and demonstrate that they may serve as attractive targets for novel anthelmintics.

'Border Country': health law in a devolved UK.

How are we to understand and research health law under devolution in the UK? Building on work in law and geography, we argue that the figure of the border is key to the production and implementation of devolved health law and the variety of forms that this takes. The utility of border thinking in this context is shown through a review of thematic areas, including infectious disease control, access to health care, and abortion, each instantiating a distinct bordering process. In each, we consider recent developments in policy and legislation, framed with reference to constitutional change, and the politics of devolution in the UK. Taking Wales as an exemplary site, we argue that health law produces borders in traditional and non-traditional places. It creates and blurs territories. It is equally constituted by pluralistic bordering practices. On the basis of this theoretically informed review, we conclude by proposing a cross-disciplinary legal, ethical, and socio-legal research agenda for future research.

ADHD prescription patterns and medication adherence in children and adolescents during the COVID-19 pandemic in an urban academic setting.

BACKGROUND: COVID-19 impacted all students, especially those with attention deficit hyperactivity disorder (ADHD), putting them at risk for disruption to their medication regimen and school performance. Our study aimed to identify if ADHD medication regimens were disrupted through analyzing prescription refills and if telehealth management demonstrated a higher rate of adherence. METHODS: A total of 396 patients from the General Academic Pediatrics (GAP) clinic at Children's Hospital of The King's Daughters (CHKD) were included in the study. Patients were between the ages of 8-18 with a history of ADHD for three or more years that was medically managed with four or more prescription refills between January 2019 and May 2022. A retrospective chart review collected age, sex, race, refill schedule, appointment schedule, and number of telehealth appointments. Data analysis compared the variables and defined "pre-pandemic months" as January 2019 through March 2020 and "pandemic months" as April 2020 through June 2022. RESULTS: The total percentage of patients who had their ADHD medications during pre-pandemic months ranged from 40 to 66% versus 31-44% during pandemic months. Additionally, the total percentage of patients who had quarterly ADHD management appointments during pre-pandemic months ranged between 59 and 70% versus 33-50% during pandemic months. The number of months with ADHD prescription refills over the last three years was significantly higher among those who had both virtual and in-person visits than those who had just in-person visits, p < 0.001. Regarding race, Black patients had a lower number of medication refills compared to White patients when controlled for appointment type. They also had a lower number of total appointments, but there was not a significant difference in the number of virtual appointments. CONCLUSIONS: Since the start of the pandemic, ADHD patients have both refilled their prescriptions and returned to clinic less frequently. This data suggests a need to re-evaluate the ADHD symptoms of GAP patients periodically and return them to a more consistent medication regimen. Telehealth appointments are a potential solution to increase adherence. However, racial inequities found in this study need to be addressed.

Navigating quality and safety in your health system: understanding the alphabet soup.

Entering any new healthcare system today requires thorough knowledge about its quality and safety structure and culture. Learning that language is generally the first step in gaining a better understanding of how systems function. This overview of common mnemonics in the quality and safety world will provide the reader with better comprehension of their quality systems within their institutions. Healthcare providers should understand how patient safety organizations were established and the importance of our safety event classification system, along with the ability to recognize gaps in care that highlight opportunities for improvement. In addition, this review provides explanations of error prevention tools used every day to help new colleagues communicate better and share situational awareness to keep patients safe. Lastly, utilization of standard quality improvement tools can facilitate quality improvement projects and assist all healthcare systems to become highly reliable organizations.

MOF-based heterogeneous catalysis in continuous flow via incorporation onto polymer-based spherical activated carbon supports.

We present an approach to harnessing the tuneable catalytic properties of complex nanomaterials for continuous flow heterogeneous catalysis by combining them with the scalable and industrially implementable properties of carbon pelleted supports. This approach, in turn, will enable these catalytic materials, which largely currently exist in forms unsuitable for this application (e.g. powders), to be fully integrated into large scale, chemical processes. A composite heterogeneous catalyst consisting of a metal-organic framework-based Lewis acid, MIL-100(Sc), immobilised onto polymer-based spherical activated carbon (PBSAC) support has been developed. The material was characterised by focused ion beam-scanning electron microscopy-energy dispersive X-ray analysis, powder X-ray diffraction, N2 adsorption, thermogravimetric analysis, atomic absorption spectroscopy, light scattering and crush testing with the catalytic activity studied in continuous flow. The mechanically robust spherical geometry makes the composite material ideal for application in packed-bed reactors. The catalyst was observed to operate without any loss in activity at steady state for 9 hours when utilised as a Lewis acid catalyst for the intramolecular cyclisation of (±)-citronellal as a model reaction. This work paves the way for further development into the exploitation of MOF-based continuous flow heterogeneous catalysis.

Asthma and landscape fire smoke: A Thoracic Society of Australia and New Zealand position statement.

Landscape fires are increasing in frequency and severity globally. In Australia, extreme bushfires cause a large and increasing health and socioeconomic burden for communities and governments. People with asthma are particularly vulnerable to the effects of landscape fire smoke (LFS) exposure. Here, we present a position statement from the Thoracic Society of Australia and New Zealand. Within this statement we provide a review of the impact of LFS on adults and children with asthma, highlighting the greater impact of LFS on vulnerable groups, particularly older people, pregnant women and Aboriginal and Torres Strait Islander peoples. We also highlight the development of asthma on the background of risk factors (smoking, occupation and atopy). Within this document we present advice for asthma management, smoke mitigation strategies and access to air quality information, that should be implemented during periods of LFS. We promote clinician awareness, and the implementation of public health messaging and preparation, especially for people with asthma.

Determination of climatologically suitable places in Türkiye for feedlot cattle production using the Comprehensive Climate Index model.

The purpose of this study was to determine climatologically suitable places to raise feedlot cattle in Türkiye. The Comprehensive Climate Index (CCI), a model that enables one to quantify beef cattle performance based on environmental conditions (temperature, relative humidity, wind speed, solar radiation) at any time in the year, was used to predict dry matter intake (DMI), average daily gain (ADG), and feed efficiency (FE) of feedlot cattle. Thirty years of daily average temperature, relative humidity, and wind speed values were obtained for 15 cities, namely, Antalya, Balikesir, Çorum, Diyarbakir, Edirne, Elazig, Erzincan, Erzurum, Eskisehir, Isparta, Izmir, Kayseri, Konya, Sivas, and Van. Measured daily solar radiation values were not available and values were calculated based on a formula that takes hemisphere, latitude, and day of the year into account. Since mostly dairy breed calves are placed into a feedlot in Türkiye, the Holstein option in the CCI model was chosen to calculate the maintenance energy requirement. Based on previous feedlot feeding studies conducted in Türkiye, it was assumed that calves would be placed on feed at 250 kg and be marketed at 520 kg, that the diet would have 2600 kcal/kg metabolic energy, and that DMI would be 2.31% of the body weight. Results indicate that cattle raised in Antalya (the hottest place) and Erzurum (the coldest place) had the lowest and highest DMI, respectively (P<0.05). Summer months depressed the DMI of cattle in hotter cities and winter months increased the DMI of cattle in colder cities (P<0.05). Feedlot cattle raised in hotter and colder regions of Türkiye had lower ADG than other places having a more temperate climate (P<0.05). In general, cattle raised in a hotter climate had better FE than those raised in a cold climate (P<0.05).

Impact of Landscape Fire Smoke Exposure on Patients With Asthma With or Without Laryngeal Hypersensitivity.

BACKGROUND: Individuals with asthma experienced severe and prolonged symptoms after the Australian 2019 to 2020 landscape fire. Many of these symptoms, such as throat irritation, occur in the upper airway. This suggests that laryngeal hypersensitivity contributes to persistent symptoms after smoke exposure. OBJECTIVE: This study examined the relationship between laryngeal hypersensitivity and symptoms, asthma control, and health impacts on individuals exposed to landscape fire smoke. METHOD: The study was a cross-sectional survey of 240 participants in asthma registries who were exposed to smoke during the 2019 to 2020 Australian fire. The survey, completed between March and May 2020, included questions about symptoms, asthma control, and health care use, as well as the Laryngeal Hypersensitivity Questionnaire. Daily concentration levels of particulate matter less than or equal to 2.5 µm in diameter were measured over the 152-day study period. RESULTS: The 49 participants with laryngeal hypersensitivity (20%) had significantly more asthma symptoms (96% vs 79%; P = .003), cough (78% vs 22%; P < .001), and throat irritation (71% vs 38%; P < .001) during the fire period compared with those without laryngeal hypersensitivity. Participants with laryngeal hypersensitivity had greater health care use (P ≤ .02), more time off work (P = .004), and a reduced capacity to participate in usual activities (P < .001) during the fire period, as well as poorer asthma control during the follow-up (P = .001). CONCLUSIONS: Laryngeal hypersensitivity is associated with persistent symptoms, reports of lower asthma control, and increased health care use in adults with asthma who were exposed to landscape fire smoke. Management of laryngeal hypersensitivity before, during, or immediately after landscape fire smoke exposure might reduce the symptom burden and health impact.

Severe asthma ILC2s demonstrate enhanced proliferation that is modified by biologics.

BACKGROUND AND OBJECTIVE: Type 2 (T2) innate lymphoid cells (ILC2s) contribute to airway inflammation and disease in asthma. We hypothesize that ILC2s isolated from people with severe allergic and eosinophilic asthma would exhibit an enhanced T2 inflammatory activity that would be altered following treatment with mepolizumab and omalizumab. We compare peripheral blood (PB) isolated ILC2's proliferative capacity, IL-5 and IL-13 secretion and phenotype between healthy without asthma (HC), non-asthma allergic (NAA), mild asthma (MA) and severe allergic and eosinophilic asthma (SA) subjects. We then determined the impact of 6 months treatment with either mepolizumab or omalizumab on ILC2s physiology of SA subjects. METHODS: ILC2s were sorted and cultured in the presence of IL-2, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) for 14 days. ILC2s proliferation, phenotypes and functions were assessed using flowcytometry. The ILC2s response was then reassessed following clinically successful treatment of SA subjects with mepolizumab and omalizumab. RESULTS: SA ILC2s demonstrated increased proliferative capacity, TSLP receptor (TSLPR), GATA3 and NFATc1 protein expressions and increased IL-5 and IL-13 release. ILC2s were also capable of releasing IL-6 in response to stimulation. Mepolizumab treatment reduced ILC2s proliferative capacity and expression of TSLPR, GATA3 and NFATc1. Both mepolizumab and omalizumab were associated with reduced ILC2s release of IL-5 and IL-13, only mepolizumab reduced IL-6. CONCLUSION: ILC2s from severe allergic and eosinophilic asthma demonstrated an active phenotype typified by increased proliferation, TSLPR, GATA3 and NFATc1 expression and increased IL-5, IL-13 and IL-6 release. Mepolizumab reduced markers of ILC2s activation.

Mitochondria in health, disease, and aging.

Mitochondria are well known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. Although oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.

A rodent model for Dirofilaria immitis, canine heartworm: parasite growth, development, and drug sensitivity in NSG mice.

Heartworm disease, caused by Dirofilaria immitis, remains a significant threat to canines and felines. The development of parasites resistant to macrocyclic lactones (ML) has created a significant challenge to the control of the infection. The goal of this study was to determine if mice lacking a functional immune response would be susceptible to D. immitis. Immunodeficient NSG mice were susceptible to the infection, sustaining parasites for at least 15 weeks, with infective third-stage larvae molting and developing into the late fourth-stage larvae. Proteomic analysis of host responses to the infection revealed a complex pattern of changes after infection, with at least some of the responses directed at reducing immune control mechanisms that remain in NSG mice. NSG mice were infected with isolates of D. immitis that were either susceptible or resistant to MLs, as a population. The susceptible isolate was killed by ivermectin whereas the resistant isolate had improved survivability, while both isolates were affected by moxidectin. It was concluded that D. immitis survives in NSG mice for at least 15 weeks. NSG mice provide an ideal model for monitoring host responses to the infection and for testing parasites in vivo for susceptibility to direct chemotherapeutic activity of new agents.

Parent-Child Interaction Therapy for Children with Disruptive Behaviors and Autism: A Randomized Clinical Trial.

A relatively large number of children with autism spectrum disorder (ASD) exhibit disruptive behavioral problems. While accumulating data have shown behavioral parent training programs to be efficacious in reducing disruptive behaviors for this population, there is a dearth of literature examining the impact of such programs across the range of ASD severity. To evaluate the effectiveness of Parent-Child Interaction Therapy (PCIT), an evidence-based treatment for children with problem behaviors and their families, in reducing disruptive behaviors among children (4-10 years) with ASD (without intellectual disabilities). Fifty-five children (85.5% male, 7.15 years; SD 1.72) were enrolled from pediatric offices and educational settings into a randomized clinical trial (PCIT: N = 30; Control: N = 25). PCIT families demonstrated a significant reduction in child disruptive behaviors, increase in positive parent-child communication, improvement in child compliance, and reduction in parental stress compared to the control group. Exploratory analyses revealed no differential treatment response based on ASD severity, receptive language, and age. Results are promising for the use of PCIT with children demonstrating disruptive behaviors across the autism spectrum.

Parent's Hesitation with COVID-19 Vaccinations in Infants and Children Aged 6 Months to 5 Years.

We implemented an in-person survey of parents/guardians concerning COVID-19 vaccine for a predominantly African-American Medicaid pediatric patient population between the ages of 6-59 months at a Children's Hospital General Pediatric Clinic in Norfolk, VA. Vaccine hesitancy was predominantly based on concerns surrounding safety and overall need for the vaccine.

Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. METHODS AND FINDINGS: In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. CONCLUSION: We present a first comprehensive molecular characterization of differences between two ARDS etiologies-COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS.

Background: Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. Methods and Findings: In this study, we compared COVID-19 ARDS (n=43) and bacterial sepsis-induced (non-COVID-19) ARDS (n=24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within-ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. Conclusion: We present a first comprehensive molecular characterization of differences between two ARDS etiologies - COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

Multidisciplinary care in chronic airway diseases: the Newcastle model.

Chronic airway diseases including asthma and COPD are prevalent and high-burden conditions with the majority of patients successfully managed in the primary care setting. However, for some patients with more complex disease such as difficult-to-treat or severe asthma, or complex COPD, tertiary care is required. This review provides an overview of the successful tertiary care multidisciplinary respiratory service that operates in Newcastle, New South Wales, Australia, which has been integrated into the tertiary care outpatient clinics for almost three decades. The service is multifaceted in terms of the clinical care it provides; it includes an "Inpatient Service", "Asthma Management Service", "Difficult Airways Clinic", "Drug Administration Clinic", "Rapid Access Clinic" and "Pulmonary Rehabilitation", and has an integrated research programme. The core of the multidisciplinary approach to airway diseases is a person-centred model of care, the "Treatable Traits" approach. The staffing of this service comprises consultant physicians, respiratory advanced trainees, respiratory scientists, physiotherapists, speech pathologists, nurse specialists and a nurse consultant. Patients that present to this service undergo an initial assessment and clinical review by team members, synthesis of relevant data, and development of a diagnosis and management plan. Based on this clinical review, specific interventions are determined according to the traits identified. Over time the service has evolved to accommodate the increasing numbers of patients requiring access to the Difficult Airways Clinic assessment and therapies. This has been facilitated by partnering with the Centres of Excellence in Severe Asthma and Treatable Traits to develop educational and practice management tools.

COVID- 19 and human right to food: lived experiences of the urban poor in Kenya with the impacts of government's response measures, a participatory qualitative study.

BACKGROUND: Globally, governments put in place measures to curb the spread of COVID-19. Information on the effects of these measures on the urban poor is limited. This study aimed to explore the lived experiences of the urban poor in Kenya in the context of government's COVID-19 response measures and its impact on the human right to food. METHODS: A qualitative study was conducted in two informal settlements in Nairobi between January and March 2021. Analysis draws on eight focus group discussions, eight in-depth interviews, 12 key informant interviews, two photovoice sessions and three digital storytelling sessions. Phenomenology was applied to understand an individual's lived experiences with the human right to food during COVID - 19. Thematic analysis was performed using NVIVO software. RESULTS: The human right to food was affected in various ways. Many people lost their livelihoods, affecting affordability of food, due to response measures such as social distancing, curfew, and lockdown. The food supply chain was disrupted causing limited availability and access to affordable, safe, adequate, and nutritious food. Consequently, hunger and an increased consumption of low-quality food was reported. Social protection measures were instituted. However, these were inadequate and marred by irregularities. Some households resorted to scavenging food from dumpsites, skipping meals, sex-work, urban-rural migration and depending on food donations to survive. On the positive side, some households resorted to progressive measures such as urban farming and food sharing in the community. Generally, the response measures could have been more sensitive to the human rights of the urban poor. CONCLUSIONS: The government's COVID-19 restrictive measures exacerbated the already existing vulnerability of the urban poor to food insecurity and violated their human right to food. Future response measures should be executed in ways that respect the human right to food and protect marginalized people from resultant vulnerabilities.