Allergic Fungal Rhinosinusitis Linked to Other Hyper-IgE Syndromes Through Defective Th17 Responses.

BACKGROUND: In a gene expression analysis comparing sinus mucosa from allergic fungal rhinosinusitis (AFRS) to that from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) subjects, the antimicrobial peptide (AMP), histatin 1 (HTN1), was found to be the most differentially down-regulated gene in AFRS. OBJECTIVE: To identify the molecular etiology of the down regulated expression of HTN1 METHODS: We used RT-PCR to compare the expression of AMPs and utilized a fungistasis assay to evaluate the anti-fungal activity of sinus secretions. Using flow cytometry, we characterized the presence of Th17/22 cells and STAT signaling from AFRS, non-AFRS CRSwNP patients, and healthy controls. RESULTS: We confirm the decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. We show that IL-22 and IL-22-producing T cells are deficient within sinus mucosa of AFRS subjects. In vitro studies demonstrated a defect in IL-6/STAT3 signaling critical for TH17/TH22 differentiation. Epithelial cells from AFRS patients could express AMPs when stimulated with exogenous IL-22/IL-17 and circulating Th17 cell abundance was normal. CONCLUSION: Similar to other hyper-IgE syndromes, but distinct from CRSwNP, AFRS patients express a defect in STAT3 activation limited to IL-6-dependent STAT3 phosphorylation that is critical for Th17/TH22 differentiation. This defect leads to a local deficiency of IL-17/IL-22 cytokines and deficient AMP expression within diseased sinus mucosa of AFRS patients. Our findings support evaluation of therapeutic approaches that enhance airway AMP production in AFRS.

A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Providing environmentally sustainable nephrology care: focus in low- and middle-income countries.

Health care on a global scale significantly contributes to carbon emissions, with high-income countries being the primary culprits. Within health care, dialysis plays a significant role as a major source of emissions. Low- and middle-income countries have a high burden of kidney disease and are facing an increasing demand for dialysis. This reality presents multiple opportunities to plan for environmentally sustainable and quality kidney care. By placing a stronger emphasis on primary and secondary prevention of kidney disease and its progression, within the framework of universal health coverage, as well as empowering patients to enhance self-care, we can significantly reduce the need for costly and environmentally detrimental kidney replacement therapy. Mandating the adoption of lean and innovative low-carbon dialysis practices while also promoting the growth of kidney transplantation would enable low- and middle-income countries to take the lead in implementing environmentally friendly nephrology practices and reducing costs, thus optimizing sustainability and the well-being of individuals living with kidney disease.

Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis.

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid ß (Aß)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. Recognition of Aß-like peptides and candidalysin promotes fungal clearance from the brain, and disruption of candidalysin recognition through CD11b markedly prolongs C. albicans cerebral mycosis. Thus, C. albicans is cleared from the brain through innate immune mechanisms involving Saps, Aß, candidalysin, and CD11b.

Initial impact of the COVID-19 pandemic on public health training: participatory action research to understand experiences in the East Midlands.

BACKGROUND: Specialty public health training consists of 48 months of practice across the domains of health protection, healthcare public health and health improvement.With the onset of the COVID-19 pandemic, activity pivoted towards pandemic management and the response became a significant element of registrar practice.This research aimed to understand the impact of this shift in focus on registrars' role and training. METHODS: Participatory action research comprising (i) a reflective survey sent to all specialty registrars in the East Midlands training region and (ii) Delphi rounds with survey respondents to generate consensus and define themes. RESULTS: Sixteen (44%) registrars completed the survey with 12 (75%) participating in the Delphi rounds. The early pandemic response stages both challenged and re-affirmed registrars' role and identity in public health and training while providing unique and diverse learning and development. Underpinning these themes is a variability in experience depending on prior experience, placement and training stage. CONCLUSIONS: The pandemic impacted the practice, training and home-life of registrars who were required to negotiate significant challenge and uncertainty. This original work adds to a growing body of correspondence and opinion pieces articulating the experiences and challenges of medical and public health education during a pandemic.

Fit for Duty: Lessons Learned from Outpatient and Homebound Hematopoietic Cell Transplantation to Prepare Family Caregivers for Home-Based Care.

In the past decade, the demand for home-based care has been amplified by the Coronavirus disease 2019 pandemic. Home-based care has significant benefits for patients, their families, and healthcare systems, but it relies on the often-invisible workforce of family and friend caregivers who shoulder essential health care responsibilities, frequently with inadequate training and support. Hematopoietic cell transplantation (HCT), a potentially curative but intensive treatment for many patients with blood disorders, is being increasingly offered in home-based care settings and necessitates the involvement of family caregivers for significant patient care responsibilities. However, guidelines for supporting and preparing HCT caregivers to effectively care for their loved ones at home have not yet been established. Here, informed by the literature and our collective experience as clinicians and researchers who care for diverse patients with hematologic malignancies undergoing HCT, we provide considerations and recommendations to better support and prepare family caregivers in home-based HCT and, by extension, family caregivers supporting patients with other serious illnesses at home. We suggest tangible ways to screen family caregivers for distress and care delivery challenges, educate and train them to prepare for their caregiving role, and create an infrastructure of support for family caregivers within this emerging care delivery model.

Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

On the identity of the banded gourami Trichogaster fasciata with notes on the taxonomic status of Trichopodus bejeus (Teleostei: Perciformes: Osphronemidae).

Based on its original description and putative topotypes, the identity of the banded gourami Trichogaster fasciata is resolved. Trichogaster lalia is a synonym of T. fasciata, and the name Trichogaster bejeus is applied to the species hitherto identified as T. fasciata. T. fasciata is distinguished from its congeners in the shape of caudal fin, colouration, lip morphology and meristic and mensural characters.

Accurate Measurement of the Optical Properties of Single Aerosol Particles Using Cavity Ring-Down Spectroscopy.

New approaches for the sensitive and accurate quantification of aerosol optical properties are needed to improve the current understanding of the unique physical chemistry of airborne particles and to explore their roles in fields as diverse as chemical manufacturing, healthcare, and atmospheric science. We have pioneered the use of cavity ring-down spectroscopy (CRDS), with concurrent angularly resolved elastic light scattering measurements, to interrogate the optical properties of single aerosol particles levitated in optical and electrodynamic traps. This approach enables the robust quantification of optical properties such as extinction cross sections for individual particles of known size. Our measurements can now distinguish the scattering and absorption contributions to the overall light extinction, from which the real and imaginary components of the complex refractive indices can be retrieved and linked to chemical composition. In this Feature Article, we show that this innovative measurement platform enables accurate and precise optical measurements for spherical and nonspherical particles, whether nonabsorbing or absorbing at the CRDS probe wavelength. We discuss the current limitations of our approach and the key challenges in physical and atmospheric chemistry that can now be addressed by CRDS measurements for single aerosol particles levitated in controlled environments.

Robust but weak winter atmospheric circulation response to future Arctic sea ice loss.

The possibility that Arctic sea ice loss weakens mid-latitude westerlies, promoting more severe cold winters, has sparked more than a decade of scientific debate, with apparent support from observations but inconclusive modelling evidence. Here we show that sixteen models contributing to the Polar Amplification Model Intercomparison Project simulate a weakening of mid-latitude westerlies in response to projected Arctic sea ice loss. We develop an emergent constraint based on eddy feedback, which is 1.2 to 3 times too weak in the models, suggesting that the real-world weakening lies towards the higher end of the model simulations. Still, the modelled response to Arctic sea ice loss is weak: the North Atlantic Oscillation response is similar in magnitude and offsets the projected response to increased greenhouse gases, but would only account for around 10% of variations in individual years. We further find that relationships between Arctic sea ice and atmospheric circulation have weakened recently in observations and are no longer inconsistent with those in models.

Soil organic nitrogen: an overlooked but potentially significant contribution to crop nutrition.

BACKGROUND: For more than a century, crop N nutrition research has primarily focused on inorganic N (IN) dynamics, building the traditional model that agricultural plants predominantly take up N in the form of NO3 - and NH4 +. However, results reported in the ecological and agricultural literature suggest that the traditional model of plant N nutrition is oversimplified. SCOPE: We examine the role of organic N (ON) in plant N nutrition, first by reviewing the historical discoveries by ecologists of plant ON uptake, then by discussing the advancements of key analytical techniques that have furthered the cause (stable isotope and microdialysis techniques). The current state of knowledge on soil ON dynamics is analyzed concurrently with recent developments that show ON uptake and assimilation by agricultural plant species. Lastly, we consider the relationship between ON uptake and nitrogen use efficiency (NUE) in an agricultural context. CONCLUSIONS: We propose several mechanisms by which ON uptake and assimilation may increase crop NUE, such as by reducing N assimilation costs, promoting root biomass growth, shaping N cycling microbial communities, recapturing exuded N compounds, and aligning the root uptake capacity to the soil N supply in highly fertilized systems. These hypothetical mechanisms should direct future research on the topic. Although the quantitative role remains unknown, ON compounds should be considered as significant contributors to plant N nutrition.

Development and evaluation of a novel pre-operative surgery school and behavioural change intervention for patients undergoing elective major surgery: Fit-4-Surgery School.

Group pre-operative education has usually been limited to conditioning expectations and providing education. Prehabilitation has highlighted modifiable lifestyle factors that are amenable to change and may improve clinical outcomes. We instituted a pre-operative 'Fit-4-Surgery School' for patients scheduled for major surgery, to educate and promote healthy behaviour. We evaluated patients' views having attended the school, and after surgery we asked how it had changed their behaviour with a lifestyle questionnaire. The school was launched in May 2016 and was attended by 586/1017 (58%) of invited patients. Patients who did not attend: lived further away, median (IQR [range]) 8 (4-19 [0-123]) miles vs. 5 (3-14 [0-172]) miles, p < 0.001; and were more deprived, Index of Multiple Deprivation Rank decile median (IQR [range]), 6 (4-8 [1-10]) vs. 7 (4-9 [1-10]), p = 0.04. Of the 492/586 (84%) participants who completed an evaluation questionnaire, 462 (94%) would recommend the school to a friend having surgery and 296 (60%) planned lifestyle changes. After surgery, 232/586 (40%) completed a behavioural change questionnaire, 106 (46%) of whom reported changing at least one lifestyle factor, most commonly by increasing exercise. The pre-operative school was acceptable to patients.

Evaluation of biochars as carriers for Rhizobium leguminosarum.

Peat is the standard carrier material used for commercial microbial inoculants produced in Canada and the United States. Peat is a slowly renewable resource and its production is extremely vulnerable to variable weather conditions. Furthermore, it may not be widely available in all countries. We investigated the potential to develop biochar as a carrier material. Our goal was to evaluate if different biochars perform comparably in supporting rhizobial survival, and what characteristics contribute to their ability to support rhizobial survival. Evaluation included characterization of the biochars, assessment of biochar phytotoxicity, survival of Rhizobium on biochars, and growth chamber evaluation of two biochars as Rhizobium carriers for inoculating pea. Of the original nine biochars evaluated, six supported Rhizobium leguminosarum for 84 days at 4 °C; of this six, two supported numbers >1 × 106 cfu·(g biochar)-1. The only characteristics that correlated with survival were C/N ratio and percent C. The two biochars evaluated delivered R. leguminosarum to pea that initiated nodulation, biomass production, and biomass N at levels higher than a noninoculated control and heat-killed inoculated biochars. We demonstrate that there is considerable potential to develop biochar as a carrier for rhizobial inoculants.

Pre-Transplant Marital Status and Hematopoietic Cell Transplantation Outcomes

Background: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. Methods: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. Results: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). Conclusions: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.