Development of the Squaramide Scaffold for High Potential and Multielectron Catholytes for Use in Redox Flow Batteries.

Nonaqueous organic redox flow batteries (N-ORFBs) are a promising technology for grid-scale storage of energy generated from intermittent renewable sources. Their primary benefit over traditional aqueous RFBs is the wide electrochemical stability window of organic solvents, but the design of catholyte materials, which can exploit the upper range of this window, has proven challenging. We report herein a new class of N-ORFB catholytes in the form of squaric acid quinoxaline (SQX) and squaric acid amide (SQA) materials. Mechanistic investigation of decomposition in battery-relevant conditions via NMR, HRMS, and electrochemical methods enabled a rational design approach to optimizing these scaffolds. Three lead compounds were developed: a highly stable one-electron SQX material with an oxidation potential of 0.51 V vs Fc/Fc+ that maintained 99% of peak capacity after 102 cycles (51 h) when incorporated into a 1.58 V flow battery; a high-potential one-electron SQA material with an oxidation potential of 0.81 V vs Fc/Fc+ that demonstrated negligible loss of redox active material as measured by pre- and postcycling CV peak currents when incorporated in a 1.63 V flow battery for 110 cycles over 29 h; and a proof-of-concept two-electron SQA catholyte material with oxidation potentials of 0.48 and 0.85 V vs Fc/Fc+ that demonstrated a capacity fade of just 0.56% per hour during static H-cell cycling. These findings expand the previously reported space of high-potential catholyte materials and showcase the power of mechanistically informed synthetic design for N-ORFB materials development.

Retrospective validation of MetaSystems' deep-learning-based digital microscopy platform with assistance compared to manual fluorescence microscopy for detection of mycobacteria.

This study aimed to validate Metasystems' automated acid-fast bacilli (AFB) smear microscopy scanning and deep-learning-based image analysis module (Neon Metafer) with assistance on respiratory and pleural samples, compared to conventional manual fluorescence microscopy (MM). Analytical parameters were assessed first, followed by a retrospective validation study. In all, 320 archived auramine-O-stained slides selected non-consecutively [85 originally reported as AFB-smear-positive, 235 AFB-smear-negative slides; with an overall mycobacterial culture positivity rate of 24.1% (77/320)] underwent whole-slide imaging and were analyzed by the Metafer Neon AFB Module (version 4.3.130) using a predetermined probability threshold (PT) for AFB detection of 96%. Digital slides were then examined by a trained reviewer blinded to previous AFB smear and culture results, for the final interpretation of assisted digital microscopy (a-DM). Paired results from both microscopic methods were compared to mycobacterial culture. A scanning failure rate of 10.6% (34/320) was observed, leaving 286 slides for analysis. After discrepant analysis, concordance, positive and negative agreements were 95.5% (95%CI, 92.4%-97.6%), 96.2% (95%CI, 89.2%-99.2%), and 95.2% (95%CI, 91.3%-97.7%), respectively. Using mycobacterial culture as reference standard, a-DM and MM had comparable sensitivities: 90.7% (95%CI, 81.7%-96.2%) versus 92.0% (95%CI, 83.4%-97.0%) (P-value = 1.00); while their specificities differed 91.9% (95%CI, 87.4%-95.2%) versus 95.7% (95%CI, 92.1%-98.0%), respectively (P-value = 0.03). Using a PT of 96%, MetaSystems' platform shows acceptable performance. With a national laboratory staff shortage and a local low mycobacterial infection rate, this instrument when combined with culture, can reliably triage-negative AFB-smear respiratory slides and identify positive slides requiring manual confirmation and semi-quantification. IMPORTANCE: This manuscript presents a full validation of MetaSystems' automated acid-fast bacilli (AFB) smear microscopy scanning and deep-learning-based image analysis module using a probability threshold of 96% including accuracy, precision studies, and evaluation of limit of AFB detection on respiratory samples when the technology is used with assistance. This study is complementary to the conversation started by Tomasello et al. on the use of image analysis artificial intelligence software in routine mycobacterial diagnostic activities within the context of high-throughput laboratories with low incidence of tuberculosis.

Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis.

Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD.

Characterizing re-triage guidelines: A scoping review of states' rules and regulations.

BACKGROUND: State guidelines for re-triage, or emergency inter-facility transfer, have never been characterized across the United States. METHODS: All 50 states' Department of Health and/or Trauma System websites were reviewed for publicly available re-triage guidelines within their rules and regulations. Communication was made via phone or email to state agencies or trauma advisory committees to obtain or confirm the absence of guidelines where public data was unavailable. Guideline criteria were abstracted and grouped into domains of Center for Disease Control Field Triage Criteria: pattern/anatomy of injury, vital signs, special populations, and mechanisms of injury. Re-triage criteria were summarized across states using median and interquartile ranges for continuous data and frequencies for categorical data. Demographic data of states with and without re-triage guidelines were compared using the Wilcoxon rank sum test. RESULTS: Re-triage guidelines were identified for 22 of 50 states (44%). Common anatomy of injury criteria included head trauma (91% of states with guidelines), spinal cord injury (82%), chest injury (77%), and pelvic injury (73%). Common vital signs criteria included Glasgow Coma Score (91% of states) ranging from 8 to 14, systolic blood pressure (36%) ranging from 90 to 100 mm Hg, and respiratory rate (23%) with all using 10 respirations/minute. Common special populations criteria included mechanical ventilation (73% of states), age (68%) ranging from <2 or >60 years, cardiac disease (59%), and pregnancy (55%). No significant demographic differences were found between states with versus without re-triage guidelines. CONCLUSION: A minority of US states have re-triage guidelines. Characterizing existing criteria can inform future guideline development.

Gordonia sputi-associated bloodstream infection in a renal transplant patient with chronic indwelling central venous catheter: a case report and literature review.

Introduction: Although rare, human infections caused by Gordonia spp. have been reported, especially within the immunocompromised population and those with long-term indwelling devices. We report a case of Gordonia spp. bacteraemia in a renal transplant patient and present a literature review on microbiological identification methods of this organism. Case Presentation: A 62-year-old female renal transplant recipient admitted to hospital with a 2-month history of dry cough and fevers occurring weekly when receiving electrolyte replacement infusions via a Groshong line. Over 2 weeks, blood cultures repeatedly isolated a Gram-positive bacillus solely in aerobic bottles, and this was initially reported as Rhodococcus spp. by the local microbiology laboratory. Chest computed tomography (CT) showed multiple ground-glass lung opacities suggestive of septic pulmonary emboli. As central line-associated bloodstream infection was suspected, empirical antibiotics were initiated and the Groshong line was removed. The Gram-positive bacillus was later confirmed by the reference laboratory as Gordonia sputi via 16S rRNA sequencing. Vancomycin and ciprofloxacin for a duration of 6 weeks were completed as targeted antimicrobial therapy. After treatment, the patient remained symptom-free with marked improvement on repeat CT chest imaging. Conclusion: This case illustrates the challenges surrounding identification of Gordonia spp. and other aerobic actinomycetes. 16S rRNA gene sequencing may be a preferred identification method, especially when initial workup of a weakly acid-fast organism fails to make an identification or shows discrepant results using traditional diagnostic modalities.

Non-biologic systemic treatments for atopic dermatitis: Current state of the art and future directions.

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin condition with an unpredictable clinical course, associated with a significant impact on quality of life. The pathophysiology of AD involves a complex interplay between impaired skin barrier function, immune dysregulation, genetic susceptibility and environmental factors. Advances in understanding of the immunological mechanisms that underpin AD have heralded the recognition of multiple novel therapeutic targets to bolster the systemic treatment armamentarium for patients with severe AD. This review examines current and future directions of non-biologic systemic treatments for AD, with a focus on their mechanism of action, efficacy and safety, and the key considerations to help inform treatment decisions. We summarize new developments in small molecule systemic therapies which have the potential to further advance our management of AD in this new era of precision medicine.

Biomarkers associated with the development of comorbidities in patients with atopic dermatitis: A systematic review.

Biomarkers associated with the development of comorbidities in atopic dermatitis (AD) patients have been reported, but have not yet been systematically reviewed. Seven electronic databases were searched, from database inception to September 2021. English language randomized controlled trials, prospective and retrospective cohort, and case-control studies that investigated the association between a biomarker and the development of comorbidities in AD patients were included. Two authors independently screened the records for eligibility, one extracted all data, and critically appraised the quality of studies and risk of bias. Fifty six articles met the inclusion criteria, evaluating 146 candidate biomarkers. The most frequently reported biomarkers were filaggrin mutations and allergen specific-IgE. Promising biomarkers include specific-IgE and/or skin prick tests predicting the development of asthma, and genetic polymorphisms predicting the occurrence of eczema herpeticum. The identified studies and biomarkers were highly heterogeneous, and associated with predominately moderate-to-high risk of bias across multiple domains. Overall, findings were inconsistent. High-quality studies assessing biomarkers associated with the development of comorbidities in people with AD are lacking. Harmonized datasets and independent validation studies are urgently needed.

The effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis: Results from the global SECURE-AD registry.

BACKGROUND: Limited data are available on the effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis (AD). OBJECTIVE: To investigate COVID-19 outcomes in patients with AD treated with or without systemic immunomodulatory treatments, using a global registry platform. METHODS: Clinicians were encouraged to report cases of COVID-19 in their patients with AD in the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Atopic Dermatitis (SECURE-AD) registry. Data entered from 1 April 2020 to 31 October 2021 were analysed using multivariable logistic regression. The primary outcome was hospitalization from COVID-19, according to AD treatment groups. RESULTS: 442 AD patients (mean age 35.9 years, 51.8% male) from 27 countries with strongly suspected or confirmed COVID-19 were included in analyses. 428 (96.8%) patients were treated with a single systemic therapy (n = 297 [67.2%]) or topical therapy only (n = 131 [29.6%]). Most patients treated with systemic therapies received dupilumab (n = 216). Fourteen patients (3.2%) received a combination of systemic therapies. Twenty-six patients (5.9%) were hospitalized. No deaths were reported. Patients treated with topical treatments had significantly higher odds of hospitalization, compared with those treated with dupilumab monotherapy (odds ratio (OR) 4.65 [95%CI 1.71-14.78]), including after adjustment for confounding variables (adjusted OR (aOR) 4.99 [95%CI 1.4-20.84]). Combination systemic therapy which did not include systemic corticosteroids was associated with increased odds of hospitalization, compared with single agent non-steroidal immunosuppressive systemic treatment (OR 8.09 [95%CI 0.4-59.96], aOR 37.57 [95%CI 1.05-871.11]). Hospitalization was most likely in patients treated with combination systemic therapy which included systemic corticosteroids (OR 40.43 [95%CI 8.16-207.49], aOR 45.75 [95%CI 4.54-616.22]). CONCLUSIONS: Overall, the risk of COVID-19 complications appears low in patients with AD, even when treated with systemic immunomodulatory agents. Dupilumab monotherapy was associated with lower hospitalization than other therapies. Combination systemic treatment, particularly combinations including systemic corticosteroids, was associated with the highest risk of severe COVID-19.

Atopic dermatitis and risk of autoimmune conditions: Population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is associated with immune dysregulation, but epidemiologic data on the pattern of autoimmune comorbidity in people with AD are limited. OBJECTIVE: We sought to determine the risk of autoimmune conditions in people newly diagnosed with AD. METHODS: Retrospective cohort analysis (January 2009 to December 2018), using the UK-based Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care database. We compared baseline prevalence and incidence after diagnosis of autoimmune conditions in 173,709 children and adults with new-onset AD and 694,836 age-, sex-, and general practitioner practice-matched controls. Outcomes were a composite of any autoimmune condition (Crohn disease, ulcerative colitis, celiac disease, pernicious anemia, type 1 diabetes, autoimmune hypothyroidism, Graves disease, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, Sjögren syndrome, vitiligo, alopecia areata, and multiple sclerosis) and each individual autoimmune condition. RESULTS: Preexisting autoimmune conditions were more common in people diagnosed with AD compared to controls (composite 5.8% vs 4.3%). Excluding people with preexisting autoimmune disease, there was an association between AD and incidence of new-onset autoimmune disease (composite adjusted hazard ratio [aHR] 1.28; 95% confidence interval [CI] 1.23-1.34). Risk was highest for more severe AD (aHR 1.99; 95% CI 1.77-2.23) than moderate AD (aHR 1.33; 95% CI 1.19-1.49) or mild AD (aHR 1.22; 95% CI 1.16-1.28). People with AD were at significantly increased risk of developing psoriatic arthritis, Sjögren syndrome, Crohn disease, vitiligo, alopecia areata, pernicious anemia, ulcerative colitis, rheumatoid arthritis, and hypothyroidism (aHR range 1.17-2.06), but not other autoimmune conditions. CONCLUSION: People with AD have an increased risk of multiple autoimmune conditions, especially those with more severe AD.

The power and potential of BIOMAP to elucidate host-microbiome interplay in skin inflammatory diseases.

The two most common chronic inflammatory skin diseases are atopic dermatitis (AD) and psoriasis. The underpinnings of the remarkable degree of clinical heterogeneity of AD and psoriasis are poorly understood and, as a consequence, disease onset and progression are unpredictable and the optimal type and time point for intervention are as yet unknown. The BIOMAP project is the first IMI (Innovative Medicines Initiative) project dedicated to investigating the causes and mechanisms of AD and psoriasis and to identify potential biomarkers responsible for the variation in disease outcome. The consortium includes 7 large pharmaceutical companies and 25 non-industry partners including academia. Since there is mounting evidence supporting an important role for microbial exposures and our microbiota as factors mediating immune polarization and AD and psoriasis pathogenesis, an entire work package is dedicated to the investigation of skin and gut microbiome linked to AD or psoriasis. The large collaborative BIOMAP project will enable the integration of patient cohorts, data and knowledge in unprecedented proportions. The project has a unique opportunity with a potential to bridge and fill the gaps between current problems and solutions. This review highlights the power and potential of the BIOMAP project in the investigation of microbe-host interplay in AD and psoriasis.

The epidemiology of eczema in children and adults in England: A population-based study using primary care data.

BACKGROUND: Whilst eczema is a common inflammatory skin condition, we lack contemporary estimates of disease incidence and prevalence across the lifespan. OBJECTIVE: To estimate the incidence and prevalence of eczema in children and adults in England and variation by sociodemographic factors (sex, socio-economic status, ethnicity, and geography). METHODS: We used the Royal College of General Practitioners Research and Surveillance Centre primary care research database of 3.85 million children and adults registered with participating general practitioner practices between 2009 and 2018 inclusive. Eczema incidence was defined as the first-ever diagnosis of eczema recorded in the primary care record, and eczema prevalence was defined as fulfilment of criteria for active eczema (two eczema records appearing in the primary care record within any one-year period). RESULTS: Eczema incidence was highest in infants younger than 1 year (15.0 per 100 person-years), lowest in adults aged 40-49 (0.35 p/100 person-years), and increased from middle age to a second smaller peak in people 80 years or older (0.79 p/100 person-years). Eczema prevalence was highest in children aged 2 (16.5%) and lowest in adults aged 30-39 (2.8%). Eczema incidence was higher in male infants (<2) and male adults older than 70; for all other ages, incidence was higher in females. Eczema was more common in Asian and black ethnic groups than in people of white ethnicity. Higher socio-economic status was associated with a greater incidence of eczema in infants younger than 2, but the reverse was seen for all other age groups. Both incidence and prevalence of eczema were greater in urban settings and in North-West England. CONCLUSIONS AND CLINICAL RELEVANCE: Eczema has a bimodal distribution across the lifespan. We observed differences in incidence and prevalence of eczema by ethnicity, geography, sex, and socio-economic status, which varied in magnitude throughout life.

Patterns and trends in eczema management in UK primary care (2009-2018): A population-based cohort study.

BACKGROUND: Despite the high disease burden of eczema, a contemporary overview of the patterns and trends in primary care healthcare utilization and treatment is lacking. OBJECTIVE: To quantify primary care consultations, specialist referrals, prescribing, and treatment escalation, in children and adults with eczema in England. METHODS: A large primary care research database was used to examine healthcare and treatment utilization in people with active eczema (n = 411,931). Management trends and variations by age, sex, socioeconomic status, and ethnicity were described from 2009 to 2018 inclusive. RESULTS: Primary care consultation rates increased from 87.8 (95% confidence interval [95% CI] 87.3-88.3) to 112.0 (95% CI 111.5-112.6) per 100 person-years over 2009 to 2018. Specialist referral rates also increased from 3.8 (95% CI 3.7-3.9) to 5.0 (95% CI 4.9-5.1) per 100 person-years over the same period. Consultation rates were highest in infants. Specialist referrals were greatest in the over 50s and lowest in people of lower socioeconomic status, despite a higher rate of primary care consultations. There were small changes in prescribing over time; emollients increased (prescribed to 48.5% of people with active eczema in 2009 compared to 51.4% in 2018) and topical corticosteroids decreased (57.3%-52.0%). Prescribing disparities were observed, including less prescribing of potent and very potent topical corticosteroids in non-white ethnicities and people of lower socioeconomic status. Treatment escalation was more common with increasing age and in children of non-white ethnicity. CONCLUSION AND CLINICAL RELEVANCE: The management of eczema varies by sociodemographic status in England, with lower rates of specialist referral in people from more-deprived backgrounds. There are different patterns of healthcare utilization, treatment, and treatment escalation in people of non-white ethnicity and of more-deprived backgrounds.

Epidemiology and management of atopic dermatitis in England: an observational cohort study protocol.

INTRODUCTION: Atopic dermatitis (AD) is one of the most common inflammatory skin conditions in both children and adults. Despite this, contemporary descriptions of the incidence, prevalence and current management of the condition in the UK are lacking. METHODS AND ANALYSIS: We will perform a series of retrospective studies using a large population-based cohort derived from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database to explore two key research themes: AD epidemiology and AD management.In the epidemiology theme, we will describe the incidence and prevalence of AD in children and adults in England from 2009 to 2018 inclusive. We will stratify findings by age, national Index of Multiple Deprivation (IMD), ethnicity, urban-rural environment and geographic location; and explore independent associations of these features with AD in multivariable models.In the management theme, we will explore healthcare utilisation and treatment in people with AD. Regarding healthcare utilisation, we will evaluate rates of AD-associated primary care visits and specialist dermatology referrals in people with AD. Rates will be stratified by age, gender, socioeconomic IMD quintile and ethnicity. We will describe contemporary treatment by estimating prescribing rates across medication classes used in AD (emollients, topical corticosteroids by potency, topical calcineurin inhibitors, topical antimicrobials, antihistamines, oral corticosteroids and systemic immunomodulatory therapies) overall, and by age and sociodemographic groupings. We will also examine trends in prescribing over the study period. In people first diagnosed with AD during the study period, we will describe differences in treatment escalation by sociodemographic factors using time-to-event analysis. ETHICS AND DISSEMINATION: The Health Research Authority decision tool classed this a study of 'usual practice', ethics approval was not required. Study approval was granted by the RCGP RSC Study Approval Committee. Results will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03823794.