Corticosteroid monotherapy versus combined cytarabine continuous rate infusion and corticosteroid therapy in dogs with meningoencephalitis of unknown origin: A blinded, randomized, controlled trial.

BACKGROUND: Treatment options available for meningoencephalitis of unknown origin (MUO) in dogs are suboptimal, and currently, no single treatment protocol appears to be superior. OBJECTIVES: Compare neurological deterioration rates at 7 days between dogs with MUO treated with corticosteroids alone or combined with cytosine arabinoside (CA) continuous rate infusion (CRI) and compare clinical deterioration and survival at 30 and 100 days. ANIMALS: Sixty-nine dogs with magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) features or both compatible with MUO. METHODS: Parallel, blinded, randomized controlled trial. Simple randomization into 2 treatment groups: 4 mg/kg/day prednisolone (or dexamethasone equivalent) for 2 days or 200 mg/m2 CA CRI over 8 hours plus 2 mg/kg/day prednisolone. Blinding of the treatment protocol was carried out using reversible redaction of clinical records, and treatment failure was defined as deterioration of neurological assessment or death. Using intention-to-treat analysis, proportions failing treatment at 7, 30, and 100 days were compared using Fisher's exact test. All-cause mortality at 100 days was compared using Kaplan-Meier survival curves. RESULTS: Thirty-five dogs were allocated to corticosteroid only, and 34 dogs were allocated to combined CA CRI and corticosteroid. Proportions failing treatment at 7, 30, and 100 days were 7/35 (20%), 9/35 (26%), and 15/35 (43%) in the corticosteroid-only group and 8/34 (24%), 11/34 (32%), and 23/34 (68%) in the corticosteroid and CA CRI group. All-cause mortality at 100 days was not significantly different between groups (P = .62). Clinically relevant treatment-related adverse effects were not observed. CONCLUSIONS AND CLINICAL IMPORTANCE: We found no difference in outcome between corticosteroid monotherapy and combined cytarabine CRI and corticosteroid therapy at 7, 30, and 100 days after diagnosis in dogs with MUO.

Diagnosis and Severity Assessment of COPD Using a Novel Fast-Response Capnometer and Interpretable Machine Learning.

INTRODUCTION: Spirometry is the gold standard for COPD diagnosis and severity determination, but is technique-dependent, nonspecific, and requires administration by a trained healthcare professional. There is a need for a fast, reliable, and precise alternative diagnostic test. This study's aim was to use interpretable machine learning to diagnose COPD and assess severity using 75-second carbon dioxide (CO2) breath records captured with TidalSense's N-TidalTM capnometer. METHOD: For COPD diagnosis, machine learning algorithms were trained and evaluated on 294 COPD (including GOLD stages 1-4) and 705 non-COPD participants. A logistic regression model was also trained to distinguish GOLD 1 from GOLD 4 COPD with the output probability used as an index of severity. RESULTS: The best diagnostic model achieved an AUROC of 0.890, sensitivity of 0.771, specificity of 0.850 and positive predictive value (PPV) of 0.834. Evaluating performance on all test capnograms that were confidently ruled in or out yielded PPV of 0.930 and NPV of 0.890. The severity determination model yielded an AUROC of 0.980, sensitivity of 0.958, specificity of 0.961 and PPV of 0.958 in distinguishing GOLD 1 from GOLD 4. Output probabilities from the severity determination model produced a correlation of 0.71 with percentage predicted FEV1. CONCLUSION: The N-TidalTM device could be used alongside interpretable machine learning as an accurate, point-of-care diagnostic test for COPD, particularly in primary care as a rapid rule-in or rule-out test. N-TidalTM also could be effective in monitoring disease progression, providing a possible alternative to spirometry for disease monitoring.

Flexible, Transparent, and Bifacial Perovskite Solar Cells and Modules Using the Wide-Band Gap FAPbBr3 Perovskite Absorber.

Perovskite solar cells (PSCs) offer impressive performance and flexibility, thanks to their simple, low-temperature deposition methods. Their band gap tunability allows for a wide range of applications, transitioning from opaque to transparent devices. This study introduces the first flexible, bifacial PSCs using the FAPbBr3 perovskite. We investigated the impact of optimizing electron and hole transport layers on the cells' bifaciality, transparency, and stability. PSCs achieved a maximum power conversion efficiency (PCE) of 6.8 and 18.7% under 1 sun and indoor light conditions (1200 lx), respectively, showing up to 98% bifaciality factor and an average visible transmittance (AVT) of 55%. Additionally, a P1-P2-P3 laser ablation scheme has been developed on the flexible poly(ethylene terephthalate) (PET) substrate for perovskite solar modules showing a PCE of 4.8% and high geometrical fill factor (97.8%). These findings highlight the potential of flexible, bifacial PSCs for diverse applications such as building-integrated photovoltaics (BIPV), agrivoltaics, automotive technology, wearable sensors, and Internet of things (IoT).

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

A device for magnetic-field angle control in magneto-optical filters using a solenoid-permanent magnet pair.

Atomic bandpass filters are used in a variety of applications due to their narrow bandwidths and high transmission at specific frequencies. Predominantly, these filters are in the Faraday (Voigt) geometry, using an applied axial (transverse) magnetic field with respect to the laser propagation direction. Recently, there has been interest in filters realized with arbitrary-angle magnetic fields, which have been made by rotating permanent magnets with respect to the k-vector of the interrogating laser beam. However, the magnetic field angle achievable with this method is limited as field uniformity across the cell decreases as the rotation angle increases. In this work, we propose and demonstrate a new method of generating an arbitrary-angle magnetic field, using a solenoid to produce a small, and easily alterable, axial field, in conjunction with fixed permanent magnets to produce a large transverse field. We directly measure the fields produced by both methods, finding them to be very similar over the length of the vapor cell. We then compare the transmission profiles of filters produced using both methods, again finding excellent agreement. Finally, we demonstrate the sensitivity of the filter profile to changing magnetic field angle (solenoid current), which becomes easier to exploit with the much improved angle control and precision offered by our new design.

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles.

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

MISSION ABC: transforming respiratory care through one-stop multidisciplinary clinics - an observational study.

OBJECTIVES: The Modern Innovative Solutions to Improve Outcomes in Asthma, Breathlessness and Chronic Obstructive Pulmonary Disease (COPD) (MABC) service aimed to enhance disease management for chronic respiratory conditions through specialist multidisciplinary clinics, predominantly in the community. This study assesses the outcomes of these clinics. DESIGN: This study used a prospective, longitudinal, participatory action research approach. SETTING: The study was conducted in primary care practices across Hampshire, UK. PARTICIPANTS: Adults aged 16 years and above with poorly controlled asthma or COPD, as well as those with undifferentiated breathlessness not under specialist care, were included. INTERVENTIONS: Participants received care through the multidisciplinary, specialist-led MABC clinics. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes included disease activity, quality of life and healthcare utilisation. Secondary outcomes encompassed clinic attendance, diagnostic changes, patient activation, participant and healthcare professional experiences and cost-effectiveness. RESULTS: A total of 441 participants from 11 general practitioner practices were recruited. Ninety-six per cent of participants would recommend MABC clinics. MABC assessments led to diagnosis changes for 64 (17%) participants with asthma and COPD and treatment adjustments for 252 participants (57%). Exacerbations decreased significantly from 236 to 30 after attending the clinics (p<0.005), with a mean reduction of 0.53 exacerbation events per participant. Reductions were also seen in unscheduled and out-of-hours primary care attendance, emergency department visits and hospital admissions (all p<0.005). Cost savings from reduced exacerbations and healthcare utilisation offset increased medication costs and clinic expenses. CONCLUSIONS: Specialist-supported multidisciplinary teams in MABC clinics improved diagnosis accuracy and adherence to guidelines. High patient satisfaction, disease control improvements and reduced exacerbations resulted in decreased unscheduled healthcare use and cost savings. TRIAL REGISTRATION NUMBER: NCT03096509.

Protocol for precision editing of endogenous Chlamydomonas reinhardtii genes with CRISPR-Cas.

CRISPR-Cas genome engineering in the unicellular green algal model Chlamydomonas reinhardtii has until recently suffered from low integration efficiencies despite traditional genetics being well established. Here, we present a protocol for efficient homology-directed knockin mutagenesis in all commonly used strains of Chlamydomonas. We describe steps for scarless integration of fusion tags and sequence modifications of almost all proteins without the need for a preceding mutant line. We further empower this genetic-editing approach by efficient crossing and highly robust screening protocols. For complete details on the use and execution of this protocol, please refer to Nievergelt et al. (2023).1.

Mepolizumab incompletely suppresses clinical flares in a pilot study of episodic angioedema with eosinophilia.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.

Shear bond strength of orthodontic brackets bonded to high-translucent dental zirconia with different surface treatments: An in vitro study.

PURPOSE: The objective of this study was to compare the shear bond strengths of orthodontic brackets bonded to translucent dental zirconia samples which are anatomically accurate and treated with various surface treatments. METHODS: This in vitro study included 156 samples from 3 brands of high-translucent zirconia split into a control group and 4 surface treatment groups: 9.6% hydrofluoric acid etching, 50-micron aluminium oxide particle air abrasion, and 30-micron tribochemical silica coating (TBS) particle air abrasion with and without silane application. After surface treatment, all groups were primed with a 10-MDP primer and bonded to metal orthodontic brackets. Shear bond strength (SBS) was tested and results were compared between all groups. Data analysis consisted of a balanced two-factor factorial ANOVA, a Shapiro-Wilks test, and a non-parametric permutation test. The significance level was set at 0.05. RESULTS: Among all surface treatments, aluminium oxide particle abrasion produced significantly higher SBS (P≤0.002). Lava™ Plus zirconia samples had significantly higher SBS than Cercon® samples (P<0.0001). TBS surface treatment produced significantly higher SBS on Lava™ Plus samples than it did on the other zirconia brands (P=0.032). CONCLUSIONS: This study indicated that mechanical abrasion using aluminium oxide in combination with a 10-MDP primer creates a higher SBS to high-translucent zirconia than the bond created by tribochemical silica coating. Also, there was no significant difference in ARI regardless of zirconia brand or surface preparation.

Sarin-Induced Neuroinflammation in Mouse Brain Is Attenuated by the Caspase Inhibitor Q-VD-OPh.

Organophosphates cause hyperstimulation of the central nervous system, leading to extended seizures, convulsions, and brain damage. Sarin is a highly toxic organophosphate nerve agent that has been employed in several terrorist attacks. The prolonged toxicity of sarin may be enhanced by the neuroinflammatory response initiated by the inflammasome, caspase involvement, and generation/release of proinflammatory cytokines. Since neurodegeneration and neuroinflammation are prevalent in sarin-exposed animals, we were interested in evaluating the capacity of quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh), a pan caspase inhibitor to attenuate neuroinflammation following sarin exposure. To test this hypothesis, sarin-exposed C57BL/6 mice were treated with Q-VD-OPh or negative control quinolyl-valyl-O-methylglutamyl-[-2,6-difluorophenoxy]-methyl ketone, sacrificed at 2- and 14-day time points, followed by removal of the amygdala and hippocampus. A Bio-Rad 23-Plex cytokine analysis was completed on each tissue. The results suggest that exposure to sarin induced a dramatic increase in interleukin-1ß and 6 other cytokines and a decrease in 2 of the 23 cytokines at 2 days in the amygdala compared with controls. Q-VD-OPh attenuated these changes at the 2-day time point. At 14 days, six of these cytokines were still significantly different from controls. Hippocampus was less affected at both time points. Diazepam, a neuroprotective drug against nerve agents, caused an increase in several cytokines but did not have a synergistic effect with Q-VD-OPh. Treatment of sarin exposure with apoptosis inhibitors appears to be a worthwhile approach for further testing as a comprehensive counteragent against organophosphate exposure. SIGNIFICANCE STATEMENT: A pan inhibitor of caspases (Q-VD-OPh) was proposed as a potential antidote for sarin-induced neuroinflammation by reducing the level of inflammation via inflammasome caspase inhibition. Q-VD-OPh added at 30 minutes post-sarin exposure attenuated the inflammatory response of a number of cytokines and chemokines in the amygdala and hippocampus, two brain regions sensitive to organophosphate exposure. Apoptotic marker reduction at 2 and 14 days further supports further testing of inhibitors of apoptosis as a means to lessen extended organophosphate toxicity in the brain.

Impact of sex on severe asthma: a cross-sectional retrospective analysis of UK primary and specialist care.

INTRODUCTION: After puberty, females are more likely to develop asthma and in a more severe form than males. The associations between asthma and sex are complex with multiple intrinsic and external factors. AIM: To evaluate the sex differences in the characteristics and treatment of patients with severe asthma (SA) in a real-world setting. METHODS: Demographic, clinical and treatment characteristics for patients with SA in the UK Severe Asthma Registry (UKSAR) and Optimum Patient Care Research Database (OPCRD) were retrospectively analysed by sex using univariable and multivariable logistic regression analyses adjusted for year, age and hospital/practice. RESULTS: 3679 (60.9% female) patients from UKSAR and 18 369 patients (67.9% female) from OPCRD with SA were included. Females were more likely to be symptomatic with increased Asthma Control Questionnaire-6 (UKSAR adjusted OR (aOR) 1.14, 95% CI 1.09 to 1.18) and Royal College of Physicians-3 Question scores (OPCRD aOR 1.29, 95% CI 1.13 to 1.47). However, they had a higher forced expiratory volume in 1 second per cent (FEV1%) predicted (UKSAR 68.7% vs 64.8%, p<0.001) with no significant difference in peak expiratory flow. Type 2 biomarkers IgE (UKSAR 129 IU/mL vs 208 IU/mL, p<0.001) and FeNO (UKSAR 36ppb vs 46ppb, p<0.001) were lower in females with no significant difference in blood eosinophils or biological therapy. Females were less likely to be on maintenance oral corticosteroids (UKSAR aOR 0.86, 95% CI 0.75 to 0.99) but more likely to be obese (UKSAR aOR 1.67, 95% CI 145 to 1.93; OPCRD SA aOR 1.46, 95% CI 1.34 to 1.58). CONCLUSIONS: Females had increased symptoms and were more likely to be obese despite higher FEV1% predicted and lower type 2 biomarkers with consistent and clinically important differences across both datasets.

Hands-On Photonic Education Kits: empowering the integrated photonics workforce through practical training.

The Hands-On Photonic Education (HOPE) Kits, developed with AIM Photonics, address the need for skilled workers in integrated photonics. This paper highlights the role of the HOPE Kits in advancing the training ecosystem and bridging the skills gap. The kits include fully packaged photonic integrated circuits (PICs), enabling instructors to educate and train students on PIC testing and characterization. Covering a wide range of devices and circuits, from waveguides to wavelength division multiplexing for data communication, the kits offer a hands-on experience. Engaging with actual PICs, students gain practical insights, enhancing their understanding of key principles, and preparing them for real-world skill sets in integrated photonics.

An examination of factorial invariance of the Asthma Control Questionnaire among adults with severe asthma.

BACKGROUND: The Asthma Control Questionnaire (ACQ) is used to assess asthma symptom control. The relationship between the questionnaire items and symptom control has not been fully studied in severe asthmatic patients, and its validity for making comparisons between subgroups of patients is unknown. METHODS: Data was obtained from patients in the United Kingdom Severe Asthma Registry whose symptom control was assessed using the five-item ACQ (ACQ5) (n = 2,951). Confirmatory factor analysis determined whether a latent factor for asthma symptom control, as measured by the ACQ5, was consistent with the data. Measurement invariance was examined in relation to ethnicity, sex and age; this included testing for approximate measurement invariance using Bayesian Structural Equation Modelling (BSEM). The fitted models were used to estimate the internal consistency reliability of the ACQ5. Invariance of factor means across subgroups was assessed. RESULTS: A one-factor construct with residual correlations for the ACQ5 was an excellent fit to the data in all subgroups (Root Mean Square Error Approximation 0.03 [90%CI 0.02,0.05], p-close fit 0.93, Comparative Fit Index 1.00, Tucker Lewis Index 1.00}. Expected item responses were consistent for Caucasian and non-Caucasian patients with the same absolute level of symptom control. There was some evidence that females and younger adults reported wakening more frequently during the night than males and older adults respectively with the same absolute level of symptom control (p<0.001). However approximate measurement invariance was tenable and any failure to observe strong measurement invariance had minimal impact when comparing mean levels of asthma symptom control between patients of different sexes or ages. Average levels of asthma symptom control were lower for non-Caucasians (p = 0.001), females (p<0.01)and increased with age (p<0.01). Reliability of the instrument was high (over 88%) in all subgroups studied. CONCLUSION: The ACQ5 is informative in comparing levels of symptom control between severe asthmatic patients of different ethnicities, sexes and ages. It is important that analyses are replicated in other severe asthma registries to determine whether measurement invariance is observed.

Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry.

BACKGROUND: Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort. METHODS: This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 <1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline. RESULTS: 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria. CONCLUSIONS: 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.

A systematic review of methods of scoring inhaler technique.

Many inhaler devices are currently used in clinical practice to deliver medication, with each inhaler device offering different benefits to overcome technique issues. Inhaler technique remains poor, contributing to reduced airway drug deposition and consequently poor disease control. Scoring inhaler technique has been used within research as an outcome measure of inhaler technique assessment, and this systematic review collates and evaluates these scoring methods. The review protocol was prospectively registered in PROSPERO (CRD42020218869). A total of 172 articles were screened with 77 included, and the results presented using narrative synthesis due to the heterogeneity of the study design and data. The most frequently used scoring method awarded one point per step in the inhaler technique checklist and was included in 59/77 (77%) of articles; however limited and varied guidance was provided for score interpretation. Other inhaler technique scoring methods included grading the final inhaler technique score, expressing the total score as a percentage/ratio, deducting points from the final score when errors were made, and weighting steps within the checklist depending on how crucial the step was. Vast heterogeneity in the number of steps and content in the inhaler technique checklists was observed across all device types (range 5-19 steps). Only 4/77 (5%) of the inhaler technique measures had undertaken fundamental steps required in the scale development process for use in real world practice. This review demonstrates the demand for a tool that measures inhaler technique and highlights the current unmet need for one that has undergone validation.

Microglia are dispensable for experience-dependent refinement of visual circuitry.

Microglia are proposed to be critical for the refinement of developing neural circuitry. However, evidence identifying specific roles for microglia has been limited and often indirect. Here we examined whether microglia are required for the experience-dependent refinement of visual circuitry and visual function during development. We ablated microglia by administering the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622, and then examined the consequences for retinal function, receptive field tuning of neurons in primary visual cortex (V1), visual acuity, and experience-dependent plasticity in visual circuitry. Eradicating microglia by treating mice with PLX5622 beginning at postnatal day (P) 14 did not alter visual response properties of retinal ganglion cells examined three or more weeks later. Mice treated with PLX5622 from P14 lacked more than 95% of microglia in V1 by P18, prior to the opening of the critical period. Despite the absence of microglia, the receptive field tuning properties of neurons in V1 were normal at P32. Similarly, eradicating microglia did not affect the maturation of visual acuity. Mice treated with PLX5622 displayed typical ocular dominance plasticity in response to brief monocular deprivation. Thus, none of these principal measurements of visual circuit development and function detectibly differed in the absence of microglia. We conclude that microglia are dispensable for experience-dependent refinement of visual circuitry. These findings challenge the proposed critical role of microglia in refining neural circuitry.

Overexpression of the LAT1 in primary human trophoblast cells increases the uptake of essential amino acids and activates mTOR signaling.

The System L amino acid transporter, particularly the isoform Large Neutral Amino Acid Transporter Small Subunit 1 (LAT1) encoded by SLC7A5, is believed to mediate the transfer of essential amino acids in the human placenta. Placental System L amino acid transporter expression and activity is decreased in pregnancies complicated by IUGR and increased in fetal overgrowth. However, it remains unknown if changes in the expression of LAT1 are mechanistically linked to System L amino acid transport activity. Here, we combined overexpression approaches with protein analysis and functional studies in cultured primary human trophoblast (PHT) cells to test the hypothesis that SLC7A5 overexpression increases the uptake of essential amino acids and activates mTOR signaling in PHT cells. Overexpression of SLC7A5 resulted in a marked increase in protein expression of LAT1 in the PHT cells microvillous plasma membrane and System L amino acid transporter activity. Moreover, mTOR signaling was activated, and System A amino acid transporter activity increased following SLC7A5 overexpression, suggesting coordination of trophoblast amino transporter expression and activity to ensure balanced nutrient flux to the fetus. This is the first report showing that overexpression of LAT1 is sufficient to increase the uptake of essential amino acids in PHT cells, which activates mTOR, a master regulator of placental function. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter system in some cases of fetal overgrowth may directly contribute to changes in fetal amino acid availability and altered fetal growth in these pregnancy complications.

Long-term outcome of epileptic dogs treated with implantable vagus nerve stimulators.

BACKGROUND: The long-term effect of implantable vagus nerve stimulators (VNS) on seizures has not been evaluated in epileptic dogs. OBJECTIVES: Report seizure frequency in medication-resistant epileptic dogs before and after VNS implantation. ANIMALS: Twelve client-owned dogs with idiopathic epilepsy and >1 seizure day per 3 weeks despite 3 months of appropriate use of 2 antiseizure medications and seizure diaries maintained 6 months before and >12 months after VNS implantation. METHODS: Uncontrolled, open-label, before and after study. Mean monthly seizures and inter-seizure periods obtained from contemporaneous seizure diaries in the 6 months before implantation were compared with 0 to 6 months, 7 to 12 months, and subsequent 12-month periods after implantation. The number of dogs with >50% decrease in seizure frequency, >3 times increase in inter-ictal period interval, and seizure freedom for >3 months at the time of death or last follow-up were recorded. RESULTS: Five of 12 dogs were euthanized <12 months after implantation. All 7 remaining dogs showed >50% decrease in seizure frequency until last follow-up, starting at a median of 37 to 48 months after implantation (range, 0-6 to 61-72 months) and a >3-fold increase in mean inter-seizure interval starting a median of 25 to 36 months after implantation (range, 0-6 months to 49-60 months), 3/7 dogs were seizure-free at death or last follow-up. CONCLUSIONS AND CLINICAL IMPORTANCE: Monthly seizure frequencies decreased and inter-seizure intervals increased in all dogs 2 to 3 years after VNS implantation, but a high proportion were euthanized before this time point. Prospective clinical trials are required to establish causality and the magnitude of this association.