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Claire Emson,1 Jonathan Corren,2 Kinga Sałapa,3 Åsa Hellqvist,4 Jane R Parnes,5 Gene Colice6 1Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 2David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; 3Biometrics, Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Warsaw, Poland; 4Biometrics, Late-Stage Development, Respiratory and Immunology, AstraZeneca, Gothenburg, Sweden; 5Amgen, Thousand Oaks, CA, USA; 6Late-Stage Development Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USACorrespondence: Claire EmsonAstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USATel +13013980304Email Claire.emson@astrazeneca.comBackground: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis, from binding to its heterodimeric receptor. In the phase 2b PATHWAY study, tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control, in adults with severe, uncontrolled asthma. This post hoc analysis assessed the efficacy of tezepelumab in adults with severe, uncontrolled asthma with and without nasal polyposis (NP).Methods: In this post hoc analysis of the PATHWAY study (NCT02054130), participants (N=550) were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The AAER over 52 weeks and the change from baseline to week 52 in blood eosinophil count, fractional exhaled nitric oxide (FeNO) levels and serum levels of interleukin (IL)-5 and IL-13 with tezepelumab 210 mg (the phase 3 dose) and placebo were analyzed in patients grouped by self-reported presence (NP+) or absence (NP−) of NP at screening.Results: At baseline, NP+ patients had higher blood eosinophil counts, higher FeNO levels and higher serum IL-5 and IL-13 levels than NP− patients. Tezepelumab 210 mg reduced the AAER versus placebo to a similar extent in both NP+ and NP− patients (NP+, 75% [95% confidence interval (CI): 15, 93], n=23; NP−, 73% [95% CI: 47, 86], n=112). Patients treated with tezepelumab 210 mg demonstrated greater reductions in blood eosinophil count and levels of FeNO, IL-5 and IL-13 than placebo-treated patients, irrespective of NP status.Discussion: Tezepelumab reduced exacerbations and reduced type 2 inflammatory biomarkers in patients with and those without NP, supporting its efficacy in a broad population of patients with severe asthma.Keywords: asthma, biomarkers, nasal polyps, sinusitis, tezepelumab, thymic stromal lymphopoietin

Jonathan Corren,1 Martin Karpefors,2 Åsa Hellqvist,3 Jane R Parnes,4 Gene Colice5 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Data Science and AI, AstraZeneca, Gothenburg, Sweden; 3Biometrics, Late-Stage Development, Respiratory and Immunology, AstraZeneca, Gothenburg, Sweden; 4Amgen, Thousand Oaks, CA, USA; 5Late-Stage Development, Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USACorrespondence: Jonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USATel +1-310-312-5050Email jcorren@ucla.eduIntroduction: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in airway inflammation in asthma, from binding to its heterodimeric receptor. In the PATHWAY phase 2b study, tezepelumab significantly reduced exacerbation rates compared with placebo in adults with severe, uncontrolled asthma, irrespective of baseline disease characteristics.Objective: To evaluate the effect of tezepelumab on asthma exacerbations on a seasonal basis.Methods: This was a post hoc analysis of the PATHWAY study (NCT02054130). Adults (N=550) with severe, uncontrolled asthma were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The annualized asthma exacerbation rate (AAER), total number of days with an exacerbation, proportion of patients with at least one exacerbation or 0, 1 or ≥ 2 exacerbations, and proportion of patients experiencing an exacerbation per day were evaluated by season and over the year, by treatment in the overall study population and in subgroups according to baseline blood eosinophil count (≥ 300 cells/μL or < 300 cells/μL) or atopic asthma status (fluoro-enzyme immunoassay [FEIA]+ or FEIA−).Results: Seasonal variations in exacerbation rates were found, with peaks observed in fall and winter, and greater variations in patients with high blood eosinophil counts (≥ 300 cells/μL). Tezepelumab treatment consistently reduced exacerbation rates across all seasons compared with placebo. Furthermore, there was a trend, which was not significant, toward a reduction in the total number of days with exacerbations and in the proportion of patients with exacerbations during each season in patients treated with tezepelumab compared with those who received placebo, irrespective of blood eosinophil count or atopic asthma status.Conclusion: Tezepelumab reduced exacerbations across all seasons, irrespective of evaluated baseline disease characteristics. These data support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma.Keywords: allergens, asthma, eosinophil, seasonal variation, tezepelumab, thymic stromal lymphopoietin

Topic: Retinopathy of prematurity (ROP) is a severe retinal vascular disorder affecting preterm infants, potentially leading to retinal detachment and blindness. This review aims to elucidate the relationship between systemic VEGF levels and ROP. Clinical Relevance: This systematic review aims to consolidate evidence from available studies to guide future research and inform clinical practice. In particular, the role of circulating VEGF-A levels in predicting ROP onset and progression, and evaluating the impact of anti-VEGF therapy on these levels, is crucial in ensuring efficacy and safety in patient care. Methods: Scopus and PubMed were searched to identify studies investigating circulating VEGF-gene products in ROP patients using immunologic assays. Two authors independently screened the literature and extracted data, employing a random-effects meta-analysis to compare VEGF levels as the ratio of means between ROP patients and controls before and after treatment, heterogeneity was reported by I2-statistics. Risks of bias and publication bias were assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and funnel plots/Egger’s tests, respectively. Results: Out of 941 papers, 54 were included, with 26 providing posttreatment data and 31 providing biomarker data. Findings show a significant decrease in VEGF-A levels in the first week after ROP treatment (ratio of means [95% confidence interval] 0.34 [0.25–0.45], I2 = 97%, 17 publications). Anti-VEGF therapy showed a significantly more pronounced decrease (0.31 [0.25–0.38], I2 = 40%, 7 publications) than laser treatment in the first week after treatment (0.77 [0.61–0.97], I2 = 42%, 2 publications, subgroup difference, P

IntroductionAortic stiffness plays a critical role in the evolution of cardiovascular diseases, but the assessment requires specialized equipment. Photoplethysmography (PPG) and single-lead electrocardiogram (ECG) are readily available in healthcare and wearable devices. We studied whether a brief PPG registration, alone or in combination with single-lead ECG, could be used to reliably estimate aortic stiffness.MethodsA proof-of-concept study with simultaneous high-resolution index finger recordings of infrared PPG, single-lead ECG, and finger blood pressure (Finapres) was performed in 33 participants [median age 44 (range 21–66) years, 19 men] and repeated within 2 weeks. Carotid–femoral pulse wave velocity (cfPWV; two-site tonometry with SphygmoCor) was used as a reference. A brachial single-cuff oscillometric device assessed aortic pulse wave velocity (aoPWV; Arteriograph) for further comparisons. We extracted 136 established PPG waveform features and engineered 13 new with improved coupling to the finger blood pressure curve. Height-normalized pulse arrival time (NPAT) was derived using ECG. Machine learning methods were used to develop prediction models.ResultsThe best PPG-based models predicted cfPWV and aoPWV well (root-mean-square errors of 0.70 and 0.52 m/s, respectively), with minor improvements by adding NPAT. Repeatability and agreement were on par with the reference equipment. A new PPG feature, an amplitude ratio from the early phase of the waveform, was most important in modelling, showing strong correlations with cfPWV and aoPWV (r = −0.81 and −0.75, respectively, both P

Introduction Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA), and AF detection can be challenged by asymptomatic and paroxysmal presentation. Long-term ECG monitoring after ischaemic stroke or TIA is recommended by all major societies in cardiology and cerebrovascular medicine as a secondary prophylactic measure. However, data on stroke reduction are lacking, and the recommendations show significant diversity.Methods and analysis AF SPICE is a multicentre, national, investigator-initiated, randomised, parallel-group, register-based trial comparing extended ECG monitoring versus standard ECG monitoring in patients admitted with ischaemic stroke or TIA, with a composite endpoint of stroke, all-cause-mortality and intracerebral bleeding. Patients aged ≥70 years without previous AF will be randomised 1:1 to control (standard ECG monitoring) or intervention (extended ECG monitoring). In the control arm, patients will undergo 48±24 hours (ie, a range of 24–72 hours) of continuous ECG monitoring according to national recommendations. In the intervention arm, patients will undergo 14+14 days of continuous ECG monitoring 3 months apart using an ECG patch device, which will provide an easy-accessed, well-tolerated 14-day continuous ECG recording. All ECG patch recordings will be read in a core facility. In cases of AF detection, oral anticoagulation will be recommended if not contraindicated. A pilot phase has been concluded in 2022, which will transcend into the main trial during 2023–2026, including approximately 30 stroke units. The sample size was calculated to be 3262 patients. The primary outcome will be collected from register data during a 36-month follow-up.Ethics and dissemination Ethical approval has been provided by the Swedish Ethical Review Authority, reference 2021–02770. The trial will be conducted according to the ethical principles of the Declaration of Helsinki and national regulatory standards. Positive results from the study have the potential for rapid dissemination in clinical practice.Trial registration number NCT05134454.

Abstract Although 11-ketotestosterone is a potent androgen and induces male secondary sex characteristics in many teleosts, androgen receptors with high binding affinity for 11-ketotestosterone or preferential activation by 11-ketotestosterone have not been identified. So, the mechanism by which 11-ketotestosterone exhibits such high potency remains unclear. Recently we cloned the cDNA of an 11-ketotestosterone regulated protein, spiggin, from three-spined stickleback renal tissue. As spiggin is the only identified gene product regulated by 11-ketotestosterone, the stickleback kidney is ideal for determination of the mechanism of 11-ketotestosterone gene regulation. A single androgen receptor gene with two splicing variants, belonging to the androgen receptor-β subfamily was cloned from stickleback kidney. A high affinity, saturable, single class of androgen specific binding sites, with the characteristics of an androgen receptor, was identified in renal cytosolic and nuclear fractions. Measurement of ligand binding moieties in the cytosolic and nuclear fractions as well as to the recombinant receptor revealed lower affinity for 11-ketotestosterone than for dihydrotestosterone. Treatment with different androgens did not up-regulate androgen receptor mRNA level or increase receptor abundance, suggesting that auto-regulation is not involved in differential ligand activation. However, comparison of the trans-activation potential of the stickleback androgen receptor with the human androgen receptor, in both human HepG2 cells and zebrafish ZFL cells, revealed preferential activation by 11-ketotestosterone of the stickleback receptor, but not of the human receptor. These findings demonstrate the presence of a receptor preferentially activated by 11-ketotestosterone in the three-spined stickleback, so far the only one known in any animal.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed‐dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1‐3). Tezepelumab exposure‐efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre‐bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2‐compartment linear disposition model with first‐order absorption and elimination following subcutaneous and intravenous administration at 2.1‐420 and 210‐700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti‐drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure‐response curve of tezepelumab. In conclusion, a fixed‐dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma. [ABSTRACT FROM AUTHOR]

This paper examines the attempts of the government of Kenya and international development agenda to achieve the objective of providing energy access for all and facilitate empowerment and poverty reduction to the rural areas within the framework of sustainable development goals. Energy has been recognised as the key enabler of economic and social development, however, the efforts to bring energy access to women within rural communities are falling short. The policy tools and economic instruments prescribed to address energy deficiency are not designed according to the local socio-economic conditions, which will be examined through empirical evidence produced from an energy access project in Kenya. In the Last Mile Connectivity Project women are integrated into the project design in a piecemeal basis. Macroeconomic and structural drivers currently hinder women's development in rural areas and prevent long-term access to economic opportunities and socio-economic growth, particularly for women suffering from rampant underdevelopment. This allows for the critical exploration of links between gender, energy, and poverty reduction within the international development framework under the United Nations Sustainable Development Goals agenda. The remote locations are cumbersome, and the solutions prescribed by the international stakeholders are proving insufficient in the spreading of energy access to women, setting the ambitions of achieving long-term sustainable development at risk. Achieving energy access has positively impacted rural areas, but more should be done to provide sufficient energy to women in rural communities to increase their economic and social development because providing small-scale energy access levels in isolation might not adequately meet these goals. This analysis relies methodologically on a case-study of the Last Mile Connectivity Project in Kenya and on data analysis and interpretation of the overall off-grid solar energy levels in Kenya provided by International Renewable Energy Agency. Keywords: Energy access, Gender, Socio-economic development, April 2021 Introduction In their efforts to eradicate poverty and achieve sustainable development and protection of the planet the United Nations (UN) developed the 17 Sustainable Development Goals (SDG) that [...]

The first case of African swine fever (ASF) was confirmed in Sweden in September 2023. This article describes the local epidemiology, including the spatiotemporal dynamics of the outbreak and some of the factors that may have contributed to its apparently successful eradication. Upon detection of the outbreak, strict control measures were put in place in a preliminarily defined infected zone. A carcass search, including geo‐localisation, removal, sampling, and destruction of found carcasses, was initiated and a preliminary core area was defined based on the results. Six months after confirmation of the first case, 93 wild boar carcasses had been found in the infected zone, of which 62 tested positive for ASF virus (ASFV). All ASFV‐positive carcasses were found inside the core area. Based on two taphonomy methods, it was assumed that the infection was introduced between early May and late June 2023. The data also indicated that the epidemic curve peaked between mid‐August and mid‐September, with the last death occurring in late September 2023. Based on the average estimated time of death, geo‐localisation of carcasses and two‐dimensional kernel density estimation, clustering in space and time was identified. An online questionnaire with questions about hunting and the wild boar population was sent to all leaders of hunting groups in the infected zone. The results showed that the wild boar population had increased in the last 10 years but with large variations and geographical heterogeneity in space use. Disease introduction through natural wild boar movements was excluded and it was assumed that the long‐distance translocation of the virus had occurred through human activities. A municipal waste collection centre without wild boar‐proof fencing is located close to the epicentre of the outbreak, attracting many wild boar and contributing to the spread of the virus once it had been introduced to the population. [ABSTRACT FROM AUTHOR]

Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.

Background. Parkinson’s disease is a neurodegenerative condition with both physical and mental consequences that affect many aspects of everyday life. Persons with Parkinson’s disease and their care partners want guidance from healthcare services in order to develop skills to adjust to life with a long-term condition. The Swedish National Parkinson School is a dyadic self-management programme to support both persons with Parkinson’s disease and care partners. Objective. To assess the outcomes of the Swedish National Parkinson School as reported by participants. Design. A quasi-experimental case-control study in clinical care using self-reported questionnaires. Participants. Swedish National Parkinson School was offered by health care professionals working in clinical care. Participants in the programme were also asked to participate in the study. A matched control group was recruited for a comparison of findings. In total, 92 persons with Parkinson’s disease and 55 care partners were included. Settings. Five Swedish geriatric and neurologic outpatient clinics. Method. Data were collected during 2015–2017, before and after participation in the National Parkinson School or before and after seven weeks of standard care. Outcomes were assessed using generic and Parkinson’s specific questionnaires. Descriptive statistics were used to describe baseline characteristics. Mann–Whitney U and Chi2 tests were used to test for between-group differences and within-group differences were tested by the Wilcoxon signed-ranks test. Results. Improvements regarding health status, constructive attitudes and approaches, and skill and technique acquisition were found after the intervention among persons with Parkinson’s disease. No changes were found among care partners. Conclusion. The findings indicate that the Swedish National Parkinson School may improve health status and self-management among persons with Parkinson’s disease, but further studies are needed to better understand the effects of the programme.