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The paper provides information on the objectives, methods, targets and some preliminary results of the expeditionary work carried out within the framework of the RSF project No.21-17-00049 by the employees of the Institute of Volcanology and Seismology of the FEB RAS, Institute of Marine Geology and Geophysics of the FEB RAS, Pacific Geographical Institute of the FEB RAS and Trofimuk Institute of Petroleum-Gas Geology and Geophysics of the SB RAS in 2022 and 2023. The main objectives of the expedition were geological volcanological, hydrogeological, geophysical, tephrochronological, and paleoseismological studies. In accordance with the set objectives, field teams were formed, which began work in February 2022. On the basis of the data obtained during the expedition, previously unknown hydrothermal manifestations and seismic events on Iturup Island were identified. A number of geophysical and paleomagnetic surveys were carried out.

Understanding the challenges faced by second language (L2) learners in lexical tone perception is crucial for effective language acquisition. This study investigates the impact of exaggerated acoustic properties on facilitating Mandarin tone learning for English speakers. Using synthesized tone stimuli, we systematically manipulated pitch contours through three key modifications: expanding the fundamental frequency (F0), increasing F0 (female voice), and extending the overall duration. Our objectives were to assess the influence of F0 expansion, higher F0, longer duration, and varied syllables on Mandarin tone learning and generalization. Participants engaged in a non-adaptive trial-by-trial tone identification task. Mixed-effects logistic regression modeling was used to analyze accuracy across learning phases, acoustic factors, and tones. Findings reveal improvements in accuracy from training to testing and generalization phases, indicating the effectiveness of perceptual training to tone perception for adult English speakers. Tone 1 emerged as the easiest to perceive, while Tone 3 posed the most challenge, consistent with established hierarchies of tonal acquisition difficulty. Analysis of acoustic factors highlighted tone-specific effects. Expanded F0 was beneficial for the identification of Tone 2 and Tone 3 but posed challenges for Tone 1 and Tone 4. Additionally, longer durations also exhibited varied effects across tones, aiding in the identification of Tone 3 and Tone 4 but hindering Tone 1 identification. The higher F0 was advantageous for Tone 2 but disadvantageous for Tone 3. Furthermore, the syllable ma facilitated the identification of Tone 1 and Tone 2 but not for Tone 3 and Tone 4. These findings enhance our understanding of the role of acoustic properties in L2 tone perception and have implications for the design of effective training programs for second language acquisition.

On the thirty-fifth anniversary of the first description of O2-sensitive K+ channels in the carotid body chemoreceptors O2 sensing remains a salient issue in the literature. Whereas much has been learned about this subject, important questions such as the identity of the specific K+ channel subtype(s) responsible for O2 sensing by chemoreceptors and the mechanism(s) by which their activities are altered by hypoxia have not yet been definitively answered. O2 sensing is a fundamental biological process necessary for the acute and chronic responses to varying environmental O2 levels which allow organisms to adapt to hypoxia. Whereas chronic responses depend on the modulation of hypoxia-inducible transcription factors which determine the expression of numerous genes encoding enzymes, transporters and growth factors, acute responses rely mainly on the dynamic modulation of ion channels by hypoxia, causing adaptive changes in cell excitability, contractility and secretory activity in specialized tissues. The most widely studied oxygen-sensitive ion channels are potassium channels, but oxygen sensing by members of both the calcium and sodium channel families has also been demonstrated. Given the explosion of information on this topic, in this review, we will focus on the mechanisms of physiological oxygen chemotransduction by PO2-dependent K+ channels, with particular emphasis on their function in carotid body chemoreceptor cells (CBCC) and pulmonary artery smooth muscle cells (PASMC), highlighting areas of consensus and controversy within the field. We will first describe the most well-established concepts, those reproduced in multiple laboratories, and then discuss selected observations or questions that remain unresolved, and that limit our progress in this field.

Abstract Background Existing financial hardship screening does not capture the multifaceted and dynamic nature of the problem. The use of existing health system data is a promising way to enable scalable and sustainable financial hardship screening. Methods We used existing data from 303 adult patients with cancer at the University of Virginia Comprehensive Cancer Center (2016–2018). All received distress screening and had a valid financial assistance screening based solely on household size‐adjusted income. We constructed a composite index that integrates multiple existing health system data (Epic, distress screening, and cancer registry) to assess comprehensive financial hardship (e.g., material conditions, psychological responses, and coping behaviors). We examined differences of at‐risk patients identified by our composite index and by existing single‐dimension criterion. Dynamics of financial hardship over time, by age, and cancer type, were examined by fractional probit models. Results At‐risk patients identified by the composite index were generally younger, better educated, and had a higher annual household income, though they had lower health insurance coverage. Identified periods to intervene for most patients are before formal diagnosis, 2 years, and 6 years after diagnosis. Within 2 years of diagnosis and more than 4 years after diagnosis appear critical for subgroups of patients who may suffer from financial hardship disparities. Conclusion Existing health system data provides opportunities to systematically measure and track financial hardship in a systematic, scalable and sustainable way. We find that the dimensions of financial hardship can exhibit different patterns over time and across patient subgroups, which can guide targeted interventions. The scalability of the algorithm is limited by existing data availability.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima–media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

As mobile and wearable devices continue to grow in popularity, there is strong yet unrealized potential to harness people's mobile sensing data to improve our understanding of their cellular and biologically-based diseases. Breakthrough technical innovations in tumor modeling, such as the three dimensional tumor microenvironment system (TMES), allow researchers to study the behavior of tumor cells in a controlled environment that closely mimics the human body. Although patients' health behaviors are known to impact their tumor growth through circulating hormones (cortisol, melatonin), capturing this process is a challenge to rendering realistic tumor models in the TMES or similar tumor modeling systems. The goal of this paper is to propose a conceptual framework that unifies researchers from digital health, data science, oncology, and cellular signaling, in a common cause to improve cancer patients' treatment outcomes through mobile sensing. In support of our framework, existing studies indicate that it is feasible to use people's mobile sensing data to approximate their underlying hormone levels. Further, it was found that when cortisol is cycled through the TMES based on actual patients' cortisol levels, there is a significant increase in pancreatic tumor cell growth compared to when cortisol levels are at normal healthy levels. Taken together, findings from these studies indicate that continuous monitoring of people's hormone levels through mobile sensing may improve experimentation in the TMES, by informing how hormones should be introduced. We hope our framework inspires digital health researchers in the psychosocial sciences to consider how their expertise can be applied to advancing outcomes across levels of inquiry, from behavioral to cellular.

IntroductionVisual sleep scoring has several shortcomings, including inter-scorer inconsistency, which may adversely affect diagnostic decision-making. Although automatic sleep staging in adults has been extensively studied, it is uncertain whether such sophisticated algorithms generalize well to different pediatric age groups due to distinctive EEG characteristics. The preadolescent age group (10–13-year-olds) is relatively understudied, and thus, we aimed to develop an automatic deep learning-based sleep stage classifier specifically targeting this cohort.MethodsA dataset (n = 115) containing polysomnographic recordings of Icelandic preadolescent children with sleep-disordered breathing (SDB) symptoms, and age and sex-matched controls was utilized. We developed a combined convolutional and long short-term memory neural network architecture relying on electroencephalography (F4-M1), electrooculography (E1-M2), and chin electromyography signals. Performance relative to human scoring was further evaluated by analyzing intra- and inter-rater agreements in a subset (n = 10) of data with repeat scoring from two manual scorers.ResultsThe deep learning-based model achieved an overall cross-validated accuracy of 84.1% (Cohen’s kappa κ = 0.78). There was no meaningful performance difference between SDB-symptomatic (n = 53) and control subgroups (n = 52) [83.9% (κ = 0.78) vs. 84.2% (κ = 0.78)]. The inter-rater reliability between manual scorers was 84.6% (κ = 0.78), and the automatic method reached similar agreements with scorers, 83.4% (κ = 0.76) and 82.7% (κ = 0.75).ConclusionThe developed algorithm achieved high classification accuracy and substantial agreements with two manual scorers; the performance metrics compared favorably with typical inter-rater reliability between manual scorers and performance reported in previous studies. These suggest that our algorithm may facilitate less labor-intensive and reliable automatic sleep scoring in preadolescent children.

Objective This study investigates a 6-month short message service (SMS) intervention to reduce adolescent sugar-sweetened beverage (SSB) intake. The objectives are to describe caregiver retention and SMS engagement as well as explore differences by caregiver characteristics. Methods Caregivers completed a baseline survey then messages were sent two times per week. Message types included the following: SSB intake assessments, educational information, infographic URLs, and strategies. Engagement was measured through interaction with these messages and included: assessment completion, reminders needed, number of strategies chosen, and URLs clicked. Results Caregivers (n = 357) had an average baseline SSB intake of 23.9 (SD = 26.8) oz/day. Of those, 89% were retained. Caregivers with a greater income and education were retained at a higher rate. Average engagement included: 4.1 (SD = 1.3) of 5 assessments completed with few reminders needed [4.1 (SD = 3.7) of 14 possible], 3.2 (SD = 1.1) of 4 strategies selected, and 1.2 (SD = 1.6) of 5 URLs clicked. Overall, average engagement was relatively high, even where disparities were found. Demographic characteristics that were statistically related to lower engagement included younger age, lower income, lower educational attainment, single caregivers, lower health literacy. Furthermore, caregivers with a reduced intention to change SSB behaviors completed fewer assessments and needed more reminders. Higher baseline SSB intake was associated with lower engagement across all indicators except URL clicks. Conclusions Results can be used to develop targeted retention and engagement strategies (e.g., just-in-time and/or adaptive interventions) in rural SMS interventions for identified demographic subsets. Trial registration Clincialtrials.gov: NCT03740113.

Abstract Background Behçet’s disease (BD) is a multisystem autoinflammatory disease characterised by mucosal ulceration, ocular, neural, joint and skin inflammation. The cause of BD is not known but there is a strong genetic association with HLA-B*51, IL10 and IL23R. Neutrophils are a first line of defence against invading pathogens and have been described as activated in patients with BD. Neutrophils can now be separated into different subsets, such as low density (LDN) and normal density (NDN) that have diverse functional roles. We wished to address neutrophil heterogeneity in patients with BD. Methods Peripheral blood neutrophils were obtained from 32 BD patients and 37 healthy aged-matched controls. Percoll isolation was used to isolate all neutrophils, while Ficol-Hypaque was used to obtain LDN and NDN. Phagocytic capacity and production of reactive oxygen species (ROS), and neutrophil extracellular traps (NET) stimulated with phorbol 12-myristate 13-acetate (PMA) and Escherichia coli (E.coli) were assessed in both groups. Results We have demonstrated reduced phagocytic capacity and ROS production but greater NET production by total neutrophils stimulated with PMA or E.coli from BD patients in comparison with healthy controls. Patients with BD had elevated numbers of LDN and lower number of NDN compared with healthy controls. However, both neutrophil subsets showed the same reduced ROS production and phagocytic function as total neutrophils in both groups. Conclusion Our novel findings indicate that the neutrophil population in BD is heterogeneous and the increased number of LDN in combination with greater NET production may contribute to the inflammatory response and pathogenesis.

Background: Bloodstream infections caused by Enterobacterales show high frequency of antimicrobial resistance (AMR) in many Low- and Middle-Income Countries. We aimed to describe the variation in circumstances for management of such resistant infections in a group of African public-sector hospitals participating in a major research study. Methods: We gathered data from eight hospitals across sub-Saharan Africa to describe hospital services, infection prevention and antibiotic stewardship activities, using two WHO-generated tools. We collected monthly cross-sectional data on availability of antibiotics in the hospital pharmacies for bloodstream infections caused by Enterobacterales. We compared the availability of these antibiotics to actual patient-level use of antibiotics in confirmed Enterobacterales bloodstream infections (BSI). Results: Hospital circumstances for institutional management of resistant BSI varied markedly. This included self-evaluated infection prevention level (WHO-IPCAF score: median 428, range 155 to 687.5) and antibiotic stewardship activities (WHO stewardship toolkit questions: median 14.5, range 2 to 23). These results did not correlate with national income levels. Across all sites, ceftriaxone and ciprofloxacin were the most consistently available antibiotic agents, followed by amoxicillin, co-amoxiclav, gentamicin and co-trimoxazole. There was substantial variation in the availability of some antibiotics, especially carbapenems, amikacin and piperacillin-tazobactam with degree of access linked to national income level. Investigators described out-of-pocket payments for access to additional antibiotics at 7/8 sites. The in-pharmacy availability of antibiotics correlated well with actual use of antibiotics for treating BSI patients. Conclusions: There was wide variation between these African hospitals for a range of important circumstances relating to treatment and control of severe bacterial infections, though these did not all correspond to national income level. For most antibiotics, patient-level use reflected in-hospital drug availability, suggesting external antibiotics supply was infrequent. Antimicrobial resistant bacterial infections could plausibly show different clinical impacts across sub-Saharan Africa due to this contextual variation.

BackgroundUveitis comprises a range of conditions that result in intraocular inflammation. Most sight-threatening uveitis falls into the broad category known as Non-infectious Posterior Segment-Involving Uveitis (PSIU). To evaluate treatments, trialists and clinicians must select outcome measures. The aim of this study was to understand healthcare professionals' perspectives on what outcomes are important to adult patients with PSIU and their carers.MethodsTwelve semi-structured telephone interviews were undertaken to understand the perspectives of healthcare professionals. Interviews were audio recorded, transcribed and thematically analysed. Findings were compared with the views of patients and carers and outcomes abstracted from a previously published systematic review.ResultsEleven core domains were identified as important to healthcare professionals: (1) visual function, (2) symptoms, (3) functional ability, (4) impact on relationships, (5) financial impact, (6) psychological morbidity and emotional well-being (7) psychosocial adjustment to uveitis, (8) doctor / patient / interprofessional relationships and access to health care, (9) treatment burden, (10) treatment side effects, (11) disease control. Healthcare professionals recognised a similar range of domains to patients and carers but placed more emphasis on certain outcomes, particularly in the disease control domain. In contrast the range of outcomes identified via the systematic review was limited.ConclusionHealthcare professionals recognise all of the published outcome domains as patients/carers in the previous publication but with subtly differing emphasis within some domains and with a priority for certain types of measures. Healthcare professionals discussed the disease control and side effects/complications to a greater degree than patients and carers in the focus groups.

Abstract Background Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea (‘silent hypoxemia’) in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). Methods Patients with COVID-19 (N = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation (mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls (N = 23) provided a normative comparison. Results The adverse composite outcome (observed in N = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. Conclusions Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.

LearnSphere is a web-based data infrastructure designed to transform scientific discovery and innovation in education. It supports learning researchers in addressing a broad range of issues including cognitive, social, and motivational factors in learning, educational content analysis, and educational technology innovation. LearnSphere integrates previously separate educational data and analytic resources developed by participating institutions. The web-based workflow authoring tool, Tigris, allows technical users to contribute sophisticated analytic methods, and learning researchers can adapt and apply those methods using graphical user interfaces, importantly, without additional programming. As part of our use-driven design of LearnSphere, we built a community through workshops and summer schools on educational data mining. Researchers interested in particular student levels or content domains can find student data from elementary through higher-education and across a wide variety of course content such as math, science, computing, and language learning. LearnSphere has facilitated many discoveries about learning, including the importance of active over passive learning activities and the positive association of quality discussion board posts with learning outcomes. LearnSphere also supports research reproducibility, replicability, traceability, and transparency as researchers can share their data and analytic methods along with links to research papers. We demonstrate the capabilities of LearnSphere through a series of case studies that illustrate how analytic components can be combined into research workflow combinations that can be developed and shared. We also show how open web-accessible analytics drive the creation of common formats to streamline repeated analytics and facilitate wider and more flexible dissemination of analytic tool kits.

BackgroundHealth interventions delivered via smart devices are increasingly being used to address mental health challenges associated with cancer treatment. Engagement with mobile interventions has been associated with treatment success; however, the relationship between mood and engagement among patients with cancer remains poorly understood. A reason for this is the lack of a data-driven process for analyzing mood and app engagement data for patients with cancer. ObjectiveThis study aimed to provide a step-by-step process for using app engagement metrics to predict continuously assessed mood outcomes in patients with breast cancer. MethodsWe described the steps involved in data preprocessing, feature extraction, and data modeling and prediction. We applied this process as a case study to data collected from patients with breast cancer who engaged with a mobile mental health app intervention (IntelliCare) over 7 weeks. We compared engagement patterns over time (eg, frequency and days of use) between participants with high and low anxiety and between participants with high and low depression. We then used a linear mixed model to identify significant effects and evaluate the performance of the random forest and XGBoost classifiers in predicting weekly mood from baseline affect and engagement features. ResultsWe observed differences in engagement patterns between the participants with high and low levels of anxiety and depression. The linear mixed model results varied by the feature set; these results revealed weak effects for several features of engagement, including duration-based metrics and frequency. The accuracy of predicting depressed mood varied according to the feature set and classifier. The feature set containing survey features and overall app engagement features achieved the best performance (accuracy: 84.6%; precision: 82.5%; recall: 64.4%; F1 score: 67.8%) when used with a random forest classifier. ConclusionsThe results from the case study support the feasibility and potential of our analytic process for understanding the relationship between app engagement and mood outcomes in patients with breast cancer. The ability to leverage both self-report and engagement features to analyze and predict mood during an intervention could be used to enhance decision-making for researchers and clinicians and assist in developing more personalized interventions for patients with breast cancer.

This study examined enrollment, retention, engagement, and behavior changes from a caregiver short message service (SMS) component of a larger school-based sugar-sweetened beverage (SSB) reduction intervention. Over 22 weeks, caregivers of seventh graders in 10 Appalachian middle schools received a two-way SMS Baseline Assessment and four monthly follow-up assessments to report their and their child’s SSB intake and select a personalized strategy topic. Between assessments, caregivers received two weekly one-way messages: one information or infographic message and one strategy message. Of 1873 caregivers, 542 (29%) enrolled by completing the SMS Baseline Assessment. Three-quarters completed Assessments 2–5, with 84% retained at Assessment 5. Reminders, used to encourage adherence, improved completion by 19–40%, with 18–33% completing after the first two reminders. Most caregivers (72–93%) selected a personalized strategy and an average of 28% viewed infographic messages. Between Baseline and Assessment 5, daily SSB intake frequency significantly (p < 0.01) declined for caregivers (−0.32 (0.03), effect size (ES) = 0.51) and children (−0.26 (0.01), ES = 0.53). Effect sizes increased when limited to participants who consumed SSB twice or more per week (caregivers ES = 0.65, children ES = 0.67). Findings indicate that an SMS-delivered intervention is promising for engaging rural caregivers of middle school students and improving SSB behaviors.

Mucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. Loss of tolerance to epithelial basement membrane proteins and generation of autoreactive T cell and/or autoantibodies are central to the disease process. The gut microbiome plays a critical role in the development of the immune system. Alteration in the gut microbiome (gut dysbiosis) affects the generation of autoreactive T cells and B cell autoantibody repertoire in several autoimmune conditions. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP by comparing OcMMP gut microbiome profiles with healthy controls. DNA was extracted from faecal samples (49 OcMMP patients, 40 healthy controls), amplified for the V4 region of the 16S rRNA gene and sequenced using Illumina Miseq platform. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. After adjusting for participant factors in the multivariable model (age, gender, BMI, diet, proton pump inhibitor use), OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. Within the OcMMP cohort, the number of OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). The linear discriminant analysis effect size scores indicated that Streptococcus and Lachnoclostridium were enriched in OcMMP patients whilst Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group were enriched in healthy controls (Log10 LDA score < 2, FDR-adjusted p

Abstract Background Non-infectious scleritis is a potentially sight-threatening condition in which the sclera, the white outer layer of the eye, becomes inflamed. Whilst scleritis can be infective, the majority of cases are due to non-infectious causes, often occurring in association with an underlying systemic autoimmune or auto-inflammatory condition. Thorough systemic work-up is crucial to identify disease aetiology and exclude infection; however, a significant proportion of disease remains idiopathic with the underlying cause unknown. Non-infectious scleritis is normally managed with systemic corticosteroid and immunosuppression, yet there is no widely agreed consensus on the most appropriate therapy, and no national or international guidelines exist for treatment of non-infectious scleritis. Methods Standard systematic review methodology will be used to identify, select and extract data from comparative studies of pharmacological interventions used to treat patients with non-infectious scleritis. Searches of bibliographic databases (Cochrane Library, MEDLINE, CINAHL and EMBASE) and clinical trial registers will be employed. No restrictions will be placed on language or date of publication. Non-English articles will be translated where necessary. The primary outcome of interest will be disease activity measured by reduction in scleritis grading according to standardised grading systems. Secondary outcomes will include change in best corrected visual acuity, reduction in concurrent dose of systemic corticosteroid, time to treatment failure, adverse events and health-related quality of life. Risk of bias assessment will be conducted appropriate to each study design. Study selection, data extraction and risk of bias assessment will be completed by two reviewers independently. Data will be presented in a table and a narrative synthesis will be undertaken. Meta-analysis will be performed where methodological and clinical homogeneity exists. Subgroup and sensitivity analysis will be undertaken if appropriate. Discussion Many studies have investigated the effectiveness of pharmacological agents used in the management of non-infectious scleritis. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review will help guide ophthalmologists managing patients with non-infectious scleritis and may form the basis for evidence-based recommendations for future clinical practice and encourage standardisation of treatment protocols. Systematic review registration PROSPERO CRD42019125198

Summary: Background: We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. Methods: Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. Findings: Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. Interpretation: This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenges. Funding: The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research Moorfields Biomedical Research Centre, Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The Seva Foundation, British Council for the Prevention of Blindness, and Christian Blind Mission. Translations: For the French, Spanish, Chinese, Portuguese, Arabic and Persian translations of the abstract see Supplementary Materials section.

Objective To evaluate whether topical therapy is linked to scores related to anxiety, depression and quality of life (QoL) in inflammatory eye disease (IED).Methods and analysis Patients with ocular surface disease (OSD, N=100) and Uveitis (N=100) completed self-administered validated questions on ocular symptoms and well-being, with supplemental questions on eye drop frequency.Results Forty (20%) patients had scores consistent with depression and 33 (17%) anxiety. Anxiety, depression, QoL and OSD index (OSDI) scores did not differ significantly between OSD and Uveitis groups. In those with anxiety or depression, QoL was significantly reduced in all WHO Quality Of Life-BREF domains (all p

Objective This study aimed to explore the British public’s healthcare-seeking beliefs concerning eye symptoms, and assess how the first COVID-19 lockdown influenced these.Methods and analysis An anonymous web-based survey was disseminated through mailing lists and social media between June and August 2020. The survey sought participants’ views on the severity and urgency of the need for medical review for four ophthalmic and two general medical scenarios on a five-point scale. Participants were asked to answer questions twice: once ignoring the COVID-19 pandemic, and once taking this into account, with additional questions asked to identify factors influencing the decision to seek medical attention and ward admission.Results A total of 402 participants completed the survey (mean age 61.6 years, 63.1% female and 87.7% of white ethnicity). Scores for symptom severity and urgency of medical review increased significantly with the severity of the clinical scenario (both p

This paper explores the possibilities of motion capture as a tool to preserve and study Intangible Cultural Heritage (ICH) practices such as playing instruments. The Uilleann pipes are both an instrument and a culture with a now strong community following and recovering after being almost extinguished several times in Ireland. The playing and making of the Uilleann pipes was incorporated into the Representative list of the UNESCO Convention of Intangible Cultural Heritage in 2017. This experience was performed in collaboration with several Uillean pipe players who contributed at every stage of the performance recording with comments and orientation. Some of these comments were also later formally kept as interviews to the players. The technical capture of the movements was done using a Rokoko Smart suit and paired Smart gloves which the piper wears for the performance. The resulting motion file was then cleaned and redirected to Blender 3D, a community made software package that allows the incorporation of a renderable avatar that helps for the dissemination of the performance. This recording process, called Inertial system, allows performers to perform almost anywhere and to capture the movements of the players with good accuracy. This process of recording and collaboration with the community is a cost-effective solution that can be of particular interest for scholars as well as for cultural communities wishing to archive these practices quickly. This design of technology and collaborative recording allows for a round experience that combined the detail of the technically enhanced recording with the interpretive nuance of the player that enriches the capturing process with mentions to how it is ‘relatively’ comfortable for the player and how efficient it is in terms of resulting detail. This collaboratively designed experience also provides the three aspects of intangible heritage preservation: supports the community -who can learn from the resulting animation; helps situating the practice within the cultural practice of the community-as they are part of the process; and helps materialise the output permitting its digital cataloguing, archival, and storage.

This paper provides a control dataset of processed prognostic indicators for analysing drug resistance in patients on antiretroviral therapy (ART). The dataset was locally sourced from health facilities in Akwa Ibom State of Nigeria, West Africa and contains 14 attributes with 1506 unique records filtered from 3168 individual treatment change episodes (TCEs). These attributes include sex, before and follow-up CD4 counts (BCD4, FCD4), before and follow-up viral load (BRNA, FRNA), drug type/combination (DTYPE), before and follow-up body weight (Bwt, Fwt), patient response to ART (PR), and classification targets (C1-C5). Five (5) output membership grades of a fuzzy inference system ranging from very high interaction to no interaction were constructed to model the influence of adverse drug reaction (ADR) and subsequently derive the PR attribute (a non-fuzzy variable). The PR attribute membership clusters derived from a universe of discourse table were then used to label the classification targets as follows: C1=no interaction, C2=very low interaction, C3=low interaction, C4=high interaction, and C5=very high interaction. The classification targets are useful for building classification models and for detecting patients with ADR. This data can be exploited for the development of expert systems, for useful decision support to treatment failure classification [1] and effectual drug regimen prescription.

Background: Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies.We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments. Methods: We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, and subjected to a progressive set of complementary analytical approaches: NOIseq, Gene Set Enrichment Analysis (GSEA), and correlation analysis of phenotypic data with gene expression. Findings: Transcriptomic profiles were generated for biopsy sets from 27 children of both sexes, under 2 years of age, of whom one-third were HIV-infected. NOIseq analysis, constructed from phenotypic group extremes, revealed 66 differentially expressed genes (DEGs) out of 21,386 mapped to the reference genome. These DEGs include genes for mucins and mucus integrity, antimicrobial defence, nutrient absorption, C-X-C chemokines, proteases and anti-proteases. Phenotype – expression correlation analysis identified 1221 genes related to villus height, including increased cell cycling gene expression in more severe enteropathy. Amino acid transporters and ZIP zinc transporters were specifically increased in severe enteropathy, but transcripts for xenobiotic metabolising enzymes were reduced. Interpretation: Transcriptomic analysis of this rare collection of intestinal biopsies identified multiple novel elements of pathology, including specific alterations in nutrient transporters. Changes in xenobiotic metabolism in the gut may alter drug disposition. Both NOIseq and GSEA identified gene clusters similar to those differentially expressed in pediatric Crohn's disease but to a much lesser degree than those identified in coeliac disease. Fund: Bill & Melinda Gates Foundation OPP1066118. The funding agency had no role in study design, data collection, data analysis, interpretation, or writing of the report. Keywords: Enteropathy, Severe acute malnutrition, Pediatric gastroenterology, RNA sequencing, Solute carriers

Background Microbial keratitis is a leading cause of preventable blindness worldwide. Conventional sampling and culture techniques are time-consuming, with over 40% of cases being culture-negative. Nanopore sequencing technology is portable and capable of generating long sequencing reads in real-time. The aim of this study is to evaluate the potential of nanopore sequencing directly from clinical samples for the diagnosis of bacterial microbial keratitis. Methods Using full-length 16S rRNA amplicon sequences from a defined mock microbial community, we evaluated and benchmarked our bioinformatics analysis pipeline for taxonomic assignment on three different 16S rRNA databases (NCBI 16S RefSeq, RDP and SILVA) with clustering at 97%, 99% and 100% similarities. Next, we optimised the sample collection using an ex vivo porcine model of microbial keratitis to compare DNA recovery rates of 12 different collection methods: 21-gauge needle, PTFE membrane (4 mm and 6 mm), Isohelix™ SK-2S, Sugi® Eyespear, Cotton, Rayon, Dryswab™, Hydraflock®, Albumin-coated, Purflock®, Purfoam and Polyester swabs. As a proof-of-concept study, we then used the sampling technique that provided the highest DNA recovery, along with the optimised bioinformatics pipeline, to prospectively collected samples from patients with suspected microbial keratitis. The resulting nanopore sequencing results were then compared to standard microbiology culture methods. Results We found that applying alignment filtering to nanopore sequencing reads and aligning to the NCBI 16S RefSeq database at 100% similarity provided the most accurate bacterial taxa assignment. DNA concentration recovery rates differed significantly between the collection methods (p < 0.001), with the Sugi® Eyespear swab providing the highest mean rank of DNA concentration. Then, applying the optimised collection method and bioinformatics pipeline directly to samples from two patients with suspected microbial keratitis, sequencing results from Patient A were in agreement with culture results, whilst Patient B, with negative culture results and previous antibiotic use, showed agreement between nanopore and Illumina Miseq sequencing results. Conclusion We have optimised collection methods and demonstrated a novel workflow for identification of bacterial microbial keratitis using full-length 16S nanopore sequencing.

As we advance towards individualized therapy, the ‘one-size-fits-all’ regimen is gradually paving the way for adaptive techniques that address the complexities of failed treatments. Treatment failure is associated with factors such as poor drug adherence, adverse side effect/reaction, co-infection, lack of follow-up, drug-drug interaction and more. This paper implements a transfer learning approach that classifies patients' response to failed treatments due to adverse drug reactions. The research is motivated by the need for early detection of patients' response to treatments and the generation of domain-specific datasets to balance under-represented classification data, typical of low-income countries located in Sub-Saharan Africa. A soft computing model was pre-trained to cluster CD4+ counts and viral loads of treatment change episodes (TCEs) processed from two disparate sources: the Stanford HIV drug resistant database (https://hivdb.stanford.edu), or control dataset, and locally sourced patients' records from selected health centers in Akwa Ibom State, Nigeria, or mixed dataset. Both datasets were experimented on a traditional 2-layer neural network (NN) and a 5-layer deep neural network (DNN), with odd dropout neurons distribution resulting in the following configurations: NN (Parienti et al., 2004) [32], NN (Deniz et al., 2018) [53] and DNN [9 7 5 3 1]. To discern knowledge of failed treatment, DNN1 [9 7 5 3 1] and DNN2 [9 7 5 3 1] were introduced to model both datasets and only TCEs of patients at risk of drug resistance, respectively. Classification results revealed fewer misclassifications, with the DNN architecture yielding best performance measures. However, the transfer learning approach with DNN2 [9 7 3 1] configuration produced superior classification results when compared to other variants/configurations, with classification accuracy of 99.40%, and RMSE values of 0.0056, 0.0510, and 0.0362, for test, train, and overall datasets, respectively. The proposed system therefore indicates good generalization and is vital as decision-making support to clinicians/physicians for predicting patients at risk of adverse drug reactions. Although imbalanced features classification is typical of disease problems and diminishes dependence on classification accuracy, the proposed system still compared favorably with the literature and can be hybridized to improve its precision and recall rates.

BackgroundMicrobial keratitis (MK) is the most common non-surgical ophthalmic emergency, and can rapidly progress, causing irreversible sight-loss. This study explored whether the COVID-19 (C19) national lockdown impacted upon the clinical presentation and outcomes of MK at a UK tertiary-care centre.MethodsMedical records were retrospectively reviewed for all patients with presumed MK requiring corneal scrapes, presenting between 23rd March and 30th June in 2020 (Y2020), and the equivalent time windows in 2017, 2018 and 2019 (pre-C19).ResultsIn total, 181 and 49 patients presented during the pre-C19 and Y2020 periods, respectively. In Y2020, concurrent ocular trauma (16.3% vs. 5.5%, p = 0.030) and immunosuppression use (12.2% vs 1.7%, p = 0.004) were more prevalent. Despite proportionately fewer ward admissions during the pandemic (8.2% vs 32.6%, pConclusionsPatient characteristics, MK severity and final visual outcomes did not appear to be affected in the first UK lockdown, despite fewer patients being admitted for care. Concurrent trauma and systemic immunosuppression use were greater than in previous years. The difference in spectra of isolated organisms may relate to behavioural changes, such as increased hand hygiene.

Oxygen is such an essential element for life that multiple mechanisms have evolved to maintain oxygen homeostasis, including those which detect decreases in arterial O2 and generate adaptive responses to hypoxia [...]

The study assessed gender mainstreaming in West African Agricultural Productivity Programme in aquaculture value chain of the Kainji Lake Basin, Nigeria. A two stage sampling technique was used to select 294 value chain actors across 20 communities. Also, Pie charts, logistics regression analysis, 3 point Likert-type scale rating technique and strategic decision matrix were used to analyse primary data. The result shows that 40% of the beneficiaries of fingerlings, fish feed and fish ponds in the programme were men, 26% were women and 34% were youths. Also, 49% of the beneficiaries of improved variety of crop seeds were men, 30% were youths and 21% were women while 66% of the beneficiaries of the NIFFR-WAAPP improved smoking kilns were women, 13% were men and 21% were youths. The determinants of participation in the programme were marital status, extension visits, membership of an association and experience. Furthermore, there were moderate financial requirements (need for loan and equipment) in feed milling (2.23), fish processing (2.30) and wholesale marketing (2.02), while the financial requirement in table-size fish farming was high (2.59). There were moderate development potentials (impacts on income, employment, poverty reduction and food security) in feed milling (2.33), fish processing (2.32) and wholesale marketing (1.99), while the development potential of table-size fish farming was high (2.55). It is therefore recommended that future interventions/programmes in the value chain should make necessary provisions for the financial needs of each value chain with the adoption of backward-forward integration of women and youths in the value chain.

Objective Uveitis, a group of disorders characterised by intraocular inflammation, causes 10%–15% of total blindness in the developed world. The most sight-threatening forms of non-infectious uveitis are those affecting the posterior segment of the eye, collectively known as posterior segment-involving uveitis (PSIU). Numerous different clinical outcomes have been used in trials evaluating treatments for PSIU, but these may not represent patients’ and carers’ concerns. Therefore, the aims of this study were to understand the impact of PSIU on adult patients’ and carers’ lives and to explore what outcomes of treatment are important to them.Methods and Analysis Four focus group discussions were undertaken to understand the perspectives of adult patients (=18) and carers (10) with PSIU. Participants were grouped according to whether or not their uveitis was complicated by the sight-threatening condition uveitic macular oedema. Discussions were audio-recorded, transcribed and analysed using the framework analytical approach. Outcomes were identified and grouped into outcome domains.Results Eleven core domains were identified as important to patients and carers undergoing treatment for PSIU, comprising (1) visual function, (2) symptoms, (3) functional ability, (4) impact on relationships, (5) financial impact, (6) psychological morbidity and emotional well-being, (7) psychosocial adjustment to uveitis, (8) doctor/patient/interprofessional relationships and access to healthcare, (9) treatment burden, (10) treatment side effects, and (11) disease control.Conclusion The domains identified represent patients’ and carers’ experience and perspectives and can be used to reflect on outcomes assessed in PSIU. They will directly inform the development of a core outcome set for PSIU clinical trials.

Background: Online interventions for insomnia can increase access to treatments for those with limited access to services. What remains unknown is whether individuals from more isolated (vs. more densely populated) regions engage with, and benefit as much from, an online intervention. This secondary analysis examined the relationship of geographical indices with engagement and outcomes of an efficacious, fully automated online cognitive behavioral therapy for insomnia (CBTI) program (Sleep Healthy Using the Internet-SHUTi). Method: 303 participants (Mage = 43.3; SD = 11.6) were randomly assigned to SHUTi or an online patient education condition and assessed at baseline and post intervention. Rural code of participants was determined using participant zip codes. Distance to the nearest sleep medicine provider was calculated as the distance between the center of the nearest provider's city (from a publicly available list of CBT-I providers) and the center of the participants' zip code. Adherence outcomes were number of intervention core completions, sleep diaries, and logins. Sleep outcomes were insomnia severity as well as sleep onset latency and wake after sleep onset derived from online sleep diaries. Results: Individuals were from a range of geographic locations. Most lived in fairly densely populated areas; however, there was a large variation in distance to the nearest sleep medicine provider. Findings indicate that the efficacy, adherence, and engagement with SHUTi were not impacted by where people lived. Controlling for age and gender did not impact any of the relationships among geography variables (i.e., distance, ruralness) and adherence or sleep related outcomes. Conclusions: Internet interventions must demonstrate that they can overcome obstacles posed by geography. This is the first study to examine the geographic location of participants and its association with engagement with, and outcomes of, online CBT-I. Keywords: eHealth, Insomnia, Cognitive behavioral therapy, Geography

Abstract Background Non-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation. If untreated, the intraocular inflammation may progress to severe visual impairment and blindness. Current treatment is heavily reliant on systemic corticosteroid, often at doses associated with severe side effects. There is a need for efficacious corticosteroid-sparing immunomodulatory therapy for these patients. Current immunomodulators include various immunosuppressants and biologics but mammalian target of rapamycin (mTOR) inhibitors (such as sirolimus and everolimus) may also be contenders for this role. The systematic review proposed here will evaluate the evidence for the use of sirolimus and everolimus in the context of non-infectious uveitis. Method/design Standard systematic review methodology will be used to identify, select and extract data from any comparative or non-comparative study of mTOR inhibitors in patients with non-infectious uveitis excluding case reports. Searches of bibliographic databases (MEDLINE, EMBASE, The Cochrane Library and CINAHL) and clinical trials registers will be performed, with no restriction on language or date of publication. Translation of non-English language articles will be undertaken where necessary. The primary outcome of interest will be uveitis activity as measured by vitreous haze. Secondary outcomes will include other pre-specified measures of uveitis activity (such as anterior chamber cells or central macular thickness) best corrected visual acuity, heath-related quality of life, requirement for concurrent treatment and adverse events. Risk of bias assessment will be performed appropriate to each study design. Study selection, data extraction and risk of bias assessment will be undertaken by two reviewers independently. Data will be grouped, tabulated and narratively synthesised. Meta-analysis will be undertaken where appropriate clinical and methodological homogeneity exists. The review will be published according to PRISMA guidance. Discussion Studies of various designs have investigated the clinical use of mTOR inhibitors for non-infectious uveitis, and a large international randomised controlled trail of sirolimus for non-infectious uveitis is due to report. The findings of this systematic review will help inform ophthalmologists and aid the improvement of treatment protocols for non-infectious uveitis with regard to the use of mTOR inhibitors. Systematic review registration PROSPERO CRD42017056390

Abstract Background Divergent selection for meat and egg production in poultry has resulted in strains of birds differing widely in traits related to these products. Modern strains of meat birds can reach live weights of 2 kg in 35 d, while layer strains are now capable of producing more than 300 eggs per annum but grow slowly. In this study, RNA-Seq was used to investigate hepatic gene expression between three groups of birds with large differences in growth potential; meat bird, layer strain as well as an F1 layer x meat bird. The objective was to identify differentially expressed (DE) genes between all three strains to elucidate biological factors underpinning variations in growth performance. Results RNA-Seq analysis was carried out on total RNA extracted from the liver of meat bird (n = 6), F1 layer x meat bird cross (n = 6) and layer strain (n = 6), males. Differential expression of genes were considered significant at P

Abstract Background This study investigated learning outcomes and user perceptions from interactions with a hybrid intelligent tutoring system created by combining the AutoTutor conversational tutoring system with the Assessment and Learning in Knowledge Spaces (ALEKS) adaptive learning system for mathematics. This hybrid intelligent tutoring system (ITS) uses a service-oriented architecture to combine these two web-based systems. Self-explanation tutoring dialogs were used to talk students through step-by-step worked examples to algebra problems. These worked examples presented an isomorphic problem to the preceding algebra problem that the student could not solve in the adaptive learning system. Results Due to crossover issues between conditions, experimental versus control condition assignment did not show significant differences in learning gains. However, strong dose-dependent learning gains were observed that could not be otherwise explained by either initial mastery or time-on-task. User perceptions of the dialog-based tutoring were mixed, and survey results indicate that this may be due to the pacing of dialog-based tutoring using voice, students judging the agents based on their own performance (i.e., the quality of their answers to agent questions), and the students’ expectations about mathematics pedagogy (i.e., expecting to solving problems rather than talking about concepts). Across all users, learning was most strongly influenced by time spent studying, which correlated with students’ self-reported tendencies toward effort avoidance, effective study habits, and beliefs about their ability to improve in mathematics with effort. Conclusions Integrating multiple adaptive tutoring systems with complementary strengths shows some potential to improve learning. However, managing learner expectations during transitions between systems remains an open research area. Finally, while personalized adaptation can improve learning efficiency, effort and time-on-task for learning remains a dominant factor that must be considered by interventions.

Purpose: To report a case of bilateral iridoschisis with cataracts and corneal decompensation in a patient who underwent cataract extraction and superficial iridectomy followed by Descemet membrane endothelial keratoplasty (DMEK). Observations: A 58-year-old man with previously diagnosed iridoschisis, cataracts, and diabetes mellitus experienced progressive vision loss bilaterally due to corneal decompensation. Slit lamp examination revealed iridoschisis with iris fibrils contacting the corneal endothelium, stromal edema, and mild guttate changes bilaterally. Corneal findings were more severe in the right eye, including the presence of bullous keratopathy at the time of presentation. Cataract extraction with intraocular lens implantation and superficial iridectomy were performed in the right eye, followed by DMEK. These same procedures were performed subsequently in the left eye. Postoperatively, the patient had significant improvement in visual acuity and corneal edema. Conclusions and importance: DMEK can be performed safely and successfully after staged cataract surgery with superficial iridectomy in eyes with endothelial decompensation caused by iridoschisis.

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

Abstract Background Uveitis, a group of disorders characterised by intraocular inflammation, causes 10–15% of total blindness in the developed world. The most sight-threatening uveitis affects the posterior segment of the eye (posterior-segment involving uveitis (PSIU)). Numerous different outcomes have been used in clinical trials evaluating alternative treatments for uveitis, limiting inter-trial comparison and aggregation of data. We aim to develop a core outcome set (COS) that would provide a standardised set of outcomes to be measured and reported in all effectiveness trials for PSIU. Methods A three-phase design will be used informed by recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Phase 1: a comprehensive list of outcomes will be identified through both a systematic review of effectiveness trials of PSIU and qualitative research with stakeholders. The qualitative study will comprise focus groups with patients and their carers in parallel with one-to-one telephone interviews with health professionals and policy-makers. In the focus groups, patients will be grouped according to whether or not their uveitis is complicated by the sight-threatening condition uveitic macular oedema (UMO) since it is hypothesised that the presence of UMO may significantly impact on patient experience of PSIU. Phase 2: Delphi methodology will be used to reduce the range of potential outcomes for the core set. Up to three Delphi rounds will be used through an online survey. Participants will be asked to rate the importance of each outcome on a 9-point Likert scale where 9 is most important. Phase 3: a consensus meeting will be held with key stakeholders to discuss the Delphi results and ratify the final outcomes to be included in the COS. Discussion The development of an agreed COS for PSIU would help ensure that outcomes which matter to key stakeholders are captured and reported in a consistent way. A COS for PSIU would allow greater comparison and aggregation of data across trials for the better evaluation of established and emerging therapies through evidence synthesis and meta-analysis to inform clinical guidelines and health policy. Trial registration COMET. http://comet-initiative.org/studies/details/640 . August 2015.

Abstract Background The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid (FA) metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as well as genes involved with FA metabolism, immunity and cellular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil: lymphocyte ratios, relative organ weights and bodyweight data were also compared. Results Broiler bodyweight (n = 12) was four times that of layers (n = 12) by d 14 and had significantly higher carcass fat percentage compared to the cross (n = 6; P = 0.002) and layers (P = 0.017) which were not significantly different from each other (P = 0.523). The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite all being raised on the same diet. Genes associated with FA synthesis and β-oxidation were upregulated in the broilers compared to the layers indicating a net overall increase in FA metabolism, which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as well as organelle stress indicators ERN1 and XBP1 were found to be non-significant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additionally there was no difference in heterophil: lymphocytes between any of the birds. Conclusions The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cellular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.

Abstract Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare oculorenal inflammatory condition that was first described in 1975. In 2001 a major review identified 133 cases in the world literature and proposed key diagnostic criteria for the condition. Although acknowledged as rare, the limited data available prevented reliable estimates of the prevalence of the condition, and hampered elucidation of the relationship between genetic and environmental factors that contribute to its pathogenesis. In this review we have performed a systematic search on the epidemiology, demographics and proposed risk factors for TINU. Estimates of prevalence based on studies that explicitly report TINU cases suggest that it is diagnosed in 0.2–2% of patients attending specialist uveitis services, with variation reflecting a number of factors including level of diagnostic certainty required. The prevalence of uveitis in patients with tubulointerstitial nephritis (TIN) may be higher than currently recognised, particularly in the paediatric population. The prevalence of TINU is higher in younger age groups and there is a female preponderance although this gender effect appears weaker than suggested by early studies. Although important genetic contributions have been proposed, the small size of studies and variation between reports currently preclude identification of a ‘pro-TINU’ haplotype. Drugs and infections have been proposed as the leading acquired risk factors for the development of TINU; whilst the small size of TINU cohorts and issues of study design limit interpretation of many studies. Larger datasets from the renal literature suggest that the majority of these cases are precipitated by a drug-induced hypersensitivity reaction; however in many ophthalmic cases no clear precipitant is identified.

Abstract ᅟ Behçet’s disease (BD) is a systemic vasculitis characterised by a relapsing remitting course, affecting multiple organ systems. In the eye, it is a cause of potentially blinding inflammation in the form of uveitis. Management of uveitis in BD often requires the use of systemic immunosuppression, in order to reduce disease activity and prevent accumulation of irreversible damage. Whilst corticosteroids remain the mainstay of treatment, long-term use is limited by the development of adrenocorticotrophic side effects. There has therefore been significant interest in the use of corticosteroid-sparing immunosuppressive agents, and more recently, biologic therapies. Recent publications have demonstrated biologic therapy to have beneficial effects both on overall disease control, and quality of life for patients with BD. Widespread use of such agents is however limited, partly by the lack of high quality research evidence, and partly by the prohibitive cost of biologic treatments. In this review, we discuss the most recent research investigating the use of biologic therapy in uveitis due to BD, with consideration of health economics and quality of life outcomes.

Drug component interactions are most likely to trigger unexpected pharmacological effects with unknown causal mechanisms, hence, demanding the discovery of patterns to establish suitable and effective regimens. This paper proposes a novel framework that embeds machine learning (ML) and multidimensional scaling (MDS) techniques, for efficient prediction of patient response to antiretroviral therapy (ART). To achieve this, experiment databases were created from two independent sources: a publicly available HIV domain datasets of patients with failed treatment – hosted by the Stanford University, hereinafter referred to as the Stanford HIV database, and locally sourced datasets gathered from 13 prominent healthcare facilities treating HIV patients in Akwa Ibom State of Nigeria, hereinafter referred to as the Akwa-Ibom HIV database: with 5,780 and 3,168 individual treatment change episodes (TCEs) of HIV treatment indicators (baseline CD4 count (BCD4), followup CD4 count (FCD4), baseline viral load (BRNA), followup viral load (FRNA), and drug type combination (DType)), observed from 1,521 and 1,301 unique patient records, respectively. A hybridised (two-stage) classification system consuming the Interval Type-2 Fuzzy Logic (IT2FL) and Deep Neural Network (DNN) was employed to model and optimise patients’ response to ART with appreciable error pruning achieved through MDS. Visualisation of the experiment databases showed remarkable immunological changes in the Akwa-Ibom HIV database, as the FCD4 of TCEs clustered far above the BCD4, compared to the Stanford HIV database, where over 40% of FCD4 clustered below the BCD4. Similar changes were noticed for the RNA, as more FRNA copies clustered below the BRNA for the Akwa-Ibom datasets, compared to the Stamford datasets. DNN classification results for both databases showed best performance metrics for the Levenberg-Marquardt algorithm when compared with the resilient backpropagation algorithm, with improved drug pattern predictions for experiment with MDS. This paper is most likely to evolve an avenue that triggers interesting combination(s) for optimum patient response, while ensuring minimal side effects, as further findings revealed the superiority of the proposed approach over existing approaches.

Premise Glyptostrobus pensilis (Cupressaceae) is a critically endangered conifer native to China, Laos, and Vietnam, with only a few populations remaining in the wild. Methods and Results Using a complete chloroplast genome sequence, we designed 70 cpSSR loci and tested them for amplification success and polymorphism in 16 samples. Ten loci were found to be polymorphic and their genetic diversity was characterized using a total of 83 individuals from three populations in China. A total of 43 haplotypes were present, the effective number of haplotypes varied from 4.55 to 13.36, and the haplotypic richness ranged from 8.04 to 16.00. Gene diversity ranged from 0.81 to 0.97 (average 0.89). The number of alleles per locus and population ranged from one to eight, and the effective number of alleles ranged from 1.00 to 3.90. All polymorphic loci were successfully amplified in the related species Cryptomeria japonica var. sinensis, Taxodium distichum, T. ascendens, and Cunninghamia lanceolata. Conclusions These newly developed chloroplast microsatellites will be useful for population genetic and phylogeographic analyses of G. pensilis and related species.

While there is extensive evidence for the Late Devensian, less is known about Early and Middle Devensian (approx. 110–30 ka) climates and environments in the UK. The Greenland ice-core record suggests the UK should have endured multiple changes, but the terrestrial palaeo-record lacks sufficient detail for confirmation from sites in the British Isles. Data from deposits at Finningley, South Yorkshire, can help redress this. A channel with organic silts, dated 40 314–39 552 cal a BP, contained plant macrofossil and insect remains showing tundra with dwarf-shrub heath and bare ground. Soil moisture conditions varied from free draining to riparian, with ponds and wetter vegetated areas. The climate was probably low arctic with snow cover during the winter. Mutual climatic range (MCR), based on Coleoptera, shows the mean monthly winter temperatures of −22 to −2°C and summer ones of 8–14°C. Periglacial structures within the basal gravel deposits and beyond the glacial limits indicate cold-climate conditions, including permafrost. A compilation of MCR reconstructions for other Middle Devensian English sites shows that marine isotope stage 3—between 59 and 28 ka—experienced substantial variation in climate consistent with the Greenland ice-core record. The exact correlation is hampered by temporal resolution, but the Finningley site stadial at approximately 40 ka may correlate with the one of the Greenland stadials 7–11.