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Victoria S Benson,1,* James Siddall,2,* Adam Haq,2 Mark Small,2 Zhiliu Tang,3 Tao Ye,4 Peter Howarth,5 Anna Richards,6 Rafael Alfonso-Cristancho7 1Epidemiology, Value Evidence & Outcomes, GSK, London, UK; 2Adelphi Real World, Bollington, UK; 3Value Evidence & Outcomes, GSK, Shanghai, People’s Republic of China; 4Medical Affairs, Respiratory, GSK, Shanghai, People’s Republic of China; 5Global Respiratory Franchise, GSK, Brentford, UK; 6Value Evidence & Outcomes, GSK, London, UK; 7Value Evidence & Outcomes, GSK, Philadelphia, Pennsylvania, USA*These authors contributed equally to this workCorrespondence: Tao Ye, Medical Affairs, Respiratory, GSK, 902 halei Road, Pudong, Shanghai, People’s Republic of China, Email ark.x.ye@gsk.comPurpose: To inform effective management strategies for severe asthma in China, this study aimed to comprehensively characterize clinical characteristics, treatment patterns, disease control status, and healthcare resource utilization among patients on GINA Step 4/5 therapies by analyzing data from the Adelphi Asthma Disease Specific Program conducted in China.Patients and methods: All information was retrieved from medical records or collected from physicians and patients on the survey date (August–December 2018); no follow-up was conducted. Results were summarized descriptively for patients on GINA Step 4/5 therapies, who were pooled from a consecutive sample (comprising three or more consecutive patients with physician-diagnosed asthma from each participating physician) and an oversample (comprising the next two patients with physician-perceived severe asthma from each participating physician).Results: Of the included patients (n=754), 51.5% had ever had a blood eosinophil measurement taken, 22.1% had available records for their most recent blood eosinophil measurements (68.9% of them had an elevated level ≥ 150 cells/μL), 39.9% had ever been tested for specific immunoglobulin E or radioallergosorbent, and 8.0% were prescribed maintenance oral corticosteroids. Asthma was not well controlled in 69.2% of patients. In the prior year, 27.1% experienced at least one severe exacerbation and 22.8% experienced at least one hospitalization (emergency visit or overnight stay) due to asthma.Conclusion: In Chinese patients with asthma on GINA Step 4/5 therapies, biomarker testing was underutilized, asthma was not well controlled, and severe exacerbations were not infrequent. These findings highlight the urgent need for optimized asthma management for patients on GINA Step 4/5 therapies in China.Keywords: severe asthma, type-2 high asthma, real-world, phenotype, exacerbations, health care resource utilization, eosinophils

The article discusses the development of online tutorials to support the Academic Librarians' information literacy instruction during the first lockdown of the COVID-19 pandemic. The content and development of the activities are presented in relation to information literacy (IL) standards. At the University of Northampton, the first-year students each receive two IL sessions from an Academic Librarian that support their information skills development. The first session focuses on identifying an information need and how to search for relevant information. The second session supports students to understand the referencing process and how to use information ethically. The IL sessions are based on the principles of Active Blended Learning and focus on providing interactive and engaging workshops for students. The activities were designed to support the students on health programmes who began their studies in April 2020 and the students who were receiving their final IL session. The reflections on the IL sessions highlight lessons learnt during the online delivery.

Victoria S Benson,1,* James Siddall,2,* Adam Haq,2 Mark Small,2 Rafael Alfonso-Cristancho,3 Zhiliu Tang,4 Peter Howarth,5 Tao Ye,6 Anna Richards7 1Epidemiology, Value Evidence & Outcomes, GSK, London, UK; 2Adelphi Real World, Bollington, UK; 3Value Evidence & Outcomes, GSK, Philadelphia, Pennsylvania, USA; 4Value Evidence & Outcomes, GSK, Shanghai, People’s Republic of China; 5Global Respiratory Franchise, GSK, Brentford, UK; 6Medical Affairs, Respiratory, GSK, Shanghai, People’s Republic of China; 7Value Evidence & Outcomes, GSK, Brentford, UK*These authors contributed equally to this workCorrespondence: Tao Ye, Medical Affairs, Respiratory, GSK, 902 halei Road, Pudong, Shanghai, People’s Republic of China, Email ark.x.ye@gsk.comPurpose: To inform better asthma management in China, this study aimed to comprehensively investigate clinical characteristics, treatment patterns, asthma control status, exacerbations, and humanistic burden among adult patients seeking hospital-based asthma care by analyzing data from Adelphi Asthma Disease Specific Program conducted in China.Patients and Methods: All information was collected on survey date (August–December 2018) from medical records, physicians, or patients, without follow-up being conducted. Results are summarized descriptively for the overall population as well as subgroups defined by GINA 2018 treatment step.Results: Of the included 765 patients, 46.0%, 40.4%, and 29.2% had undergone lung function, blood eosinophil count, and specific immunoglobulin E/radioallergosorbent testing, and 17.2%, 24.1%, and 58.7% were managed at GINA Steps 1– 2, 3, and 4– 5, respectively. Asthma was not well controlled in 57.3% of patients based on definitions adapted from the ERS/ATS and 10.7% of patients had experienced ≥ 1 severe exacerbation in the preceding year. According to patient self-reporting (n=603), the mean (SD) was 0.9 (0.1) for utility on EQ-5D-3L and was 7.8% (10.4%), 36.9% (20.0%), 40.8% (22.2%), and 37.9% (22.3%) for absenteeism, presenteeism, work productivity loss, and activity impairment, respectively, on WPAI. Both asthma control and humanistic burden worsened with progressive GINA treatment steps.Conclusion: In patients seeking hospital-based asthma care in China, lung function and biomarker tests were underutilized, impairment in productivity and quality of life was observed, and more than half did not achieve well-controlled asthma despite approximately 60% being managed at GINA treatment Steps 4– 5. These findings highlight the urgent need for optimizing asthma management in China.Keywords: asthma control, exacerbation, treatment patterns, health care resource utilization, humanistic burden

Abstract Background Eosinophilic esophagitis is a chronic inflammatory disorder of the esophagus. This real-world study used patient and physician surveys to describe the clinical characteristics and disease burden of eosinophilic esophagitis—overall and in a subgroup of patients with dysphagia despite treatment. Methods Data analyzed in this study were collected in 2020 from US and EU patients with eosinophilic esophagitis. Eligible patients were aged ≥ 12 years with a diagnosis of eosinophilic esophagitis, had an esophageal count of ≥ 15 eosinophils/high-power field at diagnosis, and were currently prescribed treatment for eosinophilic esophagitis. Results Overall, 1001 patients were included, of whom 356 (36%) had dysphagia despite treatment. Demographics and clinical characteristics were similar in both populations. The severity of eosinophilic esophagitis was mild in more patients overall (69%) versus those with dysphagia despite treatment (48%). Patient disease history was similar in both populations, with some exceptions: common patient-reported symptoms were dysphagia (70% and 86%) and heartburn/acid reflux (55% and 49%), and common physician-reported symptoms were dysphagia (75% and 91%) and food impaction (46% and 52%). Treatment history was similar in both populations; overall, the most common treatments were proton pump inhibitors (83%) and topical corticosteroids (51%). Patients reported slightly more days with symptoms, higher impacts on activities of daily living, and slightly higher anxiety or depression in the dysphagia-despite-treatment population versus the overall population. Conclusions Eosinophilic esophagitis presents severe symptoms and comorbidities that substantially impact patients’ well-being and quality of life. Greater awareness of and novel treatments for eosinophilic esophagitis are needed.

What happens when you cannot get the buy-in from your colleagues and the workload is driving you mad? In this presentation we showed what we do to disrupt and rewrite the game. Using a fictional scenario, the wise three guided you through the trials and tribulations of embedded support for key academic skills. You were invited to share your experiences in advance of the conference so our agony aunts can come up with ideas and suggestions to help you succeed in your role. Academic skills are most successful when embedded within the curriculum (Coulson et al., 2021; Wyatt, 2011). However, in our experience getting buy-in from academic staff and professional colleagues can be difficult. Engaging students with an active teaching approach can be even harder (Armellini et al., 2021; Hicks and Sinkinson, 2021). Using the model of Integrated Learner Support (ILS) developed at the University of Northampton for undergraduate support (Library and Learning Services, 2022), the workshop highlighted different approaches that can be used to navigate through difficulties, and offered potential solutions to collaborative working between Learning Developers and Academic Librarians.

RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.

Abstract Homing-based gene drives are recently proposed interventions promising the area-wide, species-specific genetic control of harmful insect populations. Here we characterise a first set of gene drives in a tephritid agricultural pest species, the Mediterranean fruit fly Ceratitis capitata (medfly). Our results show that the medfly is highly amenable to homing-based gene drive strategies. By targeting the medfly transformer gene, we also demonstrate how CRISPR-Cas9 gene drive can be coupled to sex conversion, whereby genetic females are transformed into fertile and harmless XX males. Given this unique malleability of sex determination, we modelled gene drive interventions that couple sex conversion and female sterility and found that such approaches could be effective and tolerant of resistant allele selection in the target population. Our results open the door for developing gene drive strains for the population suppression of the medfly and related tephritid pests by co-targeting female reproduction and shifting the reproductive sex ratio towards males. They demonstrate the untapped potential for gene drives to tackle agricultural pests in an environmentally friendly and economical way.

A bistable mechanism has two stable states with energy input required to move from one stable state to another. This energy barrier allows for energy storage and release which can be used to improve systems characteristics. Bistability has been used to increase the frequency range over which a kinetic energy harvester is effective, and it has been proposed that bistability can increase the efficiency of biomimetic swimming robots. However, experiments involving bistable swimming robots have typically used bistability as a means of overcoming limitations inherent to soft actuators, rather than to increase overall performance. This article implements bistability into a swimming robotic and compares performance with and without bistable action. The static thrust generation and power consumption for bistable and nonbistable configurations for five different tail morphologies are compared. Bistability is generally found to increase the system efficiency, particularly at lower frequencies where increases are observed up to 250%. The untethered swimming speed of the robot in open water is also found to increase by approximately 30%. The results show that bistability can offer direct performance benefits for biomimetic swimming, but that the bistable transmission must be well tuned to the dynamics of the rest of the system.

Abstract Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.

Preference assessments identify foods that might be valued by an animal but do not capture differences in the magnitude of value. In combination with demand, the more effort required to acquire the commodity – the more valued and likely it is to function as an effective reinforcer for use in dog training. In the current experiment, two preference assessments' applicability was measured using a combination of choice assessment and effortful runway task. Eight dogs experienced a paired stimulus preference assessment and multiple stimulus without replacement preference assessments combined with a 3-m runway task. The preference assessments identified different most-preferred foods, but the same least-preferred foods. The reinforcer assessment results showed that the dogs moved faster to obtain their most preferred food as identified by the multiple stimulus without replacement assessment compared to the most preferred foods identified in the paired stimulus assessment. The paired- or multiple-stimulus-without-replacement preference assessments identified highly valued foods; however, the applicability of that commodity as a reinforcer was not independent of the assessment method. To ensure accurate reinforcer identification and consistency, a preference assessment should be conducted under similar conditions to that experienced when the reinforcer is used in training. Overall, the multiple stimulus without replacement preference assessment would be more useful to trainers, owners or scientists wanting to identify high-value foods for their animals to function as effective reinforcers for the elicitation of behaviors in a training context.

Abstract Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

The development of robots as tools for biological research, sometimes termed “biorobotics”, has grown rapidly in recent years, fueled by the proliferation of miniaturized computation and advanced manufacturing techniques. Much of this work is focused on the use of robots as biomechanical models for natural systems. But, increasingly, biomimetic robots are being employed to interact directly with animals, as component parts of ethology studies in the field and behavioral neuroscience studies in the laboratory. While it has been possible to mechanize and automate animal behavior experiments for decades, only recently has there been the prospect of creating at-scale robotic animals containing the sensing, autonomy and actuation necessary for complex, life-like interaction. This not only opens up new avenues of enquiry, but also provides important ways to improve animal welfare, both by reducing or replacing the use of animal subjects, and by minimizing animal distress (if robots are used judiciously). This article will discuss the current state of the art in robotic lab rats, providing perspective on where research could be directed to enable the safe and effective use of biorobotic animals.

Abstract The Drosophila ovary is regenerated from germline and somatic stem cell populations that have provided fundamental conceptual understanding on how adult stem cells are regulated within their niches. Recent ovarian transcriptomic studies have failed to identify mRNAs that are specific to follicle stem cells (FSCs), suggesting that their fate may be regulated post-transcriptionally. We have identified that the RNA-binding protein, Musashi (Msi) is required for maintaining the stem cell state of FSCs. Loss of msi function results in stem cell loss, due to a change in differentiation state, indicated by upregulation of Lamin C in the stem cell population. In msi mutant ovaries, Lamin C upregulation was also observed in posterior escort cells that interact with newly formed germ cell cysts. Mutant somatic cells within this region were dysfunctional, as evidenced by the presence of germline cyst collisions, fused egg chambers and an increase in germ cell cyst apoptosis. The msi locus produces two classes of mRNAs (long and short). We show that FSC maintenance and escort cell function specifically requires the long transcripts, thus providing the first evidence of isoform-specific regulation in a population of Drosophila epithelial cells. We further demonstrate that although male germline stem cells have previously been shown to require Msi function to prevent differentiation this is not the case for female germline stem cells, indicating that these similar stem cell types have different requirements for Msi, in addition to the differential use of Msi isoforms between soma and germline. In summary, we show that different isoforms of the Msi RNA-binding protein are expressed in specific cell populations of the ovarian stem cell niche where Msi regulates stem cell differentiation, niche cell function and subsequent germ cell survival and differentiation.

Background: The COVID-19 pandemic has caused unprecedented health care challenges mandating surgical service reconfiguration. Within our hospital, emergency and elective streams were separated and self-contained Protected Elective Surgical Units were developed to mitigate against infection-related morbidity. Aims of this study were to determine the risk of COVID-19 transmission and mortality and whether the development of Protected Elective Surgical Units can result in significant reduction in risk. Methods: A retrospective observational study of consecutive patients from 18 specialties undergoing elective or emergency surgery under general, spinal, or epidural anaesthetic over a 12-month study period was undertaken. Primary outcome measures were 30-day postoperative COVID-19 transmission rate and mortality. Secondary adjusted analyses were performed to ascertain hospital and Protected Elective Surgical Unit transmission rates. Results: Between 15 March 2020 and 14 March 2021, 9,925 patients underwent surgery: 6,464 (65.1%) elective, 5,116 (51.5%) female, and median age 57 (39–70). A total of 69.5% of all procedures were performed in Protected Elective Surgical Units. Overall, 30-day postoperative COVID-19 transmission was 2.8% (3.4% emergency vs 1.2% elective P 70, male sex, American Society of Anesthesiologists grade >2, and emergency surgery were all independently associated with mortality. Conclusion: This study has demonstrated that Protected Elective Surgical Units can facilitate high-volume elective surgical services throughout peaks of the COVID-19 pandemic while minimising viral transmission and mortality. However, mortality risk associated with perioperative COVID-19 infection remains high.

Objectives In this study we analyse the potential impact of the renewable energy transition on the local economic development of lagging-behind regions, focusing in particular on the causal impact of offshore wind farms on the economic development of local onshore coastal communities in the UK, which are usually deprived left-behind regions. Methods We consider the current impact of this transition on the economic development of places, analysing employment and productivity growth in local industries directly affected, as well as the magnitude of potential externalities along the supply-chain. Linking publicly available data on offshore wind farms, offshore wind suitability, and local economic outcomes, we develop an instrumental variable approach to address endogeneity, modelling the probability of wind farms’ locations based on offshore natural characteristics, such as water depth, distance to shorelines, and wind speed factors. Results This is the first study providing empirically robust analysis at a granular level on this topic. After mapping the location of offshore wind farms and link these to onshore local communities through the location of ports and other infrastructures servicing these farms, we estimate a significant positive effect on local employment and productivity growth in the offshore wind energy sector, as well as the indirect effect along the supply chain. Conclusion The rapidly growing renewable energy sector could become a key player in the local economic development of peripheral and lagging-behind regions. This could allow many peripheral regions across developed countries, once dependent on mature declining industries, to regenerate their local economies by sustainably transitioning towards new higher added-value green industries.

Summary: Background: Avoidant restrictive food intake disorder (ARFID) is a new eating disorder with a heterogeneous clinical presentation. It is unclear which patient characteristics contribute to its heterogeneity. Methods: To identify these patient characteristics, we performed symptom-level correlation and driver-level regression analyses in our cross-sectional study in up to 261 ARFID patients (51% female; median age = 12.7 years) who were assessed at the Maudsley Centre for Child and Adolescent Eating Disorders, London between November 2019 and July 2022. Findings: Symptoms across the three drivers 1) avoidance based on sensory characteristics of food; 2) apparent lack of interest in eating; and 3) concern about aversive consequences positively correlated with each other. Patients' anxiety traits showed the greatest positive correlations with symptoms of concern about aversive consequences of eating. Patient sex was not significantly associated with any of the three ARFID drivers. Patients with comorbid autism spectrum disorder (ASD; 28%) showed more food-related sensory sensitivities (RR = 1.26) and greater lack of interest in eating (RR = 1.18) than those of patients without ASD (49%). Interpretation: In our clinical sample, the ARFID drivers occurred together and did not show clinically meaningful differences between the sexes. ASD may accentuate food-related sensory sensitivities and lack of interest, but may not drive a completely different symptom presentation. ARFID is multi-faceted and heterogenous, requiring a comprehensive multidisciplinary assessment to sufficiently understand the drivers of the restrictive eating behaviour. Results need replication in larger samples with more statistical power. Funding: None.

Stem cell maintenance and differentiation can be regulated via the differential activity of transcription factors within stem cells and their progeny. For these factors to be active, they need to be transported from their site of synthesis in the cytoplasm into the nucleus. A tissue-specific requirement for factors involved in nuclear importation is a potential mechanism to regulate stem cell differentiation. We have undertaken a characterization of male sterile importin alpha 1 (Dα1) null alleles in Drosophila and found that Dα1 is required for maintaining germline stem cells (GSCs) in the testis niche. The loss of GSCs can be rescued by ectopic expression of Dα1 within the germline but the animals are still infertile, indicating a second role for Dα1 in spermatogenesis. Expression of a Dα1 dominant negative transgene in GSCs confirmed a functional requirement for Dα1 in GSC maintenance but expression of the transgene in differentiating spermatogonia did not exhibit a phenotype indicating a specific role for Dα1 within GSCs. Our data indicate that Dα1 is utilized as a regulatory protein within GSCs to facilitate nuclear importation of proteins that maintain the stem cell pool.

Soft robotics can be used not only as a means of achieving novel, more lifelike forms of locomotion, but also as a tool to understand complex biomechanics through the use of robotic model animals. Herein, the control of the undulation mechanics of an entirely soft robotic subcarangiform fish is presented, using antagonistic fast‐PneuNet actuators and hyperelastic eutectic gallium–indium (eGaIn) embedded in silicone channels for strain sensing. To design a controller, a simple, data‐driven lumped parameter approach is developed, which allows accurate but lightweight simulation, tuned using experimental data and a genetic algorithm. The model accurately predicts the robot's behavior over a range of driving frequencies and a range of pressure amplitudes, including the effect of antagonistic co‐contraction of the soft actuators. An amplitude controller is prototyped using the model and deployed to the robot to reach the setpoint of a tail‐beat amplitude using fully soft and real‐time strain sensing.

Mediation is a novel concept in language teaching and learning, and the needs and attitudes of language teachers towards it are largely unexplored. This article provides a brief overview of European language policy and discusses the action-oriented approach in the context of this paradigm shift in language learning and teaching. Finally, an exploratory study is presented that examined the needs and attitudes of language teachers from four European universities regarding mediation, as it has been formulated in the Common European Framework of Reference (CEFR) (Council of Europe, 2001) and redefined in the CEFR Companion Volume with New Descriptors (Council of Europe, 2018). The participating teachers were from the language centres of Charles University in the Czech Republic, Vytautas Magnus University in Lithuania, the University of Helsinki in Finland, and the University of Warsaw in Poland. The study survey measured the strength of (dis)agreement of the teachers with 12 statements concerning various aspects of mediation in the context of their teaching practice. These related to understanding what mediation is and its importance, mediating a text, mediating concepts, mediating communication, and mediation strategies. In addition, two open questions concerned the practice of promoting multilingual and intercultural education and the needs of teachers in the area of mediation. Although the vast majority of the 79 participating teachers (91%) agreed that mediation is vital in language learning and teaching, only a third of them claimed that they understood the concept. Furthermore, the findings indicate that some aspects of mediation are more challenging for the teachers to embrace than others and that some fundamental aspects of mediation do not seem to be part of the current teaching practice of all teachers. Overall, the present study confirmed some of the challenges with the implementation of the CEFR into teaching practice at the higher education level.

David Mannino,1 James Siddall,2 Mark Small,2 Adam Haq,2 Marjorie Stiegler,3 Michael Bogart3 1Department of Medicine, University of Kentucky, Lexington, KY, USA; 2Respiratory DSP Franchise, Adelphi Real World, Bollington, UK; 3US Value Evidence and Outcomes, GlaxoSmithKline plc, Durham, NC, USACorrespondence: Michael Bogart, US Value Evidence and Outcomes, GlaxoSmithKline plc, 5 Moore Dr, Research Triangle Park, Durham, NC, USA, Tel +19198897413, Email michael.r.bogart@gsk.comPurpose: There is a high prevalence of chronic obstructive pulmonary disease (COPD) in the United States (US). Although guidelines are available for the treatment of COPD, evidence suggests that management of COPD in clinical practice is not always aligned with this guidance. This study aimed to further understand the current use of COPD maintenance medication in the US.Patients and Methods: This study was an analysis of data from the Adelphi Respiratory Disease Specific Programme (DSP™) 2019. Point-in-time data were collected from participating US physicians and their COPD patients. Physicians were either primary care physicians (PCPs) or pulmonologists, with a minimum workload of ≥ 3 COPD patients per month. Patients were aged ≥ 18 years with a physician-confirmed diagnosis of COPD.Results: In total, 171 physicians completed the survey (92 PCPs and 79 pulmonologists). Mean patient age was 66.4 years, 45% were female, with moderate COPD in 49.4% of patients and severe/very severe in 19.3%. Pulmonologists more frequently prescribed dual bronchodilation and triple therapy than PCPs, whereas inhaled corticosteroid/long-acting β2-agonist was more frequently prescribed by PCPs than pulmonologists. For both physician types, the most common reason for prescribing their patients’ current treatment was 24-hour symptom relief. The majority of PCPs (70.1%) and pulmonologists (71.9%) reported referring to COPD guidelines when making treatment decisions.Conclusion: Prescribing patterns for COPD patients were found to differ between PCPs and pulmonologists. Improved physician understanding of how to tailor treatment for each patient, based on current symptoms and exacerbation risk, could help optimize patient care in COPD.Keywords: COPD, inhaled corticosteroids, long-acting β2-agonist, long-acting muscarinic antagonist, maintenance therapy, survey

A national movement to change bail and pretrial detention is underway.[1] In California, bail reform advocates have attempted to pass Senate Bill 10 which would radically alter the state’s trial court administration of bail.[2] Advocates claim that reform is necessary because detention rates are too high and that the current bail system unfairly penalizes the poor.  Although the effort failed to pass last year, it regained strength after the Judicial Council and Governor Brown endorsed the concept of bail reform.[3] The bail reform debate took a radical turn in a recent decision made by the California Court of Appeals.  In In Re Humphrey, the San Francisco Public Defender’s Office filed a writ of habeas corpus, arguing that judges in California violated a defendant’s due process rights by failing to inquire about a defendant’s ability to post bail and whether there could be less restrictive conditions of release.[4] Representing a stark departure from legal precedent, the Court of Appeals and the California Attorney General agreed with the defense’s argument that judges are required to make these inquiries.[5] In light of these changes, this Article argues that: (1) detention rates are not nearly as high as reformers portray, and specifically in Los Angeles County, those held in jail are the very defendants we want, and are constitutionally required, to detain; (2) bail reform advocates have unscrupulously used Humphrey to exploit the public’s fear that indigent defendants are unfairly placed in custody for minor crimes; and (3) the California Court of Appeals and the California Attorney General undermined the state’s constitutional public safety protection provisions by ignoring legal precedent and finding that the current bail system violated due process. [1].        Jurisdictions including, New Mexico, Kentucky, New Jersey, and Washington, D.C., have all adopted or considered measures to end money bail.  See, e.g., Jon Schuppe, POST BAIL, NBC News (Aug 22, 2017), https://www.nbcnews.com/specials/bail-reform [https://perma.cc/BN85-FGWE]. [2].        S.B. 10, 2017–2018 Leg., Reg. Sess. (Cal. 2017). (Reference made to S.B. 10 in this Article refer to the original draft of the legislation.  Since the writing of this Article, an amended version of S.B. 10 was passed by the legislature and signed into law by Governor Brown.  This Article does not refer or reflect any views as to the amended version of S.B. 10.) [3].        Governor Brown, Chief Justice Cantil-Sakauye, Senator Hertzberg and Assemblymember Bonta Commit to Work Together on Reforms to California’s Bail System (Aug. 25, 2017), https://newsroom.courts.ca.gov/news/chief-justice-issues-statement-on-bail-reform [https://perma.cc/BR5H-5BTR]. [4].        In re Humphrey, 228 Cal. Rptr. 3d 513 (Ct. App. 2018). [5].        Id. at 518.

Objective: Branched chain amino acid (BCAA) catabolic defects are implicated to be causal determinates of multiple diseases. This work aimed to better understand how enhancing BCAA catabolism affected metabolic homeostasis as well as the mechanisms underlying these improvements. Methods: The rate limiting step of BCAA catabolism is the irreversible decarboxylation by the branched chain ketoacid dehydrogenase (BCKDH) enzyme complex, which is post-translationally controlled through phosphorylation by BCKDH kinase (BDK). This study utilized BT2, a small molecule allosteric inhibitor of BDK, in multiple mouse models of metabolic dysfunction and NAFLD including the high fat diet (HFD) model with acute and chronic treatment paradigms, the choline deficient and methionine minimal high fat diet (CDAHFD) model, and the low-density lipoprotein receptor null mouse model (Ldlr−/−). shRNA was additionally used to knock down BDK in liver to elucidate liver-specific effects of BDK inhibition in HFD-fed mice. Results: A rapid improvement in insulin sensitivity was observed in HFD-fed and lean mice after BT2 treatment. Resistance to steatosis was assessed in HFD-fed mice, CDAHFD-fed mice, and Ldlr−/− mice. In all cases, BT2 treatment reduced steatosis and/or inflammation. Fasting and refeeding demonstrated a lack of response to feeding-induced changes in plasma metabolites including insulin and beta-hydroxybutyrate and hepatic gene changes in BT2-treated mice. Mechanistically, BT2 treatment acutely altered the expression of genes involved in fatty acid oxidation and lipogenesis in liver, and upstream regulator analysis suggested that BT2 treatment activated PPARα. However, BT2 did not directly activate PPARα in vitro. Conversely, shRNA-AAV-mediated knockdown of BDK specifically in liver in vivo did not demonstrate any effects on glycemia, steatosis, or PPARα-mediated gene expression in mice. Conclusions: These data suggest that BT2 treatment acutely improves metabolism and liver steatosis in multiple mouse models. While many molecular changes occur in liver in BT2-treated mice, these changes were not observed in mice with AAV-mediated shRNA knockdown of BDK. All together, these data suggest that systemic BDK inhibition is required to improve metabolism and steatosis by prolonging a fasting signature in a paracrine manner. Therefore, BCAA may act as a “fed signal” to promote nutrient storage and reduced systemic BCAA levels as shown in this study via BDK inhibition may act as a “fasting signal” to prolong the catabolic state.

Serum ceramides, especially C16:0 and C18:0 species, are linked to CVD risk and insulin resistance, but details of this association are not well understood. We performed this study to quantify a broad range of serum sphingolipids in individuals spanning the physiologic range of insulin sensitivity and to determine if dihydroceramides cause insulin resistance in vitro. As expected, we found that serum triglycerides were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals. Serum ceramides were not significantly different within groups but, using all ceramide data relative to insulin sensitivity as a continuous variable, we observed significant inverse relationships between C18:0, C20:0, and C22:0 species and insulin sensitivity. Interestingly, we found that total serum dihydroceramides and individual species were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals, with C18:0 species showing the strongest inverse relationship to insulin sensitivity. Finally, we administered a physiological mix of dihydroceramides to primary myotubes and found decreased insulin sensitivity in vitro without changing the overall intracellular sphingolipid content, suggesting a direct effect on insulin resistance. These data extend what is known regarding serum sphingolipids and insulin resistance and show the importance of serum dihydroceramides to predict and promote insulin resistance in humans.

Pigments from paint palettes and a grindstone excavated from the pharaonic town of Amara West (c. 1300–1050 BCE), which lies between the Second and Third Cataracts of the Nile, were examined using polarized light microscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray diffraction, and scanning electron microscopy with energy dispersive X-ray spectroscopy. Most of the pigments were consistent with the typical ancient Egyptian palette, but the greens and some blues were unusual. Two types of green pigment were identified, chlorite (varieties clinochlore and penninite) and copper chloride hydroxide (atacamite type). The former constitutes a type of green earth which has only rarely been identified in pharaonic Egyptian contexts and may be more widespread than is currently reported. The majority of the blue pigment samples were Egyptian blue, but some were found to be a blue earth, the main component of which being sodic amphibole riebeckite. The use of this mineral as a pigment has not previously been reported in any Nile Valley context. These results prompt questions around local and potentially indigenous practices within an ancient colonial context, and highlight avenues for future research.

Siddall, Byrnes, Full, and Jusufi observe the function of the Asian flat-tailed gecko tail in gliding and landing on tree trunks in the field, complemented with mathematical and robotic models made of soft active materials. Altogether, their models show how geckos use an active tail reflex to brace the impact and reduce the risk of falling from landings on tree trunks.

Introduction Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an immune-metabolic biomarker network comprising three pathways with a >99% accuracy for detecting bacterial neonatal sepsis. In this prospective study, we will describe physiological parameters and novel biomarkers in two cohorts—healthy pregnant women and pregnant women with suspected sepsis—with the aim of mapping pathophysiological drivers and evaluating predictive biomarkers for diagnosing maternal sepsis.Methods and analysis Women aged over 18 with an ultrasound-confirmed pregnancy will be recruited to a pilot and two main study cohorts. The pilot will involve blood sample collection from 30 pregnant women undergoing an elective caesarean section. Cohort A will follow 100 healthy pregnant women throughout their pregnancy journey, with collection of blood samples from participants at routine time points in their pregnancy: week 12 ‘booking’, week 28 and during labour. Cohort B will follow 100 pregnant women who present with suspected sepsis in pregnancy or labour and will have at least two blood samples taken during their care pathway. Study blood samples will be collected during routine clinical blood sampling. Detailed medical history and physiological parameters at the time of blood sampling will be recorded, along with the results of routine biochemical tests, including C reactive protein, lactate and white blood cell count. In addition, study blood samples will be processed and analysed for transcriptomic, lipidomic and metabolomic analyses and both qualitative and functional immunophenotyping.Ethics and dissemination Ethical approval has been obtained from the Wales Research Ethics Committee 2 (SPON1752-19, 30 October 2019).Trial registration number NCT05023954.

Abstract Background Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). Methods Patients with moderate to severe RA who had received ≥12 weeks’ stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. Results A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. Conclusions These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. Trial registration ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.

Sex determination pathways in insects are generally characterised by an upstream primary signal, which is highly variable across species, and that regulates the splicing of a suite of downstream but highly-conserved genes (transformer, doublesex and fruitless). In turn, these downstream genes then regulate the expression of sex-specific characteristics in males and females. Identification of sex determination pathways has and continues to be, a critical component of insect population suppression technologies. For example, “first-generation” transgenic technologies such as fsRIDL (Female-Specific Release of Insects carrying Dominant Lethals) enabled efficient selective removal of females from a target population as a significant improvement on the sterile insect technique (SIT). Second-generation technologies such as CRISPR/Cas9 homing gene drives and precision-guided SIT (pgSIT) have used gene editing technologies to manipulate sex determination genes in vivo. The development of future, third-generation control technologies, such as Y-linked drives, (female to male) sex-reversal, or X-shredding, will require additional knowledge of aspects of sexual development, including a deeper understanding of the nature of primary signals and dosage compensation. This review shows how knowledge of sex determination in target pest species is fundamental to all phases of the development of control technologies.

Course syllabi play an important role in teaching, learning, and course design. They serve multiple functions and audiences and represent the end product of a scholarly process. In the following article, select findings from a mixed methods study examining how faculty and students conceptualize course syllabi are presented, specifically the design implications of what faculty include in their syllabi and those items students perceive to be most important and attend to most often throughout the course.

Invertebrate-derived DNA (iDNA) from terrestrial haematophagous leeches has recently been proposed as a powerful non-invasive tool with which to detect vertebrate species and thus to survey their populations. However, to date little attention has been given to whether and how this, or indeed any other iDNA-derived data, can be combined with state-of-the-art analytical tools to estimate wildlife abundances, population dynamics and distributions. In this review, we discuss the challenges that face the application of existing analytical methods such as site-occupancy and spatial capture-recapture (SCR) models to terrestrial leech iDNA, in particular, possible violations of key assumptions arising from factors intrinsic to invertebrate parasite biology. Specifically, we review the advantages and disadvantages of terrestrial leeches as a source of iDNA and summarize the utility of leeches for presence, occupancy, and spatial capture-recapture models. The main source of uncertainty that attends species detections derived from leech gut contents is attributable to uncertainty about the spatio-temporal sampling frame, since leeches retain host-blood for months and can move after feeding. Subsequently, we briefly address how the analytical challenges associated with leeches may apply to other sources of iDNA. Our review highlights that despite the considerable potential of leech (and indeed any) iDNA as a new survey tool, further pilot studies are needed to assess how analytical methods can overcome or not the potential biases and assumption violations of the new field of iDNA. Specifically we argue that studies to compare iDNA sampling with standard survey methods such as camera trapping, and those to improve our knowledge on leech (and other invertebrate parasite) physiology, taxonomy, and ecology will be of immense future value.

BackgroundNew drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.MethodsBetween April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.Findings229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.InterpretationOur results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.FundingNeuPSIG of the International Association for the Study of Pain.

Traditional methods of evaluation are limited in their ability to answer key questions often of interest to process evaluators, such as heterogeneity in the ways individuals adopt new programs. In this article, we demonstrate how a statistical approach, Latent Class Analysis, can help improve the quality of process evaluations and illustrate its use in an evaluation of an educational technology integration program in a large school district. In this illustration, we were interested in detecting variability in the ways teachers adopted the new program. We defined classes based on a set of innovative teaching strategies associated with educational technology. Results showed five distinct subgroups of teachers, based on level of program adoption. Results also demonstrate that specific school support strategies (professional development and personalized computing devices) facilitated program adoption. These findings can help to inform individualized support for teachers to optimize the ease and quality with which they are able to adopt new skills in the classroom.