An adjudication algorithm for respiratory-related hospitalisation in idiopathic pulmonary fibrosis.

Background: There is no standard definition of respiratory-related hospitalisation, a common end-point in idiopathic pulmonary fibrosis (IPF) clinical trials. As diverse aetiologies and complicating comorbidities can present similarly, external adjudication is sometimes employed to achieve standardisation of these events. Methods: An algorithm for respiratory-related hospitalisation was developed through a literature review of IPF clinical trials with respiratory-related hospitalisation as an end-point. Experts reviewed the algorithm until a consensus was reached. The algorithm was validated using data from the phase 3 ISABELA trials (clinicaltrials.gov identifiers NCT03711162 and NCT03733444), by assessing concordance between nonadjudicated, investigator-defined, respiratory-related hospitalisations and those defined by the adjudication committee using the algorithm. Results: The algorithm classifies respiratory-related hospitalisation according to cause: extraparenchymal (worsening respiratory symptoms due to left heart failure, volume overload, pulmonary embolism, pneumothorax or trauma); other (respiratory tract infection, right heart failure or exacerbation of COPD); "definite" acute exacerbation of IPF (AEIPF) (worsening respiratory symptoms within 1 month, with radiological or histological evidence of diffuse alveolar damage); or "suspected" AEIPF (as for "definite" AEIPF, but with no radiological or histological evidence of diffuse alveolar damage). Exacerbations ("definite" or "suspected") with identified triggers (infective, post-procedural or traumatic, drug toxicity- or aspiration-related) are classed as "known AEIPF"; "idiopathic AEIPF" refers to exacerbations with no identified trigger. In the ISABELA programme, there was 94% concordance between investigator- and adjudication committee-determined causes of respiratory-related hospitalisation. Conclusion: The algorithm could help to ensure consistency in the reporting of respiratory-related hospitalisation in IPF trials, optimising its utility as an end-point.

Perspectives on the role of the nurse ethicist.

This paper offers four contrasting perspectives on the role of the nurse ethicist from authors based in different areas of world, with different professional backgrounds and at different career stages. Each author raises questions about how to understand the role of the nurse ethicist. The first author reflects upon their career, the scope and purpose of their work, ultimately arguing that the distinction between 'nurse ethicist' and 'clinical ethicist' is largely irrelevant. The second author describes the impact and value that a nurse in an ethics role plays, highlighting the 'tacit knowledge' and 'lived experience' they bring to clinical ethics consultation. However, the second author also warns that the 'nurse ethicist' must be cautious in their approach to avoid being viewed as a resource only for nurses. The third author questions the introduction of additional professional distinctions such as 'nurse ethicist' on the basis that distinctions threaten the creation of egalitarian healthcare systems, while also acknowledging that clinical ethicists ought not strive for objective attachment in their work. In direct contrast, the final author suggests that the nurse ethicist can play a pivotal role in highlighting and addressing ethical challenges that are specific to nurses. These four short pieces raise questions and point to concepts that will be expanded upon and debated throughout this special issue of Nursing Ethics.

Overcoming barriers to informed consent in neurological research: Perspectives from a national survey.

The ethical recruitment of participants with neurological disorders in clinical research requires obtaining initial and ongoing informed consent. The purpose of this study is to characterize barriers faced by research personnel in obtaining informed consent from research participants with neurological disorders and to identify strategies applied by researchers to overcome those barriers. This study was designed as a web-based survey of US researchers with an optional follow-up interview. A subset of participants who completed the survey were selected using a stratified purposeful sampling strategy and invited to participate in an in-depth qualitative interview by phone or video conference. Data were analyzed using a mixed methods approach, including content analysis of survey responses and thematic analysis of interview responses. Over 1 year, 113 survey responses were received from US research personnel directly involved in obtaining informed consent from participants in neurological research. Frequently identified barriers to informed consent included: cognitive and communication impairments (e.g. aphasia), unrealistic expectations of research participants, mistrust of medical research, time constraints, literacy barriers, lack of available social support, and practical or resource-related constraints. Strategies to enhance informed consent included: involving close others to support participant understanding of study-related information, collaborating with more experienced research personnel to facilitate training in obtaining informed consent, encouraging participants to review consent forms in advance of consent discussions, and using printed materials and visual references. Beyond conveying study-related information, researchers included in this study endorsed ethical responsibilities to support deliberation necessary to informed consent in the context of misconceptions about research, unrealistic expectations, limited understanding, mistrust, and/or pressure from close others. Findings highlight the importance of training researchers involved in obtaining informed consent in neurological research to address disease-specific challenges and to support the decision-making processes of potential research participants and their close others.

Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

Virtual prenatal visits associated with high measures of patient experience and satisfaction among average-risk patients: a prospective cohort study.

BACKGROUND: Virtual visits have the potential to decrease barriers to prenatal care stemming from transportation, work, and childcare concerns. However, data regarding patient experience and satisfaction with virtual visits remain limited in obstetrics. To address this gap, we explore average-risk pregnant women's experiences with virtual visits and compare satisfaction with virtual vs. in-person visits as a secondary aim. METHODS: In this IRB-approved, prospective cohort study, we surveyed pregnant women after their first virtual visit between October 7, 2019 and March 20, 2020. Using heterogeneous purposive sampling, we identified a subset of respondents with diverse experiences and opinions for interviews. For comparison, Consumer Assessment of Healthcare Providers and Systems (CAHPS) satisfaction data were collected after in-person visits during the study timeframe from a control cohort with the same prenatal providers. Logistic regression controlling for age, previous pregnancies, and prior live births compared satisfaction data between virtual and in-person visits. Other quantitative survey data were analyzed through descriptive statistics. Free text survey responses and interview data were analyzed using content analysis. RESULTS: Ninety five percent (n = 165/174) of surveys and 90% (n = 18/20) of interviews were completed. Most participants were Caucasian, married, and of middle to high income. 69% (114/165) agreed that their virtual appointment was as good as in-person; only 13% (21/165) disagreed. Almost all (148/165, 90%) would make another virtual appointment. Qualitative data highlighted ease of access, comparable provider-patient communication, confidence in care quality, and positive remote monitoring experiences. Recognizing these advantages but also inherent limitations, interviews emphasized interspersing telemedicine with in-person prenatal encounters. CAHPS responses after in-person visits were available for 60 patients. Logistic regression revealed no significant difference in three measures of satisfaction (p = 0.16, 0.09, 0.13) between virtual and in-person visits. CONCLUSIONS: In an average-risk population, virtual prenatal visits provide a patient-centered alternative to traditional in-person encounters with high measures of patient experience and no significant difference in satisfaction. Obstetric providers should explore telemedicine to improve access - and, during the ongoing pandemic, to minimize exposures - using patients' experiences for guidance. More research is needed regarding virtual visits' medical quality, integration into prenatal schedules, and provision of equitable care for diverse populations.

A 24-Week, Phase IIa, Randomized, Double-Blind, Placebo-Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: NOVESA was a 24-week, multicenter, phase IIa, double-blind, placebo-controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104-week open-label extension (OLE). RESULTS: Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (-8.9 versus -6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment-related treatment-emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. CONCLUSION: Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.

Autotaxin facilitates selective LPA receptor signaling.

Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.

GLPG1205 for idiopathic pulmonary fibrosis: a phase 2 randomised placebo-controlled trial.

BACKGROUND: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed the efficacy, safety and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF). METHODS: PINTA (ClinicalTrials.gov: NCT03725852) was a phase 2, randomised, double-blind, placebo-controlled, proof-of-concept trial. Patients with IPF were randomised 2:1 to once-daily oral GLPG1205 100 mg or placebo for 26 weeks and stratified to receive GLPG1205 alone or with local standard of care (nintedanib or pirfenidone). The primary end-point was change from baseline in forced vital capacity (FVC); other end-points were safety and tolerability, and lung volumes measured by imaging (high-resolution computed tomography). The study was not powered for statistical significance. RESULTS: In total, 68 patients received study medication. Least squares mean change from baseline in FVC at week 26 was -33.68 (95% CI -112.0-44.68) mL with GLPG1205 and -76.00 (95% CI -170.7-18.71) mL with placebo (least squares mean difference 42.33 (95% CI -81.84-166.5) mL; p=0.50). Lung volumes by imaging declined -58.30 versus -262.72 mL (whole lung) and -33.68 versus -135.48 mL (lower lobes) with GLPG1205 versus placebo, respectively. Treatment with GLPG1205 versus placebo resulted in higher proportions of serious and severe treatment-emergent adverse events and treatment-emergent discontinuations, most apparent with nintedanib. CONCLUSIONS: Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo.

Developmental activities of professional male British rugby-league players versus controls.

PURPOSE: Many rugby league clubs rely on developing youth athletes into experts in adulthood. One factor that contributes to the attainment of expertise is the activities that athletes engage in across their development. Therefore, the developmental activities of professional male British rugby league players were compared to lesser-skilled players. METHODS: Players who had progressed from youth academies to professional status, those who were released from youth academies, and those who had only played recreationally completed the Participation History Questionnaire. RESULTS: During childhood, professional players accumulated significantly greater amounts of play compared to ex-academy and recreational players, as well as greater coach-led practice compared to ex-academy . During early adolescence, this pattern continued, whereas in late adolescence the professional and ex-academy players accumulated significantly greater amounts of coach-led practice compared to their recreational counterparts. Professional players accumulated more hours in rugby league up to 18 years of age compared to ex-academy players, with both groups accumulating more hours than recreational . The number of other sports engaged in was relatively low across development and did not discriminate between performance levels. CONCLUSION: Findings from this study may inform future practice of talent development systems within rugby league in Britain.

A Case Report of Severe Factor XI Deficiency during Cardiac Surgery: Less Can Be More.

Severe congenital Factor XI (FXI) deficiency (<20% normal activity) can be associated with significant bleeding disorders, and there has been great concern for severe bleeding following cardiac surgery requiring cardiopulmonary bypass (CPB) in this patient population. Over the past four decades remarkably different approaches to this problem have been taken, including the administration of blood volumes of fresh frozen plasma, administration of activated recombinant Factor VII, and diminutive administration of heparin. We describe a case wherein the patient was assessed in the perioperative period with a point-of-care, viscoelastic hemostasis device (ROTEM), with changes in the intrinsic/Factor XII-dependent coagulation pathway determined before, during, and after CPB. Fresh frozen plasma was administered in small amounts (5−7.5 mL/kg) just before surgery began and just before cessation of CPB. Administering fresh frozen plasma to the patient to nearly normalize in vitro ROTEM hemostasis values at times when hemostasis was needed resulted in no important bleeding occurring or need of further transfusion of other blood products. In conclusion, by using small amounts of fresh frozen plasma guided by ROTEM, an evidenced-based, precision medicine approach resulted in optimized patient care and outcome.

A preliminary investigation into the evaluation of possession-based small-sided games and the influence of decision-making ability in identifying talented pre-pubertal soccer players

IntroductionThe aims of this study were 1) to assess if talented players can be identified within possession-based small-sided games (SSG), and 2) to determine if, decision making, physical, and time-motion characteristics correlated to success in a possession-based SSG.MethodsEight, highly-trained U10 soccer players (Mean ± SD; age: 10.3 ± 0.2 years; stature: 1.41 ± 0.04 m; body mass: 35.2 ± 3.3 kg) participated in this study. Six 4 vs 4 possession based SSG's were played. Time-motion characteristics were measured using micromechanical devices (MEMS). Countermovement jump, 10m and 30m speed tests were conducted. Participants were presented with 28 video clips of 5 versus 5 match-play sequences to assess decision-making ability.ResultsThe main finding of this study was a large significant relationship between Game Technical Scoring Chart (GTSC) and Total Points (TP) (r = 0.784, P <0.05). There were no significant correlations between the decision-making test and GTSC and TP. A significant and largely inverse correlation between decision-making and countermovement jump (r = -0.737, P <0.05) was observed.ConclusionsOur results demonstrate that the more talented players were also the most successful players in the possession based SSG. The players’ decision-making ability, however, did not influence their success in the SSG. (AU)

Spice authentication by fully automated chemical analysis with integrated chemometrics.

Spices had a worldwide market value greater than $20 billion in 2020. The price per kilogram or ton is high for many spices often due to intensive labor and handling requirements in their preparation, with black pepper as one example. Spices are produced in many countries, in plots ranging from fractions of a hectare to multihectare mechanized operations. From harvest through production and to final market package, spices pass through several steps in the supply chain that provide ample opportunity for fraud. Contamination with harmful plant materials, ingredient substitutions, and adulteration in spices are frequently encountered. In addition, spices in specific geographic regions can have distinctive characteristics from the localized growing conditions giving rise to changes in terpene profiles and other flavor components, creating variation in market price based on country of origin. The research reported here details a system for automated chemical analysis of 170 terpenes in spices and other botanicals by gas chromatography (GC), through enhancements to a proven bacterial identification system. The system integrates pattern recognition searches of custom spice databases to identify country of origin of most spices, aiding in the authentication of spices and detection of fraudulent ingredients.

Exit from Brain Device Research: A Modified Grounded Theory Study of Researcher Obligations and Participant Experiences.

As clinical trials end, little is understood about how participants exiting from clinical trials approach decisions related to the removal or post-trial use of investigational brain implants, such as deep brain stimulation (DBS) devices. This empirical bioethics study examines how research participants experience the process of exit from research at the end of clinical trials of implanted neural devices. Using a modified grounded theory study design, we conducted semi-structured, in-depth interviews with 16 former research participants from clinical trials of DBS and responsive neurostimulation (RNS). Open-ended questions elicited motivations for joining the trial, understanding of study procedures at the time of initial informed consent, the process of exiting from research, and decisions about device removal or post-trial device use. Thematic analysis identified categories related to: limited preparedness for the end of research participation, straightforwardness of decisions to explant or keep the device, reconciling with the end of research participation, reconciling post-trial expectations, and achieving a sense of closure after exit from research. A preliminary theoretical model describes contextual factors influencing the process and experience of exit from research. Experiences of clinical trial participants should guide research practices to enhance the ethical design and conduct of clinical trials in DBS and other brain devices.

Improving Real-World Innovation and Problem Solving in Clinical Ethics: Insights from the First Clinical Ethics Un-Conference.

Despite an abundance of academic conferences, clinical ethicists lacked a forum to share innovative practices with peers and to generate solutions to common challenges. Organizers of the first Clinical Ethics Un-Conference developed a working event centered on active participation and problem solving through peer learning, with the goal of improving real-world practice. Registrants included 95 individuals from 64 institutions. Attendees were surveyed immediately after the Un-Conference, and again eight months later. After eight months, 85 percent (n = 33/39) of the survey respondents reported that they found the event "highly impactful" or "somewhat impactful" to their clinical practice, and 23 attendees reported that they had implemented ideas or projects inspired by the event. Three sets of best practice guidelines and four white papers were published from the event. As the field of clinical ethics continues to advance and evolve, this working event format offers an innovative, disruptive alternative to a traditional conference format and may serve as a model for future efforts aimed at improving real-world clinical ethics practice.