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This article describes a laboratory experiment used to investigate the phenomenon of multiple melting in polymers. The experiment is aimed at the level of senior undergraduate chemistry students able to carry out the investigation in a research-style approach, working together in small groups. The experiment highlights characteristic thermal behavioral differences between polymers and small organic molecules. It demonstrates that shifts in observed melting temperature upon heating are typically due to inherent metastability of the polymer system and not to impurities in the sample, for example. Differential scanning calorimetry is used to demonstrate and explore this fundamental yet contemporary subject of polymer melting, using a well-known and commercially available polymer, isotactic polystyrene. Effects of thermal history of the sample, including crystallization temperature and crystallization time, as well as analysis conditions including heating rate, on the melting point of the polymer solid are each investigated. The experiment provides a hands-on example of structure-property relationships in polymer science.

Lung adenocarcinoma (ADC) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate whether CyTOF identifies cellular and molecular predictors of tumor behavior. We developed and validated a CyTOF panel of 34 antibodies in four ADC cell lines and PBMC. We tested our panel in a set of 10 ADCs, classified into long- (LPS) (n = 4) and short-predicted survival (SPS) (n = 6) based on radiomics features. We identified cellular subpopulations of epithelial cancer cells (ECC) and their microenvironment and validated our results by multiplex immunofluorescence (mIF) applied to a tissue microarray (TMA) of LPS and SPS ADCs. The antibody panel captured the phenotypical differences in ADC cell lines and PBMC. LPS ADCs had a higher proportion of immune cells. ECC clusters (ECCc) were identified and uncovered two ADC groups. ECCc with high HLA-DR expression were correlated with CD4+ and CD8+ T cells, with LPS samples being enriched for those clusters. We confirmed a positive correlation between HLA-DR expression on ECC and T cell number by mIF staining on TMA slides. Spatial analysis demonstrated shorter distances from T cells to the nearest ECC in LPS. Our results demonstrate a distinctive cellular profile of ECC and their microenvironment in ADC. We showed that HLA-DR expression in ECC is correlated with T cell infiltration, and that a set of ADCs with high abundance of HLA-DR+ ECCc and T cells is enriched in LPS samples. This suggests new insights into the role of antigen presenting tumor cells in tumorigenesis.

Global agreements in place to reduce methane emissions in livestock are a potential threat to food security. Successful but independent breeding strategies for improved production and lower methane are in place. The unanswered questions are whether these strategies can be combined and how they impact one another, physically and economically. The New Zealand economy is largely dependent on pastoral agriculture from grazing ruminants. The sheep industry produces ∼20 million lamb carcasses for export each year primarily from grass. Methane emitted from the fermentation of forage by grazing ruminants accounts for one-third of all New Zealand’s greenhouse gas emissions. Here, we use sheep selection lines bred for divergent methane production and large numbers of their relatives to determine the genetic and phenotypic correlations between enteric methane emissions, carcass yield, and meat quality. The primary objectives were to determine whether previously shown physiological differences between methane selection lines (differing by ∼12% in methane) result in a negative impact on meat production and quality by measuring close relatives. The results show no negative effects of breeding for lowered methane on meat and carcass quality. Gross methane emissions were highly correlated with liveweight and measures of carcass weight and negatively correlated with dressing-out percentage and fat yield (GR). Trends were similar but not significant for methane yield (g CH4/kg DMI). Preliminary evidence, to date, shows that breeding for low methane may result in animals with higher lean yields that are economically favorable even before carbon costs and environmental benefits are taken into account. These benefits were seen in animals measured for methane on fixed intakes and require validation on intakes that are allowed to vary.

The 52-week, phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients aged above or equal to 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo.To assess whether dupilumab improves clinical outcomes in QUEST patients with persistent airflow obstruction (PAO) defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity ratio less than 0.7 at baseline.End points were annualized rate of severe exacerbations, pre and post-bronchodilator forced expiratory volume in 1 second over time, proportion achieving reversal of PAO, and quality of life. Efficacy was evaluated in patients with or without PAO at baseline in subpopulations with eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 25 ppb or eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb.Of 1902 patients enrolled in QUEST, 1039 (55%) had PAO at baseline. Dupilumab vs placebo rapidly and significantly improved lung function in patients with PAO and elevated type 2 inflammatory biomarkers at baseline. Dupilumab improved probability of reversing airflow obstruction (hazard ratio vs placebo 1.616 [95% confidence interval, 1.272-2.052] and 1.813 [1.291-2.546]; both P.001) and significantly reduced severe exacerbations by 69% (relative risk, 0.411; 95% confidence interval [0.327-0.516]; P.0001) and by 75% (0.252 [0.178-0.356]; P.0001) in patients with PAO with eosinophils ≥ 150 cells/µL or FeNO ≥ 25 ppb and eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb, respectively. Similar results were observed in patient subgroups without PAO.In patients with uncontrolled moderate-to-severe asthma, treatment with dupilumab facilitates reversal of PAO status and improves clinical outcomes.ClinicalTrials.gov identifier: NCT02414854.

Although eosinophils are the hallmark of eosinophilic esophagitis (EoE) with threshold levels required for diagnosis, their exact role in EoE is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses endoscopic inflammatory (edema/exudate/furrows) and remodeling (rings/strictures) features. We assessed the correlations between peak esophageal intraepithelial eosinophil count (eos/high-power field [hpf]) and EREFS in placebo-treated EoE patients from two clinical trials: phase 2 proof-of-concept (POC; NCT02379052; n = 24) and part A of phase 3 TREET (Phase3-PartA; NCT03633617; n = 39). POC was a 12-week trial in adults and Phase3-PartA was a 24-week trial in adults and adolescents. Endoscopic examination of the esophagus was performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory and remodeling subscores and total score using EREFS (higher scores indicate greater severity). Peak eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. Pearson correlations were performed between total/proximal/mid/distal eos/hpf and EREFS total, subscores, and components at BL, EOT, and for change from BL at EOT. Some strong correlations (r > 0.5) were observed between total peak eos/hpf and EREFS at BL in both studies and at EOT in Phase3-Part A (Table). Moderate-to-strong correlations (r > 0.3) were observed between total peak eos/hpf and EREFS inflammation subscore and edema/exudates/furrows individual components (some P > 0.5) in both studies. Correlations of total peak eos/hpf with EREFS remodeling subscore and rings/stricture components were not significant (P = 0.07–0.94). Peak eos/hpf in the proximal, mid, or distal esophagus were more strongly associated with EREFS inflammation subscore (majority moderate-to-strong correlations; P = 0.001–0.66) than EREFS remodeling subscore (weak correlations, P = 0.22–0.99) at BL/EOT for both studies. In these EoE patients, moderate-to-strong correlations were observed between eos/hpf and endoscopic markers of inflammation. No strong correlations were observed between total, proximal, mid, or distal peak eos/hpf and endoscopic parameters of remodeling. These data support a role for intact eosinophils in inflammatory changes in the esophagus in EoE and demonstrate the need for both histology and endoscopic evaluation. Further study, with larger sample sizes, is required to verify these findings in other contexts.

The Histologic Scoring System (HSS) assesses severity/extent of histologic features (eosinophil density [ED]/basal zone hyperplasia [BZH]/eosinophil abscesses [EA]/eosinophil surface layering [SL]/surface epithelial alteration [SEA]/dyskeratotic epithelial cells [DEC]/dilated intercellular spaces [DIS]/lamina propria fibrosis [LPF]) in eosinophilic esophagitis (EoE). The Endoscopic Reference Score (EREFS) assesses endoscopic feature severity (edema/exudates/furrows/rings/strictures). We correlated HSS components with inflammatory/remodeling EREFS components in placebo-treated EoE patients from 2 trials—phase 2 proof-of-concept (POC; NCT02379052), phase 3 TREET part A (Phase3-PartA; NCT03633617). POC was a 12-week trial in adults, and Phase3-PartA was a 24-week trial in adults and adolescents. Proximal/mid/distal esophagus biopsies were collected at baseline/end of treatment (EOT) and scored by HSS for grade (severity)/stage (extent)/components (higher scores = greater severity). Endoscopies were scored by EREFS (higher scores = greater severity) and inflammatory (edema+exudates+furrows) and remodeling (rings+stricture) subscores calculated. Pearson correlation and single co-variate regression model analyses were performed between baseline HSS grade/stage, total/individual components scores and EREFS total/components scores and subscores, and for the change in scores from baseline at EOT (ΔEOT). Moderate-to-strong correlations (r > 0.3) were observed between total EREFS and HSS grade/stage for baseline/ΔEOT in POC and baseline in Phase3-PartA (Table). Moderate correlations were observed between BZH and EREFS remodeling subscore and rings for ΔEOT in Phase3-PartA; DIS grade and EREFS remodeling subscore and strictures for baseline and ΔEOT in POC but not Phase3-PartA; and EREFS inflammation and remodeling subscores and components for SEA and SL at baseline and ΔEOT in POC. Moderate-to-strong correlations were observed between EREFS inflammation subscore and DIS stage and between edema and DIS grade/stage at baseline in both studies. Similar results were observed using regression analyses. Specific components of HSS and EREFS, reflecting inflammatory and remodeling processes, are closely correlated, when examined by Pearson correlations or regression analyses, and can aid identification of fibrostenotic or inflammatory phenotypes in EoE. Correlations of DIS with endoscopic inflammatory and remodeling features reflect the role of barrier dysfunction in maintaining chronic inflammation that ultimately leads to remodeling.

Prolonged hyperglycemia causes long-term vision complications and an increased risk of cognitive deficits. High blood sugar also confers an osmotic load/stress to cells. We assessed behavioral and neurochemical changes in zebrafish brain and retina following prolonged hyperglycemia for 4-weeks or 8-weeks. At each time point, behavior was assessed using 3-chamber choice task and optomotor response; tissue was then collected and levels of inflammatory markers, tight junction proteins, and neurotransmitters determined using Western Blots. After 4-weeks, brain levels of v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RelA; NF-kB subunit), IkB kinase (IKK), and glial fibrillary acidic protein (GFAP) were significantly elevated; differences in zonula occludens-1 (ZO-1), claudin-5, glutamic acid decarboxylase (GAD), and tyrosine hydroxylase (TH) were not significant. In retina, significant differences were observed only for TH (decreased), Rel A (increased), and GFAP (increased) levels. Glucose-specific differences in initial choice latency and discrimination ratios were also observed. After 8-weeks, RelA, GAD, and TH were significantly elevated in both tissues; IKK and GFAP levels were also elevated, though not significantly. ZO-1 and claudin-5 levels osmotically decreased in retina but displayed an increasing trend in glucose-treated brains. Differences in discrimination ratio were driven by osmotic load. OMRs increased in glucose-treated fish at both ages. In vivo analysis of retinal vasculature suggested thicker vessels after 4-weeks, but thinner vessels at 8-weeks. In vitro, glucose treatment reduced formation of nodes and meshes in 3B-11 endothelial cells, suggesting a reduced ability to form a vascular network. Overall, hyperglycemia triggered a strong inflammatory response causing initial trending changes in tight junction and neuronal markers. Most differences after 4-weeks of exposure were observed in glucose-treated fish suggesting effects on glucose metabolism independent of osmotic load. After 8-weeks, the inflammatory response remained and glucose-specific effects on neurotransmitter markers were observed. Osmotic differences impacted cognitive behavior and retinal protein levels; protein levels in brain displayed glucose-driven changes. Thus, we not only observed differential sensitivities of retina and brain to glucose-insult, but also different cellular responses, suggesting hyperglycemia causes complex effects at the cellular level and/or that zebrafish are able to compensate for the continued high blood glucose levels.

Coexisting chronic rhinosinusitis and nasal polyps (CRS-NPs) substantially increases the disease burden of asthma. Dupilumab, a fully human monoclonal antibody, has established efficacy and an acceptable safety profile in asthma and CRS with NP.To evaluate long-term dupilumab efficacy in TRAVERSE (NCT02134028) patients with uncontrolled, moderate-to-severe (QUEST) or oral corticosteroid (OCS)-dependent (VENTURE) asthma with or without coexisting CRS-NP.In TRAVERSE, 317 of 1530 (21%) QUEST and 61 of 187 (48%) VENTURE patients had self-reported CRS-NP; they received subcutaneous 300 mg dupilumab every 2 weeks up to 96 weeks. Patients were categorized by parent study treatment group (placebo/dupilumab, dupilumab/dupilumab). End points included annualized asthma exacerbation rates and mean change from parent study baseline in prebronchodilator forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, Asthma Quality of Life Questionnaire score, and OCS dose.Patients with coexisting CRS-NP had higher OCS dose and a history of more exacerbations. Concluding TRAVERSE, exacerbation rates decreased from 2.39 to 0.32 and 2.32 to 0.35 in dupilumab/dupilumab and 2.36 to 0.41 and 2.36 to 0.45 in placebo/dupilumab by week 96 from QUEST and VENTURE baselines, respectively. Non-CRS-NP results were similar. Improvements in forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, and Asthma Quality of Life Questionnaire score during parent studies were maintained in TRAVERSE; placebo/dupilumab patients achieved similar improvements to dupilumab/dupilumab by week 48. By week 96, 71% and 39% of OCS-dependent patients with CRS-NP and 83% and 47% without CRS-NP treated with dupilumab/dupilumab and placebo/dupilumab, respectively, stopped OCS.Long-term dupilumab efficacy was maintained in patients with asthma with or without self-reported coexisting CRS-NP, including OCS-sparing effects observed in OCS-dependent severe asthma.ClinicalTrials.gov Identifiers: NCT02528214, NCT02414854, and NCT02134028.

PurposeThe purpose of this research is to develop a validated general measure of supply chain risk management maturity (SCRMM) to assess organizational risk management maturity in the context of the supply chain (SC).Design/methodology/approachDimensions and statements measuring SCRMM were developed through a literature review and consultation with experts. The instrument was refined through a pilot study and a full-scale study of 140 SC managers in the USA. A final SCRMM instrument, consisting of 25 statements, was obtained through scale purification, exploratory factor analysis, reliability analysis, and confirmatory factor analysis of construct validity. Cluster analysis was conducted to characterize the organizational groupings with respect to the instrument dimensions.FindingsSCRMM was found to be comprised of the three main dimensions of SC Risk Management Orientation, Enterprise Risk Management Integration (ERMI), and SC Risk Collaboration. ERMI was found to be comprised of the three sub-dimensions of SC Risk Mitigation, Improvement of Risk Management Processes, and Organization Internal Risk Management. Cluster analysis revealed three groups characterized according to SCRMM as leaders, followers, and laggards.Research limitations/implicationsThe findings are based on a sample in the USA, so the SCRMM scale may not generalize to supply chains in other countries or geographic regions.Practical implicationsThe instrument provides a self-assessment and benchmark tool for businesses to advance their SC risk management through different stages of maturity.Originality/valueThis is a pioneering general instrument that treats risk management maturity of the organization in the context of the SC. Participants span many industries and SC positions.

To determine any factors that predict how an individual will adapt to post-stroke hemianopic visual field loss, with close monitoring of the adaptation process from an early stage.The Hemianopia Adaptation Study (HAST) is a prospective observational longitudinal cohort clinical study. Adult stroke survivors (Several baseline variables were found to be good predictors of adaptation. Three variables were associated with adaptation status at 12-weeks post-stroke: inferior % visual field, % total MAC omissions, and MAC completion time (seconds). Baseline measurements of these variables can predict the adaptation at 12 weeks with moderate to high accuracy (area under ROC curve, 0.82, 95% CI 0.74-0.90). A cut-off score of ≤25% target omissions is suggested to predict which individuals are likely to adapt by 12-weeks post-stroke following gold standard care.Adaptation to hemianopia is a personal journey with several factors being important for prediction of its presence, including MAC outcomes and extent of inferior visual field loss. A clinical recommendation is made for inclusion of the MAC as part of a functional assessment for hemianopia.Implications for rehabilitationThe mobility assessment course (MAC) should be considered as an assessment of mobility/scanning in the rehabilitation of patients with homonymous hemianopia.A cut-off score of ≤25% omissions on MAC could be employed to determine those likely to adapt to hemianopia long-term.Targeted support and therapy for patients with significant visual loss in the inferior visual field area should be considered.

PurposeThis study develops and tests a model exploring the relationship between supply chain (SC) counterfeit risk management and performance in the healthcare supply chain (HCSC).Design/methodology/approachIn the proposed theoretical model, HCSC counterfeit risk management is characterized by HCSC counterfeit risk orientation (HCRO), HCSC counterfeit risk mitigation (HCRM) and HCSC risk management integration (HRMI), while performance is represented by healthcare logistics performance (HLP) and healthcare organization overall performance (HOP). Partial least squares structural equation modeling (PLS-SEM) and survey data from 55 HCSC managers are used to test the research hypotheses.FindingsHCRO has a significant positive effect on HCRM, while HCRM has a positive impact on HRMI. With respect to HLP, HCRM has a nonsignificant effect, while HRMI has a significant impact, thus confirming the important mediating role of HRMI. Finally, HLP has a significant positive effect on the overall performance of healthcare organizations.Research limitations/implicationsAll study participants were from the United States, limiting the generalizability of the study findings to different countries or regions. The sample size employed in the study did not allow the authors to distinguish among the different types of healthcare organizations.Originality/valueThis study delineates between a healthcare organization's philosophy toward counterfeiting risks vs actions taken to eliminate or reduce the impact of counterfeiting on the HCSC. By offering firm-level guidance for managers, this study informs healthcare organizations about addressing the challenge of counterfeiting in the HCSC.

Fractional exhaled nitric oxide (FeNO) may have a role both as a prognostic and predictive biomarker, in combination with eosinophils, for assessing responsiveness to some biological therapies.We evaluated the value of baseline FeNO, adjusted for baseline blood eosinophil levels and other clinical characteristics, as an independent predictor of treatment response to dupilumab in patients with uncontrolled, moderate-to-severe asthma.We performed a post-hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854), a phase 3, double-blind study in patients aged ≥ 12 years with uncontrolled moderate-to-severe asthma who received dupilumab 200/300 mg, or placebo every 2 weeks up to 52 weeks. Annualized event rate (AER) of severe exacerbations and least squares mean change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEVAER increased with increasing baseline FeNO in placebo, and decreased in dupilumab groups. The relative risk of severe exacerbations was 22·7%, 58·3%, and 69·3% lower for dupilumab vs placebo for the FeNO25, 25 to50, and ≥ 50 ppb subgroups. The magnitude of FEVIncreased baseline FeNO was associated with greater clinical effects in dupilumab vs placebo, independent of eosinophil levels and other clinical characteristics.

Reporting generalisable data across stroke populations is important. We aimed to evaluate the Impact of Visual Impairment after Stroke (IVIS) visual assessment protocol in a different UK geographical area. This was a single-centre acute stroke unit, prospective study (IVIS-extension (IVIS-e) study) with comparison to a multi-centre acute stroke cohort (IVIS study). Orthoptists reviewed all stroke survivors with a standardised assessment of visual acuity, visual fields, ocular alignment, ocular motility, visual inattention and visual perception including a standardised follow-up strategy. 123 stroke survivors underwent visual screening: 42% women, 58% men, mean age 63.6 years and 86% ischaemic strokes. Ethnicity consisted of 68.3% white British and 28.5% being Pakistani, Indian, Caribbean, Bangladeshi, Black and Chinese. Two died and 28 could not be assessed. Of the 93 remaining, 10 stroke survivors (10.8%) had a normal visual assessment and 83 (89.2%) had visual impairments detected. Fifty-seven stroke survivors were assessed at their first orthoptic visit within 3 days of stroke onset; the remainder being assessed at subsequent orthoptic visits to the stroke unit. The visual profile was similar across the IVIS-e and original IVIS cohorts for most types of visual impairment although, overall, more visual impairment was detected in IVIS-e. Differences between the cohorts were primarily related to lower age and smaller white British ethnicity in the IVIS-e cohort. This likely relates to the differing population demographics for the two cohort geographical areas. Further roll-out of the IVIS assessment protocol to other regions and countries would improve detection of post-stroke visual impairment.

Multisystem inflammatory syndrome in children (MIS-C) has been observed in temporal association with coronavirus disease 2019 (COVID-19), typically within 2 to 6 weeks of illness or exposure. We present a case of MIS-C occurring 16 weeks after initial COVID-19 illness to highlight the prolonged period of risk for developing MIS-C., We describe the presentation, diagnostic evaluation, and management of an adolescent presenting with a multisystem inflammatory process sixteen weeks following COVID-19. We highlight an expanded risk period, longer then commonly reported, for MIS-C to bring heightened awareness to its possibility.

Phytoestrogens are a group of non-steroidal polyphenolic plant-based substances, commonly used for the treatment of menopause-related conditions. They have both genomic and non-genomic effects, displaying weak affinity for estrogen receptors (ER) and preferentially binding to ER-B over ER-A. However, evidence for the benefits of phytoestrogen consumption has been limited. We conducted a review of recent literature, focusing on systematic reviews and meta-analyses reporting on postreproductive health effects of phytoestrogens. While many trials concerning dietary and supplementary phytoestrogens have been conducted, evidence of clinical efficacy is heterogeneous and inconclusive. There appears to be reduction in the vasomotor symptoms of menopause with phytoestrogen intake; however, it is likely small and slow in onset. Phytoestrogens also appear to improve bone mineral density and markers of cardiovascular risk; however, there is inadequate research regarding long-term outcomes. There appear to be no harmful effects of phytoestrogens on breast, endometrial cancer or colorectal cancer and phytoestrogens intake may in fact be protective. Research regarding the effect of phytoestrogens on cognition is mixed, with most studies reporting no significant association. Overall, individual variations in the metabolism of phytoestrogens and age-related genomic effects may account for the considerable variability in the measured effects of phytoestrogens.

Aim This study evaluates the spectrum of visual impairment in stroke survivors. Methods The Impact of Visual Impairment after Stroke (IVIS) study is a multi-centre, acute stroke unit, prospective epidemiology study. Comprehensive visual examination was offered to all stroke survivors. Results 1500 stroke admissions were recruited. 1204 stroke survivors had visual assessment. Reduced central vision was documented in 529, visual field loss in 308, ocular motility abnormalities in 533 stroke survivors, visual perception deficits in 59 stroke survivors and visual inattention in 315 stroke survivors. About half, regardless of visual impairment type, were visually asymptomatic. Recovery, whether full or partial, was best for central vision, ocular motility abnormalities and visual perception deficits (about 70% improvement) occurring over a mean follow-up period of 2-3 months. Conclusions Incidence of impaired central vision, visual field loss, ocular motility disorders and visual inattention was 29.4%, 24.8%, 39.3% and 26.2% respectively. Visual impairment was more likely to occur in more severe stroke and older stroke survivors. Asymptomatic cases raise concerns for acute stroke units where robust specialist vision screening is not routine. Those with partial/no recovery require specialist follow-up and management whilst the wide range of abnormalities highlight the need for specialist visual assessment acutely. Implications for rehabilitation Visual impairment is a common consequence of stroke. Incidence of visual impairment is about 60%. Significant numbers of stroke survivors are visually asymptomatic, highlighting the need for standardised vision assessments. Many stroke survivors have persistent long-term visual impairment, necessitating referral and access to specialist eye care services.

Claire Hopkins,1 Kathleen M Buchheit,2 Enrico Heffler,3,4 Noam A Cohen,5 Heidi Olze,6 Asif H Khan,7 Jérôme Msihid,8 Shahid Siddiqui,9 Scott Nash,9 Juby A Jacob-Nara,10 Paul J Rowe,10 Yamo Deniz9 1Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 3Personalized Medicine, Asthma & Allergy – Humanitas Clinical and Research Center IRCCS, Milan, Italy; 4Department of Biomedical Sciences, Humanitas University, Milan, Italy; 5Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 6Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany; 7Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Claire Hopkins, Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK, Tel +44 2071882215, Email clairehopkins@yahoo.comAbstract: Patients with asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, increasing disease burden and complicating treatment. These post hoc analyses investigated disease-specific health-related quality of life (HRQoL) and general health status in the randomized, placebo-controlled QUEST study (NCT02414854) in patients treated with dupilumab for moderate-to-severe asthma with comorbid CRS. Patients received 300 mg of dupilumab or placebo every 2 weeks for 52 weeks. CRS HRQoL was assessed by the 22-item Sino-Nasal Outcome Test (SNOT-22; items scored 0– 5). The 22 items are categorized into 5 domains (nasal, ear/facial, sleep, function, and emotion), and patients report the top 5 most important items affecting their health. General health status was assessed by Euro-QoL visual analog scale (EQ-VAS). Of 1902 patients, 382 (20.1%) self-reported comorbid CRS; 193 patients receiving dupilumab 300 mg q2w or matched placebo were included in this analysis. At baseline, the most impacted SNOT-22 domain was nasal, and general health status was below population norms. Patients rated “decreased sense of taste/smell,” “nasal blockage,” “cough,” “reduced productivity,” and “wake up tired” as the 5 most important SNOT-22 items affecting their health. Percentage change from baseline in SNOT-22 total score was significantly greater for dupilumab vs placebo at Weeks 24, 36, and 52 (all p < 0.05). Improvements from baseline were significantly greater for dupilumab vs placebo at Week 52 for all SNOT-22 domains (p < 0.05), except emotion. At Week 52, significant changes from baseline with dupilumab vs placebo were observed for all 5 most important SNOT-22 items affecting their health (all p < 0.05). EQ-VAS was significantly improved with dupilumab vs placebo by Week 12, with improvements sustained to Week 52 (all p < 0.01). In patients with moderate-to-severe asthma who self-reported comorbid CRS, dupilumab treatment vs placebo improved CRS-specific HRQoL and general health status.Keywords: asthma, chronic rhinosinusitis, nasal polyps, dupilumab, health-related quality of life, SNOT-22

Asif H Khan1 &ast;, Cori Gray2 &ast;, Laurent Eckert,1 Caroline Amand,1 Jaman Maroni,3 Zhixiao Wang,3 Bethan Jones,4 Thomas Berni,4 Christopher Ll Morgan,4 Paul J Rowe5 1Sanofi, Chilly-Mazarin, France; 2Sanofi, Cambridge, MA, USA; 3Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA; 4Pharmatelligence, Cardiff, UK; 5Sanofi, Bridgewater, NJ, USA&ast;These authors contributed equally to this workCorrespondence: Asif H Khan, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France, 91385, Tel +33160495076, Email Asif.Khan@sanofi.com

In January 2019, EU Member States issued three declarations concerning the “consequences of Achmea” which stated that all claims under intra- EU BIT S were contrary to the EU legal order, and that tribunals presiding over such claims have no jurisdiction as there is no valid consent to arbitrate. The declaration signed by a majority of EU Member States (“Majority Declaration”) extended this proposition to intra- EU claims under the Energy Charter Treaty. Following this, a number of EU Member States have sought to argue that the Majority Declaration is a subsequent agreement between the States Parties to intra- EU investment treaties—or evidence of a subsequent practice establishing their agreement—that the dispute resolution provisions in those treaties must be interpreted to exclude intra- EU disputes from their scope and thus from the jurisdiction of tribunals constituted thereunder, relying on Article 31(3)(a) and (b) of the Vienna Convention on the Law of Treaties (“VCLT”). This paper considers: (i) the key cases in which the Majority Declaration has been invoked to contest jurisdiction in, or seek the termination of, intra- EU arbitration proceedings; (ii) the application of Article 31(3)(a) and (b) of the VCLT; and (iii) other fundamental tenets and rules of international law discussed in relation to those cases.

How do people’s social roles change others’ perceptions of their intentions to cause harm? Three preregistered vignette-based experiments ( N = 788) manipulated the social role of someone causing harm and measured how intentional people thought the harm was. Results indicate that people judge harmful consequences as intentional when they think the actor unjustifiably caused harm. Social roles were shown to alter intention judgments by making people responsible for preventing harm (thereby rendering the harm as an intentional neglect of one’s responsibilities) or for causing the harm (thereby excusing it as an unintentional byproduct of the role). Additionally, Experiment 3 conceptually replicated and moderated the side-effect effect —revealing that people think harmful side effects are intentional when the harm is unjustified but not when a role’s responsibility justifies it. We discuss the importance of social information—including roles—in how people judge others’ intentions.

Ischemia reperfusion (IR) injury results in devastating skeletal muscle fibrosis. Here, we recapitulate this injury with a mouse model of hindlimb IR injury which leads to skeletal muscle fibrosis. Injury resulted in extensive immune infiltration with robust neutrophil extracellular trap (NET) formation in the skeletal muscle, however, direct targeting of NETs via the peptidylarginine deiminase 4 (PAD4) mechanism was insufficient to reduce muscle fibrosis. Circulating levels of IL-10 and TNFα were significantly elevated post injury, indicating toll-like receptor (TLR) signaling may be involved in muscle injury. Administration of hydroxychloroquine (HCQ), a small molecule inhibitor of TLR7/8/9, following injury reduced NET formation, IL-10, and TNFα levels and ultimately mitigated muscle fibrosis and improved myofiber regeneration following IR injury. HCQ treatment decreased fibroadipogenic progenitor cell proliferation and partially inhibited ERK1/2 phosphorylation in the injured tissue, suggesting it may act through a combination of TLR7/8/9 and ERK signaling mechanisms. We demonstrate that treatment with FDA-approved HCQ leads to decreased muscle fibrosis and increased myofiber regeneration following IR injury, suggesting short-term HCQ treatment may be a viable treatment to prevent muscle fibrosis in ischemia reperfusion and traumatic extremity injury.

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals. Fil: Ng, Bobby G.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos Fil: Eklund, Erik A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos. Lund University; Suecia Fil: Shiryaev, Sergey A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos Fil: Dong, Yin Y.. University of Oxford; Reino Unido Fil: Abbott, Mary Alice. University of Massachusetts Medical School; Estados Unidos Fil: Asteggiano, Carla Gabriela. Universidad Católica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Bamshad, Michael J.. University of Washington; Estados Unidos Fil: Barr, Eileen. University of Emory; Estados Unidos Fil: Bernstein, Jonathan A.. University of Stanford; Estados Unidos Fil: Chelakkadan, Shabeed. Monash Children's Hospital; Australia Fil: Christodoulou, John. Sydney Medical School; Australia. University of Melbourne; Australia Fil: Chung, Wendy K.. Columbia University; Estados Unidos Fil: Ciliberto, Michael A.. University of Iowa; Estados Unidos Fil: Cousin, Janice. National Human Genome Research Institute ; Estados Unidos Fil: Gardiner, Fiona. University of Melbourne; Australia Fil: Ghosh, Suman. University of Florida; Estados Unidos Fil: Graf, William D.. University of Connecticut; Estados Unidos Fil: Grunewald, Stephanie. University College London; Estados Unidos Fil: Hammond, Katherine. University of Alabama at Birmingahm; Estados Unidos Fil: Hauser, Natalie S.. Inova, Fairfax Hospital Falls Church; Estados Unidos Fil: Hoganson, George E.. University Of Illinois At Chicago; Estados Unidos Fil: Houck, Kimberly M.. Baylor College of Medicine; Estados Unidos Fil: Kohler, Jennefer N.. University of Stanford; Estados Unidos Fil: Morava, Eva. Mayo Clinic; Estados Unidos Fil: Larson, Austin A.. University Of Colorado Anschutz Medical Campus.; Estados Unidos Fil: Liu, Pengfei. Baylor Genetics; Estados Unidos. Baylor College Of Medicine; Estados Unidos Fil: Madathil, Sujana. University of Iowa; Estados Unidos Fil: McCormack, Colleen. University of Stanford; Estados Unidos Fil: Meeks, Naomi J.L.. University Of Colorado Anschutz Medical Campus.; Estados Unidos Fil: Papazoglu, Gabriela Magali. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina

Background: About two-thirds of stroke survivors experience visual problems and most patients who have a stroke limited to the occipital lobe will have visual impairments only. Aim: The V-FAST screening tool, which assesses visual symptoms, eye movements, visual field and visual extinction, and a training package to improve diagnostic accuracy of identifying visual impairment in hyperacute strokes were developed and evaluated. Methods: The educational package was developed through focus groups. The pilot study screened patients with suspected strokes in prehospital settings; the V-FAST tool was used with 43 of these patients. Each participant was also assessed in hospital using the National Institutes of Health Stroke Scale (NIHSS) and the score compared to V-FAST screening results to determine sensitivity and specificity. Results: The education package includes detailed instructions with video. In the pilot study, V-FAST detected visual impairment in 75.9% of FAST-positive and 80% of FAST-negative strokes. Sensitivity and specificity compared to NIHSS were 85.7% and 42.1% respectively. Conclusion: V-FAST has good sensitivity to detect vision impairment when screening for possible strokes. The added education package facilitates greater knowledge and understanding of potential visual problems caused by stroke.

This study addresses a critical question concerning how a firm’s succession practices for sales leaders impact the sustainability of selling strategies and the consistency of results. Our study emp...

Purpose This paper aims to examine how the efficacy of organizational routines varies and the mechanism through which organizational routines improve firm performance. Design/methodology/approach A theoretical model is proposed and tested using data from 53 interviews with financial services experts and 291 survey responses from financial advisors. Findings Operational and adaptive routines work through absorptive capacity to positively contribute to firm performance. The positive effects of adaptive routines are magnified under market governance. Research limitations/implications The examination of organizational routines is focused on routines at the firm level. Therefore, higher corporate-level routines were not measured. Response rate for the survey is a possible concern, so future research will benefit from increasing the response rate from the focal population. Practical implications This study benefits firms facing the dual role of customization and discipline in working with clients toward service delivery. The findings suggest that firms should develop both operational and adaptive routines, particularly when operating under market governance. Originality/value This study identified two categories of routines (operational and adaptive) and the circumstances in which the causal link between routines and performance varies. This study examined the potential moderating influence of a governance mode (market vs hierarchy). Absorptive capacity was identified as a mediator between the use of routines and firm performance.

Cold methane seeps were common in the Late Cretaceous Western Interior Seaway of North America. They provided a habitat for a diverse array of fauna including ammonites. Recent research has demonstrated that ammonites lived at these sites. However, it is still unknown if they hatched at the seeps or only arrived there later in ontogeny. To answer this question, we documented the abundance and size distribution of small specimens of Baculites and Hoploscaphites at eight seep sites in the Pierre Shale of South Dakota. The specimens of Hoploscaphites range from 0.8 to 8.1 mm in shell diameter, with most of them falling between 1 and 1.5 mm. The specimens of Baculites range from 0.7 to 19.2 mm in length, with most specimens falling between 6 and 8 mm. The small size and morphology of these specimens indicate that they are neanoconchs, that is, newly hatched individuals that lived for a short time after hatching. We also analyzed the isotope composition (δ13C and δ18O) of 12 small specimens of Baculites and one specimen of Hoploscaphites with excellent shell preservation from one seep deposit. The values of δ13C and δ18O range from -16.3 to -2.5‰ and -3.0 to -0.9‰, respectively. The values of δ18O translate into temperatures of 19–28°C, which are comparable to previous estimates of the temperatures of the Western Interior Seaway. The low values of δ13C suggest that the tiny animals incorporated carbon derived from anaerobic oxidation of 12C-enriched methane into their shells. Evidently, they must have lived in close proximity to seep fluids emerging at the sediment-water interface and the associated microbial food web. However, this may have contributed to their demise if they were exposed to elevated concentrations of H2S derived from the anaerobic oxidation of methane.