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IntroductionState-of-the-art multi-modal brain tumor segmentation methods often rely on large quantities of manually annotated data to produce acceptable results. In settings where such labeled data may be scarce, there may be value in exploiting cheaper or more readily available data through clinical trials, such as Response Assessment in Neuro-Oncology (RANO).MethodsThis study demonstrates the utility of such measurements for multi-modal brain tumor segmentation, whereby an encoder network is first trained to regress synthetic “Pseudo-RANO” measurements using a mean squared error loss with cosine similarity penalty to promote orthogonality of the principal axes. Using oriented bounding-boxes to measure overlap with the ground truth, we show that the encoder model can reliably estimate tumor principal axes with good performance. The trained encoder was combined with a randomly initialized decoder for fine-tuning as a U-Net architecture for whole tumor (WT) segmentation.ResultsOur results demonstrate that weakly supervised encoder models converge faster than those trained without pre-training and help minimize the annotation burden when trained to perform segmentation.DiscussionThe use of cheap, low-fidelity labels in the context allows for both faster and more stable training with fewer densely segmented ground truth masks, which has potential uses outside this particular paradigm.

Tulare County is located in the Central Valley region of California (CA). Its population is exposed to stressors that include high levels of air, water, and soil pollution, socioeconomic strain, and poor access to walkable areas and healthy foods. As a result, this population suffers from a high disease burden compared to other CA counties. We hypothesize that environmental and socioeconomic stressors interact in complex ways to raise the burden of disease in the Tulare population beyond additive impacts. We used CalEnviroScreen to select Tulare County as the subject of the study and characterized the geographical interaction of stressors. The CalEnviroScreen indicators provided the basis for population-weighted average calculations to determine the most critical environmental and socioeconomic stressors in Tulare County. We also analyzed and interpreted walkability and dietary access through open-source data. In addition, we compared disease-based mortality in Tulare County to CA state averages. Our evaluation reveals that the population living within the census tracts of Tulare County is exposed to environmental stressors at significantly higher levels relative to many other Californian census tracts, specifically for fine particulate matter, ozone, and drinking water quality. Relatively high exposures to socioeconomic stressors can compound resulting health impacts. We use dose–response curves and stressor mapping to characterize how multiple stressors may augment a population’s vulnerability and effective doses from exposure to multiple stressors. According to the Centers for Disease Control and Prevention Data, the differences in mortality rates between Tulare and CA were not significant. However, notable differences in mortality between CA and Tulare occur for Alzheimer’s disease, diseases of the circulatory system, influenza, and pneumonia, which were all statistically higher in Tulare County, and for diabetes, endocrine, nutritional and metabolic diseases, and neoplasms, which were statistically lower Tulare. Previous health-impact studies have linked individual environmental stressors to their respective measures of disease. However, many communities continue to be exposed daily to numerous stressors that individually are within regulatory limits but could significantly magnify risk due to the synergistic effects. Dose–response curves tailored to population vulnerability provide a basis for quantifying the synergistic risks of multiple stressors on specific measures of disease.

Abstract Background The health-risk assessment paradigm is shifting from single stressor evaluation towards cumulative assessments of multiple stressors. Recent efforts to develop broad-scale public health hazard datasets provide an opportunity to develop and evaluate multiple exposure hazards in combination. Methods We performed a multivariate study of the spatial relationship between 12 indicators of environmental hazard, 5 indicators of socioeconomic hardship, and 3 health outcomes. Indicators were obtained from CalEnviroScreen (version 3.0), a publicly available environmental justice screening tool developed by the State of California Environmental Protection Agency. The indicators were compared to the total rate of hospitalization for 14 ICD-9 disease categories (a measure of disease burden) at the zip code tabulation area population level. We performed principal component analysis to visualize and reduce the CalEnviroScreen data and spatial autoregression to evaluate associations with disease burden. Results CalEnviroScreen was strongly associated with the first principal component (PC) from a principal component analysis (PCA) of all 20 variables (Spearman ρ = 0.95). In a PCA of the 12 environmental variables, two PC axes explained 43% of variance, with the first axis indicating industrial activity and air pollution, and the second associated with ground-level ozone, drinking water contamination and PM2.5. Mass of pesticides used in agriculture was poorly or negatively correlated with all other environmental indicators, and with the CalEnviroScreen calculation method, suggesting a limited ability of the method to capture agricultural exposures. In a PCA of the 5 socioeconomic variables, the first PC explained 66% of variance, representing overall socioeconomic hardship. In simultaneous autoregressive models, the first environmental and socioeconomic PCs were both significantly associated with the disease burden measure, but more model variation was explained by the socioeconomic PCs. Conclusions This study supports the use of CalEnviroScreen for its intended purpose of screening California regions for areas with high environmental exposure and population vulnerability. Study results further suggest a hypothesis that, compared to environmental pollutant exposure, socioeconomic status has greater impact on overall burden of disease.

California residents may experience the highest polybrominated diphenyl ether (PBDE) flame retardant exposures in the United States, the nation with the highest body burdens worldwide. It is hypothesized that Californians' high exposures are due to the state's strict furniture flammability standards. Ingestion of PBDE-contaminated dust, to which children may be particularly susceptible, is a dominant exposure pathway. Low-income populations may also face disparately high exposures due to the presence of older, deteriorated or poorly manufactured furniture treated with PBDEs. We collected up to two dust samples per home (54 samples total), several days apart, from low-income California households in the urban community of Oakland (n=13 homes) and the agricultural community of Salinas (n=15 homes). We measured BDE-47, BDE-99 and BDE-100, the major constituents of the penta-PBDE flame retardant formulation commonly used in furniture. All three PBDE congeners were detected in every sample with concentrations (loadings) ranging from 185 to 126,000 ng/g (621–264,000 ng/m2), 367–220,000 ng/g (1550–457,000 ng/m2), and 84–41,100 ng/g (257–85,700 ng/m2) for BDE-47, BDE-99 and BDE-100, respectively. Median concentrations (loadings) observed in Salinas homes for BDE-47, BDE-99 and BDE-100 were 3100 ng/g (10,800 ng/m2), 5480 ng/g (19,500 ng/m2), and 1060 ng/g (3810 ng/m2), respectively, and in Oakland homes 2780 ng/g (10,700 ng/m2), 4450 ng/g (19,100 ng/m2), and 1050 ng/g (4000 ng/m2), respectively. Maximum concentrations for BDE-47 and BDE-99 are the highest reported to date. Indoor concentrations and loadings did not significantly differ between communities; concentrations and loadings were strongly correlated between collections for all three congeners (Spearman rho=0.79–0.97, p

The work addresses current knowledge gaps regarding causes for correlations between environmental and biomarker measurements and explores the underappreciated role of variability in disaggregating exposure attributes that contribute to biomarker levels. Our simulation-based study considers variability in environmental and food measurements, the relative contribution of various exposure sources (indoors and food), and the biological half-life of a compound, on the resulting correlations between biomarker and environmental measurements. For two hypothetical compounds whose half-lives are on the order of days for one and years for the other, we generate synthetic daily environmental concentrations and food exposures with different day-to-day and population variability as well as different amounts of home- and food-based exposure. Assuming that the total intake results only from home-based exposure and food ingestion, we estimate time-dependent biomarker concentrations using a one-compartment pharmacokinetic model. Box plots of modeled R2 values indicate that although the R2 correlation between wipe and biological (e.g., serum) measurements is within the same range for the two compounds, the relative contribution of the home exposure to the total exposure could differ by up to 20%, thus providing the relative indication of their contribution to body burden. The novel method introduced in this paper provides insights for evaluating scenarios or experiments where sample, exposure, and compound variability must be weighed in order to interpret associations between exposure data.

Background: RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score., Aim: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy., Methods: Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months., Results: 108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of "pain" (16.9±2.0pts→9.9±1.8pts/p<0.01), "GERD" (14.4±1.8→9.9±1.6/p<0.05), "disorders of bowel movements" (19.2±1.4→14.1±1.5/p<0.01), "appetite" (7.0±1.1→4.6±1.2/p<0.01) and "impaired-QoL" (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy., Discussion: In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines. Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of inflammation and cell-proliferation, was found, in parallel to FC., Competing Interests: Declaration of Competing Interest JGM reports independent grants and speaker/board honoraria from Vertex, Chiesi, Abbvie and Viatris outside the submitted work. CZ, FD and AB declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest PMN reports independent grants and speaker/board honoraria from Vertex outside the submitted work. JCD and her institution have received fees for Advisory Board participation, clinical trial leadership and speaking engagements from Vertex Pharmaceuticals in the field of CFTR modulators but not directly related to this study, and from AbbVie, Arcturus, Boehringer Ingelheim, Eloox, Enterprise Thearpeutics and Novartis outside the scope of this work., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (pwCF) aged 2 years and older with at least one F508del-CFTR allele or more. After U.S. approval in 2019, reports emerged of depression-related adverse events in pwCF treated with ELX/TEZ/IVA. Objectives: To review available evidence on depression-related events in pwCF treated with ELX/TEZ/IVA in the context of background epidemiology in pwCF. Methods: Safety data from 14 ELX/TEZ/IVA clinical trials and 10 trials of CF transmembrane conductance regulator (CFTR) modulators in which placebo was administered, along with data from CF registries in the United States and Germany and cumulative postmarketing adverse event data from 61,499 pwCF who initiated ELX/TEZ/IVA after initial approval in the United States (October 2019) through October 2022, were reviewed and used to calculate exposure-adjusted rates of depression-related adverse events and prevalence of depression. In addition, a scientific literature review was conducted to identify ELX/TEZ/IVA publications reporting depression-related events or changes in depressive symptoms after treatment initiation. Measurements and Main Results: In clinical trials, the exposure-adjusted rate of any depression-related adverse event was 3.32/100 person years (PY) in the pooled ELX/TEZ/IVA group ( n  = 1,711) and 3.24/100 PY in the pooled placebo group ( n  = 1,369). The exposure-adjusted rates of suicidal ideation and suicide attempt were also similar between the pooled ELX/TEZ/IVA group and pooled placebo group (ideation: 0.23/100 PY vs. 0.28/100 PY; attempt: 0.08/100 PY vs. 0.14/100 PY). In the postmarketing setting, the exposure-adjusted reporting rates of depression-related events were low in context of the background prevalence in pwCF (all depression-related events: 1.29/PY; suicidal ideation: 0.12/100 PY; and suicide attempt: 0.05/100 PY). Assessments of individual case reports were confounded by preexisting mental health conditions, intercurrent psychosocial stressors (including coronavirus disease [COVID-19] lockdowns), and the heterogeneous and fluctuating nature of depression. Data from CF registries in the United States and Germany showed that patterns of depression prevalence in pwCF exposed to ELX/TEZ/IVA did not change after treatment initiation. Published studies utilizing the nine-item Patient Health Questionnaire did not show evidence of worsening depression symptoms in pwCF treated with ELX/TEZ/IVA. Conclusions: Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in the CF population and do not suggest a causal relationship with ELX/TEZ/IVA treatment.

Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI 2.5 ) and FEV 1 . Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI 2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (-2.5; 95% confidence interval [CI], -3.0, -2.0) and in the percents predicted for FEV 1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (-3.46; 95% CI, -5.23, -1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1; 95% CI, -47.4, -38.9) and F508del/MF (-42.8; 95% CI, -48.5, -37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P  < 0.001). Conclusions: ETI is associated with substantial improvements in LCI 2.5 , spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT04602468).

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics., Competing Interests: Declaration of interests NM-H reports grants from the Cystic Fibrosis Foundation (CFF), the National Institutes of Health (NIH; P30 DK 089507 and UL1 TR002319), and the Food and Drug Administration (FDA); consulting fees from Enterprise Therapeutics; and data safety monitoring board (DSMB) membership for the NIH. JPC is an employee of CFF. RJ reports grants from CFF; consulting fees from Boehringer Ingelheim and Recode Therapeutics; honoraria from Vertex Pharmaceuticals; and travel support from CFF. SHD reports contracts from Calithera, CFF, NIH (P30 DK065988), Vertex Pharmaceuticals, 4D Molecular Therapeutics, and Chiesi USA; consulting fees from Polarean, 501 Ventures, Enterprise Therapeutics, and Boehringer Ingelheim; fees for participation on advisory boards for Innova Healthcare and Boehringer Ingleheim; travel fees from Enterprise Therapeutics and CFF; and participation on a board for Abbvie. IF reports grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, and Vertex Pharmaceuticals; honoraria from Vertex Pharmaceuticals; board participation for AbbVie, Boehringer Ingelheim, Kither Biotech, and Vertex Pharmaceuticals; and support to her institution from the European Cystic Fibrosis Society (ECFS). CHG reports grants and contracts from CFF, NIH (P30 DK 089507 and UL1 TR000423), and FDA; consulting fees from Enterprise Therapeutics; honoraria from Gilead Sciences and Vertex Pharmaceuticals; travel support from Vertex Pharmaceuticals and Enterprise Therapeutics; participation on the board for Novartis; stock options for Air Therapeutics; and leadership roles for the American Thoracic Society (ATS). DP reports grants from CFF (002805121), NIH, and Aclaris Pharmaceuticals; travel support from CFF; and board participation for Vertex Pharmaceuticals and Translate Bio. FR reports grants from Vertex Pharmaceuticals and consulting fees from Vertex Pharmaceuticals and Calithera. BSQ reports grants from CFF, Cystic Fibrosis Canada, Vertex Pharmaceuticals, and Gilead Sciences; honoraria from Vertex Pharmaceuticals; and travel support from CFF. ETZ reports grants from NIH, Vertex Pharmaceuticals, and CFF (002884121); consulting fees from CFF; travel support from CFF, Vertex Pharmaceuticals, and ECFS; and participation on boards for CFF and Vertex Pharmaceuticals. SCB reports grants from the National Health and Medical Research Council Australia (APP1102494), the Medical Research Futures Fund Australia, and CFF (BELL1480 and BELL19A0); and honoraria from Vertex Pharmaceuticals. JCD reports grants from the UK Cystic Fibrosis Trust (as part of their Clinical Trials Accelerator Platform), CFF, Cystic Fibrosis Ireland, the Engineering and Physical Sciences Research Council, and the National Institute for Health and Care Research; and honoraria from Vertex Pharmaceuticals, Boehringer Ingelheim, Eloxx, Algipharma, Abbvie, Arcturus, Enterprise Therapeutics, Recode, LifeArc, Genentech, and Tavanta. JCD serves as Deputy Editor for the Journal of Cystic Fibrosis. MWK reports grants from NIH (P01HL128192 and UL1TR002548) and CFF; consulting fees from AbbVie, AzurRx, Cystetic Medicines, EnBiotix, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Mylan, and PBM BC Holdings; board participation for AbbVie, CFF, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Sionna, and Vertex; and committee membership for CFF. MAM reports grants from the German Research Foundation (CRC 1449 project #431232613), the German Ministry for Education and Research (82DZL009B1), the German Innovation Fund, and Vertex Pharmaceuticals; consulting fees from Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense, and Vertex Pharmaceuticals; honoraria from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals; and participation on boards for Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari, and Vertex Pharmaceuticals. EM reports grants from Vertex Pharmaceuticals; honoraria from Vertex Phamaceuticals; travel support from Menarini; and board participation for the Cystic Fibrosis Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. JHR reports grants from Cystic Fibrosis Canada, CFF, Vertex Phamaceuticals, the Canada Foundation for Innovation, and the Canadian Institutes of Health Research; consulting fees from Sanofi; and travel support from Vertex Pharmaceuticals. SMR reports grant funding from CFF (P30DK072482), NIH (UL1TR003096), Vertex Pharmaceuticals, Galapagos/Abbvie, Eloxx, Synspira, Translate Bio, Arcturus, Astra-Zenica, and Ionis; and consulting fees from Vertex Pharmaceuticals, Synspira (including stock options), Renovion (including stock options), Cystetic Medicines, and Arcturus. SMR's potential competing interests were resolved or ended in 2022 or earlier. JLT-C reports grants and contracts from CFF, Vertex Pharmaceutics, Eloxx, and 4DMT; consulting fees from Vertex Phamaceuticals, Insmed, and 4DMT; participation on a DSMB for Abbvie; and participation on advisory boards for CFF, ATS, Journal of Cystic Fibrosis, The Lancet Respiratory Medicine, and Emily's Entourage. GR-B reports grants and contracts from Vertex Pharmaceuticals and CFF. DGD reports grants from Chiesi Farmaceutici and CFF; consulting fees from Vertex and Insmed; honoraria from Chiesi and Gilead; travel support from ECFS and CFF; board participation for Momab and CSL Behring; and support from ECFS as director of the Clinical Trials Network. MJ, NRK, TL, KP, JMP, and LQ declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Extracellular vesicles (EVs) are emerging as biomarkers of disease with diagnostic potential in CF. With the advent of highly effective modulator therapy, sputum production is less common and there is a need to identify novel markers of CF disease progression, exacerbation and response to therapies in accessible fluids such as serum., Methods: We used size exclusion chromatography (SEC) to isolate and characterise EVs from the blood of PWCF of different ages and compared to ultracentrifugation (UC). We used nanoparticle tracking analysis to measure the number of EVs present in serum obtained from children and adults with CF. Mass spectrometry based proteomics was used to characterise protein expression changes between the groups., Results: EVs were successfully isolated in SEC fractions from 250 µl serum from PWCF in greater numbers (p <0.01) than density ultracentrifugation. There was not a significant difference in EV numbers between young children with CF and controls. However, there was significantly more EVs in adults compared to children (<6yrs) (p < 0.05). EVs from PWCF before and after Kaftrio treatment were also analysed. Significant protein expression changes were observed within all 3 group. The largest changes detected were between children and adults with CF (57 proteins had a 1.5 fold change in expression with 19 significant changes p < 0.05) and PWCF taking Kaftrio (24 significant changes in EV protein expression was observed 12 months post treatment)., Conclusion: In this pilot study, we performed an initial characterisation of EVs in serum from PWCF demonstrating the potential of serum EVs for further diagnostic investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2-5 years. Methods: In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index 2.5 (LCI 2.5 , defined as the number of lung turnovers required to reduce the end tidal N 2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children ( F508del /minimal function genotypes, n  = 52; F508del / F508del genotype, n  = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L; 95% confidence interval [CI], -61.3 to -54.6; n  = 69) and LCI 2.5 (-0.83 U; 95% CI, -1.01 to -0.66; n  = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open-label study in children 2-5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI 2.5 . Clinical trial registered with www.clinicaltrials.gov (NCT04537793).

Recognising faces is widely believed to be achieved using "special" neural and cognitive mechanisms that depend on "holistic" processing, which are not used when recognising other kinds of objects. An important, but largely unaddressed, question is how much like a Human face a stimulus needs to be to engage this "special" mechanism(s). In the current study, we attempted to answer this question in 3 ways. In Experiments 1 and 2 we examined the extent to which the disproportionate inversion effect for human faces extends to the faces of other species (including a range of other primates). Results suggested that the faces of other primates engage the mechanism responsible for the inversion effect approximately as well as that mechanism is engaged by Human faces, but that non-primate faces engage the mechanism less well. And so primate faces, in general, seem to produce a disproportionate inversion effect. In Experiment 3 we examined the extent to which the Composite effect extends to the faces of a range of other primates, and found no compelling evidence of a composite effect for the faces of any other primate. The composite effect was exclusive to Human faces. Because these data differ so dramatically from a previously reported study asking similar questions Taubert (2009), we also (in Experiment 4) ran an exact replication of Taubert's Experiment 2, which reported on both Inversion and Composite effects in a range of species. We were unable to reproduce the pattern of data reported by Taubert. Overall, the results suggest that the disproportionate inversion effect extends to all of the faces of the non-human primates tested, but that the composite effect is exclusive to Human faces., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sulikowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

What happens to everyday social interactions when other-race recognition fails? Here, we provide the first formal investigation of this question. We gave East Asian international students (N = 89) a questionnaire concerning their experiences of the other-race effect (ORE) in Australia, and a laboratory test of their objective other-race face recognition deficit using the Cambridge Face Memory Test (CFMT). As a 'perpetrator' of the ORE, participants reported that their problems telling apart Caucasian people contributed significantly to difficulties socializing with them. Moreover, the severity of this problem correlated with their ORE on the CFMT. As a 'victim' of the ORE, participants reported that Caucasians' problems telling them apart also contributed to difficulties socializing. Further, 81% of participants had been confused with other Asians by a Caucasian authority figure (e.g., university tutor, workplace boss), resulting in varying levels of upset/difficulty. When compared to previously established contributors to international students' high rates of social isolation, ORE-related problems were perceived as equally important as the language barrier and only moderately less important than cultural differences. We conclude that the real-world impact of the ORE extends beyond previously identified specialized settings (eyewitness testimony, security), to common everyday situations experienced by all humans., (© 2021 The British Psychological Society.)

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13 th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen., Results: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007)., Conclusions: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2., Competing Interests: COI Statement All authors declare no conflicts of interest in relationship to this work. Outside of this work the following authors declare payments or honoraria to them or their institution for a combination of lectures, presentations, educational events, advisory boards, steering groups, grants or consultancy fees: SC-Vertex, Chiesi, Profile, Zambon. RC- Vertex, P-RB – Astra-Zeneca, Boehringer Ingelheim, GSK, Insmed, Chiesi, Pfizer, Vertex, Zambon. I deM – Vertex,LN – Vertex, Boehringer,LVS-F – Vertex, AS -Vertex., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: To evaluate the association between ophthalmic structure/function measures and five standardized quality of life (QoL) instruments, in patients with advanced age-related macular degeneration (AMD)., Methods: We examined 20 AMD patients (ages 66-93 years) recruited from the Canberra Hospital Ophthalmology Department. Visual function measures included low and high contrast visual acuity (LCVA and HCVA) and measures from 10-2 Matrix visual fields (VF). Optical coherence tomography (OCT) quantified central retinal thickness (CRT), average macular thickness (AT), and retinal nerve fibre layer thickness (RNFL). The QoL instruments were the macular degeneration-related quality of life (MacDQoL), the National Eye Institute Visual Functioning Questionnaire (VFQ), its two face-recognition questions (A6 and 11), and the Geriatric Depression Scale (GDS). Pearson correlations, Canonical Correlation Analysis (CCA), and cross-validated stepwise-regression were used to examine the relationships between structure/function measures and the QoL instruments., Results: The selected models for the five instruments had R 2 ranging from 0.65 ± 0.12 to 0.90 ± 0.05 (mean ± SD) and median F-statistics > 188. HCVA was strongly associated with all QoL except the GDS, for which CRT, AT and RNFL figured highly. RNFL was most important for MacDQoL, and 2 nd for VFQ question-A6. Centrally weighted VF measures were rarely selected but global VF measures were common, especially for the overall NEI-VFQ questionnaire. CCA revealed that the structure/function measures and QoL instruments contained 2 statistically independent mechanisms., Conclusions: In patients with advanced AMD, CRT and HCVA were strong determinants of QoL instruments in AMD patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Patients with advanced age-related macular degeneration (AMD) may have preserved visual function despite significant retinal structural changes. We aimed to evaluate the relationships among retinal thickness, macular sensitivity, and visual acuity (VA) in advanced AMD., Methods: We examined 43 eyes of 22 patients with advanced AMD (ages 66-93 years), prospectively recruited from the Canberra Hospital Ophthalmology Department. Visual function was measured on participants with low and high contrast visual acuity (LCVA and HCVA) and 10-2 Matrix visual fields. Retinal structure was determined with spectral domain optical coherence tomography (OCT), and customized software mapped the 64 OCT macular thickness regions onto the 44 regions of the 10-2 test., Results: Median retinal thickness at each 10-2 region was near normal. Just 7 of 88 regions from the OCT analysis that were thicker than the median had sensitivity that declined significantly with increasing thickness (r = -0.698 ± 0.082, mean ± SD), whereas 17 of 88 thinner regions showed significantly decreasing sensitivity with decreasing thickness (r = 0.723 ± 0.078). The absolute value of deviations from median optical coherence tomography thickness (aOCT) outside the central eight degrees was significantly correlated with HCVA (r = -0.34, P = 0.047). Thickness in the central eight degrees was not. Similarly, matrix sensitivities inside the central eight degrees were significantly correlated with outer aOCT (r = -0.49, P = 0.002)., Conclusions: Retinal thickness outside eight degrees were significantly associated with HCVA and macular sensitivity. These results suggest that outer macular thickness may be a useful prognostic indicator in AMD., Translational Relevance: Retinal structure at the borders of the macula may be a surrogate marker of vision and retinal thickness near fixation.

Background: Differentiating combined pulmonary fibrosis with emphysema (CPFE) from pure emphysema can be challenging on high-resolution computed tomography (HRCT). This has antifibrotic therapy implications., Methods: Twenty patients with suspected CPFE underwent late gadolinium-enhanced (LGE) thoracic magnetic resonance imaging (LGE-MRI) and HRCT. Data from twelve healthy control subjects from a previous study who underwent thoracic LGE-MRI were included for comparison. Quantitative LGE signal intensity (SI) was retrospectively compared in regions of fibrosis and emphysema in CPFE patients to similar lung regions in controls. Qualitative comparisons for the presence/extent of reticulation, honeycombing, and traction bronchiectasis between LGE-MRI and HRCT were assessed by two readers in consensus., Results: There were significant quantitative differences in fibrosis SI compared to emphysema SI in CPFE patients (25.8, IQR 18.4-31.0 versus 5.3, IQR 5.0-8.1, p < 0.001). Significant differences were found between LGE-MRI and HRCT in the extent of reticulation (12.5, IQR 5.0-20.0 versus 25.0, IQR 15.0-26.3, p = 0.038) and honeycombing (5.0, IQR 0.0-10.0 versus 20.0, IQR 10.6-20.0, p = 0.001) but not traction bronchiectasis (10.0, IQR 5-15 versus 15.0, IQR 5-15, p = 0.878). Receiver operator curve analysis of fibrosis SI compared to similarly located regions in control subjects showed an area under the curve of 0.82 (p = 0.002). A SI cutoff of 19 yielded a sensitivity of 75% and specificity of 86% in differentiating fibrosis from similarly located regions in control subjects., Conclusion: LGE-MRI can differentiate CPFE from pure emphysema and may be a useful adjunct test to HRCT in patients with suspected CPFE.

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare relating to this work., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Information is lacking on the clinical impact of the novel coronavirus, SARS-CoV-2, on people with cystic fibrosis (CF). Our aim was to characterise SARS-CoV-2 infection in people with cystic fibrosis., Methods: Anonymised data submitted by each participating country to their National CF Registry was reported using a standardised template, then collated and summarised., Results: 40 cases have been reported across 8 countries. Of the 40 cases, 31 (78%) were symptomatic for SARS-CoV-2 at presentation, with 24 (60%) having a fever. 70% have recovered, 30% remain unresolved at time of reporting, and no deaths have been submitted., Conclusions: This early report shows good recovery from SARS-CoV-2 in this heterogeneous CF cohort. The disease course does not seem to differ from the general population, but the current numbers are too small to draw firm conclusions and people with CF should continue to strictly follow public health advice to protect themselves from infection., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare relating to this work., (Copyright © 2020. Published by Elsevier B.V.)

We investigate perception of, and responses to, facial expression authenticity for the first time in social anxiety, testing genuine and polite smiles. Experiment 1 ( N  = 141) found perception of smile authenticity was unaffected, but that approach ratings, which are known to be reduced in social anxiety for happy faces, are more strongly reduced for genuine than polite smiles. Moreover, we found an independent contribution of social anxiety to approach ratings, over and above general negative affect (state/trait anxiety, depression), only for genuine smiles, and not for polite ones. We argue this pattern of results can be explained by genuine smilers signalling greater potential for interaction - and thus greater potential for the scrutiny that is feared in social anxiety - than polite smiles. Experiment 2 established that, relative to polite smilers, genuine smilers are indeed perceived as friendlier and likely to want to talk for longer if approached. Critically, the degree to which individual face items were perceived as wanting to interact correlated strongly with the amount that social anxiety reduced willingness to approach in Experiment 1. We conclude it is the potential for social evaluation and scrutiny signalled by happy expressions, rather than their positive valence, that is important in social anxiety.

Poor recognition of other-race faces is ubiquitous around the world. We resolve a longstanding contradiction in the literature concerning whether interracial social contact improves the other-race effect. For the first time, we measure the age at which contact was experienced. Taking advantage of unusual demographics allowing dissociation of childhood from adult contact, results show sufficient childhood contact eliminated poor other-race recognition altogether (confirming inter-country adoption studies). Critically, however, the developmental window for easy acquisition of other-race faces closed by approximately 12 years of age and social contact as an adult - even over several years and involving many other-race friends - produced no improvement. Theoretically, this pattern of developmental change in plasticity mirrors that found in language, suggesting a shared origin grounded in the functional importance of both skills to social communication. Practically, results imply that, where parents wish to ensure their offspring develop the perceptual skills needed to recognise other-race people easily, childhood experience should be encouraged: just as an English-speaking person who moves to France as a child (but not an adult) can easily become a native speaker of French, we can easily become "native recognisers" of other-race faces via natural social exposure obtained in childhood, but not later.

Previous studies of age-related macular degeneration (AMD) report impaired facial expression recognition even with enlarged face images. Here, we test potential benefits of caricaturing (exaggerating how the expression's shape differs from neutral) as an image enhancement procedure targeted at mid- to high-level cortical vision. Experiment 1 provides proof-of-concept using normal vision observers shown blurred images as a partial simulation of AMD. Caricaturing significantly improved expression recognition (happy, sad, anger, disgust, fear, surprise) by ∼4%-5% across young adults and older adults (mean age 73 years); two different severities of blur; high, medium, and low intensity of the original expression; and all intermediate accuracy levels (impaired but still above chance). Experiment 2 tested AMD patients, running 19 eyes monocularly (from 12 patients, 67-94 years) covering a wide range of vision loss (acuities 6/7.5 to poorer than 6/360). With faces pre-enlarged, recognition approached ceiling and was only slightly worse than matched controls for high- and medium-intensity expressions. For low-intensity expressions, recognition of veridical expressions remained impaired and was significantly improved with caricaturing across all levels of vision loss by 5.8%. Overall, caricaturing benefits emerged when improvement was most needed, that is, when initial recognition of uncaricatured expressions was impaired.

There are multiple well-established situations in which humans' face recognition performance is poor, including for low-resolution images, other-race faces, and in older adult observers. Here we show that caricaturing faces-that is, exaggerating their appearance away from an average face-can provide a useful applied method for improving face recognition across all these circumstances. We employ a face-name learning task offering a number of methodological advantages (e.g., valid comparison of the size of the caricature improvement across conditions differing in overall accuracy). Across six experiments, we (a) extend previous evidence that caricaturing can improve recognition of low-resolution (blurred) faces; (b) show for the first time that caricaturing improves recognition and perception of other-race faces; and (c) show for the first time that caricaturing improves recognition in observers across the whole adult life span (testing older adults, M age = 71 years). In size, caricature benefits were at least as large where natural face recognition is poor (other-race, low resolution, older adults) as for the naturally best situation (own-race high-resolution faces in young adults). We discuss potential for practical applicability to improving face recognition in low-vision patients (age-related macular degeneration, bionic eye), security settings (police, passport control), eyewitness testimony, and prosopagnosia. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In everyday life, other peoples' distress is sometimes genuine (e.g., real sadness) and sometimes pretended (e.g., feigned sadness aimed at manipulating others). Here, we present the first study of how psychopathic traits affect responses to genuine versus posed distress. Using facial expression stimuli and testing individual differences across the general population ( N = 140), we focus on the affective features of psychopathy (e.g., callousness, poor empathy, shallow affect). Results show that although individuals low on affective psychopathy report greater arousal and intent to help toward faces displaying genuine relative to posed distress, these differences weakened or disappeared with higher levels of affective psychopathy. Strikingly, a key theoretical prediction-that arousal should mediate the association between affective psychopathy and intent to help-was supported only for genuine distress and not for posed distress. A further novel finding was of reduced ability to discriminate the authenticity of distress expressions with higher affective psychopathy, which, in addition to and independently of arousal, also mediated the association between affective psychopathy and reduced prosociality. All effects were specific to distress emotions (did not extend to happiness, anger, or disgust), and to affective psychopathy (did not extend to Factor 2 psychopathy, disinhibition, or boldness). Overall, our findings are highly consistent with Blair's theorizing that atypical processing of distress emotions plays a key etiological role in the affective aspects of psychopathy. We go beyond these ideas to add novel evidence that unwillingness to help others is also associated with a failure to fully appreciate the authenticity of their distress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).