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Pancreatic cystic lesions are often asymptomatic, incidentally detected and include a range of entities with varying degrees of concern for malignancy. Among these, intraductal papillary mucinous neoplasms (IPMN) are considered premalignant pancreatic lesions, with a broad pathological spectrum ranging from lesions without dysplasia, which can be managed conservatively, to malignant lesions that require surgical resection. The increasing use of CT and MRI has led to increased recognition of this entity incidentally, with branch-duct IPMN representing the most common subtype and the most challenging lesions in terms of patient management. The main imaging modality involved in diagnosis and surveillance of IPMN is MRI. Radiologists play an important role in the management of patients with IPMN, including lesion detection, characterization, follow-up and prognostication, allowing early MRI identification of features that are concerning for malignancy. The main aim of this pictorial review is to illustrate MRI features of IPMN and to discuss risk stratification scores based on different guidelines, with a main focus on branch-duct IPMN. The secondary aims include the presentation of common and uncommon imaging evolution of BD-IPMN as well as the discussion on current controversies on the appropriate management of IPMN., Competing Interests: 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., (© 2023 The Authors. Published by Elsevier Ltd.)

Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. Fractional exhaled nitric oxide (FeNO) is a reliable, quantitative, non-invasive, simple, and safe biomarker for assessing airways inflammation in asthma. Previous genome-wide and genetic association studies have shown that different genes and single nucleotide polymorphisms (SNPs) are linked to FeNO. We aimed at identifying SNPs in candidate genes or gene regions that are associated with FeNO in asthma. We evaluated 264 asthma cases (median age 42.8 years, female 47.7%) who had been identified in the general adult population within the Gene Environment Interactions in Respiratory Diseases survey in Verona (Italy; 2008-2010). Two hundred and twenty-one tag-SNPs, which are representative of 50 candidate genes, were genotyped by a custom GoldenGate Genotyping Assay. A two-step association analysis was performed without assuming an a priori genetic model: step (1) a machine learning technique [gradient boosting machine (GBM)] was used to select the 15 SNPs with the highest variable importance measure; step (2) the GBM-selected SNPs were jointly tested in a linear regression model with natural log-transformed FeNO as the normally distributed outcome and with age, sex, and the SNPs as covariates. We replicated our results within an independent sample of 296 patients from the European Community Respiratory Health Survey III. We found that SNP rs987314 in family with sequence similarity 13 member A ( FAM13A ) and SNP rs3218258 in interleukin 2 receptor subunit beta ( IL2RB ) gene regions are significantly associated with FeNO in adult subjects with asthma. These genes are involved in different mechanisms that affect smooth muscle constriction and endothelial barrier function responses ( FAM13A ), or in immune response processes ( IL2RB ). Our findings contribute to the current knowledge on FeNO in asthma by identifying two novel SNPs associated with this biomarker of airways inflammation., (Creative Commons Attribution license.)

Nanoparticles used for medical applications commonly possess coatings or surface functionalities intended to provide specific behavior in vivo , for example, the use of PEG to provide stealth properties. Direct, quantitative measurement of the surface chemistry and composition of such systems in a hydrated environment has thus far not been demonstrated, yet such measurements are of great importance for the development of nanomedicine systems. Here we demonstrate the first use of cryo-XPS for the measurement of two PEG-functionalized nanomedicines: a polymeric drug delivery system and a lipid nanoparticle mRNA carrier. The observed differences between cryo-XPS and standard XPS measurements indicate the potential of cryo-XPS for providing quantitative measurements of such nanoparticle systems in hydrated conditions.

Background: Previous studies have reported an association between warm temperature and asthma hospitalisation. They have reported different sex-related and age-related vulnerabilities; nevertheless, little is known about how this effect has changed over time and how it varies in space. This study aims to evaluate the association between asthma hospitalisation and warm temperature and investigate vulnerabilities by age, sex, time and space., Methods: We retrieved individual-level data on summer asthma hospitalisation at high temporal (daily) and spatial (postcodes) resolutions during 2002-2019 in England from the NHS Digital. Daily mean temperature at 1 km×1 km resolution was retrieved from the UK Met Office. We focused on lag 0-3 days. We employed a case-crossover study design and fitted Bayesian hierarchical Poisson models accounting for possible confounders (rainfall, relative humidity, wind speed and national holidays)., Results: After accounting for confounding, we found an increase of 1.11% (95% credible interval: 0.88% to 1.34%) in the asthma hospitalisation risk for every 1°C increase in the ambient summer temperature. The effect was highest for males aged 16-64 (2.10%, 1.59% to 2.61%) and during the early years of our analysis. We also found evidence of a decreasing linear trend of the effect over time. Populations in Yorkshire and the Humber and East and West Midlands were the most vulnerable., Conclusion: This study provides evidence of an association between warm temperature and hospital admission for asthma. The effect has decreased over time with potential explanations including temporal differences in patterns of heat exposure, adaptive mechanisms, asthma management, lifestyle, comorbidities and occupation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Poverty is strongly associated with all-cause and chronic obstructive pulmonary disease (COPD) mortality. Less is known about the contribution of poverty to spirometrically defined chronic airflow obstruction (CAO)-a key characteristic of COPD. Using cross-sectional data from an asset-based questionnaire to define poverty in 21 sites of the Burden of Obstructive Lung Disease study, we estimated the risk of CAO attributable to poverty. Up to 6% of the population over 40 years had CAO attributable to poverty. Understanding the relationship between poverty and CAO might suggest ways to improve lung health, especially in low-income and middle-income countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into ten sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), extensions and additional analyses, data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 24 months., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Burgess S et al.)

The quantification of the drug associated to nanoparticle carriers, often expressed in terms of encapsulation efficiency, is a regulatory requirement. The establishment of independent methods to evaluate this parameter provides a means for measurement validation, which is critical in providing confidence in the methods and enabling the robust characterization of nanomedicines. Chromatography is traditionally used to measure drug encapsulation into nanoparticles. Here, we describe an additional independent strategy based on analytical centrifugation. The encapsulation of diclofenac into nanocarriers was quantified based on the mass difference between placebo (i.e. unloaded) and loaded nanoparticles. This difference was estimated using particle densities measured by differential centrifugal sedimentation (DCS) and size and concentration values measured by particle tracking analysis (PTA). The proposed strategy was applied to two types of formulations, namely poly(lactic-co-glycolic acid) (PLGA) nanoparticles and nanostructured lipid carriers, which were analysed by DCS operated in sedimentation and flotation modes, respectively. The results were compared to those from high performance liquid chromatography (HPLC) measurements. Additionally, X-ray photoelectron spectroscopy analysis was used to elucidate the surface chemical composition of the placebo and loaded nanoparticles. The proposed approach enables the monitoring of batch-to-batch consistency and the quantification of diclofenac association to PLGA nanoparticles from 0.7 ng to 5 ng of drug per 1 μg of PLGA, with good linear correlation between DCS and HPLC results (R 2  = 0.975). Using the same approach, similar quantification in lipid nanocarriers was possible for a loading of diclofenac ≥1.1 ng per 1 μg of lipids, with results in agreement with the HPLC method (R 2  = 0.971). Hence, the strategy proposed here expands the analytical tools available for evaluating nanoparticles encapsulation efficiency, being thus significant for increasing the robustness of drug-delivery nanocarriers characterization., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The allergic asthma phenotype is characterized by a T helper type 2 (Th2) immune response, based on Immunoglobulin E (IgE)-mediated type 1 hypersensitivity reactions. Total IgE is the sum of all IgE types produced by the human body and is used as a biomarker of inflammation in asthma. We analysed data collected in 143 asthma cases (median age 42.1 years) from the general Italian population (GEIRD survey; 2008-2010) to identify single nucleotide polymorphisms (SNPs) in candidate genes that are associated with total IgE in adult subjects with asthma. These patients reported respiratory symptoms in response to perennial allergens and provided data on 166 SNPs tagging 50 candidate genes or gene regions. Replication of the statistically significant results was performed in 842 asthma cases from other European countries (ECRHS II survey; 1998-2002). SNP rs549908 in interleukin 18 ( IL18) gene was significantly associated with total IgE in GEIRD, and this result was replicated in ECRHS II. SNP rs1063320 in the human leukocyte antigen G ( HLA-G ) gene was identified in GEIRD, but this association was not replicated in ECRHS II. Further investigating IL18 and its biological pathways could be important for developing new therapeutic targets, due to its involvement in inflammatory response processes.

Background: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related., Methods: A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available., Results: GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997-1.000; p=0.245)., Conclusions: We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated., Competing Interests: Conflict of interest: R.G. Jenkins reports grants from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, RedX, Pliant and Genetech, consulting fees from Bristol-Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant and Chiesi, and advisory board participation with Boehringer Ingelheim, Galapagos, Vicore and Roche, outside the submitted work, and has a leadership role with NuMedii, and a leadership role and is a trustee for Action for Pulmonary Fibrosis. T.M. Maher reports consulting fees from Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Bayer, Blade Therapeutics, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant, Theravance and Veracyte, and lecture honoraria from Boehringer Ingelheim and Roche/Genentech, outside the submitted work. P.L. Molyneaux reports grants from AstraZeneca, consulting fees from Hoffman-La Roche, Boehringer Ingelheim, Trevi, Redex and AstraZeneca, and lecture honoraria from Boehringer Ingelheim and Hoffman-La Roche, outside the submitted work. L.V. Wain reports grants from Orion Pharma, GlaxoSmithKline, Genentech and AstraZeneca, consulting fees from Galapagos and Boehringer Ingelheim, travel support from Genentech, and advisory board participation with Galapagos, outside the submitted work; and is an Associate Editor for the European Respiratory Journal. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Objective: To explore the link between COVID-19 incidence, socio-economic covariates, and NHL incidence., Design: Ecological study design., Setting: Sardinia, Italy., Participants: We used official reports on the total cases of COVID-19 in 2020, published data on NHL incidence, and socio-economic indicators by administrative unit, covering the whole regional population., Main Outcomes and Measures: We used multivariable regression analysis to explore the association between the natural logarithm (ln) of the 2020 cumulative incidence of COVID-19 and the ln-transformed NHL incidence in 1974-2003, weighing by population size and adjusting by socioeconomic deprivation and other covariates., Results: The cumulative incidence of COVID-19 increased in relation to past incidence of NHL (p < 0.001), socioeconomic deprivation (p = 0.006), and proportion of elderly residents (p < 0.001) and decreased with urban residency (p = 0.001). Several sensitivity analyses confirmed the finding of an association between COVID-19 and NHL., Conclusion: This ecological study found an ecological association between NHL and COVID-19. If further investigation would confirm our findings, shared susceptibility factors should be investigated among the plausible underlying mechanisms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sara 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.)

Background: Asbestos has been hypothesised as the cause of the recent global increase in the incidence of 'idiopathic' pulmonary fibrosis (IPF). Establishing this has important diagnostic and therapeutic implications. The association between occupational asbestos exposure and IPF, and interaction with a common (minor allele frequency of 9% in European populations) genetic variant associated with IPF, MUC5B rs35705950, is unknown., Methods: Multicentre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 UK hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was assessed at interview using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs35705950 was investigated using a genetic dominant model., Results: 327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls had cumulative exposure estimates ≥25 fibre ml⁻¹ years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1 (95% CI 0.8 to 1.4; p=0.6) and there was no gene-environment interaction (p=0.3). Ever smoking was associated with IPF, OR 1.4 (95% CI 1 to 1.9; p=0.04) and interacted with occupational asbestos exposure, OR 1.9 (95% CI 1 to 3.6; p=0.04). In a further non-specified analysis, when stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs35705950., Conclusion: Occupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. Exposure to asbestos and smoking interact to increase IPF risk in carriers of a common genetic variant, the minor allele of MUC5B rs35705950., Trial Registration Number: NCT03211507., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The British Lung Foundation (BLF) has previously estimated that there are 2.2 million people in the UK who have symptoms, but no diagnosis, of chronic obstructive pulmonary disease (COPD)., Aim: To investigate the proportion of patients with a missed COPD diagnosis among those with COPD as the cause of death on their death certificate, and how this has changed over a period of 17 years (2000-2017)., Design & Setting: Clinical Practice Research Datalink (CPRD) Aurum and GOLD primary care data were linked with Office for National Statistics (ONS) mortality data and Hospital Episode Statistics (HES) data. Adults who died between 2000 and 2017 with COPD as their main cause of death were included., Method: Using a range of diagnostic COPD criteria, the proportion of patients with a missed COPD diagnosis was estimated, and the demographic and clinical characteristics of patients with and without prior COPD diagnosis were described, using a mixed-effect logistic regression model., Results: Depending on the COPD definition used, between 96% and 27% of the 78 621 patients included received a diagnosis of COPD before death. Using presence of a COPD Read or SNOMED CT code and performed spirometry as a main definition, just over half of the patients (52%) had received a COPD diagnosis overall, with a proportion of those who did not decreasing from 91% in 2000 to 31% in 2017 ( P trend <0.001)., Conclusion: The proportion of people with COPD-recorded death and who had received a diagnosis of COPD has improved (increased) over time, and currently represents the majority of them. This suggests that few patients are now being missed., (Copyright © 2022, The Authors.)

Background: There is emerging evidence suggesting a link between ambient heat exposure and chronic obstructive pulmonary disease (COPD) hospitalisations. Individual and contextual characteristics can affect population vulnerabilities to COPD hospitalisation due to heat exposure. This study quantifies the effect of ambient heat on COPD hospitalisations and examines population vulnerabilities by age, sex and contextual characteristics., Methods: Individual data on COPD hospitalisation at high geographical resolution (postcodes) during 2007-2018 in England was retrieved from the small area health statistics unit. Maximum temperature at 1 km ×1 km resolution was available from the UK Met Office. We employed a case-crossover study design and fitted Bayesian conditional Poisson regression models. We adjusted for relative humidity and national holidays, and examined effect modification by age, sex, green space, average temperature, deprivation and urbanicity., Results: After accounting for confounding, we found 1.47% (95% Credible Interval (CrI) 1.19% to 1.73%) increase in the hospitalisation risk for every 1°C increase in temperatures above 23.2°C (lags 0-2 days). We reported weak evidence of an effect modification by sex and age. We found a strong spatial determinant of the COPD hospitalisation risk due to heat exposure, which was alleviated when we accounted for contextual characteristics. 1851 (95% CrI 1 576 to 2 079) COPD hospitalisations were associated with temperatures above 23.2°C annually., Conclusion: Our study suggests that resources should be allocated to support the public health systems, for instance, through developing or expanding heat-health alerts, to challenge the increasing future heat-related COPD hospitalisation burden., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Most of the Brazilian population relies on public healthcare and stroke is a major cause of disability in this country of continental dimensions. There is limited information about access to rehabilitation after stroke in Brazil., Objective: To provide comprehensive information about Access to Rehabilitation After discharge from public hospitals in Brazil (AReA study), up to 6 months after stroke., Methods: The present study intends to collect information from 17 public health centers in 16 Brazilian cities in the 5 macroregions of the country. Each center will include 36 participants ( n  = 612). The inclusion criteria are: age ≥ 18 years old; ischemic or hemorrhagic stroke, from 6 months to 1 year prior to the interview; admission to a public hospital in the acute phase after stroke; any neurological impairment poststroke; patient or caregiver able to provide informed consent and answer the survey. Patients can only be recruited in public neurology or internal medicine outpatient clinics. Outcomes will be assessed by a standard questionnaire about rehabilitation referrals, the rehabilitation program (current status, duration in months, number of sessions per week) and instructions received. In addition, patients will be asked about preferences for locations of rehabilitation (hospitals, clinics, or at home)., Trial Status: The study is ongoing. Recruitment started on January 31 st , 2020 and is planned to continue until June 2022., Conclusion: The AReA study will fill a gap in knowledge about access to stroke rehabilitation in the public health system in different Brazilian regions., Competing Interests: The authors have no conflict of interests to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Control over the agglomeration state of manufactured particle systems for drug and oligonucleotide intracellular delivery is paramount to ensure reproducible and scalable therapeutic efficacy. Ultrasonication is a well-established mechanism for the deagglomeration of bulk powders in dispersion. Its use in manufacturing requires strict control of the uniformity and reproducibility of the cavitation field within the sample volume to minimise within-batch and batch-to-batch variability. In this work, we demonstrate the use of a reference cavitating vessel which provides stable and reproducible cavitation fields over litre-scale volumes to assist the controlled deagglomeration of a novel non-viral particle-based plasmid delivery system. The system is the Nuvec delivery platform, comprising polyethylenimine-coated spiky silica particles with diameters of ∼ 200 nm. We evaluated the use of controlled cavitation at different input powers and stages of preparation, for example before and after plasmid loading. Plasmid loading was confirmed by X-ray photoelectron spectroscopy and gel electrophoresis. The latter was also used to assess plasmid integrity and the ability of the particles to protect plasmid from potential degradation caused by the deagglomeration process. We show the utility of laser diffraction and differential centrifugal sedimentation in quantifying the efficacy of product de-agglomeration in the microscale and nanoscale size range respectively. Transmission electron microscopy was used to assess potential damages to the silica particle structure due to the sonication process., 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 © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers., Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540., Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04])., Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting., Funding: COALITION COVID-19 Brazil and EMS., Competing Interests: AA reports consultant and lectures fees from Bayer, NovoNordisk and Lilly outside of this submitted work, and research grants from Bayer, EMS Pharma and Population Health Research Institute. GBFO received honoraria for lectures from Novartis and Janssen outside of this submitted work; AD reports lecture fees from Bayer, Libbs, Apsen, and Biolab outside of this submitted work. ASS reports lectures fees from BioLab, Torrents and Servier. AVS reported research grants from AstraZeneca, MSD, Esperion, Clover Biopharm e Enanta Pharmaceutical outside of this submitted work. ABC received honoraria for lectures from EMS Pharma. LCPA reports personal fees from Baxter, Pfizer, and Halex-Istar; and grants from Ache Laboratorios Farmaceuticos, outside of this submitted work. OB reports grants from AstraZeneca, Pfizer, Bayer, Boehringer Ingelheim, Servier, and Amgen, and advisory board and personal fees from Novartis, outside of this submitted work. RBA reports to be an EMS employee. RDL reports grants and personal fees from Bristol Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and personal fees from Amgen, Bayer, and Boehringer Ingelheim, outside of this submitted work. RCR received honoraria for lectures from Novartis outside of this submitted work; VCV reports grants from Aspen Pharma, Pfizer, and Cristalia, outside of this submitted work. The other authors have no conflict to declare., (© 2022 The Authors.)

The Brazilian Practice Guidelines for Stroke Rehabilitation - Part II, developed by the Scientific Department of Neurological Rehabilitation of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, in Portuguese), focuses on specific rehabilitation techniques to aid recovery from impairment and disability after stroke. As in Part I, Part II is also based on recently available evidence from randomized controlled trials, systematic reviews, meta-analyses, and other guidelines. Part II covers disorders of communication, dysphagia, postural control and balance, ataxias, spasticity, upper limb rehabilitation, gait, cognition, unilateral spatial neglect, sensory impairments, home rehabilitation, medication adherence, palliative care, cerebrovascular events related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the future of stroke rehabilitation, and stroke websites to support patients and caregivers. Our goal is to provide health professionals with more recent knowledge and recommendations for better rehabilitation care after stroke., Competing Interests: The authors have no conflict of interests to declare., (Brazilian Academy of Neurology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The Guidelines for Stroke Rehabilitation are the result of a joint effort by the Scientific Department of Neurological Rehabilitation of the Brazilian Academy of Neurology aiming to guide professionals involved in the rehabilitation process to reduce functional disability and increase individual autonomy. Members of the group participated in web discussion forums with predefined themes, followed by videoconference meetings in which issues were discussed, leading to a consensus. These guidelines, divided into two parts, focus on the implications of recent clinical trials, systematic reviews, and meta-analyses in stroke rehabilitation literature. The main objective was to guide physicians, physiotherapists, speech therapists, occupational therapists, nurses, nutritionists, and other professionals involved in post-stroke care. Recommendations and levels of evidence were adapted according to the currently available literature. Part I discusses topics on rehabilitation in the acute phase, as well as prevention and management of frequent conditions and comorbidities after stroke.

Background and Aims: Communication of personalised disease risk can motivate smoking cessation. We assessed whether routine implementation of this intervention by general practitioners (GPs) in England is cost-effective or whether we need further research to better establish its effectiveness., Design: Cost-effectiveness analysis (CEA) with value of information (VoI) analysis from the UK National Health Service perspective, using GP communication of personalised disease risk on smoking cessation versus usual care., Setting: GP practices in England., Study Population: Healthy smokers aged 35-60 years attending the GP practice., Measurements: Effectiveness of GP communication of personalised disease risk on smoking cessation was estimated through systematic review and meta-analysis. A Bayesian CEA was then performed using a lifetime Markov model on smokers aged 35-60 years that measured lifetime costs and quality-adjusted life-years (QALYs) assigned to the four diseases contributing the most to smoking-related morbidity, mortality and costs: chronic obstructive pulmonary disease, lung cancer, myocardial infarction and stroke. Costs and QALYs for each disease state were obtained from the literature. VoI analysis identified sources of uncertainty in the CEA and assessed how much would be worth investing in further research to reduce this uncertainty., Findings: The meta-analysis odds ratio for the effectiveness estimate of GP communication of personalised disease risk was 1.48 (95% credibility interval, 0.91-2.26), an absolute increase in smoking cessation rates of 3.84%. The probability of cost-effectiveness ranged 89-94% depending on sex and age. VoI analysis indicated that: (i) uncertainty in the effectiveness of the intervention was the driver of the overall uncertainty in the CEA; and (ii) a research investment to reduce this uncertainty is justified if lower than £27.6 million (£7 per smoker)., Conclusions: Evidence to date shows that, in England, incorporating disease risk communication into general practitioners' practices to motivate smoking cessation is likely to be cost-effective compared with usual care., (© 2021 Society for the Study of Addiction.)

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles.

Background: Stroke is one of the leading causes of death and neurological disability in the world. Several scales help professionals in the early recognition of the disease. However, none of these were developed in Brazil., Objectives: To translate the Los Angeles Prehospital Stroke Screen (LAPSS) into Brazilian Portuguese, and cross-culturally adapt and validate the scale in a representative sample of the Brazilian population., Methods: This study was carried out in two phases: the first consisted in the translation and cross-cultural validation of the LAPSS, and the second in a cross-sectional study with prospectively collected data in patients with suspected stroke treated in a Brazilian prehospital and referred to a stroke center. Statistical analysis was used to assess the sensitivity, specificity, and accuracy of the scale. Cohen's Kappa coefficient (κ) was used for psychometric assessment., Results: After translation and cross-cultural adaptation, the scale was applied to 86 patients. The scale presented a sensitivity of 83.8%, positive predictive value of 79.50%, specificity of 40.70%, negative predictive value of 47.80%, and accuracy of 77%. Cohen's kappa coefficient was calculated using data from 26 (30.23%) patients and the results showed excellent inter-rater reliability in the majority of the items (52.96%)., Conclusions: The scale was translated and cross-culturally adapted for use in Brazil. The scale presented high sensitivity and accuracy but low specificity, and the Cohen's kappa demonstrated inter-rater reliability. The greatest difficulties occurred when the evaluation included subjective identifications. The scale excluded patients < 45 years old as stroke suspects.

Aims We aimed to assess the rate of persisting severe symptomatic secondary mitral regurgitation (MR) in a newly diagnosed heart failure (HF) population following optimisation of guideline directed medical therapy (GDMT), cardiac resynchronisation therapy (CRT) and revascularisation. Methods We assessed all new patients referred to our hospital group’s HF clinics. We retrospectively reviewed these patients at HF clinic enrolment, HF programme completion, as well as most recent follow up. Results Of the 242 new patients referred to our HF clinics, there were 10 patients (4.1%) who had either persisting symptomatic severe secondary MR at HF programme completion, or had undergone mitral valve surgery. There were no percutaneous mitral valve repairs at the time of these patients’ referrals. The rates of ACE/ARB/ARNI, BB and MRA use were 87.8%, 94.1%, and 49.8% in those with mid ranged, or reduced ejection fraction. The rates of ICD and CRT therapy were 15.1% and 4.4% at follow up. Patients with severe MR had higher time adjusted rates of death or hospitalization for heart failure. Conclusion In a well-treated newly diagnosed HF population, repeat assessment at HF programme completion suggests 4.1% of patients have a persisting indication for percutaneous mitral valve repair based on persisting severe symptomatic secondary MR., Competing Interests: None of the authors report any conflicts of interest.

Background: Distinguishing between mortality attributed to respiratory causes and other causes among people with asthma, COPD, and asthma-COPD overlap (ACO) is important. This study used electronic health records in England to estimate excess risk of death from respiratory-related causes after accounting for other causes of death., Methods: We used linked Clinical Practice Research Datalink (CPRD) primary care and Office for National Statistics mortality data to identify adults with asthma and COPD from 2005 to 2015. Causes of death were ascertained using death certificates. Hazard ratios (HR) and excess risk of death were estimated using Fine-Gray competing risk models and adjusting for age, sex, smoking status, body mass index and socioeconomic status., Results: 65,021 people with asthma and 45,649 with COPD in the CPRD dataset were frequency matched 5:1 with people without the disease on age, sex and general practice. Only 14 in 100,000 people with asthma are predicted to experience a respiratory-related death up to 10 years post-diagnosis, whereas in COPD this is 98 in 100,000. Asthma is associated with an 0.01% excess incidence of respiratory related mortality whereas COPD is associated with an 0.07% excess. Among people with asthma-COPD overlap (N = 22,145) we observed an increased risk of respiratory-related death compared to those with asthma alone (HR = 1.30; 95% CI 1.21-1.40) but not COPD alone (HR = 0.89; 95% CI 0.83-0.94)., Conclusions: Asthma and COPD are associated with an increased risk of respiratory-related death after accounting for other causes; however, diagnosis of COPD carries a much higher probability. ACO is associated with a lower risk compared to COPD alone but higher risk compared to asthma alone., (© 2022. The Author(s).)

Background: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types., Methods: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints., Results: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year., Conclusion: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes., Competing Interests: Conflict of interest The Authors declare no conflict of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM 2.5 ) using negative binomial regression. The prevalence of CAO was not independently associated with PM 2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised., Competing Interests: Competing interests: RN reports grants and personal fees from Boehringer Ingelheim, AstraZeneca and Novartis outside the submitted work. EDB reports personal fees from Novartis, AstraZeneca, Orion, Menarirni, Boehringer Ingelheim and ALK outside the submitted work. KM reports grants from GlaxoSmithKline during the conduct of the study. TW reports grants from Boehringer Ingelheim and Pfizer during the conduct of the study. FM reports fees from Medycyba Praktyczna, Sandoz and Chiesi outside the submitted work. DM reports salary and shares from GlaxoSmithKline outside the submitted work. IH reports grants from Boehringer Ingelheim during the conduct of the study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Classifying individuals at high chronic obstructive pulmonary disease (COPD)-risk creates opportunities for early COPD detection and active intervention., Objective: To develop and validate a statistical model to predict 10-year probabilities of COPD defined by post-bronchodilator airflow obstruction (post-BD-AO; forced expiratory volume in 1 s/forced vital capacity<5th percentile)., Setting: General Caucasian populations from Australia and Europe, 10 and 27 centres, respectively., Participants: For the development cohort, questionnaire data on respiratory symptoms, smoking, asthma, occupation and participant sex were from the Tasmanian Longitudinal Health Study (TAHS) participants at age 41-45 years (n=5729) who did not have self-reported COPD/emphysema at baseline but had post-BD spirometry and smoking status at age 51-55 years (n=2407). The validation cohort comprised participants from the European Community Respiratory Health Survey (ECRHS) II and III (n=5970), restricted to those of age 40-49 and 50-59 with complete questionnaire and spirometry/smoking data, respectively (n=1407)., Statistical Method: Risk-prediction models were developed using randomForest then externally validated., Results: Area under the receiver operating characteristic curve (AUC ROC ) of the final model was 80.8% (95% CI 80.0% to 81.6%), sensitivity 80.3% (77.7% to 82.9%), specificity 69.1% (68.7% to 69.5%), positive predictive value (PPV) 11.1% (10.3% to 11.9%) and negative predictive value (NPV) 98.7% (98.5% to 98.9%). The external validation was fair (AUC ROC 75.6%), with the PPV increasing to 17.9% and NPV still 97.5% for adults aged 40-49 years with ≥1 respiratory symptom. To illustrate the model output using hypothetical case scenarios, a 43-year-old female unskilled worker who smoked 20 cigarettes/day for 30 years had a 27% predicted probability for post-BD-AO at age 53 if she continued to smoke. The predicted risk was 42% if she had coexistent active asthma, but only 4.5% if she had quit after age 43., Conclusion: This novel and validated risk-prediction model could identify adults aged in their 40s at high 10-year COPD-risk in the general population with potential to facilitate active monitoring/intervention in predicted 'COPD cases' at a much earlier age., Competing Interests: Competing interests: JP received a travel grant supported by Boehringer-Ingelheim, and together with MJA, EHW, AL, CL and SCD, holds an investigator-initiated grant from GlaxoSmithKline for unrelated research. SCD additionally holds an investigator-initiated grant from AstraZeneca for unrelated research. MJA also holds investigator-initiated grants from Pfizer, Boehringer-Ingelheim and Sanofi for unrelated research; has undertaken an unrelated consultancy for and received assistance with conference attendance from Sanofi; and received a speaker’s fee from GlaxoSmithKline. BRT has received unrelated speaker and consultancy fees from Chiesi, Mundipharma and 4D medical. KH has received personal fees and non-financial support from Astra Zeneca, GlaxoSmithKline, Novartis, Chiesi, Boehringer Ingelheim and Teva outside the submitted work. AL has additionally received non-financial support from Primus Pharmaceuticals for unrelated research. No other authors reported financial disclosures., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: With genome-wide association data for many exposures and outcomes now available from large biobanks, one-sample Mendelian randomization (MR) is increasingly used to investigate causal relationships. Many robust MR methods are available to address pleiotropy, but these assume independence between the gene-exposure and gene-outcome association estimates. Unlike in two-sample MR, in one-sample MR the two estimates are obtained from the same individuals, and the assumption of independence does not hold in the presence of confounding., Methods: With simulations mimicking a typical study in UK Biobank, we assessed the performance, in terms of bias and precision of the MR estimate, of the fixed-effect and (multiplicative) random-effects meta-analysis method, weighted median estimator, weighted mode estimator and MR-Egger regression, used in both one-sample and two-sample data. We considered scenarios differing by the: presence/absence of a true causal effect; amount of confounding; and presence and type of pleiotropy (none, balanced or directional)., Results: Even in the presence of substantial correlation due to confounding, all two-sample methods used in one-sample MR performed similarly to when used in two-sample MR, except for MR-Egger which resulted in bias reflecting direction and magnitude of the confounding. Such bias was much reduced in the presence of very high variability in instrument strength across variants (IGX2 of 97%)., Conclusions: Two-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger. MR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrument strength is very high., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV 1 -to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Laser diffraction (LD) is a well-established tool for the measurement of particle size distribution. Recently, its demand and use for the measurement of complex biological systems have increased. Among the challenges that these types of samples present, there is the presence of multiple particle populations whose modal size may span across several orders of magnitude. In this study, we assessed the accuracy of LD for the measurement of the modal diameter of both single and mixed populations of polystyrene particles with diameters ranging from 60 nm to 40 μm. We discuss the application of different available algorithms to the analysis of the data and their impact on the measurement results. Independent methods were applied to guide the selection of the algorithms and validate the measured size distributions. We found that the modal diameters of the particle size distribution measured by LD for the mixed suspension was accurate within 2 % for particles larger than 1 μm and generally within 25 % for the particles tested. Method repeatability was found to be robust, with deviations below 1%. The method was also found to be useful for estimating the relative concentration of the particle populations in the mixed samples. This study provides confidence in the use of LD for the measurement of complex multimodal colloidal samples., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes., Competing Interests: Competing interests: The following authors report potential competing interests: L.V.W.: Louise V. Wain has received grant support from GSK. M.D.T.: Martin D. Tobin has received grant support from GSK. I.P.H.: Ian P. Hall has received support from GSK and BI., (Copyright: © 2021 Fawcett KA et al.)

Background: Pars plana vitrectomy (PPV), a surgical procedure used to treat different ophthalmic pathologies, could be associated with moderate to severe eye pain. The aim of the present study was to evaluate the incidence of postoperative eye pain and its risk factors following PPV in a selected population of patients with non-painful eye disease, receiving regional anesthesia and moderate sedation with benzodiazepines, without use of narcotics., Methods: Single-center, prospective observational cohort study. We recorded the presence of pain at operating room discharge, at 6 and 24 hours, using the numeric rating scale (NRS). We recorded also age, sex, ethnic origin, American Society of Anaesthesia physical status (ASA PS) classification, Charlson Comorbidity Index, the etiology of the vitreoretinal pathology, length of surgery, and type of surgical procedure performed., Results: Eye pain (NRS>3) was present in three patients (0.7%) at operating room discharge, 59 (13.2%) at six and 65 (14.6%) at 24 hours after surgery. LASSO logistic regression analysis identified age, ASA PS, race, along with tamponade as independent risk factors for eye pain at six hours. Scleral buckling was selected for eye pain at 24 hrs., Conclusions: A protocol for pain control after PPV should be considered, especially in younger, non-Caucasian people, and patients with high ASA PS grade. Moreover, attention must be paid when additional surgical procedures are requested, restricting them to selected patients, and using the appropriate agent for intraocular tamponade.

Background: Use of internationally standardized instruments to assist healthcare professionals in accurately recognizing stroke early is recommended. The process of translation and cross-cultural adaptation is important for ensuring that scales are interpreted in the same way in different languages, thus ensuring applicability in several countries., Objective: To translate into Brazilian Portuguese, cross-culturally adapt and validate the Cincinnati Prehospital Stroke Scale, using a representative sample of the Brazilian population., Method: The present study included patients with suspected stroke who were treated at a Brazilian emergency medical service and referred to a stroke center. A systematic process of translation and cross-cultural adaptation of the original scale and application of the final instrument was performed. Statistical analysis was used to assess the sensitivity, specificity and accuracy of the scale. Cohen's kappa coefficient was used to assess inter-rater reliability., Results: After translation and cross-cultural adaptation, the scale was applied to 64 patients. It showed 93.0% accuracy and 92.4% sensitivity in relation to the final "gold standard" diagnosis. Cohen's kappa coefficient was calculated using data from 26 patients (40.6%) and showed excellent inter-rater reliability between items on the scale (0.8385 to 1.0000)., Conclusion: The scale demonstrated excellent accuracy, sensitivity and inter-rater reliability. It was a useful tool for assisting healthcare professionals during initial assessments on patients with suspected stroke and significantly contributed to early recognition of stroke in a simple and quick manner.

Raising tobacco prices effectively reduces smoking, the main risk factor for chronic obstructive pulmonary disease (COPD). Using the Health Impact Assessment tool "DYNAMO-HIA", this study quantified the reduction in COPD burden that would occur in Italy, England and Sweden over 40 years if tobacco prices were increased by 5%, 10% and 20% over current local prices, with larger increases considered in secondary analyses. A dynamic Markov-based multi-state simulation modelling approach estimated the effect of changes in smoking prevalence states and probabilities of transitioning between smoking states on future smoking prevalence, COPD burden and life expectancy in each country. Data inputs included demographics, smoking prevalences and behaviour and COPD burden from national data resources, large observational cohorts and datasets within DYNAMO-HIA. In the 20% price increase scenario, the cumulative number of COPD incident cases saved over 40 years was 479,059 and 479,302 in Italy and England (populous countries with higher smoking prevalences) and 83,694 in Sweden (smaller country with lower smoking prevalence). Gains in overall life expectancy ranged from 0.25 to 0.45 years for a 20 year-old. Increasing tobacco prices would reduce COPD burden and increase life expectancy through smoking behavior changes, with modest but important public health benefits observed in all three countries.

X-ray photoelectron spectroscopy is a highly surface-sensitive analytical technique, capable of providing quantitative information on the chemical composition of materials within the top ∼10 nm of their surface. For samples consisting of distinct underlayer and overlayer materials, the thickness of the coating can also be determined if it falls within this ∼10 nm information depth, which is often the case for peptide layers. Such measurements are simple to perform for flat samples and can also be performed on nanoparticulate samples provided that either the core radius or total particle radius are known. Here, we describe a straightforward protocol for obtaining such measurements from peptide coatings on both flat surfaces and nanoparticles, including preparation of nanoparticle samples from suspension, data acquisition, and analysis.

Rationale: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. Objectives: To systematically investigate the effects of lung development genes on adult lung function. Methods: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV 1 /FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger subset to select the most promising signals and the smaller subset for replication. Measurements and Main Results: We identified 55 genes, of which 36 (16 for FVC, 19 for FEV 1 /FVC, and one for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 replicated at nominal significance level. Of the 55 genes, 53 fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-to-cell adhesion; extracellular matrix), suggesting that these specific processes are important for adult lung health. Conclusions: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.

The measurement of nanoparticle size, and size distribution, is important to the development of pharmaceutical nanoparticle products and their manufacturing processes. In this work we report on the use of 4 widely-used liquid-phase techniques, dynamic light scattering, differential centrifugal sedimentation, particle tracking analysis, and tuneable resistive pulse sensing to measure 4 different batches of AZD2811NPs. The techniques rely on different physical principles to measure nanoparticle size. The batches cover a range of different manufacturing scales and different sites of manufacture, and were made to support toxicity, clinical, and engineering studies. The results from the different techniques and different batches are compared in terms of the average size, and size distribution, measured. In addition, we discuss the suitability of techniques for different applications, for example, QC and process understanding., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation., Methods: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV 1 , FVC, and FEV 1 /FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2., Results: In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs., Conclusions: To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI.

Development and application of nanotechnology-enabled medical products, including drugs, devices, and in vitro diagnostics, are rapidly expanding in the global marketplace. In this review, the focus is on providing the reader with an introduction to the landscape of commercially available nanotechnology-enabled medical products as well as an overview of the international documentary standards and reference materials that support and facilitate efficient regulatory evaluation and reliable manufacturing of this diverse group of medical products. We describe the materials, test methods, and standards development needs for emerging medical products. Scientific and measurement challenges involved in the development and application of innovative nanoenabled medical products motivate discussion throughout this review.

Oxidative stress occurs when antioxidant defences, which are regulated by a complex network of genes, are insufficient to maintain the level of reactive oxygen species below a toxic threshold. Outdoor air pollution has long been known to adversely affect health and one prominent mechanism of action common to all pollutants is the induction of oxidative stress. An individual's susceptibility to the effects of air pollution partly depends on variation in their antioxidant genes. Thus, understanding antioxidant gene-pollution interactions has significant potential clinical and public health impacts, including the development of targeted and cost-effective preventive measures, such as setting appropriate standards which protect all members of the population. In this review, we aimed to summarize the latest epidemiological evidence on interactions between antioxidant genes and outdoor air pollution, in the context of respiratory and cardiovascular health. The evidence supporting the existence of interactions between antioxidant genes and outdoor air pollution is strongest for childhood asthma and wheeze, especially for interactions with GSTT1, GSTM1 and GSTP1, for lung function in both children and adults for several antioxidant genes (GSTT1, GSTM1, GSTP1, HMOX1, NQO1, and SOD2) and, to a more limited extent, for heart rate variability in adults for GSTM1 and HMOX1. Methodological challenges hampering a clear interpretation of these findings and understanding of true potential heterogeneity are discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Investigating COPD trends may help healthcare providers to forecast future disease burden. We estimated sex- and smoking-specific incidence trends of pre-bronchodilator airflow obstruction (AO) among adults without asthma from 11 European countries within a 20-year follow-up (ECRHS and SAPALDIA cohorts). We also quantified the extent of misclassification in the definition based on pre-bronchodilator spirometry (using post-bronchodilator measurements from a subsample of subjects) and we used this information to estimate the incidence of post-bronchodilator AO (AO post-BD ), which is the primary characteristic of COPD. AO incidence was 4.4 (95% CI: 3.5-5.3) male and 3.8 (3.1-4.6) female cases/1,000/year. Among ever smokers (median pack-years: 20, males; 12, females), AO incidence significantly increased with ageing in men only [incidence rate ratio (IRR), 1-year increase: 1.05 (1.03-1.07)]. A strong exposure-response relationship with smoking was found both in males [IRR, 1-pack-year increase: 1.03 (1.02-1.04)] and females [1.03 (1.02-1.05)]. The positive predictive value of AO for AO post-BD was 59.1% (52.0-66.2%) in men and 42.6% (35.1-50.1%) in women. AO post-BD incidence was 2.6 (1.7-3.4) male and 1.6 (1.0-2.2) female cases/1,000/year. AO incidence was considerable in Europe and the sex-specific ageing-related increase among ever smokers was strongly related to cumulative tobacco exposure. AO post-BD incidence is expected to be half of AO incidence.

Background: Post-traumatic cerebral infarction (PTCI) is common after traumatic brain injury (TBI). It is unclear what the occurrence of a PTCI is, how it impacts the long-term outcome, and whether it adds incremental prognostic value to established outcome predictors., Methods: This was a prospective multicenter cohort study of moderate and severe TBI patients. The primary objective was to evaluate if PTCI was an independent risk factor for the 6-month outcome assessed with the Glasgow Outcome Scale (GOS). We also assessed the PTCI occurrence and if it adds incremental value to the International Mission for Prognosis and Clinical Trial design in TBI (IMPACT) core and extended models., Results: We enrolled 143 patients, of whom 47 (32.9%) developed a PTCI. In the multiple ordered logistic regression, PTCI was retained in both the core and extended IMPACT models as an independent predictor of the GOS. The predictive performances increased significantly when PTCI was added to the IMPACT core model (AUC = 0.73, 95% C.I. 0.66-0.82; increased to AUC = 0.79, 95% CI 0.71-0.83, p = 0.0007) and extended model (AUC = 0.74, 95% C.I. 0.65-0.81 increased to AUC = 0.80, 95% C.I. 0.69-0.85; p = 0.00008). Patients with PTCI showed higher ICU mortality and 6-month mortality, whereas hospital mortality did not differ between the two groups., Conclusions: PTCI is a common complication in patients suffering from a moderate or severe TBI and is an independent risk factor for long-term disability. The addition of PTCI to the IMPACT core and extended predictive models significantly increased their performance in predicting the GOS., Trial Registration: The present study was registered in ClinicalTrial.gov with the ID number NCT02430324.

Background: Stroke population-based studies in the same setting comparing time trends of rates are a gold standard method to determine the primary prevention status of stroke. Twelve years ago, we measured the stroke incidence and mortality in Matão city, Southeast of Brazil., Objective: This second Matão stroke registry study aimed to determine the time trends in the incidence, mortality, case fatality, and functional status of patients with stroke., Methods: This was a prospective, population-based study known as the Matão Preventing Stroke (MAPS). We determined all incident stroke events that occurred between August 1, 2015, and July 31, 2016. Between the periods of November 1, 2003, to October 31, 2004, and August 1, 2015, to July 31, 2016, the rates were age adjusted to the Brazilian and world population. Functional status was measured by Barthel scale 1 year after the index event., Results: We registered 81 cases of incident stroke. Demographic and cardiovascular risk factors were similar in both periods. The mean age increased by 9%, from 65.2 (95% CI 62.6-67.8) to 71.0 (95% CI 68.1-73.8) years. Between 2003-2004 and 2015-2016, the age-adjusted incidence decreased by 39% (incidence rate ratio [IRR] 0.61; 95% CI 0.46-0.79) and mortality by 50% (IRR 0.50; 95% CI 0.31-0.94). The 1-year case fatality was 26%; approximately 56% of the patients were functionally independent, while 7% had a recurrent stroke. Compared with the results of our first registry study, these outcomes did not differ significantly., Conclusion: Our findings agree with those of previous studies, showing a decline in the incidence and mortality of stroke in Brazil. Improvements in local public health care might explain these declines., (© 2019 S. Karger AG, Basel.)

Objectives: We aimed to investigate whether there has been a geographic shift in the distribution of mesothelioma deaths in Great Britain given the decline of shipbuilding and progressive exposure regulation., Methods: We calculated age-adjusted mesothelioma mortality rates and estimated rate ratios for areas with and without a dockyard. We compared spatial autocorrelation statistics (Moran's I) for age-adjusted rates at local authority district level for 2002-2008 and 2009-2015. We measured the mean distance of the deceased's postcode to the nearest dockyard at district level and calculated the association of average distance to dockyard and district mesothelioma mortality using simple linear regression for men, for 2002-2008 and 2009-2015., Results: District age-adjusted male mortality rates fell during 2002-2015 for 80 of 348 districts (23%), rose for 267 (77%) and were unchanged for one district; having one or more dockyards in a district was associated with rates falling (OR=2.43, 95% CI 1.22 to 4.82, p=0.02). The mortality rate ratio for men in districts with a dockyard, compared with those without a dockyard was 1.41 (95% CI 1.35 to 1.48, p<0.05) for 2002-2008 and 1.18 (95% CI 1.13 to 1.23, p<0.05) for 2009-2015. Spatial autocorrelation (measured by Moran's I) decreased from 0.317 (95% CI 0.316 to 0.319, p=0.001) to 0.312 (95% CI 0.310 to 0.314, p=0.001) for men and the coefficient of the association between distance to dockyard and district level age-adjusted male mortality (per million population) from -0.16 (95% CI -0.21 to -0.10, p<0.01) to -0.13 (95% CI -0.18 to -0.07, p<0.01) for men, when comparing 2002-2008 with 2009-2015., Conclusion: For most districts age-adjusted mesothelioma mortality rates increased through 2002-2015 but the relative contribution from districts with a dockyard fell. Dockyards remain strongly spatially associated with mesothelioma mortality but the strength of this association appears to be falling and mesothelioma deaths are becoming more dispersed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Burgess S et al.)

In observational studies, early menopause is associated with lower forced vital capacity (FVC) and a higher risk of spirometric restriction, but not airflow obstruction. It is, however, unclear if this association is causal. We therefore used a Mendelian randomisation (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function.We included 94 742 naturally post-menopausal women from the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1 s (FEV 1 ), FVC, FEV 1 /FVC, spirometric restriction (FVC1 /FVC1 /FVC and a 15% lower risk of airflow obstruction for women with early (<45 years) compared to normal (45-55 years) menopause. Despite some evidence of pleiotropy, the results were consistent when using MR methods robust to pleiotropy. Similar results were found among never- and ever-smokers, while the protective effect seemed less strong in women who had ever used menopause hormone treatment and in overweight women. There was no strong evidence of an association with FVC or spirometric restriction. In observational analyses of the same dataset, early menopause was associated with a pronounced reduction in FVC and a 13% higher risk of spirometric restriction.Our MR results suggest that early menopause has a protective effect on airflow obstruction. Further studies are warranted to better understand the inconsistency with observational findings, and to investigate the underlying mechanisms and role of female sex hormones., Competing Interests: Conflict of interest: D.A. van der Plaat has nothing to disclose. Conflict of interest: M. Pereira has nothing to disclose. Conflict of interest: G. Pesce has nothing to disclose. Conflict of interest: J.F. Potts has nothing to disclose. Conflict of interest: A.F.S. Amaral has nothing to disclose. Conflict of interest: S.C. Dharmage has nothing to disclose. Conflict of interest: J.M. Garcia-Aymerich has nothing to disclose. Conflict of interest: J.R. Thompson has nothing to disclose. Conflict of interest: F. Gómez Real has nothing to disclose. Conflict of interest: D.L. Jarvis reports grants from European Union, during the conduct of the study. Conflict of interest: C. Minelli has nothing to disclose. Conflict of interest: B. Leynaert has nothing to disclose., (Copyright ©ERS 2019.)

Background: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma., Objective: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood., Methods: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed., Results: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10 -8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10 -6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10 -7 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10 -6 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10 -6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings., Conclusions and Clinical Relevance: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms., (© 2019 John Wiley & Sons Ltd.)