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Background: Studies estimating risks following cardiac surgery for patients receiving kidney replacement therapy have been limited by the size and generalizability of those cohorts. This study used data linked between registries to estimate short-term postoperative outcomes for large patient cohorts receiving kidney replacement therapy at the time of surgery., Methods: This population-based observational cohort study included adult patients who had undergone cardiac surgery in Australia between 2010 and 2019. Patient data were linked with a kidney replacement therapy registry to accurately identify cohorts and extract relevant data. Multivariable logistic regression estimated risk of operative (30-day) mortality and other postoperative outcomes for long-term dialysis and functioning kidney transplant cohorts compared with each other and the general cardiac surgical population., Results: Of 114,496 surgeries, 1,241 were for patients receiving long-term dialysis and 298 for those with a kidney transplant. The mortality rate was highest for valve-with-coronary artery bypass grafting for dialysis (18.78 per 100 surgeries (95% CI 13.37,25.25) and transplant patients (14.00 [5.82,26.74]). Dialysis patients had higher adjusted odds of mortality (odds ratio [OR] 4.17 [95% CI 3.31,5.25]) and all other measured outcomes than the general population. Kidney transplant recipients had similarly elevated odds of mortality (OR 3.52 [95% CI 2.16,5.72])., Conclusions: Despite the younger age of dialysis and transplant cohorts at surgery, operative mortality rates were higher, and for valve-with-coronary artery bypass grafting were 3.7- to 5-fold those of the general population. Dialysis patients were a high risk for cardiac surgery, and the prognosis for kidney transplant recipients was similarly poor., (Copyright © 2024. Published by Elsevier Inc.)

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor two conditionally distinct, non-coding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR=0.180; MAFEUR=0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation., (Copyright © 2024 American Society of Hematology.)

Correlative species distribution modeling (SDM) is an important tool to predict distributions of invasive species. A unique challenge of implementing SDMs in aridland stream networks is identifying which streams are perennial and which of those offer suitable habitat for obligate aquatic species. Here, we map perennial streams and habitat suitability of invasive virile crayfish (Faxonius virilis) in the Lower Colorado River Basin (LCRB) in the southwestern USA, and quantify drivers of uncertainty in these projections. First, we surveyed F. virilis at 122 stream sites in May-July of 2021, 2022, and 2023. We then implemented an ensemble of SDMs fit using combinations of randomly drawn sites, categories of environmental covariates measured at different spatial scales, survey years, and statistical algorithms. Next, we used open-source street view images from May-July of 2022 and 2023 to assess dry-wet status at 326 road-stream intersections and the same ensemble framework to map perennial stream reaches. Lastly, we quantified drivers of variation in predictive accuracy and mapped habitat suitability across replicates. Median true skill statistic (TSS) across F. virilis replicates was 0.613 and habitat suitability was highest in mountain ecoregions and lowest in desert ecoregions. Of the 130,847 stream km in the LCRB, we estimate 29,078 km (22.2 %) have wetted channels during the May-June dry season and median 50.3 % of these perennial streams provide suitable habitat for F. virilis. The statistical algorithm was the strongest driver of TSS variation across replicates, whereas the spatial scale at which covariates were measured was the strongest driver of variation in mapped habitat suitability across replicates. We confirm the widespread invasion of F. virilis throughout the LCRB, particularly in perennial mountain streams. The modest predictive accuracy highlights the generalistic niche of F. virilis. Overall, we demonstrate that spatiotemporally comprehensive datasets combined with ensemble modeling can guide management at regional extents., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: During 2017-18, the Northern Territory (NT) introduced a Banned Drinker Register (BDR) and Minimum Unit Price (MUP) NT-wide; Police Auxiliary Liquor Inspectors (PALIs) in three regional towns; and restrictions on daily purchases/opening hours (DPOH) in one regional town. The BDR is an individual-level alcohol ban; MUP is a pricing policy; and PALIs enforce bans on restricted areas at takeaway outlets. This study examines the impact of these policies on adult domestic and family violence (DFV)., Methods: We examined DFV assaults and breaches of violence orders from January 2014 - February 2020 using interrupted time series models for NT, Greater Darwin, Katherine, Tennant Creek, and Alice Springs. To account for increasing numbers of individuals on the BDR we tested two timepoints (Sept 2017, March 2018)., Findings: Following DPOH, assaults (78 %) and alcohol-involved assaults (92 %) decreased in Tennant Creek. After PALIs, assaults (79 %) in Tennant Creek, and breaches (39 %) and alcohol-involved breaches (58 %) in Katherine decreased. After MUP, assaults (11 %), alcohol-involved assaults (21 %) and alcohol-involved breaches (21%) decreased NT wide. After MUP/PALIs in Alice Springs, alcohol-involved assaults (33 %), breaches (42 %), and alcohol-involved breaches (57 %) decreased. BDR (Sept 2017) found increases in assaults (44 %) and alcohol-involved assaults (39 %) in Katherine and assaults (10%) and alcohol-involved assaults NT-wide (17 %). There were increases of 21 %-45 % in breaches NT-wide, in Darwin, Katherine, and Alice Springs. Following March 2018 found increases in assaults (33 %) and alcohol-involved assaults (48 %) in Katherine. There were increases - from 20 % to 56 % - in breaches in NT-wide, Katherine, and Alice Springs., Conclusion: PALIs and DPOH were associated with some reductions in DFV; the BDR was associated with some increases. The upward trend commences prior to the BDR, so it is also plausible that the BDR had no effect on DFV outcomes. Although MUP was associated with reductions in the NT-wide model, there were no changes in sites without cooccurring PALIs., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) are a suite of harmful chemicals (hereafter collectively referred to as 'dioxins'), and their emission into aquatic habitats leads to persistent contamination of sediments, aquatic food-webs, and seafoods. Quantifying contaminant levels in seafood species is important for the ongoing management of exposure risk by fishers, particularly after any remediation actions. We present dioxin concentrations in four seafood species (Yellowfin Bream Acanthopagrus australis, Sea Mullet Mugil cephalus, Eastern School Prawn Metapenaeus macleayi, and Eastern King Prawn Penaeus plebejus) in a recreationally fished estuary, in relation to a contaminated site that has undergone a remediation process, partially removing contaminated sediments (Homebush Bay, Port Jackson, New South Wales, Australia). Dioxin concentrations in these species were measured before (2005/6) and after (2015/16) remediation at a range of locations in and around the remediated site. Dioxin concentrations and congener profiles differed substantially among taxa, and concentrations were frequently higher than Australian screening criteria. The two prawn species showed evidence of a decline in dioxin concentrations after remediation, but the fish species only showed a declining dioxin concentration with distance from the contaminated site (not between periods). There were some minor changes in the congener profile for some species following remediation. While there was evidence for greatly reduced dioxin concentrations in prawn species following remediation, the complex patterns for fish were likely affected by environmental changes, species-specific and temporal changes in lipid content, and animal movement patterns. Future monitoring may aid interpretation of the patterns and modelling of exposure risk associated with seafood consumption into the future., 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., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis., Methods: The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40-90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed., Findings: Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI -54·4 to -19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group., Interpretation: In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research., Funding: The Jon Moulton Charity Trust., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Mental health difficulties are common in children and young people with chronic health conditions, but many of those in need do not access evidence-based psychological treatments. The study aim was to evaluate the clinical effectiveness of integrated mental health treatment for children and young people with epilepsy, a common chronic health condition known to be associated with a particularly high rate of co-occurring mental health difficulties., Methods: We conducted a parallel group, multicentre, open-label, randomised controlled trial of participants aged 3-18 years, attending epilepsy clinics across England and Northern Ireland who met diagnostic criteria for a common mental health disorder. Participants were randomised (1:1; using an independent web-based system) to receive the Mental Health Intervention for Children with Epilepsy (MICE) in addition to usual care, or assessment-enhanced usual care alone (control). Children and young people in both groups received a full diagnostic mental health assessment. MICE was a modular psychological intervention designed to treat common mental health conditions in children and young people using evidence-based approaches such as cognitive behaviour therapy and behavioural parenting strategies. Usual care for mental health disorders varied by site but typically included referral to appropriate services. Participants, along with their caregivers, and clinicians were not masked to treatment allocation but statisticians were masked until the point of analysis. The primary outcome, analysed by modified intention-to-treat, was the parent-report Strengths and Difficulties Questionnaire (SDQ) at 6 months post-randomisation. The study is complete and registered with ISRCTN (57823197)., Findings: 1401 young people were potentially deemed eligible for study inclusion. Following the exclusion of 531 young people, 870 participants were assessed for eligibility and completed the SDQ, and 480 caregivers provided consent for study inclusion between May 20, 2019, and Jan 31, 2022. Between Aug 28, 2019, and Feb 21, 2022, 334 participants (mean ages 10·5 years [SD 3·6] in the MICE group vs 10·3 [4·0] in control group at baseline) were randomly assigned to an intervention using minimisation balanced by age, primary mental health disorder, diagnosis of intellectual disability, and autistic spectrum disorder at baseline. 168 (50%) of the participants were female and 166 (50%) were male. 166 participants were randomly assigned to the MICE group and 168 were randomly assigned to the control group. At 6 months, the mean SDQ difficulties for the 148 participants in the MICE group was 17·6 (SD 6·3) and 19·6 (6·1) for the 148 participants in the control group. The adjusted effect of MICE was -1·7 (95% CI -2·8 to -0·5; p=0·0040; Cohen's d, 0·3). 14 (8%) patients in the MICE group experienced at least one serious adverse event compared with 24 (14%) in the control group. 68% percent of serious adverse events (50 events) were admission due to seizures., Interpretation: MICE was superior to assessment-enhanced usual care in improving symptoms of emotional and behavioural difficulties in young people with epilepsy and common mental health disorders. The trial therefore shows that mental health comorbidities can be effectively and safely treated by a variety of clinicians, utilising an integrated intervention across ages and in the context of intellectual disability and autism. The evidence from this trial suggests that such a model should be fully embedded in epilepsy services and serves as a model for other chronic health conditions in young people., Funding: UK National Institute for Health Research Programme Grants for Applied Research programme and Epilepsy Research UK Endeavour Project Grant., Competing Interests: Declaration of interests JB was funded in part by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research (PGfAR) to work on the MICE project in his substantive employment as a Clinical Project Manager at the UCL Comprehensive Clinical Trials Unit. RM-M and SV were funded by NIHR PGfAR. RS was funded by NIHR PGfAR with payment going to UCL for her time on the project. SB was funded by NIHR PGfAR with payments made to her institution King's College London. SDB was funded by NIHR PGfAR to work on the MICE project in her substantive employment as Principal Research Fellow at UCL. BC has received grants from the William T Grant Foundation, Wellcome Trust, and National Institute of Mental Health as principal investigator or co-principal investigator. JHC has received grants from Stoke Therapeutics, Ultragenyx, NIHR, Great Ormond Street Hospital Children's Charity, LifeARC, Waterloo Foundation, and Action Medical Research. SDB has received grants from Epilepsy Research UK and NIHR PGfAR. SV has received grants from the NIHR. RM-M has received grants from MS Society, Crohn's and Colitis UK, and NIHR. BC receives royalties from MATCH-ADTC. PF receives royalties from books with Guildford Press, American Psychiatric Publishing, Oxford University Press. SDB and RS receive royalties from Oxford University Press. RM-M is a beneficiary of license between King's College London and Mahana Therapeutics and has received consulting fees from Mahana Therapeutics and 11 London. PF's honoraria payments for lectures, presentations, and workshops are sent to the Anna Freud centre and he does not receive direct payment for them. JHC's honoraria payments from Biocodex, Nutricia, Jazz Pharmaceuticals, Takeda, and UCB are sent to UCL. SV's honoraria payments from LivaNova for speaking engagements are sent to Great Ormond Street Hospital. RM-M has received payment or honoraria from the European Association of Psychosomatic Medicine, British Association for Behavioural and Cognitive Psychotherapies, and Central and North West London NAtional Health Service (NHS) Foundation Trust. BC received support for attending the OMNI Inventive Care Omaha conference, a children's mental health gathering. TS was reimbursed for travel costs to the annual Royal College of Paediatrics & Child Health Meeting attending to present trial findings. RM-M has received support for attending meetings and for travel from the American Psychosomatic Society, European Association of Psychosomatic Medicine, and British Association for Behavioural and Cognitive Psychotherapies. JHC does not receive personal remuneration for participation in data safety and monitoring boards for Stoke Therapeutics. SV's remuneration for participation in data safety and monitoring boards for advisory board participation from Biocodex is sent to GOSH. BC is a board member of PracticeWise, which owns the MATCH-ADTC protocol on which the Mental Health Intervention for Children with Epilepsy programme is based. PracticeWise was paid for training and consulting during the trial setup phase, and provided supervision of the study supervisors to ensure integrity of treatment implementation. JHC is the Elected President for the International League Against Epilepsy, Chair Medical Board for Matthews Friends, Chair of Medical Board for Dravet UK, Chair of Medical Board for Hope for Hypothalamic Hamartoma, and President of Epilepsy Research UK. PF is Chief Executive of the Anna Freud National Centre for Children and Families, Director for Mental Health and Behaviour Change Programmes for UCLPartners, and National Senior Clinical Advisor for Children and Young People's mental health at NHS England. RS is a director of Bespoke Mental Health. SDB is a psychologist in private practice and a co-director of Mind and Body London. BC did not interact with participants or study therapists and was not involved in the analysis. TS was not involved with the research ethics application for this study. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There have been dramatic clinical improvements in people with cystic fibrosis (PwCF) commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in PwCF., Methods: Sputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry., Results: Post-ETI, mean FEV 1  % increased by 13.7 % (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged., Conclusions: Sputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established., Competing Interests: Declaration of Competing Interest PB declares speaker fees (Vertex and Chiesi) and Advisory board participation (Vertex and Insmed)., (Copyright © 2023. Published by Elsevier B.V.)

Objective: There is no consensus on the optimal anticoagulant regimen following lower extremity bypass. Historically, warfarin has been utilized for prosthetic or compromised vein bypasses. Direct-acting oral anticoagulants (DOACs) are increasingly replacing warfarin in this context, but their efficacy in bypass preservation has not been well-studied. Recent studies have shown that DOACs may improve outcomes following bypasses; however, it is unclear if this is dependent upon type of bypass conduit. The goal of this study was to evaluate whether a difference exists between vein and prosthetic infra-geniculate bypasses outcomes based on the anticoagulant utilized on discharge, warfarin or DOAC., Methods: The Vascular Quality Initiative infra-inguinal bypass database was queried for all patients who underwent an infra-geniculate bypass and were anticoagulation-naive at baseline but were discharged on either warfarin or DOACs. A survival analysis was performed for patients up to 1 year to determine whether the choice of discharge anticoagulation was associated with differences between those with vein vs prosthetic conduits in overall survival, primary patency, risk of amputation, or risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in baseline demographic factors between the groups., Results: During the study period (2003-2020), 57,887 patients underwent infra-geniculate bypass. Of these, 3230 (5.5%) were anticoagulated on discharge. There was a similar distribution of anticoagulation between vein (n = 1659; 51.4%) and prosthetic conduits (n = 1571; 48.6%). Thirty-two percent were discharged on DOACs, and 68.0% were discharged on warfarin. For prosthetic conduits, being discharged on a DOAC was associated with improved outcomes on univariate and multivariable analyses revealing lower risk of overall mortality (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41-0.93; P = .021), loss of primary patency (HR, 0.70; 95% CI, 0.55-0.89; P = .003), risk of amputation (HR, 0.71; 95% CI, 0.54-0.93; P = .013), and risk of MALE (HR, 0.80; 95% CI, 0.64-1.00; P = .048). Patients with a vein bypass had improved univariate outcomes for survival and primary patency; however, with multivariable analysis, there were no significant differences in outcomes between DOAC and warfarin., Conclusions: Anticoagulation-naive patients who underwent an infra-geniculate prosthetic bypass had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged on a DOAC compared with warfarin. Those with vein bypasses had similar outcomes regardless of the choice of anticoagulation., Competing Interests: Disclosures None., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The Biering-Sørensen test is commonly used to assess paraspinal muscle endurance. Research using a single repetition of the test has provided conflicting evidence for the contribution of impaired paraspinal muscle endurance to low back pain (LBP). This study investigated how Sørensen test duration, muscle activation, and muscle fatigability are affected by multiple repetitions of the test and determined predictors of Sørensen test duration in young adults with and without a history of LBP. Sixty-four young individuals performed three repetitions of the Sørensen test. Amplitude of activation and median frequency slope (fatigability) were calculated for the lumbar and thoracic paraspinals and hamstrings. Duration of the test was significantly less for the 3rd repetition in individuals with LBP. In individuals without LBP, test duration was predicted by fatigability of the lumbar paraspinals. In individuals with LBP, Sørensen test duration was predicted by fatigability of the hamstrings and amplitude of activation of the thoracic and lumbar paraspinals. Our findings demonstrate that it is necessary to amplify the difficulty of the Sørensen test to reveal impairments in young, active adults with LBP. Training programs aiming to improve lumbar paraspinal performance should monitor performance of other synergist muscles during endurance exercise., 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 Elsevier Ltd. All rights reserved.)

Objective: Sex disparities in outcomes after carotid revascularization have long been a concern, with several studies demonstrating increased postoperative death and stroke for female patients after either carotid endarterectomy or transfemoral stenting. Adverse events after transfemoral stenting are higher in female patients, particularly in symptomatic cases. Our objective was to investigate outcomes after transcarotid artery revascularization (TCAR) stratified by patient sex hypothesizing that the results would be similar between males and females., Methods: We analyzed prospectively collected data from the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER)1 (pivotal), ROADSTER2 (US Food and Drug Administration indicated postmarket), and ROADSTER Extended Access TCAR trials. All patients had verified carotid stenosis meeting criteria for intervention (≥80% for asymptomatic patients and ≥50% in patient with symptomatic disease), and were included based on anatomical or clinical high-risk criteria for carotid stenting. Neurological assessments (National Institutes of Health Stroke Scale, Modified Rankin Scale) were obtained before and within 24 hours from procedure end by an independent neurologist or National Institutes of Health Stroke Scale-certified nurse. Patients were stratified by sex (male vs female). Baseline demographics were compared using χ 2 and Fisher's exact tests where appropriate; primary outcomes were combination stroke/death (S/D) and S/D/myocardial infarction (S/D/M) at 30 days, and secondary outcomes were the individual components of S/D/M. Univariate logistic regression was conducted., Results: We included 910 patients for analysis (306 female [33.6%], 604 male [66.4%]). Female patients were more often <65 years old (20.6% vs 15%) or ≥80 years old (22.6% vs 20.2%) compared with males, and were more often of Black/African American ethnicity (7.5% vs 4.3%). There were no differences by sex in term of comorbidities, current or prior smoking status, prior stroke, symptomatic status, or prevalence of anatomical and/or clinical high-risk criteria. General anesthetic use, stent brands used, and procedure times did not differ by sex, although flow reversal times were longer in female patients (10.9 minutes male vs 12.4 minutes female; P = .01), as was more contrast used in procedures for female patients (43 mL male vs 48.9 mL female; P = .049). The 30-day S/D and S/D/M rates were similar between male and female patients (S/D, 2.7% male vs 1.6% female [P = .34]; S/D/M, 3.6% male vs 2.6% female [P = .41]), which did not differ when stratified by symptom status. Secondary outcomes did not differ by sex, including stroke rates at 30 days (2.2% male vs 1.6% female; P = .80), nor were differences seen with stratification by symptom status. Univariate analysis demonstrated that history of a prior ipsilateral stroke was associated with increased odds of S/D (odds ratio [OR], 4.19; P = .001) and S/D/M (OR, 2.78; P = .01), as was symptomatic presentation with increased odds for S/D (OR, 2.78; P = .02)., Conclusions: Prospective TCAR trial data demonstrate exceptionally low rates of S/D/MI, which do not differ by patient sex., Competing Interests: Disclosures P.A.S. served as a national Co-Principal Investigator for ROADSTER 2 without remuneration. Consultant for Silk Road Medical, Surmodics, Philips, Boston Scientific, Medtronic, Cagent, and LimFlow. C.J.K. served as a national Co-Principal Investigator for ROADSTER 1. V.S.K. served as a national Co-Principal Investigator for ROADSTER 2 without remuneration., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Young males experience markedly poorer mental health outcomes. Organised sport settings provide novel prospects to improve the mental health of this subpopulation., Aim: This systematic review aimed to evaluate interventions targeted at the promotion of mental health and wellbeing among young males in organised sporting contexts., Methods: Six databases (SportDiscus, PsycInfo, Medline, Web of Science, Scopus, CINAHL) were searched from inception to June 2022 (and updated in September 2023). Eligible studies examined interventions targeting the mental health and wellbeing (e.g., depression, anxiety, resilience) or mental health literacy (e.g., stigmatising attitudes, help-seeking) of young males aged 10-24 years (or associated stakeholder samples; e.g., parents or coaches of male youth)., Results: A total of 15 studies were included in this review. Overall, the findings indicate promising effects of sport-based interventions on the mental health and mental health literacy outcomes of young males., Conclusions: This review suggests that there is scope to improve the capacity of sports-based interventions to affect positive change in the mental health of male youth. The findings from this review also have important implications for the development and evaluation of sports-based interventions targeted at young males in future., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Practice guidelines recommend elective repair for abdominal aortic aneurysms (AAAs) ≥ 5.5 cm in men and ≥ 5 cm in women to prevent rupture; however, some rupture at smaller diameters. We identify risk factors for rupture AAA (rAAA) below this threshold and compare outcomes following rAAA repair above/below size criteria., Methods: The Vascular Quality Initiative (2013-2019) was queried for patients undergoing repair for rAAA and stratified based on diameter into small and large cohorts [Small: < 5.5 cm (men), < 5.0 cm (women)]. Univariate analysis was performed, and Kaplan-Meier analysis compared overall survival, aneurysm-related mortality, and reintervention at 12 months., Results: Five thousand one hundred sixty two rAAA were identified. Small rAAA patients [n = 588] were more likely to have hypertension (81.3% vs. 77.0%, P < 0.02), diabetes (18.2% vs. 14.9%, P < 0.04), and end-stage renal disease (2.9% vs. 0.9%, P < 0.01) and be on optimal medical therapy (32.1% vs. 26.8%, P < 0.01). Women were more likely to rupture at smaller diameters compared to men (P < 0.01). Small rAAA patients were more likely to undergo endovascular aortic repair (EVAR) (70.2% vs. 56.0%, P < 0.01) and had lower in-hospital mortality (17.7% vs. 27.7%, P < 0.01) and fewer perioperative complications across all categories. At 12 months, small rAAA patients had better overall survival, freedom from aneurysm-related mortality, and freedom from reintervention, largely driven by EVAR approach., Conclusions: More than 11% of patients presenting with ruptured AAA were below the recommended size threshold for repair, and they tended to be younger, non-White, and have hypertension, diabetes, and/or renal failure. Patients with small rAAA experienced lower in-hospital morbidity and mortality and improved 1-year survival, and EVAR was associated with better outcomes than open repair. However, women more frequently rupture at smaller diameters compared to men. Given contemporary elective outcomes for women, a randomized controlled trial for EVAR versus surveillance at a sex-specific size threshold is needed., (Published by Elsevier Inc.)

Polyetheretherketone (PEEK) is a high performing thermoplastic that has established itself as a 'gold-standard' material for cranial reconstruction. Traditionally, milled PEEK patient specific cranial implants (PSCIs) exhibit uniform levels of smoothness (excusing suture/drainage holes) to the touch (<1 μm) and homogenous coloration throughout. They also demonstrate predictable and repeatable levels of mechanical performance, as they are machined from isotropic material blocks. The combination of such factors inspires confidence from the surgeon and in turn, approval for implantation. However, manufacturing lead-times and affiliated costs to fabricate a PSCI are high. To simplify their production and reduce expenditure, hospitals are exploring the production of in-house PEEK PSCIs by material extrusion-based additive manufacturing. From a geometrical and morphological perspective, such implants have been produced with good-to-satisfactory clinical results. However, lack of clinical adoption persists. To determine the reasoning behind this, it was necessary to assess the benefits and limitations of current printed PEEK PSCIs in order to establish the status quo. Afterwards, a review on individual PEEK printing variables was performed in order to identify a combination of parameters that could enhance the aesthetics and performance of the PSCIs to that of milled implants/cranial bone. The findings from this review could be used as a baseline to help standardize the production of PEEK PSCIs by material extrusion in the hospital., 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 Ltd.. All rights reserved.)

Background: Cryoprecipitate is often transfused in patients undergoing cardiac surgery. However, its safety and effectiveness remain uncertain., Methods: This study was a propensity score-matched analysis of data from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. The study included adults undergoing cardiac surgery between 2005 and 2018 across 38 sites. The association between perioperative cryoprecipitate transfusion and clinical outcomes was estimated, with a primary outcome of operative mortality., Results: Of 119,132 eligible patients, 11,239 (9.43%) patients received cryoprecipitate. The median cumulative dose was 8 U (interquartile range, 5-10 U). After propensity score matching, we matched 9055 cryoprecipitate recipients to 9055 control subjects. Postoperative cryoprecipitate transfusion was associated with reduced operative mortality (odds ratio [OR], 0.82; 99% CI, 0.69-0.97; P = .002) and long-term mortality (hazard ratio, 0.92; 99% CI, 0.87-0.97; P = .0042). It was also associated with a reduction in acute kidney injury (OR, 0.85; 99% CI, 0.73-0.98; P = .0037) and all-cause infection (OR, 0.77; 99% CI, 0.67-0.88; P < .0001). These findings were observed despite increased rates of return to the operating room (OR, 1.36; 99% CI, 1.22-1.51; P < .0001) and cumulative 4-hour postoperative chest tube output (adjusted mean difference in mL, 97.69; 99% CI, 81.65;113.74; P < .0001)., Conclusions: In a large, multicenter cohort study and after propensity score matching, perioperative transfusion of cryoprecipitate was associated with reduced operative and long-term mortality., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Objective: Intravascular ultrasound (IVUS) use in lower extremity interventions is growing in popularity owing to its imaging in the axial plane, superior detail in imaging lesion characteristics, and its enhanced ability to delineate lesion severity and extent compared with catheter angiograms. However, there are conflicting data regarding whether IVUS affects outcomes. The purpose of this study was to assess the effect associated with IVUS implementation in femoropopliteal interventions., Methods: This retrospective cohort study used Vascular Quality Initiative data. Patients undergoing an index endovascular femoropopliteal revascularization from 2016 to 2021 were included. Patients were differentiated by whether or not IVUS was used to assess the femoropopliteal segment during intervention (no IVUS, IVUS). Propensity score matching, based on preoperative demographics and measures of disease severity was used. Primary outcomes were major amputation-free survival (AFS), femoropopliteal reintervention-free survival (RFS), and primarily patent survival (PPS) at 12 months., Results: IVUS use grew steadily throughout the study period, comprising 0.6% of interventions in 2016 and increasing to 8.2% of interventions by 2021; growth was most dramatic in ambulatory surgical center or office-based laboratory settings where IVUS use grew from 4.4% to 43% to 47% of interventions. In unmatched cohorts, patients receiving interventions using IVUS tended to have lower prevalence of multiple cardiovascular comorbidities (eg, congestive heart failure, hypertension, diabetes, and dialysis dependence) and presented more often with claudication and less often with chronic limb-threatening ischemia (CLTI). Intraoperatively, IVUS was used more often in complex femoropopliteal lesions (Transatlantic Intersociety grade D vs A), and more often in conjunction with stenting and/or atherectomy. IVUS use was associated with improved AFS, but similar RFS and PPS at 12 months. However, in multivariable analysis IVUS was not associated with any of the primary outcomes independently; rather, all outcomes were influenced primarily by CLTI, dialysis dependence, and prior major amputation status; technical outcomes (ie, RFS and PPS loss) were further driven by complexity of lesion (worse in Transatlantic Intersociety grade D vs A lesions) and treatment setting (ie, ambulatory surgical center or office-based laboratory setting associated with increased hazard for RFS and PPS loss)., Conclusions: IVUS implementation in femoropopliteal interventions is growing, with rapid adoption among interventions in ambulatory surgical centers and office-based laboratories. IVUS was not associated with an effect on technical outcomes at 12 months; improvement in major AFS was observed; however, multivariable analysis suggests this finding may be an effect of confounding by multiple factors highly associated with IVUS use, namely, in patients with lower prevalence of CLTI, dialysis dependence, and prior major amputations, thus conveying baseline lower risk for major amputation and death., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Acute kidney injury (AKI) is a frequent yet understudied postoperative total joint arthroplasty complication. This study aimed to describe cardiometabolic disease co-occurrence using latent class analysis, and associated postoperative AKI risk., Methods: This retrospective analysis examined patients ≥18 years old undergoing primary total knee or hip arthroplasties within the US Multicenter Perioperative Outcomes Group of hospitals from 2008 to 2019. AKI was defined using modified Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Latent classes were constructed from eight cardiometabolic diseases including hypertension, diabetes, and coronary artery disease, excluding obesity. A mixed-effects logistic regression model was constructed for the outcome of any AKI and the exposure of interaction between latent class and obesity status adjusting for preoperative and intraoperative covariates., Results: Of 81 639 cases, 4007 (4.9%) developed AKI. Patients with AKI were more commonly older and non-Hispanic Black, with more significant comorbidity. A latent class model selected three groups of cardiometabolic patterning, labelled 'hypertension only' (n=37 223), 'metabolic syndrome (MetS)' (n=36 503), and 'MetS+cardiovascular disease (CVD)' (n=7913). After adjustment, latent class/obesity interaction groups had differential risk of AKI compared with those in 'hypertension only'/non-obese. Those 'hypertension only'/obese had 1.7-fold increased odds of AKI (95% confidence interval [CI]: 1.5-2.0). Compared with 'hypertension only'/non-obese, those 'MetS+CVD'/obese had the highest odds of AKI (odds ratio 3.1, 95% CI: 2.6-3.7), whereas 'MetS+CVD'/non-obese had 2.2 times the odds of AKI (95% CI: 1.8-2.7; model area under the curve 0.76)., Conclusions: The risk of postoperative AKI varies widely between patients. The current study suggests that the co-occurrence of metabolic conditions (diabetes mellitus, hypertension), with or without obesity, is a more important risk factor for acute kidney injury than individual comorbid diseases., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: 'Overweight and obesity' is the second biggest preventable cause of cancer after smoking. In 2018, Cancer Research UK launched an awareness raising campaign about the link between overweight and obesity and cancer risk. This study aimed to evaluate the reach and impact of the campaign., Study Design: This study was a repeated cross-sectional online survey., Methods: The campaign consisted of six elements including the main message that 'Obesity is a cause of cancer'. UK adults and Members of Parliament (MPs) were surveyed before the campaign (W1; n = 2124 and n = 151), 1 month (W2; n = 2050 and n = 151) and 3 months after the campaign (W3; n = 2059 and MPs not surveyed). Outcome measures were campaign reach, awareness of overweight and obesity as risk factors for cancer, attitudes towards individuals who are overweight or obese, support for policies to reduce obesity and reactions to the campaign., Results: Overall, 76.2% of MPs and just under half of the public (47.5% in W2 and 36.8% in W3) reported having seen the campaign. Unprompted awareness of obesity as a risk factor increased among the public from 17.1% at W1 to 43.3% in W2 (odds ratio 3.71, 95% confidence interval 3.18-4.33) and 30.3% in W3 (odds ratio 2.11, 95% confidence interval 1.80-2.47). A similar pattern was seen for prompted awareness and among MPs. There were no consistent changes in attitudes towards overweight individuals or support for policies to reduce obesity., Conclusions: This evaluation suggests that the campaign achieved the primary objective of increasing awareness of the link between obesity and cancer without increasing negative attitudes towards individuals who are overweight or obese., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Data regarding the safety and efficacy of paclitaxel (PTX)-coated peripheral arterial devices for femoropopliteal artery (FPA) atherosclerotic disease is derived from studies that mainly evaluated patients with claudication. Outcomes of PTX treatment for patients with chronic limb-threatening ischemia (CLTI) is incompletely defined. This study compares outcome in patients with CLTI treated with and without PTX., Methods: We retrospectively studied patients who underwent FPA intervention for an indication of CLTI in the Vascular Quality Initiative peripheral vascular intervention database from 2016 to 2020. Patients who had concomitant iliac or tibial interventions were included. One limb per patient was studied. Propensity score matching based on demographics, comorbidities, indication, and pharmacological therapy was performed to generate balanced cohorts. Kaplan-Meier survival analysis and multivariate Cox regression compared limb salvage, overall survival, primary patency, and major adverse limb events (MALE) between patients treated with and without PTX., Results: Demographics, comorbidities, indications, and procedural details were similar between 14,065 PTX and 14,065 non-PTX propensity-matched patients. Kaplan-Meier analysis at 18-month follow-up demonstrated that the PTX group compared with the non-PTX group had a significantly higher rates of limb salvage (89.2% vs 86.5%; P < .001), primary patency (80.3% vs 76.9%; P < .001), and freedom from MALE (72.6% vs 67.9%; P < .001). Multivariate analysis also showed that PTX treatment was associated with a lower risk of major amputation (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.67-0.82; P < .001), loss of primary patency (HR, 0.80; 95% CI, 0.74-0.87; P < .001), and MALE (HR, 0.77; 95% CI, 0.72-0.82; P < .001). Overall, 21% of patients had a prior ipsilateral peripheral vascular intervention. Removing these patients from the analysis yielded similar results at 18 months. Overall survival at 54 months was not statistically different between the PTX and non-PTX groups in the overall cohort (73.5 vs 71.3%; P = .07), but significant in the de-novo treated patients (73.9% vs 70.7%; P = .02).Multivariate analyses showed a lower mortality risk in the PTX patients (HR, 0.93; 95% CI, 0.87-0.98; P = .02)., Conclusions: FPA intervention with a PTX-coated device is associated with improved limb salvage, primary patency, and freedom from MALE at the 18-month follow-up compared with uncoated devices. This benefit was not associated with an increase in all-cause mortality out to 4.5 years. Further study is necessary to determine the optimal role for PTX in the treatment of the FPA for patients with CLTI and to understand its long-term outcome., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: No consensus has yet been reached regarding the optimal antiplatelet and anticoagulant regimen for patients after lower extremity bypass. Usually, patients who have undergone below-the-knee bypass will begin oral anticoagulation therapy. Historically, the bypass has been with prosthetic conduits and the anticoagulation therapy has been warfarin. However, the use of direct-acting oral anticoagulants (DOACs) has been increasing owing to their relative ease of dosing. The goal of the present study was to evaluate whether a difference exists in the postoperative outcomes for patients who have undergone infrageniculate bypass stratified by the use of on DOACs vs warfarin., Methods: The Vascular Quality Initiative infrainguinal bypass database was queried for all patients who had undergone infrageniculate bypass, been anticoagulation naive at baseline, and been discharged with anticoagulation therapy. A survival analysis was performed for patients for ≤2 years postoperatively to determine whether discharge with warfarin vs DOACs was associated with differences in overall mortality, loss of primary patency, risk of amputation, and risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in the baseline demographic factors between the two groups., Results: During the study period (2007-2020) 57,887 patients had undergone infrageniculate bypass. Of these patients, 2786 had been anticoagulation naive and discharged with either warfarin (n = 1889) or DOACs (n = 897). Discharge with a DOAC was associated with a lower risk of overall mortality (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.83; P = .001), loss of primary patency (HR, 0.74; 95% CI, 0.62-0.87; P < .001), risk of amputation (HR, 0.70; 95% CI, 0.57-0.86; P = .001), and risk of MALE (HR, 0.83; 95% CI, 0.71-0.97; P = .017)., Conclusions: Anticoagulation-naive patients who had undergone infrageniculate bypass had had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged with a DOAC than with warfarin., (Copyright © 2022 Society for Vascular Surgery. All rights reserved.)

Introduction: People with HIV (PWH) of African ancestry have faster decline of kidney function and faster progression to end-stage renal disease than PWH of European ancestry. DNA methylation have been associated with kidney function in the general population, however, their relationships are unclear for PWH of African ancestry., Methods: We performed epigenome-wide association studies (EWAS) of estimated glomerular filtration rate (eGFR) among PWH of African ancestry in 2 subsets of the Veterans Aging Cohort Study cohort ( N  = 885), followed by a meta-analysis to combine the results. Replication was conducted among independent African American samples without HIV., Results: DNA methylation sites cg17944885 near Zinc Finger Family Member 788 ( ZNF788 ) and Zinc Finger Protein 20 ( ZNF20 ), and cg06930757 in SHANK1 were significantly associated with eGFR among PWH of African ancestry (false discovery rate < 0.05). DNA methylation site cg17944885 was also associated with eGFR among different populations including African Americans without HIV., Conclusions: Our study attempted to address an important gap in the literature and to understand the role of DNA methylation in renal diseases in PWH of African ancestry. Replication of cg17944885 among different populations suggests there may be a common pathway for renal diseases progression among PWH and people without HIV, and across different ancestral groups. Our results suggest that genes ZNF788/ZNF20 and SHANK1 could be involved in a pathway linking DNA methylation to renal diseases among PWH and are worth further investigation.

Rationale: Chronic cough is a common problem, substantially affecting quality of life. Effective treatments and diagnostic clinical tools for refractory chronic cough are lacking which remains a diagnosis of exclusion., Objectives: To investigate capsaicin evoked cough responses in healthy volunteers and refractory chronic cough patients and assess the discriminatory ability of novel endpoints., Methods: Dose-response capsaicin cough challenges were performed, and receiver operating characteristic curves constructed to evaluate the discriminatory value of novel endpoints; Emax (maximum number of coughs evoked by any capsaicin concentration) and ED50 (capsaicin concentration evoking at least half of Emax)., Measurements and Main Results: Ninety-three healthy volunteers (median age 39yrs(IQR; 29-52), 47 females) and 51 refractory chronic cough patients (59yrs(53-67), 31 females) were studied. Emax was significantly higher in the patient group compared to healthy volunteers (p < 0.001) and ED50 was significantly lower (p = 0.001). Both parameters were influenced by gender; females had a higher Emax (p = 0.009) and more sensitive ED50 (p < 0.001) but there were no correlations with other patient demographics. There was a significant relationship between Emax and cough frequency in the patient group (p < 0.001). Emax effectively discriminated between the groups (AUC = 0.83, 95% CI; 0.75-0.90, p < 0.001) independently of ED50 which was less favourable (AUC = 0.66, 95% CI; 0.57-0.76, p = 0.002). Emax and ED50 were shown to be repeatable, and the dose-response method well tolerated., Conclusion: Novel capsaicin dose-response endpoints effectively discriminate between healthy controls and refractory chronic cough patients, which may better represent pathophysiological mechanisms and show promise for development as a tool to identify patients with cough hyper-excitability., Clinical Trial Registration: www.isrctn.com; ISRCTN23684347., Competing Interests: Declaration of competing interest The VitaloJAK algorithm has been licensed by Manchester University Foundation Trust (MFT) and the University of Manchester to Vitalograph Ltd and Vitalograph Ireland (Ltd). MFT receives royalties which may be shared with the clinical division in which JAS works. Declarations of interest for KJH and JB: none., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa., Methods: We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without C-reactive protein (CRP) adjustment to examine the role of inflammation., Results: We identified 208 and 87 significant CpG sites associated with fibrinogen from the 450K (p-value<1.03×10 -7 ) and EPIC arrays (p-value<5.78×10 -8 ), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for the overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. Examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations for all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant., Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP., (Copyright © 2023 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background: Proteomics can reveal molecular pathways of disease and provide translational perspectives to inform clinical decision making. Although several studies have previously reported the cystic fibrosis airway proteome, the relationship with severity of lung disease has not been characterised. The objectives of this observational study were to investigate differences in the CF sputum proteome associated with disease severity and identify potential markers of disease with translational potential., Methods: Sputum samples from healthy volunteers and cystic fibrosis subjects (some prescribed modulator therapies) were analysed using liquid-chromatography tandem mass spectrometry. Severity of lung disease was based on baseline spirometry (percentage predicted forced expiratory volume in 1 s, FEV1%)., Results: Multiple sputum proteins (108 increased; 202 decreased) were differentially expressed in CF (n = 38) and healthy volunteers (n = 32). Using principal component analysis and hierarchical clustering, differences in sputum proteome were observed associated with progressive lung function impairment. In CF subjects, baseline FEV1% correlated with 87 proteins (positive correlation n = 20, negative n = 67); most were either neutrophil derived, or opposed neutrophil-driven oxidant and protease activity., Conclusion: Predictable and quantifiable changes in the CF sputum proteome occurred associated with progressive lung function impairment, some of which might have value as markers of disease severity in CF sputum. Further work validating these markers in other patient cohorts and exploring their clinical utility is needed., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The epidemiology of persistent postoperative opioid use at least 3 months after cardiac surgery is poorly characterised despite its potential public health importance., Methods: We searched MEDLINE, Embase, and Google Scholar from inception to December 2021 and included studies reporting the rate and risk factors of persistent postoperative opioid use after cardiac surgery in opioid-naive and opioid-exposed patients. We recorded incidence rates and odds ratios (ORs) with 95% confidence intervals (CIs) for risk factors from individual studies and used random-effects inverse variance modelling to generate pooled estimates., Results: From 10 studies involving 112 298 patients, the pooled rate of persistent postoperative opioid use in opioid-naive patients was 5.7% (95% CI: 4.2-7.2%). Risk factors included female sex (OR 1.18; 95% CI: 1.09-1.29), smoking (OR 1.34; 95% CI: 1.06-1.69), alcohol use (OR 1.43; 95% CI: 1.17-1.76), congestive cardiac failure (OR 1.17; 95% CI: 1.08-1.27), diabetes mellitus (OR 1.21; 95% CI: 1.07-1.37), chronic lung disease (OR 1.42; 95% CI: 1.16-1.75), chronic kidney disease (OR 1.35; 95% CI: 1.08-1.68), and length of hospital stay (per day) (OR 1.03; 95% CI: 1.02-1.04)., Conclusions: Persistent postoperative opioid use after cardiac surgery affects at least one in 20 patients. The identification of risk factors, such as female sex, smoking, alcohol use, congestive cardiac failure, diabetes mellitus, chronic lung disease, chronic kidney disease, and length of hospital stay, should help target interventions aimed at decreasing its prevalence., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: Physician-modified endografts (PMEG) and parallel grafting (PG) are important techniques for endovascular repair of complex aortic aneurysms using off-the-shelf devices. However, there are few data regarding the relative efficacy and outcomes of these techniques in thoracoabdominal extent aneurysms. This study sought to compare the outcomes of PG and PMEG across different extents of thoracoabdominal aneurysms (TAAAs) for which they can be used., Methods: The Society for Vascular Surgery Vascular Quality Initiative thoracic endovascular aortic repair/complex endovascular aortic repair module was queried for all patients undergoing repair of an unruptured, TAAA (extents I-IV) from 2012 to 2020; aneurysm types were defined by repair extent as determined by proximal and distal seal zones. Patients were differentiated based on whether they underwent repair with a PMEG or PG. The primary outcomes for this study were overall survival and freedom from aneurysm- or procedure-related mortality at 1 year determined via Kaplan-Meier analysis, with a Cox hazard regression analysis conducted to examine the independent association of repair modality with primary outcomes., Results: There were 813 patients who met the inclusion criteria (TAAA I-III, n = 362; TAAA IV, n = 451; PG, n = 426; PMEG, n = 387). PMEG repairs were performed at centers with a nearly two- to three-fold higher annual volume of endovascular TAAA repairs. Type Ia endoleaks were reduced with PMEG repair, most significantly in TAAA IV (TAAA I-III, 2.2% PMEG vs 10% PG [P = .2]; TAAA IV, 1.2% PMEG vs 21.6% PG [P < .001]). Thoracoabdominal repairs demonstrated improved survival at 1 year with PMEG devices, significant for TAAA I to III repairs (TAAA I-III, PMEG 85% vs PG 74% [P = .01]; TAAA IV, 84% PMEG vs PG 78% [P = .08]). Freedom from aneurysm- or procedure-related mortality was also improved with PMEG repairs, remaining significant at 1 year in the case of TAAA IV (TAAA I-III:, PMEG 94% vs PG 86% [P = .06]; TAAA IV, PMEG 94% vs PG 88% [P = .02]). PMEG demonstrated decreases in several measures of postoperative morbidity, including stroke, death, major adverse cardiovascular events, and postoperative complications. In the multivariate analysis, repair modality was not associated with either primary outcome; rather, several perioperative complications conveyed the greatest hazard for both primary outcomes across repair extents., Conclusions: Survival after endovascular TAAA repair is improved with the use of PMEG compared with PG. Several key factors of this study demonstrate the shortcomings of PG in complex aneurysm repair, namely, high rates of critical endoleaks, the need for adjunctive access sites, and an increase in perioperative complications that influence longer term outcomes., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Patterns and practices of agricultural expansion threaten the persistence of global biodiversity. Wildlife species surviving large-scale land use changes can be exposed to a suite of contaminants that may deleteriously impact their health. There is a paucity of data concerning the ecotoxicological impacts associated with the global palm oil (Elaeis guineensis) industry. We sampled wild Malay civets (Viverra tangalunga) across a patchwork landscape degraded by oil palm agriculture in Sabah, Malaysian Borneo. Using a non-lethal methodology, we quantified the levels of 13 essential and non-essential metals within the hair of this adaptable small carnivore. We robustly assessed the biological and environmental drivers of intrapopulation variation in measured levels. Metal concentrations were associated with civet age, weight, proximity to a tributary, and access to oxbow lakes. In a targeted case study, the hair metal profiles of 16 GPS-collared male civets with differing space use patterns were contrasted. Civets that entered oil palm plantations expressed elevated aluminium, cadmium, and lead, and lower mercury hair concentrations compared to civets that remained exclusively within the forest. Finally, we paired hair metal concentrations with 34 blood-based health markers to evaluate the possible sub-lethal physiological effects associated with varied hair metal levels. Our multi-facetted approach establishes these adaptable carnivores as indicator species within an extensively altered ecosystem, and provides critical and timely evidence for future studies., (Copyright © 2021. Published by Elsevier Inc.)

Background: Gefapixant is an oral P2X 3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough., Methods: COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2)., Findings: From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9-0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1-1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2)., Interpretation: Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests LPM has received grants and personal fees from Afferent Pharmaceuticals and Merck Sharp & Dohme; personal fees from Applied Clinical Intelligence; grants from Asthma UK, Northern Ireland Chest Heart and Stroke, NC3Rs, British Heart Foundation, and Chiesi; travel and subsistence for attendance at scientific meetings from Boehringer Ingelheim, GlaxoSmithKline, and Chiesi; and advisory board or consultancy fees from Almirall, NAPP, GlaxoSmithKline, and Boehringer Ingelheim. SSB has received scientific advisory board or consultancy fees from Merck Sharp & Dohme, Bayer, Bellus, Shionogi, Nocion, Nerre, and Boehringer Ingelheim. AHM has received grants and personal fees from Afferent Pharmaceuticals and Merck Sharp & Dohme; and is a consultant to Bayer, Bellus, Shionogi, and Nocion. PVD is a consultant to Merck Sharp & Dohme, Bayer, Bellus, and Shionogi. IDP has received research grants, speaker's honoraria, travel expenses, and advisory board fees from AstraZeneca and Chiesi; speaker's honoraria, travel expenses, advisory boards from GlaxoSmithKline, Boehringer Ingelheim, and Teva; advisory board fees from Sanofi and Regeneron, Merck Sharp & Dohme, Novartis, Knopp, and Roche and Genentech; and speaker fees from Cirassia and Mundipharma. JS, AMN, QL, AT, BI, SAG, CLR, and DRM are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, and own stock in the company. JAS has received grants and personal fees from Afferent Pharmaceuticals and Merck Sharp & Dohme; grants and personal fees from Ario Pharma, GlaxoSmithKline, NeRRe Theraputics, Menlo, and Bayer; personal fees from Boehringer Ingelheim, Genentech, and Neomed; non-financial support from Vitalograph; and personal fees from Chiesi. JAS is funded by the National Institute of Health Research (NIHR) Manchester Biomedical Research Centre and a Wellcome Investigator Award, and is an NIHR senior investigator. Additionally, JAS is a named inventor on a patent describing detection of cough from sound recordings. The patent is owned by University Hospital of South Manchester and licensed to Vitalograph., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To the best of our knowledge, no published clinical guidelines have ever undergone an economic evaluation to determine whether their implementation represented an efficient allocation of resources. Here, we perform an economic evaluation of national clinical guidelines designed to reduce unnecessary blood transfusions before, during, and after surgery published in 2012 by Australia's sole public blood provider, the National Blood Authority (NBA)., Methods: We performed a cost analysis from the government perspective, comparing the NBA's cost of implementing their perioperative patient blood management guidelines with the estimated resource savings in the years after publication. The impact on blood products, patient outcomes, and medication use were estimated for cardiac surgeries only using a large national registry. We adopted conservative counterfactual positions over a base-case 3-year time horizon with outcomes predicted from an interrupted time-series model controlling for differences in patient characteristics and hospitals., Results: The estimated indexed cost of implementing the guidelines of A$1.5 million (2018-2019 financial year prices) was outweighed by the predicted blood products resource saving alone of A$5.1 million (95% confidence interval A$1.4 million-A$8.8 million) including savings of A$2.4 million, A$1.6 million, and A$1.2 million from reduced red blood cell, platelet, and fresh frozen plasma use, respectively. Estimated differences in patient outcomes were highly uncertain and estimated differences in medication were financially insignificant., Conclusions: Insofar as they led to a reduction in red blood cell, platelet, and fresh frozen plasma use during cardiac surgery, implementing the perioperative patient blood management guidelines represented an efficient use of the NBA's resources., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objective: Thoracic endovascular aortic repair (TEVAR) for blunt traumatic aortic injuries (BTAIs) can be complicated by inaccurate aortic measurements at the initial computed tomography angiography secondary to hypovolemic shock. The use of intravascular ultrasound (IVUS) has been proposed for more accurate aortic sizing, with prior data demonstrating larger aortic sizes measured by IVUS, potentially altering the vast majority of chosen endograft sizes. At present, and to the best of our knowledge, no studies have examined whether IVUS affects the clinical outcomes. The purpose of the present study was to examine the effect of IVUS on the clinical outcomes after TEVAR for BTAIs., Methods: A retrospective cohort study was performed of patients who had undergone TEVAR for BTAIs in the VQI registry. The cohorts were defined by the use of IVUS. The primary outcomes were mortality and reintervention at 1 year., Results: A total of 919 patients who had undergone TEVAR for BTAIs were included in the present analysis. The IVUS patients had presented with higher injury severity scores (36.2 vs 42; P = .0004) largely because of more extremity and external trauma. IVUS was more often used for patients with grade III injuries (49.1% vs 56.9%; P = .02) and less often for patients with rupture (21.1% vs 12.4%; P = .001). A trend toward a delay in TEVAR was seen for the patients for whom IVUS was used (1.8 vs 3.5 days; P = .38), with additional trends toward reduced intraoperative resuscitation and blood loss. The hemodynamic status of the patients and differences in aortic or endograft sizes could not be assessed with the available data. IVUS use was not associated with any differences in survival or reintervention rates in-hospital or at 1 year (Kaplan-Meier survival estimates: 0.91 no IVUS vs 0.92 IVUS; P = .46). Fifteen aortic-related reinterventions occurred across the entire patient cohort for all-available follow-up with comparable rates of type I endoleaks (1 no IVUS vs 2 IVUS), with no recorded cases of sizing-related complications such as device rupture, migration, or dissection., Conclusions: IVUS usage during TEVAR for BTAIs was associated with clinical scenarios in which patients were more stable and interventions to address BTAIs can be delayed. Despite this, the overall clinical outcomes were similar between cases in which IVUS was used and for which it was not., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Missing data is a common, difficult problem for network studies. Unfortunately, there are few clear guidelines about what a researcher should do when faced with incomplete information. We take up this problem in the third paper of a three-paper series on missing network data. Here, we compare the performance of different imputation methods across a wide range of circumstances characterized in terms of measures, networks and missing data types. We consider a number of imputation methods, going from simple imputation to more complex model- based approaches. Overall, we find that listwise deletion is almost always the worst option, while choosing the best strategy can be difficult, as it depends on the type of missing data, the type of network and the measure of interest. We end the paper by offering a set of practical outputs that researchers can use to identify the best imputation choice for their particular research setting.

The first natural product isolation studies of Nothofagus gunnii (Hook.f.) Oerst and Nothofagus cunninghamii (Hook.f.) Oerst have been undertaken. A previously unreported stilbene derivative, pinosylvin monoacetate, was isolated from the leaves of N. gunnii, in addition to 14 known compounds; including the flavonoids galangin, pinobanksin, catechin and quercetin; sesquiterpenoids such as, ilicol and (+)-β-costol acetate; 2,4-dihydroxy-6-methoxychalcone and pinosylvin. Four known flavonoid natural products, catechin, quercetin, ayanin, and avicularin were isolated from the leaves of N. cunninghamii. This study reveals that N. gunnii is a rich source of flavonoid, chalcone and stilbene compounds, while primarily hydroxyflavonoid compounds are found in N. cunninghamii. The isolated phytochemicals are consistent with the evolutionary relationships suggested to exist among Nothofagus species., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Insulin derivatives such as insulin detemir and insulin degludec are U.S. Food and Drug Administration (FDA)-approved long-acting insulin currently used by millions of people with diabetes. These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity. New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin. Herein, we report a new method using sortase A (SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain. This new insulin molecule (Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives. We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and in vivo bioactivity. This enzymatic method can therefore be used for future insulin design and development., Competing Interests: The authors declare no competing interest., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Ylang-ylang (YY) essential oil (EO) is distilled from the fresh-mature flowers of the Annonaceae family tropical tree Cananga odorata [Lam.] Hook. f. & Thomson, and is widely used in perfume and cosmetic industries for its fragrant character. Herein, two different metabolomic profiles obtained using high-performance thin-layer chromatography (HPTLC), applying different stains, namely 2,2-diphenyl-1-picrylhydrazyl (DPPH·) and p-anisaldehyde, were used for discrimination of 52 YY samples across geographical origins and distillation grades. The first profile is developed using the DPPH· stain based on the radical scavenging activity (RSA) of YY EOs. Results of the HPTLC-DPPH· assay confirmed that RSA of YY EOs is in proportion to the length of distillation times. Major components contributing to the RSA of YY EOs were tentatively identified as germacrene D and α-farnesene, eugenol and linalool, by gas chromatography-mass spectrometry (GC-MS) and GC-flame ionisation detector (GC-FID). The second profile was developed using the general-purpose p-anisaldehyde stain based on the general chemical composition of YY EOs. Untargeted metabolomic discrimination of YY EOs from different geographical origins was performed based on the HPTLC-p-anisaldehyde profiles, followed by principal component analysis (PCA). A discrimination and prediction model for identification of YY distillation grade was developed using PCA and partial least squares regression (PLS) based on binned HPTLC-ultraviolet (254 nm) profiles, which was successfully applied to distillation grade determination of blended YY Complete EOs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship., Methods: This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms., Results: Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism., Discussion: These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: An innovative low-cost parenting intervention, implemented through health services in Jamaica showed benefits to children's cognitive development at 18 months and parent's attitudes concerning childcare. We assessed the impact of the intervention on child and parent outcomes at 6 years of age., Methods: A cluster randomized trial of 2 parenting interventions was conducted through 20 health centers in Jamaica. Interventions were implemented from age 3 to 18 months and each intervention benefited cognitive development at 18 months (effect size 0.34-0.38 standard deviation). Children were reassessed at 6 years (n = 262, 80.1% of those assessed at 18 months) to determine any benefits to cognition, behavior, and parenting behavior. Loss to follow-up was not significantly different by treatment. Inverse probability weighting and Lee bounds were used to adjust for loss to follow-up, and multilevel regression analyses conducted with random effects at the health center level., Results: There were no significant benefits to any child outcomes at age 6 years or to parenting behavior. Results are robust using the wild cluster bootstrap procedure and using Lee bounds for attrition. The initial trial benefits were reproduced with the current sample and methods., Conclusion: Lack of sustained benefits may be related to the initial effect size and low intensity of the intervention that ended very young at age 18 months. It may also be related to lack of initial impact on home environment and fade-out of effects in a country with near universal preschool. The findings have implications for intervention design and targeting., (Copyright © 2021. Published by Elsevier Inc.)

Polydimethylsiloxane (PDMS) materials are widely adopted in the manufacture of facial prostheses, lab-on-chip devices and scaffolds for soft-tissue engineering applications; however, their processing by additive manufacturing (AM) has proved challenging. Liquid silicone rubbers (LSRs) are favoured for their high shape fidelity when cast, but their low viscosity and surface tension often prevent self-support, post-extrusion. Poly(ether) ether ketone (PEEK) particle reinforcement through interfacial bonding has proven to enhance key properties of PDMS, expanding their end-use functionality. Still, the impact of such particles on the printability of LSR-PDMS is not explored. In this study, for the first time, solvent-free biocompatible PDMS-PEEK composites (up to 30 wt% PEEK) were successfully characterised for material extrusion (ME) printing. Rheological analysis confirmed shear-thinning of all PDMS-PEEK composites under applied load (within the tolerances of the printer) and dominant storage moduli at rest (i.e. prints can self-support), considered highly desirable for ME-based printing. Attained rheological datasets were used to guide initial printability studies, which revealed finer track fidelity with rising fractional content of PEEK, at comparable print speed and displacement values. Composites with higher PEEK content demonstrated significant increases in Shore A hardness and stiffness (in tension and compression) in bulk form. Last but not least, enhanced shape fidelity (thanks to PEEK reinforcement) and geometrical autonomy further expanded the manufacturing freedom of PDMS, whereby infill density could be controlled in order to increase the range of mechanical performance, previously unachievable with conventional casting fabrication. Fundamentally, this could lead to the manufacture of bespoke spatially graded multi-material structures and devices that could be used to replicate the heterogenous properties of soft human tissues and in other advanced material applications., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients., (Copyright © 2020. Published by Elsevier Inc.)

Strategies to mitigate watershed nitrogen export are critical in managing water resources. Green infrastructure (GI) has shown the ability to remove nitrogen from stormwater, but the removal mechanism is unclear. Denitrification removes nitrate from water permanently, making it the most desirable removal mechanism. The year-round field performance of a roadside infiltration GI practice (bioretention) in Northern Virginia was monitored to investigate the transport of nitrogen and the occurrence and contribution of denitrification. Stormwater runoff volumes, nitrogen concentrations, and nitrate isotope ratios (δ 15 N-NO 3 - and δ 18 O-NO 3 - ) were measured at the inlet and outlet of the bioretention during 24 storm events over 14 months. Nitrate concentration reductions (inlet vs. outlet) displayed seasonal trends, with higher reductions happening during warmer events and lower reductions or increases occurring during colder events. Cumulative bioretention nitrate and total dissolved nitrogen load reductions were 73% and 70%, respectively. Two out of 24 monitored events displayed denitrification isotope trends, indicating that although bioretention has denitrification potential, it is infrequent and other nitrogen removal mechanisms (i.e. infiltration and plant uptake) are primarily responsible for nitrogen surface effluent reductions. Only approximately 1.4% of the total reduced nitrate surface effluent load over the monitoring period was attributable to denitrification. Denitrification occurred during two of the largest monitored events, suggesting increased hydraulic retention time (HRT) promotes denitrification. Future GI designs should consider increasing HRT to encourage the important ecosystem service denitrification provides., 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 © 2020 Elsevier B.V. All rights reserved.)

Objective: To develop an alternative approach to provide oncology pharmacy practice residents' education and training in the management of gynecologic malignancies in the absence of a specialist in this area at their institution., Setting: Gynecologic oncology is a unique specialty in oncology. There is a need for more oncology clinical pharmacy specialists to participate in the care of patients with gynecologic malignancies as many do not have specific education in this area., Practice Description: A virtual learning experience was developed that included all aspects of a typical experience with the exception of direct patient care. Postgraduate year 2 oncology pharmacy residents from 3 different programs were included., Practice Innovation: Although the number of oncology clinical pharmacy specialists who are subspecialized in gynecologic oncology has grown, it is difficult to find experienced preceptors in gynecology oncology. We set to offer a virtual learning environment for programs that did not have a dedicated or highly specialized pharmacist in this area., Evaluation: A pre- and postlearning assessment of the resident's knowledge of gynecologic malignancies was administered. Each trainee independently completed a validated 20-question gynecologic oncology knowledge assessment tool before and again after completion of all sessions. Midpoint and end-of-experience evaluations were completed via the phone with each resident. All evaluations were documented in PharmAcademic (McCreadie Group, Ann Arbor, MI), a required software program for postgraduate residency training programs., Results: To date, 7 oncology pharmacy practice residents completed the virtual experience. A 42% improvement in scores pertaining to gynecologic oncology knowledge was identified. Residents were also satisfied with the overall virtual experience. Based on the assessment tool, all the residents gave positive evaluations with "always true" for 6 of the 7 questions., Conclusions: This pilot of a virtual experience was a successful platform to provide clinical knowledge and skills for oncology pharmacy residents in gynecologic oncology., (Copyright © 2020 American Pharmacists Association®. All rights reserved.)

Background: Excess sodium intake and insufficient potassium intake are risk factors for hypertension, but there is limited knowledge regarding genetic factors that influence intake. Twenty-hour or half-day urine samples provide robust estimates of sodium and potassium intake, outperforming other measures such as spot urine samples and dietary self-reporting., Objective: The aim of this study was to investigate genomic regions associated with sodium intake, potassium intake, and sodium-to-potassium ratio measured from 24-h or half-day urine samples., Methods: Using samples of European ancestry (mean age: 54.2 y; 52.3% women), we conducted a meta-analysis of genome-wide association studies in 4 cohorts with 24-h or half-day urine samples (n = 6,519), followed by gene-based analysis. Suggestive loci (P < 10-6) were examined in additional European (n = 844), African (n = 1,246), and Asian (n = 2,475) ancestry samples., Results: We found suggestive loci (P < 10-6) for all 3 traits, including 7 for 24-h sodium excretion, 4 for 24-h potassium excretion, and 4 for sodium-to-potassium ratio. The most significant locus was rs77958157 near cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) , a gene involved in eating behavior and appetite regulation (P = 2.3 × 10-8 with sodium-to-potassium ratio). Two suggestive loci were replicated in additional samples: for sodium excretion, rs12094702 near zinc finger SWIM-type containing 5 (ZSWIM5) was replicated in the Asian ancestry sample reaching Bonferroni-corrected significance (P = 0.007), and for potassium excretion rs34473523 near sodium leak channel (NALCN) was associated at a nominal P value with potassium excretion both in European (P = 0.043) and African (P = 0.043) ancestry cohorts. Gene-based tests identified 1 significant gene for sodium excretion, CDC42 small effector 1 (CDC42SE1), which is associated with blood pressure regulation., Conclusions: We identified multiple suggestive loci for sodium and potassium intake near genes associated with eating behavior, nervous system development and function, and blood pressure regulation in individuals of European ancestry. Further research is needed to replicate these findings and to provide insight into the underlying genetic mechanisms by which these genomic regions influence sodium and potassium intake., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Biological treatment of high salinity organic wastewater is a significant challenge because many microorganisms involved in the anaerobic digestion process cannot survive high osmotic pressures. In order to alleviate some of the stresses associated with the treatment of high salinity wastewater, two lab-scale up-flow anaerobic sludge bed reactors with or without magnetite (100 g/L) were used to treat high salinity organic wastewater. This study showed that the bioreactor amended with magnetite had higher chemical oxygen demand removal efficiencies (90.2% ± 0.54% vs 73.1% ± 1.9%) and methane production rates (4082 ± 334 ml (standard temperature and atmospheric pressure, STP)/d vs 2640 ± 120 ml (STP)/d) than the non-amended control reactor. In addition, the consumption of volatile fatty acids (20.9 ± 3.4 mM vs 61.7 ± 2.0 mM) was accelerated. Microbial community analysis revealed that the addition of magnetite caused the enrichment of many bacterial genera known to form robust biofilms (i.e. Pseudomonas) that are also capable of extracellular electron transfer and methanogens from the genus Methanosarcina which have been shown to participate in direct interspecies electron transfer. These results show that magnetite addition could enhance the performance of anaerobic digesters treating high salinity wastewater., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Children younger than 36 months with fever without a source (FWS) are at risk of serious bacterial infections (SBI). The risk of occult bacteremia (OB) has been greatly reduced in vaccinated children. The aim of this study is to describe the epidemiology of SBI in children with FWS in our setting and to evaluate the performance of our management algorithm., Methods: We designed a prospective cohort study. We included children aged 0-36 months presenting with FWS in our emergency unit. Demographic and clinical characteristics, investigations, and management procedures were recorded at the time of inclusion. Information on clinical evolution, final diagnosis, and immunization history were obtained after 10 days. Potential predictors of SBI were compared between patients with and without SBI., Results: Between October 2015 and September 2017, 173 children were recruited, with a median age of 4.4 months (2.1-1). Of these children, 166 (96%) were up to date with their vaccinations. A total of 47 children (27%) had a final diagnosis of SBI, which were all urinary tract infections (UTI). Presence of chills (odds ratio [OR] 5.6, 95% confidence interval [CI] 1.3-24.3), fever for>2 days (OR 29.1, 95% CI 3.5-243.5), and age<9 months (OR: 45.3, 95% CI: 4.9-415.7) were statistically significant predictors of UTI in a multivariate logistic regression. The sensitivity and specificity of our management algorithm were 100% (95% CI: 92.4-100%) and 21.4% (14.6-29.6%), respectively., Conclusions: In the setting of high vaccination coverage, we only identified SBI related to UTIs. We could not identify any OB. Our management algorithm was able to identify all SBI, but specificity was low. Refined criteria for screening of UTI could slightly increase this., (Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Winter deicing salt application has led to water quality impairment as stormwater carries salt ions (Na + and Cl - ) through watersheds. Green infrastructure (GI) is a promising urban stormwater management practice, but its efficacy in managing salt is unknown. GI is not yet designed to remove salt, but may have potential to mitigate its loading to surface waters. Two roadside infiltration-based GI practices in Northern Virginia (bioretention and bioswale) were monitored year-round over 28 precipitation events to investigate the transport of salt through modern stormwater infrastructure. Stormwater runoff volumes and concentrations of salt ions entering and exiting each GI were monitored to determine reductions of salt ions. Both the bioretention and bioswale significantly reduced effluent surface loads of Cl - and Na + (76% to 82%), displaying ability to temporarily retain and infiltrate salts and delay their release to surface waters. Changes in bioretention soil chemistry revealed a small percentage of Na + was stored long-term by ion exchange, but no long-term Cl - storage was observed. Limited soil storage along with groundwater observations suggest the majority of salt removed from stormwater by the bioretention infiltrates into groundwater. Infiltration GI can buffer surface waters from salt, but are also an avenue for groundwater salt loading., 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 © 2020 Elsevier B.V. All rights reserved.)

Background: Lumbar manipulation is a commonly used treatment for low back pain, but little research evidence exists regarding practitioner biomechanics during manipulation. Most existing evidence describes rate of force production through the hands into instrumented manikins and it is unclear how the practitioner moves their body and legs to generate this force., Objectives: To identify and characterize important kinetic and kinematic factors in practitioners of varying experience performing lumbar manipulation in order to identify which factors distinguish experts from less experienced practitioners., Study Design: This was a cohort observational laboratory study., Methods: 43 male physical therapists (PT) and PT students (4 experts, 11 residents, 13 third year, and 15 first year students) performed 4 manipulations each on asymptomatic patient models. Angular and linear kinematics of the pelvis were measured using motion capture, and ground reaction forces were measured with force plates under the practitioner's feet., Results: Peak pelvic angular velocity was greater and in the opposite direction in experts compared to other groups in the frontal plane (p = 0.020) and transverse plane (p = 0.000). Experts had greater downward pelvic linear velocity than third year students and first year students (p = 0.000). Experts also demonstrated faster rate of vertical ground reaction force unloading during the manipulation (p = 0.002)., Conclusions: Expert performance of manipulation was characterized by increased speed of linear and angular pelvic motion, and increased modulation of vertical ground reaction force. These results help to inform educators and practitioners that teach and use this complex manual skill., Competing Interests: Declaration of competing interest NoneEthical approval: Approval for the study was provided by the Institutional Review Body of the University of Southern California., (Copyright © 2020 Elsevier Ltd. All rights reserved.)