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BACKGROUND: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy. OBJECTIVES: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. METHODS: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week26. RESULTS: Patients were assigned to initial triple (n=123) or initial double therapy (n=124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P=0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died. CONCLUSIONS: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy.

Background This pre-clinical study evaluated the efficacy of a novel shielding system to reduce scatter radiation in the cardiac catheterization laboratory. Methods Using a scatter radiation phantom in a standard cardiac catheterization laboratory, a radiation physicist recorded radiation measurements at 20 reference points on the operator side of the table. Measurements were made with fluoroscopy and cine with the C-arm in the posterior-anterior (PA) and 40 degrees left anterior oblique (LAO) orientations. Scatter radiation doses were compared with and without use of the shielding system. Results Use of the shielding system was associated with >94.2% reduction in scatter radiation across all reference points in the PA and LAO projections with fluoroscopy and cine. With the shielding system, dose reductions at the location of the primary operator ranged from 97.8% to 99.8%. At locations of maximum scatter radiation, use of the shielding system resulted in dose reductions ranging from 97.8% to 99.8% with fluoroscopy and from 97.9% to 99.8% with cine. Conclusions In this pre-clinical study, a novel radiation shielding system was observed to dramatically reduce scatter radiation doses. Based on these results, clinical testing is warranted to determine whether the shielding system will enable operators and staff to perform interventional procedures with less radiation exposure that may obviate the need to wear standard lead apparel. Indexing words Radiation safety; occupational health; occupational hazard.

Background and ObjectivesTo investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes.MethodsAt baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation—serum C-reactive protein (CRP)—and an epigenetic measure (DNA methylation [DNAm] signature of CRP). Linear models were used to examine the inflammation–brain health associations; mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning.ResultsWe demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = −0.197, 95% confidence interval [CI] −0.28 to −0.12, pFDR = 8.42 × 10−6), gray matter volume (β = −0.200, 95% CI −0.28 to −0.12, pFDR = 1.66 × 10−5), and white matter volume (β = −0.150, 95% CI −0.23 to −0.07, pFDR = 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP–cognitive association (up to 29.7%), dependent on lifestyle and health factors.DiscussionThese results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status.Classification of EvidenceThis study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.

BACKGROUND Gastric ischemic conditioning (GIC) is a strategy to promote neovascularization of the gastric conduit to reduce the risk of anastomotic complications following esophagectomy. Despite a number of studies and reviews published on the concept of ischemic conditioning, there remains no clear consensus regarding its utility. We performed an updated systematic review and meta-analysis to determine the impact of GIC, particularly on anastomotic leaks, conduit ischemia, and strictures. METHODS A systematic search of MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library was performed on February 5th, 2020 by a university librarian after selection of key search terms with the research team. Inclusion criteria included human participants undergoing esophagectomy with gastric conduit reconstruction, age ≥ 18, N ≥ 5, and GIC performed prior to esophagectomy. Our primary outcome of interest was anastomotic leaks. Our secondary outcome was gastric conduit ischemia, anastomotic strictures, and overall survival. Meta-analysis was performed with RevMan 5.4.1 using a Mantel-Haenszel fixed-effects model. RESULTS A total of 1712 preliminary studies were identified and 23 studies included for final review. GIC was performed in 1178 (53.5%) patients. Meta-analysis revealed reduced odds of anastomotic leaks (OR 0.67; 95% CI 0.46-0.97; I2 = 5%; p = 0.03) and anastomotic strictures (OR 0.48; 95% CI 0.29-0.80; I2 = 65%; p = 0.005). Meta-analysis revealed no difference in odds of conduit ischemia (OR 0.40; 95% CI 0.13-1.23; I2 = 0%; p = 0.11) and no difference in odds of overall survival (OR 0.54; 95% CI 0.29-1.02; I2 = 22%; p = 0.06). CONCLUSION GIC is associated with reduced odds of anastomotic leaks and anastomotic strictures and may decrease morbidity in patients undergoing esophagectomy. Further prospective randomized trials are needed to better identify the optimal patient population, timing, and techniques used to best achieve GIC.

Background The aim of the study was to examine the impact of diagnostic status (i.e., having a clinical diagnosis of irritable bowel syndrome (IBS) or being symptomatic but undiagnosed on quality of life (QoL)). We also examined whether the relationships between QoL and variables such as symptom frequency, pain catastrophizing, visceral sensitivity, and psychological distress are moderated by diagnostic status. Methods The online sample comprised 404 participants (Mage = 33.59, SD = 12.43), of which 98 had been diagnosed with IBS and 306 were symptomatic but undiagnosed. Results The findings suggest that even after adjusting for symptom frequency, those diagnosed with IBS experience poorer QoL, relative to those without a diagnosis. Moreover, there was evidence that the relationship between specific QoL domains (namely, sex, food avoidance, and health worry) and psychological variables (namely, pain catastrophizing, and depression) was moderated by diagnostic status. Conclusion The results indicate that diagnostic status in relation to IBS has psychological implications for QoL outcomes distinct from symptom frequency, age, and gender. This highlights a substantial gap in our current understanding of how a diagnosis of IBS can impact the lives of those suffering from IBS symptomology and calls into question the intended purpose of diagnosis.

Purpose Real-time spiral phase contrast MR (PCMR) enables rapid free-breathing assessment of flow. Target spatial and temporal resolutions require high acceleration rates often leading to long reconstruction times. Here we propose a deep artifact suppression framework for fast and accurate flow quantification. Methods U-Nets were trained for deep artifact suppression using 520 breath-hold gated spiral PCMR aortic datasets collected in congenital heart disease patients. Two spiral trajectories (uniform and perturbed) and two losses (Mean Absolute Error -MAE- and average structural similarity index measurement -SSIM-) were compared in synthetic data in terms of MAE, peak SNR (PSNR) and SSIM. Perturbed spiral PCMR was prospectively acquired in 20 patients. Stroke Volume (SV), peak mean velocity and edge sharpness measurements were compared to Compressed Sensing (CS) and Cartesian reference. Results In synthetic data, perturbed spiral consistently outperformed uniform spiral for the different image metrics. U-Net MAE showed better MAE and PSNR while U-Net SSIM showed higher SSIM based metrics. In-vivo, there were no significant differences in SV between any of the real-time reconstructions and the reference standard Cartesian data. However, U-Net SSIM had better image sharpness and lower biases for peak velocity when compared to U-Net MAE. Reconstruction of 96 frames took ~59 s for CS and 3.9 s for U-Nets. Conclusion Deep artifact suppression of complex valued images using an SSIM based loss was successfully demonstrated in a cohort of congenital heart disease patients for fast and accurate flow quantification.

Background/objectives Despite a high prevalence and association with poor outcomes, screening to identify cognitive impairment (CI) in the emergency department (ED) is uncommon. Identification of high-risk subsets of older adults is a critical challenge to expanding screening programs. We developed and evaluated an automated screening tool to identify a subset of patients at high risk for CI. Methods In this secondary analysis of existing data collected for a randomized control trial, we developed machine-learning models to identify patients at higher risk of CI using only variables available in electronic health record (EHR). We used records from 1736 community-dwelling adults age > 59 being discharged from three EDs. Potential CI was determined based on the Blessed Orientation Memory Concentration (BOMC) test, administered in the ED. A nested cross-validation framework was used to evaluate machine-learning algorithms, comparing area under the receiver-operator curve (AUC) as the primary metric of performance. Results Based on BOMC scores, 121 of 1736 (7%) participants screened positive for potential CI at the time of their ED visit. The best performing algorithm, an XGBoost model, predicted BOMC positivity with an AUC of 0.72. With a classification threshold of 0.4, this model had a sensitivity of 0.73, a specificity of 0.64, a negative predictive value of 0.97, and a positive predictive value of 0.13. In a hypothetical ED with 200 older adult visits per week, the use of this model would lead to a decrease in the in-person screening burden from 200 to 77 individuals in order to detect 10 of 14 patients who would fail a BOMC. Conclusion This study demonstrates that an algorithm based on EHR data can define a subset of patients at higher risk for CI. Incorporating such an algorithm into a screening workflow could allow screening efforts and resources to be focused where they have the most impact.

This study provides a comprehensive examination of the Oligocene–Miocene Ethiopian Flood Basalt Province (EFBP) within the Blue Nile (Abay) Basin (BNB), Ethiopia. Extensive logging through 29 new sections has enabled an updated stratigraphic account of the BNB to be elucidated and reveals the significance of intravolcanic sedimentary systems within the EFBP. Five sub- and intra-volcanic surfaces were modelled using spot heights to generate isopach maps that were used to constrain the thickness variations within the stratigraphy. Additionally, lineaments, Strahler stream segments and volcanic cones were mapped out from digital elevation models (SRTM DEM) and satellite data (ASTER and LANDSAT 8 imagery). These data were used in conjunction with the isopach maps to better understand the basinal controls on the distribution of intravolcanic sedimentary systems within the BNB. The study reveals how NNE and ESE/SE structural trends have influenced the distribution of volcanoes within the basin, which has in turn disrupted the distribution and lithofacies architecture of the volcanic sequences. The presence of intrabasinal ridges parallel to the major structural trends are also revealed, which formed relatively short-lived drainage divides. The implications of these intrabasinal highs on the composition and the reservoir potential of intravolcanic sedimentary successions are discussed.

The 2021 National report from IBD UK included responses from over 10 000 patients with inflammatory bowel disease, over 70% of whom reported having at least one flare in the last 12 months. As the first-line treatment for patients with mild and moderate ulcerative colitis, the action and delivery mechanisms of mesalazine are crucial for successful management of the disease. The choice of the most appropriate formulation of mesalazine and securing patient concordance and adherence to treatment remains a challenge for healthcare professionals. This article details the outcome of a roundtable discussion involving a group of gastroenterology consultants and specialist nurses which considered the importance of ensuring that patients have individualised mesalazine therapy before escalation to other treatments and gives recommendations for the management of patients with mild or moderate ulcerative colitis.

The uEXPLORER total-body PET/CT system provides a very high level of detection sensitivity and simultaneous coverage of the entire body for dynamic imaging for quantification of tracer kinetics. This article describes the fundamentals and potential benefits of total-body kinetic modeling and parametric imaging focusing on the noninvasive derivation of blood input function, multiparametric imaging, and high-temporal resolution kinetic modeling. Along with its attractive properties, total-body kinetic modeling also brings significant challenges, such as the large scale of total-body dynamic PET data, the need for organ and tissue appropriate input functions and kinetic models, and total-body motion correction. These challenges, and the opportunities using deep learning, are discussed.

This study aimed to explore the association between perceived isolation and symptoms of distress in people with GI disorders at the time of the pandemic; and to examine factors which moderate this relationship. This online cross-sectional survey was advertised in May–September 2020 via patient organisations and associated social media. Overall, 831 people (82% female, mean age 49 years) from 27 countries participated. A significant relationship between social isolation and psychological distress was noted (r = .525, p

ObjectiveThis study aimed to explore the impact of the coronavirus disease 2019 pandemic and postponement of elective surgical procedures for profoundly deaf patients awaiting cochlear implantation.MethodOpen-ended questionnaires were sent to all adult patients awaiting cochlear implantation surgery. Qualitative analysis was performed using a grounded theory approach.ResultsParticipants described a primarily negative impact on wellbeing from the surgery delay, expressing feelings of isolation or loneliness. Low mood, depression or hopelessness were commonly expressed by elderly participants; frustration and anxiety were described by young adults. Participants described a negative impact on their general daily life, describing difficulties communicating with facemasks and struggles with reliance on telephone communication because of social distancing. Despite these significant psychosocial challenges, only a minority described adaptive coping strategies.DiscussionProfoundly deaf patients may be at greater psychosocial risk because of unique challenges from their hearing disability. Our findings can be used to develop evidence-driven strategies to improve communication, wellbeing and quality of life.

Pulses of narrow line-width optical photons can be used to calibrate and test sub-2 eV full-width at half-maximum (FWHM) energy resolution transition-edge sensor (TES) microcalorimeters at low energies ( $ keV), where it is very challenging to obtain X-ray calibration lines comparable to (or narrower than) the detector resolution. This scheme depends on the ability to resolve the number of 3 eV photons in each pulse, which we have recently demonstrated up to photon numbers of about 300. At LTD-18 we showed preliminary results obtained with this technique on a 0.25 eV baseline resolution TES microcalorimeter designed for the ultra-high-resolution sub-array of the Lynx mission. The line-shape was well described by a simple Gaussian. However, the difficulty of delivering photons to the small 46 $\mathrm{\mu m}$ square absorbers resulted in a large thermal crosstalk signal, whose random nature is expected to rapidly degrade the observed energy resolution towards higher photon numbers/energies. We have since improved the coupling between the optical fiber and the TES absorber and report here our current results.

Background Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question Which factors determine the outcome of PH in COPD? Study Design and Methods We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry ClinicalTrials.gov; No.: NCT01347216 ; URL: www.clinicaltrials.gov

BACKGROUND: Controlling postprandial hyperinsulinaemia is important in insulin dysregulated (ID) horses to reduce the risk of laminitis. OBJECTIVES: To evaluate postprandial insulin responses of ID versus non-insulin dysregulated (NID) horses to feedstuffs varying in nonstructural carbohydrate (NSC) and crude protein (CP). STUDY DESIGN: Randomised crossover. METHODS: Eighteen adult mixed-breed horses (13.3 ± 2.2 years; 621 ± 78.8 kg) were individually fed [~1 g/kg body weight (BW)] specific feedstuffs within two crossover studies. Eight ID and eight NID were used in Study A, and 11 ID and 5 NID in Study B. In Study A, all horses were randomly fed once: cracked corn (CC: ~74% NSC & ~9% CP), ration balancer with low protein (RB-LP: ~15% NSC & ~17% CP), ration balancer with high protein (RB-HP: ~14% NSC and ~37% CP) and 50:50 mixture of RB-LP:RB-HP (MIX-P). In Study B, horses were randomly fed once: CC, RB-HP, steam-flaked corn (SF: ~73% NSC & ~10% CP), oat groats (OG: ~64% NSC & ~14% CP) and a low NSC pellet (L-NSC: ~6% NSC & ~12% CP). Blood was collected for insulin determination [radioimmunoassay (RIA)] before and 30, 60, 75, 90, 105, 120, 150, 180, 210 and 240-minute post-feeding in Study A and at 60-minute in Study B. Data were analysed via analysis of variance (ANOVA) for repeated measures after any required transformations. RESULTS: ID horses had significantly greater insulin responses (AUCi) than NID for all diets in both studies (P

Background Ataxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa). Objective To investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status. Design, setting, and participants This study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP). Outcome measurements and statistical analysis TURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM). Results and limitations Decreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM (p = 0.015 and p = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34–3.27, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups. Conclusions Decreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor–targeted therapies, as well as platinum-based chemotherapies. Patient summary Lower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls., Take Home Message In prostate cancer, lower ATM intensity is associated with increased cancer-specific mortality. Combining ATM with PTEN, patients with lower ATM and negative PTEN expression showed lower overall survival and prostate-specific mortality independent of Gleason grade group. Lower ATM/PTEN-negative tumors showed 2.5 times higher risk for cancer mortality compared with controls. Lower ATM/PTEN negative expression showed a decrease in overall survival and an increase in cancer mortality of about 3 and 4 yr, respectively.

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD’s association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised β: −0.201; 95% CI: [−0.36, −0.04]; pFDR = 0.022) and processing speed (−0.222; [−0.40, −0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD’s association with greater decline in general cognitive ability remained significant, prior to FDR correction (−0.222; [−0.39, −0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.

BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

BACKGROUND Gastrointestinal ultrasound is increasingly used for point of care assessment of inflammatory bowel disease. AIMS To explore the utility of gastrointestinal ultrasound as a point-of-care assessment tool from the perspectives of the clinician and patient. METHODS A prospective, observational cohort study was designed utilising routine outpatient consultations. Adult patients with inflammatory bowel disease were allocated to receive gastrointestinal ultrasound or not at the discretion of their treating clinician. Patients completed self-reported session experience questionnaires at study entry, immediately after their consultation, and 4 and 16 weeks later. Clinicians reported disease activity status, therapeutic decisions and clinical management. RESULTS Of 259 participants, mean age 40 (SD: 13) years, 54% male, 73 (28%) underwent ultrasound. Time since diagnosis was 9.2 (8.5) years (ultrasound) and 11.3 (9.2) years (no ultrasound). Immediately after ultrasound, patients who self-reported active disease reported better understanding of all aspects of their disease and disease symptoms were more confident in their ability to make informed decisions about managing their disease and had improved knowledge domain scores compared with the non-ultrasound group (all P

Background Staging guidelines for lung cancer recommend endobronchial ultrasound (EBUS) and systematic biopsy of at least three mediastinal lymph node (LN) stations for accurate staging. A four-point ultrasonographic score (Canada Lymph Node Score [CLNS]) was developed to determine the probability of malignancy in each LN. A LN with a CLNS of Research Question Do LNs considered triple normal on CT scanning, PET scanning, and CLNS evaluation require routine biopsy? Study Design and Methods LNs were evaluated for ultrasonographic features at the time of EBUS and the CLNS was applied. Triple-normal LNs were defined as cN0 on CT scanning (short axis, Results In total, 143 LNs from 57 cN0 patients were assessed. Triple-normal LNs showed a specificity and NPV of 60% (95% CI, 51.2%-68.3%) and 93.1% (95% CI, 85.6%-97.4%), respectively. After pathologic assessment, only 5.6% (n = 8/143) of triple-normal nodes were proven to be malignant. Interpretation At the time of staging for lung cancer, combining CT scanning, PET scanning, and CLNS criteria can identify triple-normal LNs that have a high NPV for malignancy. This raises the question of whether triple-normal LNs require routine sampling during EBUS and transbronchial needle aspiration. A prospective trial is required to confirm these findings.

Particle-unresolved Eulerian/Lagrangian simulations (DEM/CFD) of static homogenous particle ensembles are compared to direct numerical simulations (DNS) performed with the Lattice-Boltzmann method (LBM). Eliminating particles’ motion, the accuracy of the CFD can be examined in a targeted way. Local quantities at the particle scale such as drag, lift and Nusselt numbers are thus evaluated in detail. In particular, the influence of particles’ shape on numerical accuracy of the non-resolved DEM/CFD utilizing different correlations is studied. As particle shapes spheres, cylinders and cubes are examined applying the widely used multi-sphere method (MSM) for particle approximation. The simulations are conducted for two different exemplary voidages of e = 0.6 and e = 0.8 in the Reynolds number range of Re p = 10 - 300 and the Prandtl number Pr = 1 . The study reveals issues related to non-resolved DEM/CFD simulations especially in the case of non-spherical particles and provides important details for general DEM/CFD applications as well as for future closure derivations.

Background: Vaccine hesitancy has affected COVID-19 adult vaccination programs in many countries. Data on hesitancy amongst child and adolescent populations is largely confined to parent opinion. We investigated the characteristics of vaccine hesitant children and adolescents using results from a large, school-based self-report survey of the willingness to have a COVID-19 vaccination in students aged 9 –18 years in England. Methods: Data from the OxWell Student Survey on mental health, life experiences and behaviours were used, collected from four counties across England. Local authority partners recruited schools. The vaccine hesitancy question gave six response options and were clustered to inform delivery: eager and willing were categorised as vaccination ‘opt-in’, don't know and not bothered categorised as ‘undecided’, and unwilling and anti-vaccination categorised as ‘opt-out’. We conducted a multinomial regression to determine associations between vaccine hesitancy and sociodemographic, health behaviour and social connection variables. Findings: 27,910 students from 180 schools answered the vaccine hesitancy question between 14th May and 21st July 2021, of whom 13984 (50.1%) would opt-in to take a vaccination, 10322 (37.0%) were undecided, and 3604 (12.9%) would opt-out. A lower percentage of younger students reported that they would opt-in to vaccination, for example, 35.7% of 9-year-olds and 51.3% of 13-year-olds compared to 77.8% of 17-year-olds would opt-in to take a vaccination. Students who were ‘opt-out’ or ‘undecided’ (a combined ‘vaccine hesitant’ group) were more likely to come from deprived socioeconomic contexts with higher rates of home rental versus home ownership and their school locations were more likely to be in areas of greater deprivation. They were more likely to smoke or vape, spend longer on social media, feel that they did not belong in their school community but had lower levels of anxiety and depression. The vaccine hesitant students- the undecided and opt-out groups- were similar in profile, although the opt-out students had higher reported confirmed or probable previous COVID-19 infection than the opt-in group, whereas those undecided, did not. Interpretation: If government vaccination strategies move towards vaccinating younger school-aged students, efforts to increase vaccination uptake may be necessary. Compared with students who would opt-in, those who were vaccine hesitant had greater indicators of social deprivation and felt a lack of community cohesion by not feeling a sense of belonging at their school. There were indications that those students who would opt-out had higher levels of marginalisation and mistrust. If programmes are rolled out, focus on hesitant younger students will be important, targeting more marginalised and deprived young people with information from trusted sources utilising social media; improving access to vaccination centres with provision both in and outside school; and addressing fears and worries about the effects of the vaccine. The main limitation of this study is that the participant group may not be wholly representative of England or the UK, which may bias population-level estimates of willingness to be vaccinated. Funding: The Westminster Foundation, the National Institute for Health Research (NIHR) Applied Research Collaboration Oxford and Thames Valley at Oxford Health NHS Foundation Trust and the NIHR Oxford Health Biomedical Research Centre.

Objective The study aimed to determine long-term outcomes in patients with intraoperative electrical conduction block in an anatomically intact facial nerve (FN). Methods Single center retrospective review of prospectively collected database of all vestibular schwannoma surgeries between January 1, 2008 and August 25, 2015. Operative notes were reviewed and patients with anatomically intact FNs, but complete conduction block at the end of surgery were included for analysis. Results In total, 371 patients had vestibular schwannoma surgery of which 18 met inclusion criteria. Mean follow-up was 34.28 months and average tumor size was 28.00 mm. Seventeen patients had House-Brackmann Grade VI facial palsy immediately postoperatively and one patient was grade V. At 1 year, three patients remained grade VI (17%), two improved to grade V (11%), seven to grade IV (39%), six to grade III (33%), and one patient to grade II (6%). On extended follow-up, five patients (28%) had additional 1 to 2 score improvement in facial function. Subset analysis revealed no correlation of tumor size, vascularity, adherence to nerve, operative approach, extent of resection, splaying of FN, and recurrent tumor or sporadic tumors to the extent of FN recovery. Conclusion Intraoperative conduction block does not condemn a patient to permanent FN palsy. There is potential for a degree of recovery comparable with those undergoing nerve grafting. Our data do not clearly support a policy of same-surgery or early-postoperative primary nerve grafting in the event of a complete conduction block, and instead we favor monitoring for recovery in an anatomically intact nerve.

Background:\ud The pathophysiology of changes in magnetic resonance imaging (MRI) detected after a seizure is not fully understood.\ud \ud Objective:\ud To characterize and describe seizure‐induced changes detected by MRI.\ud \ud Animals:\ud Eighty‐one client‐owned dogs diagnosed with idiopathic epilepsy.\ud \ud Methods:\ud Data collected retrospectively from medical records and included anatomical areas affected, T1‐, T2‐weighted and T2‐FLAIR (fluid‐attenuated inversion recovery) appearance, whether changes were unilateral or bilateral, symmetry, contrast enhancement, mass effect, and, gray and white matter distribution. Diffusion‐ and perfusion weighted maps were evaluated, if available.\ud \ud Results:\ud Seizure‐induced changes were T2‐hyperintense with no suppression of signal on FLAIR. Lesions were T1‐isointense (55/81) or hypointense (26/81), local mass effect (23/81) and contrast enhancement (12/81). The majority of changes were bilateral (71/81) and symmetrical (69/71). The most common areas affected were the hippocampus (39/81) cingulate gyrus (33/81), hippocampus and piriform lobes (32/81). Distribution analysis suggested concurrence between cingulate gyrus and pulvinar thalamic nuclei, the cingulate gyrus and parahippocampal gyrus, hippocampus and piriform lobe, and, hippocampus and parahippocampal gyrus. Diffusion (DWI) characteristics were a mixed‐pattern of restricted, facilitated, and normal diffusion. Perfusion (PWI) showed either hypoperfusion (6/9) or hyperperfusion (3/9).\ud \ud Conclusions and Clinical Importance:\ud More areas, than previously reported, have been identified that could incur seizure‐induced changes. Similar to human literature, DWI and PWI changes have been identified that could reflect the underlying metabolic and vascular changes.

Background: Hippocampal atrophy is a key pathologic and magnetic resonance imaging (MRI) feature of human Alzheimer’s disease (AD). Hippocampal atrophy has not been documented via MRI in canine cognitive dysfunction (CCD), which is considered as the dog model of human AD.Aim: The purpose of this retrospective comparative volumetric MRI study was to compare total hippocampal volumes between successfully aging (control) dogs and dogs diagnosed with CCD.Methods: Mimics® software was used to derive total hippocampal volumes and total brain volumes from the MRI studies of 42 aging dogs (≥ 9 years): 16 dogs diagnosed with CCD and 26 successfully aging controls. Hippocampal volumes were normalized to total brain volume and these values were compared between groups using Mann–Whitney U tests.Results: Total hippocampal volume normalized to total brain volume was significantly less for CCD patients compared with control dogs (p = 0.04).Conclusion: The results of this study suggest that – similar to human AD – hippocampal atrophy is a pathological feature of CCD. This finding has potential importance for both investigating disease mechanisms related to dementia as well as future hippocampal-targeted therapies.

AimThe current study evaluated the feasibility and preliminary efficacy of a psychosocial intervention, the Kidney Optimal Health Program, in reducing symptoms of depression and anxiety in individuals with advanced chronic kidney disease.MethodsPatients with stage 4 or 5 chronic kidney disease were randomized to either a nine‐session psychosocial intervention programme or usual care. Feasibility was assessed through recruitment and retention rates and programme acceptability. Participants completed assessments of depression, anxiety and psychosocial health at baseline and at 3‐, 6‐ and 12‐month follow‐up. A repeated‐measures analysis of variance was used to compare groups on outcomes over time.ResultsOne hundred and twenty‐eight patients were screened for eligibility; 84 consented to participant and were randomized to receive the intervention (N = 42) or usual care (N = 42). 27 (32.1%) participants withdrew prior to baseline assessment. Of those who completed the baseline assessment (N = 57), trial retention was high (75.4% at 3‐month, 80.7% at 6‐month and 70.2% at 12‐month follow‐up). Participants reported high levels of programme acceptability. The patients who completed the intervention (N = 17) demonstrated significantly decreased depression at 12‐month follow‐up compared to the usual care group (N = 13).ConclusionThe results support the feasibility of the Kidney Optimal Health Program intervention in recruitment, retention and programme acceptability with an improved screening protocol. Preliminary support is provided for improvement in depressive symptoms in patients with advanced chronic kidney disease. Further investigation through a fully powered randomized controlled trial is warranted.

Highlights • First study of both serum and DNAm CRP associations with depression/neuroimaging. • Serum CRP is associated with somatic symptoms and reduced entorhinal cortex thickness. • DNAm CRP is associated with widespread reductions in white matter integrity. • Evidence for central effects of peripheral inflammation from serum and DNAm markers., Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases = 271, Ncontrols = 609). Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β = 0.145, PFDR = 6 × 10−4) and energy levels (β = 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β = −0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA= −0.12 to −0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = −0.15 versus βaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

Psychological distress is often observed in patients with gastrointestinal illness. To date, there has been limited research conducted to assess the prevalence and impact of post-traumatic stress disorder (PTSD) in gastrointestinal cohorts. The aim of this systematic review is to review the evidence for the prevalence of PTSD in gastrointestinal cohorts versus comparator groups (healthy controls and chronic illness groups), predictive factors associated with the development and management of PTSD and the impact on patient outcomes. Adult studies were identified through systematic searches of eight databases (MEDLINE, Embase, Emcare, PsycINFO, Ovid Nursing, CINAHL, Informit Health Collection, and Cochrane Library) in February 2020. The overall pooled prevalence rate of PTSD in GI cohorts was 36%; however, the prevalence rate in non-veteran-specific gastrointestinal cohorts of 18% across all GI classification groups is likely to be the more representative rate. The non-gastrointestinal chronic illness cohort PTSD prevalence rate was 11%. Predictors identified in the development of post-traumatic stress in gastrointestinal cohorts include: female gender, poor social support, life adversity, subjective pain, and dietary choices. Post-traumatic stress was found to exacerbate gastrointestinal symptoms in a Crohn’s Disease sample, whereby disease exacerbation was four times in those who met the criteria for probable PTSD. Post-traumatic stress symptoms affect around one in five individuals (non-veteran status) with a gastrointestinal condition. Further research is needed to understand the psychological and biological mechanisms by which PTSD increases the risk of developing and exacerbating gastrointestinal symptoms.

This article explores the reconfigurations of fish consumption practices in Myanmar in a context of rapid urbanization and changing availability of wild and farmed fish. Using a social practice lens, we analyze how everyday fish consumption practices change as people move from the rural Ayeyarwady Delta to Yangon city. We show how these reconfigurations are shaped by new routines in urban areas and the transition from capture fisheries to aquaculture. Our analysis reveals a growing detachment of consumers from production processes but, at the same time, a continuity in their everyday food routines through the upholding of “mother’s traditional cuisine”, and a general drive to preserve commensality. We demonstrate the value of using a social practices lens integrating micro- and meso-scale socio-cultural processes to understand dietary change by examining how rural-urban migration influence the sourcing, cooking, and eating of wild and farmed fish. These insights have implications for the everyday geography of consumption, including the persistence of socio-culturally appropriate food practices and the hybridisation of rural-urban food environments. As such, social practice approaches to the study of food consumption open up a means of understanding and even steering complex food system transitions in dynamically changing regions such as Southeast Asia.

Background The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model. Results Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (−37.30 ± 3.67 vs. −46.33 ± 0.73%) and white matter integrity (−19.66 ± 5.58 vs. −30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs. Conclusion The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients., Highlights • Tanshinone IIA loaded nanoparticles demonstrate antioxidative capabilities in neural stem cell cultures. • Tanshinone IIA loaded nanoparticles leads to reduced lesion volume, midline shift, and white matter damage post-stroke. • Tanshinone IIA loaded nanoparticle treatment leads to marked improvements in spatiotemporal and kinetic gait parameters.

Identification of specific antibodies in patient plasma is an essential part of many diagnostic procedures and is critical for safe blood transfusion. Current techniques require laboratory infrastructure and long turnaround times which limits access to those nearby tertiary healthcare providers. Addressing this challenge, a novel and rapid paper-based antibody test is reported. We validate antibody detection with reverse blood typing using IgM antibodies and then generalise the validity by adapting to detect SARS CoV-2 (COVID-19) antibodies in patient serum samples. Reagent red blood cells (RBC) are first combined with the patient plasma containing the screened antibody and a droplet of the mixture is then deposited onto paper. The light intensity profile is analyzed to identify test results, which can be detected by eye and/or with image processing to allow full automation. The efficacy of this test to perform reverse blood typing is demonstrated and the performance and sensitivity of this test using different paper types and RBC reagents was investigated using clinical samples. As an example of the flexibility of this approach, we labeled the RBC reagent with an antibody-peptide conjugate to detect SARS CoV-2 (COVID-19) antibodies in patient serum samples. This concept could be generalized to any agglutination-based antibody diagnostics with blood plasma.

Introduction There are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor MLN0128 (sapanisertib) in combination with the glutaminase inhibitor CB-839 HCl. Methods Phase 1 dose finding will use the queue-based variation of the 3 + 3 dose escalation scheme with the primary endpoint of identifying the recommended expansion dose. To confirm the acceptable tolerability of the recommended expansion dose, patients will subsequently enroll onto 1 of 4 expansion cohorts (n = 14 per cohort): (1) LSCC harboring NFE2L2 or (2) KEAP1 mutations, or (3) LUAD harboring KRAS/(KEAP1 or NFE2L2) coalterations, or (4) LSCC wild type for NFE2L2 and KEAP1. The primary endpoint of the dose expansion is to determine the preliminary efficacy of MLN0128/CB-839 combination therapy. Conclusion This phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced non–small-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations.

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV 1, FEV 1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species–capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

Funder: Samantha Dickson Brain Tumour Trust; doi: http://dx.doi.org/10.13039/501100000394, Purpose: Posterior fossa brain tumours (PFT) and their treatment in young children are often associated with subsequent cognitive impairment. However, reported follow-up periods rarely exceed 10 years. This study reports very long-term cognitive consequences of surviving an early childhood PFT. Methods: 62 adult survivors of a PFT, ascertained from a national register, diagnosed before 5 years of age, and a sibling control, received a single IQ assessment an average of 32 years (range 18–53) after initial diagnosis, using the Weschler Abbreviated Scale of Intelligence. Regression models were fitted to survivor–sibling pair differences on verbal and performance IQ (VIQ and PIQ) scores to investigate whether increasing time between PFT diagnosis and follow-up IQ assessment contributed to survivor–sibling IQ differences. Results: At follow-up, survivors had, on average, VIQ 15 points and PIQ 19 points lower than their siblings. There was no significant effect of time since diagnosis on survivor–sibling VIQ difference. Survivors who received radiotherapy showed no significant effect of time since diagnosis on survivor–sibling PIQ difference. Survivors who did not receive radiotherapy demonstrated a trend for it to reduce. Conclusions: VIQ and PIQ deficits persist in adulthood, suggesting the effect of a fixed injury imposing on cognitive development, rather than an ongoing pathological process. Implications for cancer survivors: The findings will help parents and others supporting survivors of an early life PFT to identify and plan for possible cognitive outcomes, and highlight the importance of early interventions to optimize cognitive function during the developmental period.

Identifying biological correlates of late life cognitive function is important if we are to ascertain biomarkers for, and develop treatments to help reduce, age-related cognitive decline. Here, we investigated the associations between plasma levels of 90 neurology-related proteins (Olink® Proteomics) and general fluid cognitive ability in the Lothian Birth Cohort 1936 (LBC1936, N = 798), Lothian Birth Cohort 1921 (LBC1921, N = 165), and the INTERVAL BioResource (N = 4451). In the LBC1936, 22 of the proteins were significantly associated with general fluid cognitive ability (β between −0.11 and −0.17). MRI-assessed total brain volume partially mediated the association between 10 of these proteins and general fluid cognitive ability. In an age-matched subsample of INTERVAL, effect sizes for the 22 proteins, although smaller, were all in the same direction as in LBC1936. Plasma levels of a number of neurology-related proteins are associated with general fluid cognitive ability in later life, mediated by brain volume in some cases., Late-life cognitive dysfunction is common, but the biological substrates are largely unknown. Here, the authors examined a panel of 90 neurology-related protein biomarkers and show that plasma levels of 22 of these proteins are associated with general fluid cognitive ability in later life.

Cross-border pharmacy sales of prescription drugs to U.S. patients by Canadian Internet pharmacies have generated significant controversy in the U.S. and Canada. Violative of U.S. legislation and Canadian professional codes of conduct, cross-border pharmacy has nonetheless flourished in response to strong demand and incomplete enforcement. Proponents laud the greater affordability of needed drugs provided by cross-border pharmacy; opponents decry the practice as unsafe, economically ill-advised and harmful to Canadian interests in the long term. This article evaluates the safety arguments that have been put forward by the U.S. Food and Drug Administration and others and concludes that they do not justify a prohibition on prescription drug imports from Canada. Similarly. Canadian professional regulatory bodies' objections to the participation of Canadian pharmacists and physicians in cross-border dispensing are a misapplication of conduct rules developed in another context. Objections to cross-border drug sates based on an economic analysis assume normative positions that should be explicitly identified and socially determined. On the other hand, if patient safety, professional responsibility and economic arguments fail to provide adequate support for a policy of prohibition, then self-interest in protecting domestic drug supplies and prices may support, at least from a Canadian perspective, some constraints on cross-border pharmacy.

This article provides insights gained during a four-year project funded by the European Cooperation in Science and Technology (COST) named «Network for Evaluation of One Health», which brought together over 250 scientists, decision-makers and practitioners with expertise and/or interest in One Health to investigate the added value of One Health and elaborate and evaluation protocol for One Health. Here, we present our reflections on the significance of these findings for our common practice as health professionals. Two initial findings lie at the core of this analysis, namely the observation that 1) One Health integrates knowledge from various sources in a transdisciplinary way and that there are as many concepts of health as participants in a specific initiative; and 2) the nature of complex One Health problems necessitates systems thinking and consideration of emergences as a One Health initiative is implemented. An analysis of eight case studies, i.e., evaluations of different One Health initiatives, found that the capacity of an initiative to facilitate knowledge integration improves with the age of the initiative, political boundaries of any nature hinder knowledge integration, and the prevailing competitive mentality in academia may be a serious obstacle to trusted collaboration required for interdisciplinary progress. The COST project also revealed a number of important knowledge gaps, namely the need for: a scalable definition of health, balancing expert advice and citizen participation to tackle health challenges, bridging the scission between the benefits and risks arising from nature, discussing whether egoism will define the boundary to sustainable health, a biocentric social justice framework, and comparative values associated with health of people, animals, plants and ecosystems. Furthermore, methodological challenges were identified such as participatory methods that are scalable to large populations, a specific skill set to facilitate transdisciplinary research, and governing mechanisms alternative to legislation and markets. Finally, as a rather unexpected outcome, the project has revealed the tension between the academic and societal demands for infallibility and predictability versus the need for honesty, authenticity, humbleness and emotion to permit the full unfolding of human creativity.

Delays in care negatively affect patients with potentially resectable thoracic malignant diseases. The Alberta Thoracic Oncology Program established an automatic referral process for patients with chest computed tomographic (CT) scans suggestive of malignant disease. The objective of this study was to determine whether automatic referral was associated with decreased time to referral or differences in the quality of referral information received.A single-center retrospective review of patients referred to a Canadian tertiary thoracic surgical center was performed. The time between the CT scan and the date of referral was calculated, and the type of information provided with the referral was tabulated. Automatic and traditional referral groups were compared using the Student t test, the Mann-Whitney U test, and multivariable analysis.A total of 689 patients met inclusion criteria, and 405 of these patients were automatic referrals. Average time to referral was shorter in the automatic referral group (4.7 days vs 23.6 days; P.001). Only 2 automatic referrals took longer than 30 days, compared with more than 25% of traditional referrals. Automatic referrals were always associated with a shorter time for referral on subgroup analysis of lung nodules, different referring physician types, and patient location. There was no difference between referral types in the number of referral data provided to the center.Automatic referrals for patients with potential thoracic malignant disease have a significant beneficial impact on delays in care, and this could result in improved outcomes, such as decreased upstaging and improved survival. This was not associated with a decrease in the amount of information provided with the referral. Thus, automatic referrals may streamline patient care without compromising quality.

Contains fulltext : 229465.pdf (Publisher’s version ) (Closed access) BACKGROUND: Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death. METHODS: This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO(2)), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed. FINDINGS: Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m(2) (SD 19·3) in the HMPO(2) group versus 46·7 mL/min per 1·73m(2) (17·1) in HMP (mean difference 3·7 mL/min per 1·73m(2), 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO(2) group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO(2) (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028). INTERPRETATION: HMPO(2) of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO(2) and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO(2) were suggested by analysis of secondary outcomes. FUNDING: European Commission 7th Framework Programme.

Laryngeal injury from intubation can substantially impact airway, voice, and swallowing, thus necessitating multidisciplinary interventions. The goals of this systematic review were (1) to review the types of laryngeal injuries and their patient-reported symptoms and clinical signs resulting from endotracheal intubation in patients intubated for surgeries and (2) to better understand the overall the frequency at which these injuries occur. We conducted a search of 4 online bibliographic databases (ie, PubMed, Embase, Cumulative Index of Nursing and Allied Health Literature [CINAHL], and The Cochrane Library) and ProQuest and Open Access Thesis Dissertations (OPTD) from database inception to September 2019 without restrictions for language. Studies that completed postextubation laryngeal examinations with visualization in adult patients who were endotracheally intubated for surgeries were included. We excluded (1) retrospective studies, (2) case studies, (3) preexisting laryngeal injury/disease, (4) patients with histories of or surgical interventions that risk injury to the recurrent laryngeal nerve, (5) conference abstracts, and (6) patient populations with nonfocal, neurological impairments that may impact voice and swallowing function, thus making it difficult to identify isolated postextubation laryngeal injury. Independent, double-data extraction, and risk of bias assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Collaboration's criteria. Twenty-one articles (1 cross-sectional, 3 cohort, 5 case series, 12 randomized controlled trials) representing 21 surgical studies containing 6140 patients met eligibility criteria. The mean patient age across studies reporting age was 49 (95% confidence interval [CI], 45-53) years with a mean intubation duration of 132 (95% CI, 106-159) minutes. Studies reported no injuries in 80% (95% CI, 69-88) of patients. All 21 studies presented on type of injury. Edema was the most frequently reported mild injury, with a prevalence of 9%-84%. Vocal fold hematomas were the most frequently reported moderate injury, with a prevalence of 4% (95% CI, 2-10). Severe injuries that include subluxation of the arytenoids and vocal fold paralysis are rare (

Objectives Mediastinal mass resection and thymectomy are complex and related operations that are core components of competency for a general thoracic surgeon and an important learning objective for thoracic surgery trainees. This study aimed to design a combined competency assessment instrument for mediastinal mass resection and thymectomy. Design A comprehensive competency assessment instrument was designed by a process of logical analysis by 3 expert thoracic surgeons with an interest in mediastinal surgery. The instrument was then assessed and refined using a modified Delphi process. Setting The Delphi questionnaire was distributed to all members of the Canadian Association of Thoracic Surgeons in 2018 to 2019. Participants The first round of the Delphi review was completed by 58 respondents (response rate 43.9%). Respondents represented all Canadian provinces with a wide range of clinical experience and a high rate of involvement in resident education. Results A first draft of the competency assessment instrument included 42 steps in 6 categories. A total of 3 rounds of Delphi review were performed. Cronbach's alpha for the final round was 0.83. Ultimately, 29 items were retained from the original instrument and two modified and three new items were added. The final instrument has 34 steps in 5 categories. Conclusions A nationwide consensus was established on the key components of assessing competence to perform mediastinal mass resection and thymectomy. The resulting instrument could be used to guide competency based assessments of thoracic surgeons and trainees.

Nonepithelial tumors of the larynx are rare and represent a minority of all laryngeal neoplasms. Imaging has an important role in the diagnosis, treatment planning, and surveillance of these entities. However, unfamiliarity with these neoplasms can cause diagnostic difficulties for radiologists, especially because many of the imaging findings are nonspecific. By using a systematic approach based on clinical history, patient age and gender, lesion location, endoscopic results, and specific imaging findings, the differential diagnosis can often be narrowed. These tumors typically affect the submucosal layer, so if a tumor has an intact mucosa at endoscopy, a nonepithelial neoplasm is the most likely diagnosis. Nonepithelial tumors of the larynx can arise from the laryngeal cartilage or muscle or from the surrounding lymphoid tissue or blood vessels. Consequently, imaging findings typically correspond to the specific cell type from which it originated. Recognizing specific features (eg, metaplastic bone formation, macroscopic fat, or enhancement pattern) can often help narrow the differential diagnosis. In addition, identification of noncircumscribed borders of the lesion and invasion of the adjacent structures is key to diagnosis of a malignant process rather than a benign neoplasm. Understanding the pathologic correlation is fundamental to understanding the radiologic manifestations and is ultimately crucial for differentiation of nonepithelial laryngeal neoplasms.

The Thai aquaculture sector faces a range of production, market and financial risks that extend beyond the private space of farms to include public spaces and shared resources. The Thai state has attempted to manage these shared risks through its Plang Yai (or ‘Big Area’) agricultural extension program. Using the lens of territorialization, this paper investigates how, through the Plang Yai program, risk management is institutionalized through spatially explicit forms of collaboration amongst farmers and between farmers and (non-)state actors. We focus on how four key policy instruments brought together under Plang Yai delimited multiple territories of risk management over shrimp and tilapia production in Chantaburi and Chonburi provinces. Our findings demonstrate how these policy instruments address risks through dissimilar but overlapping territories that are selectively biased toward facilitating the individual management of production risks, whilst enabling both the individual and collective management of market and financial risks. This raises questions about the suitability of addressing aquaculture risks by controlling farmer behavior through state-led designation of singular, spatially explicit areas. The findings also indicate the multiple roles of the state in territorializing risk management, providing a high degree of flexibility, which is especially valuable in landscapes shared by many users, connected to (global) value chains and facing diverse risks. In doing so we demonstrate that understanding the territorialization of production landscapes in a globalizing world requires a dynamic approach recognizing the multiplicity of territories that emerge in risk management processes.

Background: National immunisation programmes globally are at risk of suspension due to the severe health system constraints and physical distancing measures in place to mitigate the ongoing COVID-19 pandemic. We aimed to compare the health benefits of sustaining routine childhood immunisation in Africa with the risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through visiting routine vaccination service delivery points. Methods: We considered a high-impact scenario and a low-impact scenario to approximate the child deaths that could be caused by immunisation coverage reductions during COVID-19 outbreaks. In the high-impact scenario, we used previously reported country-specific child mortality impact estimates of childhood immunisation for diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, Streptococcus pneumoniae, rotavirus, measles, meningitis A, rubella, and yellow fever to approximate the future deaths averted before 5 years of age by routine childhood vaccination during a 6-month COVID-19 risk period without catch-up campaigns. In the low-impact scenario, we approximated the health benefits of sustaining routine childhood immunisation on only the child deaths averted from measles outbreaks during the COVID-19 risk period. We assumed that contact-reducing interventions flattened the outbreak curve during the COVID-19 risk period, that 60% of the population will have been infected by the end of that period, that children can be infected by either vaccinators or during transport, and that upon child infection the whole household will be infected. Country-specific household age structure estimates and age-dependent infection-fatality rates were applied to calculate the number of deaths attributable to the vaccination clinic visits. We present benefit–risk ratios for routine childhood immunisation, with 95% uncertainty intervals (UIs) from a probabilistic sensitivity analysis. Findings: In the high-impact scenario, for every one excess COVID-19 death attributable to SARS-CoV-2 infections acquired during routine vaccination clinic visits, 84 (95% UI 14–267) deaths in children could be prevented by sustaining routine childhood immunisation in Africa. The benefit–risk ratio for the vaccinated children is 85 000 (4900–546 000), for their siblings (60 years) is 96 (14–307). In the low-impact scenario that approximates the health benefits to only the child deaths averted from measles outbreaks, the benefit–risk ratio to the households of vaccinated children is 3 (0–10); if the risk to only the vaccinated children is considered, the benefit–risk ratio is 3000 (182–21 000). Interpretation: The deaths prevented by sustaining routine childhood immunisation in Africa outweigh the excess risk of COVID-19 deaths associated with vaccination clinic visits, especially for the vaccinated children. Routine childhood immunisation should be sustained in Africa as much as possible, while considering other factors such as logistical constraints, staff shortages, and reallocation of resources during the COVID-19 pandemic. Funding: Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation.

Background Quality of care in inflammatory bowel disease (IBD) has received much attention internationally; however, the available surveys focus on health professionals rather than patients. Aims To assess the experiences of healthcare for people living with IBD against established Australian IBD Standards. Methods An online cross-sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics and the Royal Flying Doctor Service. Participants completed a questionnaire incorporating items addressing the Australian IBD Standards 2016, the Picker Patient Experience Questionnaire, IBD Control Survey and the Manitoba Index. Results Complete data were provided by 731 respondents (71.5% female, median age 46 years, ranging from 16 to 84 years). While the majority (74.8%) were satisfied with their IBD healthcare, the care reported did not meet the Australian IBD Standards. Overall, 32.4% had access to IBD nurses, 30.9% to a dietician and 12% to a psychologist in their treating team. Participants managed by public IBD clinics were most likely to have access to an IBD nurse (83.7%), helpline (80.7%) and research trials (37%). One third of respondents reported waiting >14 days to see a specialist when their IBD flared. Participants received enough information, mostly from medical specialists (88.8%) and IBD nurses (79.4%). However, 51% wanted to be more involved in their healthcare. Conclusions These data show discordance between expectations of patients and national standards with current levels of service provision, which fail to deliver equitable and comprehensive IBD care.

Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo. Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.