• Non-invasive structural and metabolic retinal markers of disease activity in non-proliferative diabetic retinopathy.

      Weisner, Gwen; Blindbaek, Søren Leer; Tang, Fang Yao; Cheung, Carol Y; Henriksen, Jan Erik; Stefánsson, Einar; Peto, Tunde; Grauslund, Jakob; 1Department of Ophthalmology, Odense University Hospital, Odense, Denmark. 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 3Centre for Public Health, Queen's University Belfast, Belfast, UK. 4OPEN, Open Patient data Explorative Network, Odense University Hospital, Odense, Denmark. 5Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China. 6Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark. 7University of Iceland, Reykjavik, Iceland. 8Landspitali University Hospital, Reykjavik, Iceland. (Wiley, 2021-01-08)
      Purpose: Metabolic and structural microvascular retinal alterations are essential components in diabetic retinopathy (DR). The present study aimed to measure changes at different stages of non-proliferative DR (NPDR) and to explore interactions of imaging-based metrics. Methods: This cross-sectional, cohort study included 139 eyes from 80 diabetic patients. Each patient underwent dilated fundal examinations including colour fundus photography, retinal oximetry and optical coherence tomography angiography (OCTA), analysed by semi-automated and automated software. Diabetic retinopathy (DR) severity was classified according to the International Clinical Diabetic Retinopathy (ICDR) Severity Scale, ranging from no DR to severe NPDR (level 0-3). Retinal metabolism was evaluated by oximetry as retinal arteriolar (raSatO2 ) and venular oxygen saturation (rvSatO2 ), and macular microvascular structure was measured by OCTA as the area of foveal avascular zone (FAZ), vessel density (VD), vessel diameter index (VDI), FAZ circularity and fractal dimension (FD) in the superficial and deep retinal capillary plexus. Results: A trend for increasing rvSatO2 was found with increasing DR severity (51.3%, 53.3%, 54.2%, 59.8%, p = 0.02). Increasing severity of DR associated with decreasing FD in the superficial and deep plexus (p < 0.001 and p = 0.014), and in the superficial plexus decreasing VD (p < 0.001), increasing VDI (p = 0.003) and decreasing FAZ circularity (p = 0.006). A few interactions were identified between raSatO2 , rvSatO2 and VDI, but only in the deep capillary plexus (p < 0.01 and p < 0.01). Conclusion: Alterations of the venular retinal vascular oxygen saturation and microvascular structural abnormities were found continuously throughout the DR-spectrum. Given the sparse correlations between metabolic and structural abnormalities, it seems that these occur independently in DR. Keywords: diabetes; diabetic retinopathy; non-proliferative diabetic retinopathy; optical coherence tomography angiography; retinal oximetry.
    • The design of RIP belts impacts the reliability and quality of the measured respiratory signals.

      Montazeri, Kristofer; Jonsson, Sigurdur Aegir; Agustsson, Jon Skirnir; Serwatko, Marta; Gislason, Thorarinn; Arnardottir, Erna S; 1Nox Research, Nox Medical, 105, Reykjavik, Iceland. 2Nox Research, Nox Medical, 105, Reykjavik, Iceland. jons@noxmedical.com. 3Department of Engineering, Reykjavik University, Reykjavik, Iceland. 4Sleep Department, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 5Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 6Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 7Department of Computer Science, Reykjavik University, Reykjavik, Iceland. (Springer, 2021-01-07)
      Purpose: Evaluate the effect of respiratory inductance plethysmography (RIP) belt design on the reliability and quality of respiratory signals. A comparison of cannula flow to disposable cut-to-fit, semi-disposable folding and disposable RIP belts was performed in clinical home sleep apnea testing (HSAT) studies. Methods: This was a retrospective study using clinical HSAT studies. The signal reliability of cannula, thorax, and abdomen RIP belts was determined by automatically identifying periods during which the signals did not represent respiratory airflow and breathing movements. Results were verified by manual scoring. RIP flow quality was determined by examining the correlation between the RIP flow and cannula flow when both signals were considered reliable. Results: Of 767 clinical HSAT studies, mean signal reliability of the cut-to-fit, semi-disposable, and disposable thorax RIP belts was 83.0 ± 26.2%, 76.1 ± 24.4%, and 98.5 ± 9.3%, respectively. The signal reliability of the cannula was 92.5 ± 16.1%, 87.0 ± 23.3%, and 85.5 ± 24.5%, respectively. The automatic assessment of signal reliability for the RIP belts and cannula flow had a sensitivity of 50% and a specificity of 99% compared with manual assessment. The mean correlation of cannula flow to RIP flow from the cut-to-fit, semi-disposable, and disposable RIP belts was 0.79 ± 0.24, 0.52 ± 0.20, and 0.86 ± 0.18, respectively. Conclusion: The design of RIP belts affects the reliability and quality of respiratory signals. The disposable RIP belts that had integrated contacts and did not fold on top of themselves performed the best. The cut-to-fit RIP belts were most likely to be unreliable, and the semi-disposable folding belts produced the lowest-quality RIP flow signals compared to the cannula flow signal. Keywords: Obstructive sleep apnea (OSA); Respiratory airflow; Respiratory inductance plethysmography (RIP) belts; Signal quality; Signal reliability.
    • Changes in sleepiness and 24-h blood pressure following 4 months of CPAP treatment are not mediated by ICAM-1.

      Pak, Victoria M; Maislin, David G; Keenan, Brendan T; Townsend, Raymond R; Benediktsdottir, Bryndis; Dunbar, Sandra B; Pack, Allan I; Gislason, Thorarinn; Kuna, Samuel T; 1School of Nursing, Emory University, 1520 Clifton Road, 243, Atlanta, GA, 30322, USA. Victoria.m.pak@emory.edu. 2Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. 3Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 4Department of Sleep Medicine, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 5Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 6School of Nursing, Emory University, 1520 Clifton Road, 243, Atlanta, GA, 30322, USA. 7Sleep Medicine Section, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. (Springer, 2021-01-06)
      Objective: Continuous positive airway pressure (CPAP) therapy reduces circulating intercellular adhesion molecule 1 (ICAM-1) in adults with obstructive sleep apnea (OSA). ICAM-1 levels may affect the daytime sleepiness and elevated blood pressure associated with OSA. We evaluated the association of changes from baseline in ICAM-1 with changes of objective and subjective measures of sleepiness, as well as 24-h ambulatory blood pressure monitoring (ABPM) measures, following 4 months of CPAP treatment. Methods: The study sample included adults with newly diagnosed OSA. Plasma ICAM-1, 24-h ABPM, Epworth Sleepiness Scale (ESS), and psychomotor vigilance task (PVT) were obtained at baseline and following adequate CPAP treatment. The associations between changes in natural log ICAM-1 and changes in the number of lapses on PVT, ESS score, and 24-h mean arterial blood pressure (MAP) were assessed using multivariate regression models, controlling for a priori baseline covariates of age, sex, BMI, race, site, smoking status, physical activity, anti-hypertensive medications, AHI, and daily hours of CPAP use. Results: Among 140 adults (83% men), mean (± SD) body mass index (BMI) was 31.5 ± 4.2 kg/m2, and apnea-hyopnea index (AHI) was 36.8 ± 15.3 events/h. Sleepiness measures, although not ICAM-1 or ABPM measures, improved significantly following CPAP treatment. We observed no statistically significant associations between the change in ICAM-1 and changes in sleepiness, MAP, or other ABPM measures. Conclusion: Changes in ICAM-1 levels were not related to changes in sleepiness or ABPM following CPAP treatment of adults with OSA. Future work should explore whether or not other biomarkers may have a role in mediating these treatment outcomes in adults with OSA. Keywords: Ambulatory blood pressure monitoring; Continuous positive airway pressure; Intercellular adhesion molecule-1; Obstructive sleep apnea; Sleepiness.
    • Clinical practice guideline on gastrointestinal bleeding prophylaxis for critically ill patients: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

      Sverrisson, Kristinn Ö; Chew, Michelle S; Olkkola, Klaus T; Rehn, Marius; Yli-Hankala, Arvi; Møller, Morten Hylander; 1Department of Anaesthesia and Intensive Care Medicine, Landspítali University Hospital, Reykjavík, Iceland. 2Department of Anaesthesia and Intensive Care, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden. 3Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 4Division of Prehospital Services, Air Ambulance Department, Oslo University Hospital, Oslo, Norway. 5The Norwegian Air Ambulance Foundation, Drøbak, Norway. 6Faculty of Health Sciences, University of Stavanger, Stavanger, Norway. 7Department of Anaesthesia, Tampere University Hospital, Tampere, Finland. 8Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 9Department of Intensive Care, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. (Wiley, 2020-12-28)
      The Scandinavian Society of Anaesthesiology and Intensive Care Medicine Clinical practice Committee endorses the BMJ Rapid Recommendation Gastrointestinal bleeding prophylaxis for critically ill patients-a clinical practice guideline. The guideline serves as a useful decision aid for clinicians caring for critically ill patients, and can be used together with clinical experience to decide whether a specific critically ill patient may benefit from gastrointestinal bleeding prophylaxis. Keywords: AGREE II; clinical practice guideline; critical care; critically ill; gastrointestinal bleeding prophylaxis.
    • Pharmacokinetics of single and repeated oral doses of esomeprazole and gastrin elevation in healthy males and females.

      Helgadóttir, Hólmfríður; Lund, Sigrún H; Gizurarson, Sveinbjörn; Waldum, Helge; Björnsson, Einar S; 1Department of Internal Medicine, Division of Gastroenterology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 2deCODE genetics/Amgen Inc., Reykjavik, Iceland. 3Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland. 4Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. (Taylor & Francis, 2020-12-17)
      Objective: Gastrin elevation secondary to proton pump inhibitor (PPI) therapy is well documented. Recent studies have demonstrated a sex-related difference where females on PPIs have significantly higher baseline gastrin levels than males. The aim of the study was to analyse the pharmacokinetics of esomeprazole and short-term effect on serum gastrin levels and evaluate potential sex-related difference. Materials and methods: Healthy volunteers received 40 mg of esomeprazole daily for five days. After the 1st and 5th dose blood samples for fasting gastrin and pharmacokinetic analysis were collected at scheduled time-points for eight hours. Esomeprazole was analysed by liquid chromatography and gastrin concentrations were measured using radioimmunoassay. Results: A total of 30 volunteers were enrolled. Females had higher median baseline gastrin (pM) than males 12 (IQR 10-15) vs. 7 (IQR 4-11) (p = .03). In the study cohort, median gastrin levels rose from 10 (IQR 6-14) to 15 (IQR 13-20) (p = .0002). The serum levels for esomeprazole increased by an average of 299.8 ng/mL (p < .001) from day 1 to day 5. Comparison of the esomeprazole pharmacokinetic parameters between males and females revealed no significant sex-related differences. No significant correlation was found between the AUC and the gastrin level on day 5 (p = .15). Conclusions: In healthy volunteers, serum gastrin increased significantly after a four-day PPI-therapy. There was also a significant increase in serum esomeprazole from day 1 to day 5. The increase in gastrin and esomeprazole concentration was not related to sex and no significant sex-related difference was found in terms of pharmacokinetic parameters. European Clinical Trial Database (2015-002230-41). Keywords: Proton pump inhibitors; area under the serum concentration curve; gastrin; pharmacokinetics; pharmacology; sex-related difference.
    • Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.

      Modvig, S; Hallböök, H; Madsen, H O; Siitonen, S; Rosthøj, S; Tierens, A; Juvonen, V; Osnes, L T N; Vålerhaugen, H; Hultdin, M; et al. (Nature Publishing Group, Specialist Journals, 2020-12-14)
      PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p < 0.0001), 29 (HzR 2.7, p < 0.0001), and 79 (HzR 3.5, p < 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10-2 versus 5.2 × 10-3, p < 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD > 10-4 associated with a CIR5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.
    • Recent advances in the treatment of primary sclerosing cholangitis.

      Björnsson, Einar S; Kalaitzakis, Evangelos; 1Department of Internal Medicine, Faculty of Medicine, University of Iceland, Division of Gastroenterology and Hepatology, Landspitali University Hospital of Iceland. 2Department of Internal Medicine, University Hospital Heraklion, Faculty of Medicine, University of Crete , Rethymno, Greece. (Taylor & Francis, 2020-12-14)
      Introduction: PSC is a rare liver disease that leads frequently to cirrhosis and need for liver transplantation. No medical treatment is of proven value. Liver transplantation is the only curative therapy available. There is a big medical need to find medical therapy that can alter the natural history of the disease. Areas covered: The authors highlight advances in PSC, based on recent literature retrieved from PubMed until September 2020 regarding both medical and endoscopic biliary therapy. Future possibilities for treatment of PSC are discussed. Expert opinion: Biliary endoscopy is the cornerstone in the treatment of dominant strictures. Single-user peroral cholangioscopy is an emerging modality. Balloon dilatation therapy is the treatment of choice of dominant strictures. The most promising medical therapies showing efficacy in phase II trials are nor-Ursodeoxycholic acid, obethicolic acid, the non-steroidal FXR agonist Cilofexor and Aldafermin, a synthetic analogue of FGF-19. Antibiotics, particularly vancomycin have shown potential benefits, particularly in children but phase III studies are lacking. In observational studies of effects of biological therapy in patients with IBD/PSC adalimumab was associated with reduction in ALP. Results of liver transplantation are favorable but recurrence can be of clinical relevance particularly in patients transplanted before the age of 40.
    • Increased risk of inflammatory bowel disease among patients treated with rituximab in Iceland from 2001 to 2018.

      Kristjánsson, Valdimar B; Lund, Sigrún H; Gröndal, Gerður; Sveinsdóttir, Signý V; Agnarsson, Hjálmar R; Jónasson, Jón G; Björnsson, Einar S; 1Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 2Department of Internal Medicine, National University Hospital, Reykjavík, Iceland. 3Department of Pathology, National University Hospital, Reykjavík, Iceland. 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, National University Hospital, Reykjavík, Iceland. (Taylor & Francis, 2020-12-05)
      Objective: Immune-mediated diseases are on the rise after the introduction of powerful immunomodulating drugs. The objective of this study was to determine the population-based incidence rate of inflammatory bowel disease (IBD) among patients treated with the monoclonal antibody rituximab in Iceland and compare it to the baseline incidence rate of IBD in the general population. Methods: We identified all patients treated with rituximab in Iceland from 2001 to 2018 through a central medicine database. IBD cases were indexed from medical records and ICD-10 codes and further confirmed by colonoscopy- and pathology reports. An experienced pathologist compared the pathology of IBD cases with matched controls of IBD patients. Results: Lymphomas and related neoplasms were the most frequent indication for treatment with rituximab (n = 367) among the 651 patients included in the analysis. Following treatment, seven patients developed IBD: two cases of Crohn's disease, three with ulcerative colitis, and two with indeterminate IBD. The incidence rate of IBD among rituximab treated patients was 202 cases per 100,000 person-years. Comparing our data to IBD incidence in Iceland, rituximab treated patients have an age-adjusted hazard ratio of 6.6 for developing IBD. The risk did not correlate with dose or treatment duration. Prior diagnosis of an autoimmune illness did not increase the risk of IBD in rituximab treated patients. Conclusions: Patients on rituximab have a sixfold increased risk of developing IBD compared to the general population. This risk was not affected by the indication for treatment and was not associated with concurrent immune-mediated diseases. Summary This population-based retrospective cohort study included all patients receiving treatment with rituximab between 2001 and 2018 in Iceland and identified a sixfold increased risk of developing IBD when compared to the general population. Keywords: IBD-basic; IBD-clinical; Immunology; colonic-disorders; endoscopy-general.
    • Hepatotoxicity associated with ribociclib among breast cancer patients.

      Finnsdottir, Stefania; Sverrisdottir, Asgerdur; Björnsson, Einar S; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Oncology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2020-12-04)
    • Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.

      Hetland, Merete Lund; Haavardsholm, Espen A; Rudin, Anna; Nordström, Dan; Nurmohamed, Michael; Gudbjornsson, Bjorn; Lampa, Jon; Hørslev-Petersen, Kim; Uhlig, Till; Grondal, Gerdur; et al. (British Medical Association, 2020-12-02)
      Objective: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.
    • Clinical spectrum of coronavirus disease 2019 in Iceland: population based cohort study.

      Eythorsson, Elias; Helgason, Dadi; Ingvarsson, Ragnar Freyr; Bjornsson, Helgi K; Olafsdottir, Lovisa Bjork; Bjarnadottir, Valgerdur; Runolfsdottir, Hrafnhildur Linnet; Bjarnadottir, Solveig; Agustsson, Arnar Snaer; Oskarsdottir, Kristin; et al. (British Medical Association, 2020-12-02)
      Objective: To characterise the symptoms of coronavirus disease 2019 (covid-19). Design: Population based cohort study. Setting: Iceland. Participants: All individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription polymerase chain reaction (RT-PCR) between 17 March and 30 April 2020. Cases were identified by three testing strategies: targeted testing guided by clinical suspicion, open invitation population screening based on self referral, and random population screening. All identified cases were enrolled in a telehealth monitoring service, and symptoms were systematically monitored from diagnosis to recovery. Main outcome measures: Occurrence of one or more of 19 predefined symptoms during follow-up. Results: Among 1564 people positive for SARS-CoV-2, the most common presenting symptoms were myalgia (55%), headache (51%), and non-productive cough (49%). At the time of diagnosis, 83 (5.3%) individuals reported no symptoms, of whom 49 (59%) remained asymptomatic during follow-up. At diagnosis, 216 (14%) and 349 (22%) people did not meet the case definition of the Centers for Disease Control and Prevention and the World Health Organization, respectively. Most (67%) of the SARS-CoV-2-positive patients had mild symptoms throughout the course of their disease. Conclusion: In the setting of broad access to RT-PCR testing, most SARS-CoV-2-positive people were found to have mild symptoms. Fever and dyspnoea were less common than previously reported. A substantial proportion of SARS-CoV-2-positive people did not meet recommended case definitions at the time of diagnosis.
    • Economic Evaluation of Damage Accrual in an International Systemic Lupus Erythematosus Inception Cohort Using a Multistate Model Approach.

      Barber, Megan R W; Hanly, John G; Su, Li; Urowitz, Murray B; St Pierre, Yvan; Romero-Diaz, Juanita; Gordon, Caroline; Bae, Sang-Cheol; Bernatsky, Sasha; Wallace, Daniel J; et al. (Wiley, 2020-12)
      Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling. Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model. Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0. Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.
    • Decrement Evoked Potential Mapping to Guide Ventricular Tachycardia Ablation: Elucidating the Functional Substrate.

      Bhaskaran, Abhishek; Fitzgerald, John; Jackson, Nicholas; Gizurarson, Sigfus; Nanthakumar, Kumaraswamy; Porta-Sánchez, Andreu; 1University Health Network, University of Toronto, Ontario, Canada. 2University of Adelaide, Australia. 3John Hunter Hospital, Newcastle, Australia. 4Landspitali, Reykjavik, Iceland. 5Hospital Universitario Quirónsalud Madrid, Molecular Cardiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Spain. (Radcliffe Cardiology, 2020-12)
      Empirical approaches to targeting the ventricular tachycardia (VT) substrate include mapping of late potentials, local abnormal electrogram, pace-mapping and homogenisation of the abnormal signals. These approaches do not try to differentiate between the passive or active role of local signals as the critical components of the VT circuit. By not considering the functional components, these approaches often view the substrate as a fixed anatomical barrier. Strategies to improve the success of VT ablation need to include the identification of critical functional substrate. Decrement-evoked potential (DeEP) mapping has been developed to elucidate this using an extra-stimulus added to a pacing drive train. With knowledge translation in mind, the authors detail the evolution of the DeEP concept by way of a study of simultaneous panoramic endocardial mapping in VT ablation; an in silico modelling study to demonstrate the factors influencing DeEPs; a multicentre VT ablation validation study; a practical approach to DeEP mapping; the potential utility of DeEPs to identify arrhythmogenic atrial substrate; and, finally, other functional mapping strategies.
    • Development of an international Core Outcome Set (COS) for best care for the dying person: study protocol.

      Zambrano, Sofia C; Haugen, Dagny Faksvåg; van der Heide, Agnes; Tripodoro, Vilma A; Ellershaw, John; Fürst, Carl Johan; Voltz, Raymond; Mason, Stephen; Daud, María L; De Simone, Gustavo; et al. (BioMed Central, 2020-11-30)
      Background: In contrast to typical measures employed to assess outcomes in healthcare such as mortality or recovery rates, it is difficult to define which specific outcomes of care are the most important in caring for dying individuals. Despite a variety of tools employed to assess different dimensions of palliative care, there is no consensus on a set of core outcomes to be measured in the last days of life. In order to optimise decision making in clinical practice and comparability of interventional studies, we aim to identify and propose a set of core outcomes for the care of the dying person. Methods: Following the COMET initiative approach, the proposed study will proceed through four stages to develop a set of core outcomes: In stage 1, a systematic review of the literature will identify outcomes measured in existing peer reviewed literature, as well as outcomes derived through qualitative studies. Grey literature, will also be included. Stage 2 will allow for the identification and determination of patient and proxy defined outcomes of care at the end of life via quantitative and qualitative methods at an international level. In stage 3, from a list of salient outcomes identified through stages 1 and 2, international experts, family members, patients, and patient advocates will be asked to score the importance of the preselected outcomes through a Delphi process. Stage 4 consists of a face-to-face consensus meeting of international experts and patient/family representatives in order to define, endorse, and propose the final Core Outcomes Set. Discussion: Core Outcome Sets aim at promoting uniform assessment of care outcomes in clinical practice as well as research. If consistently employed, a robust set of core outcomes for the end of life, and specifically for the dying phase, defined by relevant stakeholders, can ultimately be translated into best care for the dying person. Patient care will be improved by allowing clinicians to choose effective and meaningful treatments, and research impact will be improved by employing internationally agreed clinically relevant endpoints and enabling accurate comparison between studies in systematic reviews and/or in meta-analyses. Keywords: Core outcomes set; Delphi study; End of life; Last days of life; Outcomes; Outcomes research; Palliative care.
    • Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

      Steinthorsdottir, Valgerdur; McGinnis, Ralph; Williams, Nicholas O; Stefansdottir, Lilja; Thorleifsson, Gudmar; Shooter, Scott; Fadista, João; Sigurdsson, Jon K; Auro, Kirsi M; Berezina, Galina; et al. (Nature Publishing Group, 2020-11-25)
      Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
    • Ketamine for the treatment of prehospital acute pain: a systematic review of benefit and harm.

      Sandberg, Mårten; Hyldmo, Per Kristian; Kongstad, Poul; Dahl Friesgaard, Kristian; Raatiniemi, Lasse; Larsen, Robert; Magnusson, Vidar; Rognås, Leif; Kurola, Jouni; Rehn, Marius; et al. (BMJ Publishing Group, 2020-11-24)
      Background: Few publications have addressed prehospital use of ketamine in analgesic doses. We aimed to assess the effect and safety profile of ketamine compared with other analgesic drugs (or no drug) in adult prehospital patients with acute pain. Methods: A systematic review of clinical trials assessing prehospital administration of ketamine in analgesic doses compared with other analgesic drugs or no analgesic treatment in adults. We searched PubMed, EMBASE, Cochrane Library and Epistemonikos from inception until 15 February 2020, including relevant articles in English and Nordic languages. We used the Cochrane and Grading of Recommendations Assessment, Development and Evaluation methodologies and exclusively assessed patient-centred outcomes. Two independent authors screened trials for eligibility, extracted data and assessed risk of bias. Results: We included eight studies (2760 patients). Ketamine was compared with various opioids given alone, and intranasal ketamine given with nitrous oxide was compared with nitrous oxide given alone. Four randomised controlled trials (RCTs) and one cluster randomised trial included 699 patients. One prospective cohort included 27 patients and two retrospective cohorts included 2034 patients. Five of the eight studies had high risks of bias. Pain score with ketamine is probably lower than after opioids as demonstrated in a cluster-RCT (308 patients) and a retrospective cohort (158 patients) study, Δvisual analogue scale -0.4 (-0.8 to 0.0) and Δnumeric pain rating scale -3.0 (-3.86 to -2.14), respectively. Ketamine probably leads to less nausea and vomiting (risk ratio (RR) 0.24 (0.11 to 0.52)) but more agitation (RR 7.81 (1.85 to 33)) than opioids. Conclusions: This systematic literature review finds that ketamine probably reduces pain more than opioids and with less nausea and vomiting but higher risk of agitation. Risk of bias in included studies is high.
    • Opportunistic genomic screening. Recommendations of the European Society of Human Genetics.

      de Wert, Guido; Dondorp, Wybo; Clarke, Angus; Dequeker, Elisabeth M C; Cordier, Christophe; Deans, Zandra; van El, Carla G; Fellmann, Florence; Hastings, Ros; Hentze, Sabine; et al. (Nature Publishing Group, 2020-11-22)
      If genome sequencing is performed in health care, in theory the opportunity arises to take a further look at the data: opportunistic genomic screening (OGS). The European Society of Human Genetics (ESHG) in 2013 recommended that genome analysis should be restricted to the original health problem at least for the time being. Other organizations have argued that 'actionable' genetic variants should or could be reported (including American College of Medical Genetics and Genomics, French Society of Predictive and Personalized Medicine, Genomics England). They argue that the opportunity should be used to routinely and systematically look for secondary findings-so-called opportunistic screening. From a normative perspective, the distinguishing characteristic of screening is not so much its context (whether public health or health care), but the lack of an indication for having this specific test or investigation in those to whom screening is offered. Screening entails a more precarious benefits-to-risks balance. The ESHG continues to recommend a cautious approach to opportunistic screening. Proportionality and autonomy must be guaranteed, and in collectively funded health-care systems the potential benefits must be balanced against health care expenditures. With regard to genome sequencing in pediatrics, ESHG argues that it is premature to look for later-onset conditions in children. Counseling should be offered and informed consent is and should be a central ethical norm. Depending on developing evidence on penetrance, actionability, and available resources, OGS pilots may be justified to generate data for a future, informed, comparative analysis of OGS and its main alternatives, such as cascade testing.
    • A European Research Agenda for Geriatric Emergency Medicine: a modified Delphi study.

      Mooijaart, Simon P; Nickel, Christian H; Conroy, Simon P; Lucke, Jacinta A; van Tol, Lisa S; Olthof, Mareline; Blomaard, Laura C; Buurman, Bianca M; Dundar, Zerrin D; de Groot, Bas; et al. (Springer, 2020-11-21)
      Purpose: Geriatric Emergency Medicine (GEM) focuses on delivering optimal care to (sub)acutely ill older people. This involves a multidisciplinary approach throughout the whole healthcare chain. However, the underpinning evidence base is weak and it is unclear which research questions have the highest priority. The aim of this study was to provide an inventory and prioritisation of research questions among GEM professionals throughout Europe. Methods: A two-stage modified Delphi approach was used. In stage 1, an online survey was administered to various professionals working in GEM both in the Emergency Department (ED) and other healthcare settings throughout Europe to make an inventory of potential research questions. In the processing phase, research questions were screened, categorised, and validated by an expert panel. Subsequently, in stage 2, remaining research questions were ranked based on relevance using a second online survey administered to the same target population, to identify the top 10 prioritised research questions. Results: In response to the first survey, 145 respondents submitted 233 potential research questions. A total of 61 research questions were included in the second stage, which was completed by 176 respondents. The question with the highest priority was: Is implementation of elements of CGA (comprehensive geriatric assessment), such as screening for frailty and geriatric interventions, effective in improving outcomes for older patients in the ED? Conclusion: This study presents a top 10 of high-priority research questions for a European Research Agenda for Geriatric Emergency Medicine. The list of research questions may serve as guidance for researchers, policymakers and funding bodies in prioritising future research projects. Keywords: Geriatric Emergency Medicine; Research prioritisation.
    • P300 Analysis Using High-Density EEG to Decipher Neural Response to rTMS in Patients With Schizophrenia and Auditory Verbal Hallucinations.

      Aubonnet, Romain; Banea, Ovidiu C; Sirica, Roberta; Wassermann, Eric M; Yassine, Sahar; Jacob, Deborah; Magnúsdóttir, Brynja Björk; Haraldsson, Magnús; Stefansson, Sigurjon B; Jónasson, Viktor D; et al. (Frontiers Research Foundation, 2020-11-20)
      Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment. Keywords: P300; TMS (repetitive transcranial magnetic stimulation); brain connectivity; high-density EEG; schizophrenia; spectral analysis; temporal analysis.
    • A nationwide study on inpatient opportunistic infections in patients with chronic lymphocytic leukemia in the pre-ibrutinib era.

      Steingrímsson, Vilhjálmur; Gíslason, Gauti Kjartan; Þorsteinsdóttir, Sigrún; Rögnvaldsson, Saemundur; Gottfreðsson, Magnús; Aspelund, Thor; Turesson, Ingemar; Björkholm, Magnus; Landgren, Ola; Kristinsson, Sigurdur Y; et al. (Wiley, 2020-11-19)
      Objective: Opportunistic infections in chronic lymphocytic leukemia (CLL) have been described in clinical trials, single-center studies, and case reports. We performed a nationwide study to estimate the incidence and impact of inpatient opportunistic infections. Methods: The incidence rate (IR) and incidence rate ratio (IRR) for Swedish CLL patients diagnosed 1994-2013, and matched controls were calculated, as well as the case-fatality ratio (CFR). Results: Among 8989 CLL patients, a total of 829 opportunistic infections were registered (IR 16.6 per 1000 person-years) compared with 252 opportunistic infections in 34 283 matched controls (IR 0.99). The highest incidence in the CLL cohort was for Pneumocystis pneumonia (200 infections, IR 4.03); Herpes zoster (146 infections, IR 2.94), and Pseudomonas (83 infections, IR 1.66) infections. The highest risk relative to matched controls was observed for Pneumocystis pneumonia (IRR 114, 95% confidence interval 58.7-252). The 60-day CFR for CLL patients with opportunistic infections was 23% (188/821), highest for progressive multifocal encephalopathy (5/7, 71%) and aspergillosis (25/60, 42%). Conclusion: We have uniquely depicted the incidence of rare and serious infections in CLL patients and found a relatively high incidence of Pneumocystis pneumonia. Of the most common opportunistic infections, CLL patients with aspergillosis had the poorest prognosis. Keywords: chronic lymphocytic leukemia; immunology and infectious diseases; lymphoproliferative diseases.