Continuous peripheral perfusion index in patients admitted to hospital wards - An observational study.

INTRODUCTION: Risk patients admitted to hospital wards may quickly develop haemodynamic deterioration and early recognition has high priority to allow preventive intervention. The peripheral perfusion index (PPI) may be an indicator of circulatory distress by assessing peripheral perfusion non-invasively from photoplethysmography. We aimed to describe the characteristics of PPI in hospitalized patients since this is not well-studied. MATERIALS AND METHODS: Patients admitted due to either acute exacerbation of chronic obstructive pulmonary disease (AECOPD) or after major abdominal cancer surgery were included in this study. Patients were monitored continuously up to 96 hours with a pulse oximeter. Comparisons between median PPI each day, time of day and admission type were described with mean difference (MD) and were analysed using Wilcoxon rank sum test and related to morbidity and mortality. RESULTS: PPI data from 291 patients were recorded for a total of 9279 hours. Median PPI fell from 1.4 (inter quartile range, IQR 0.9-2.3) on day 1 to 1.0 (IQR 0.6-1.6) on day 4. Significant differences occurred between PPI day vs evening (MD = 0.18, 95% CI 0.16-0.20, P = .028), day vs night (MD = 0.56, 95% CI 0.49-0.62, P < .0001) and evening vs night (MD = 0.38, 95% CI 0.33-0.42, P = .002). No significant difference in median PPI between AECOPD and surgical patients was found (MD = 0.15, 95% CI -0.08-0.38, P = .62). CONCLUSION: Lower PPI during daytime vs evening and night-time were seen for both populations. The highest frequency of serious adverse events and mortality was seen among patients with low median PPI. The clinical impact of PPI monitoring needs further confirmation.

Experimental Validation and Deployment of Observability Applications for Monitoring of Low-Voltage Distribution Grids.

Future distribution grids will be subjected to fluctuations in voltages and power flows due to the presence of renewable sources with intermittent power generation. The advanced smart metering infrastructure (AMI) enables the distribution system operators (DSOs) to measure and analyze electrical quantities such as voltages, currents and power at each customer connection point. Various smart grid applications can make use of the AMI data either in offline or close to real-time mode to assess the grid voltage conditions and estimate losses in the lines/cables. The outputs of these applications can enable DSOs to take corrective action and make a proper plan for grid upgrades. In this paper, the process of development and deployment of applications for improving the observability of distributions grids is described, which consists of the novel deployment framework that encompasses the proposition of data collection, communication to the servers, data storage, and data visualization. This paper discussed the development of two observability applications for grid monitoring and loss calculation, their validation in a laboratory setup, and their field deployment. A representative distribution grid in Denmark is chosen for the study using an OPAL-RT real-time simulator. The results of the experimental studies show that the proposed applications have high accuracy in estimating grid voltage magnitudes and active energy losses. Further, the field deployment of the applications prove that DSOs can gain insightful information about their grids and use them for planning purposes.

Physiological abnormalities in patients admitted with acute exacerbation of COPD: an observational study with continuous monitoring.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) may rapidly require intensive care treatment. Evaluation of vital signs is necessary to detect physiological abnormalities (micro events), but patients may deteriorate between measurements. We aimed to assess if continuous monitoring of vital signs in patients admitted with AECOPD detects micro events more often than routine ward rounds. In this observational pilot study (NCT03467815), 30 adult patients admitted with AECOPD were included. Patients were continuously monitored with peripheral oxygen saturation (SpO2), heart rate, and respiratory rate during the first 4 days after admission. Hypoxaemic events were defined as decreased SpO2 for at least 60 s. Non-invasive blood pressure was also measured every 15-60 min. Clinical ward staff measured vital signs as part of Early Warning Score (EWS). Data were analysed using Fisher's exact test or Wilcoxon rank sum test. Continuous monitoring detected episodes of SpO2 < 92% in 97% versus 43% detected by conventional EWS (p < 0.0001). Events of SpO2 < 88% was detected in 90% with continuous monitoring compared with 13% with EWS (p < 0.0001). Sixty-three percent of patients had episodes of SpO2 < 80% recorded by continuous monitoring and 17% had events lasting longer than 10 min. No events of SpO2 < 80% was detected by EWS. Micro events of tachycardia, tachypnoea, and bradypnoea were also more frequently detected by continuous monitoring (p < 0.02 for all). Moderate and severe episodes of desaturation and other cardiopulmonary micro events during hospitalization for AECOPD are common and most often not detected by EWS.

Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial.

BACKGROUND: Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. METHODS: Seventy CAD patients, BMI 28-40 kg/m2 and age 45-75 years were randomised to (1) 12 weeks' aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks' AIT twice weekly or (2) a low energy diet (LED) (800-1000 kcal/day) for 8-10 weeks followed by 40 weeks' weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. RESULTS: Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO2peak 20.7 mL O2/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (- 8.4; - 6.1) and waist circumference by 6.6 cm (- 7.7; - 5.5) compared to 1.7 kg (- 0.7; - 2.6) and 3.3 cm (- 5.1; - 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO2peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. CONCLUSIONS: Both interventions were feasible. Both groups obtained improvements in VO2peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).

The impact of clinical trial monitoring approaches on data integrity and cost--a review of current literature.

PURPOSE: Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and their impact on subject safety data, data integrity, and monitoring cost. METHODS: The literature search was performed by keyword searches in MEDLINE and hand search of key journals. All publications were reviewed for details on how a monitoring approach impacted subject safety data, data integrity, or monitoring costs. RESULTS: Twenty-two publications were identified. Three publications showed that SDV has some value for detection of not initially reported adverse events and centralized statistical monitoring (CSM) captures atypical trends. Fourteen publications showed little objective evidence of improved data integrity with traditional monitoring such as 100 % SDV and sponsor queries as compared to reduced SDV, CSM, and remote monitoring. Eight publications proposed a potential for significant cost reductions of monitoring by reducing SDV without compromising the validity of the trial results. CONCLUSIONS: One hundred percent SDV is not a rational method of ensuring data integrity and subject safety based on the high cost, and this literature review indicates that reduced SDV is a viable monitoring method. Alternative methods of monitoring such as centralized monitoring utilizing statistical tests are promising alternatives but have limitations as stand-alone tools. Reduced SDV combined with a centralized, risk-based approach may be the ideal solution to reduce monitoring costs while improving essential data quality.

Coronary flow velocity reserve by echocardiography: feasibility, reproducibility and agreement with PET in overweight and obese patients with stable and revascularized coronary artery disease.

BACKGROUND: Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography of the LAD is used to assess microvascular function but validation studies in clinical settings are lacking. We aimed to assess feasibility, reproducibility and agreement with myocardial flow reserve (MFR) measured by PET in overweight and obese patients. METHODS: Participants with revascularized coronary artery disease were examined by CFVR. Subgroups were examined by repeated CFVR (reproducibility) or Rubidium-82-PET (agreement). To account for time variation, results were computed for scans performed within a week (1-week) and for all scans regardless of time gap (total) and to account for scar tissue for patients with and without previous myocardial infarction (MI). RESULTS: Eighty-six patients with median BMI 30.9 (IQR 29.4-32.9) kg × m(-2) and CFVR 2.29 (1.90-2.63) were included. CFVR was feasible in 83 (97 %) using a contrast agent in 14 %. For reproducibility overall (n = 21) limits of agreement (LOA) were (-0.75;0.71), within-subjects coefficient of variation (CV) 11 %, and reliability 0.84. For reproducibility within 1-week (n = 13) LOA were (-0.33;0.25), within-subjects CV 5 %, and reliability 0.97. Agreement with MFR of the LAD territory (n = 35) was without significant bias and overall LOA were (-1.40;1.46). Agreement was best for examinations performed within 1-week of participants without MI of the LAD-territory (n = 12); LOA = (-0.68;0.88). CONCLUSIONS: CFVR was highly feasible with a good reproducibility on par with other contemporary measures applied in cardiology. Agreement with MFR was acceptable, though discrepancy related to prior MI has to be considered. CFVR of LAD is a valid tool in overweight and obese patients.

Coronary microvascular function, insulin sensitivity and body composition in predicting exercise capacity in overweight patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) has a negative impact on exercise capacity. The aim of this study was to determine how coronary microvascular function, glucose metabolism and body composition contribute to exercise capacity in overweight patients with CAD and without diabetes. METHODS: Sixty-five non-diabetic, overweight patients with stable CAD, BMI 28-40 kg/m(2) and left ventricular ejection fraction (LVEF) above 35 % were recruited. A 3-hour oral glucose tolerance test was used to evaluate glucose metabolism. Peak aerobic exercise capacity (VO2peak) was assessed by a cardiopulmonary exercise test. Body composition was determined by whole body dual-energy X-ray absorptiometry scan and magnetic resonance imaging. Coronary flow reserve (CFR) assessed by transthoracic Doppler echocardiography was used as a measure of microvascular function. RESULTS: Median BMI was 31.3 and 72 % had impaired glucose tolerance or impaired fasting glucose. VO2peak adjusted for fat free mass was correlated with CFR (r = 0.41, p = 0.0007), LVEF (r = 0.33, p = 0.008) and left ventricular end-diastolic volume (EDV) (r = 0.32, p = 0.01) while it was only weakly linked to measures of glucose metabolism and body composition. CFR, EDV and LVEF remained independent predictors of VO2peak in multivariable regression analysis. CONCLUSION: The study established CFR, EDV and LVEF as independent predictors of VO2peak in overweight CAD patients with no or only mild functional symptoms and a LVEF > 35 %. Glucose metabolism and body composition had minor impact on VO2peak. The findings suggest that central hemodynamic factors are important in limiting exercise capacity in overweight non-diabetic CAD patients.

Age-related decline in mitral peak diastolic velocities is unaffected in well-trained runners.

OBJECTIVES: We examined whether diastolic left ventricular function in young and senior lifelong endurance runners was significantly different from that in sedentary age-matched controls, and whether lifelong endurance running appears to modify the age-related decline in diastolic left ventricular function. DESIGN: The study comprised 17 senior athletes (age: 59-75 years, running distance: 30-70 km/week), 10 young athletes (age: 20-36 years, matched for running distance), and 11 senior and 12 young weight-matched sedentary controls. Peak early (E) and late (A) mitral inflow and early (e') and late (a') diastolic and systolic (s') annular longitudinal tissue Doppler velocities were measured by echocardiography during four stages (rest, supine bike exercise at 30% and 60% of maximal workload, and recovery). RESULTS: The athletes had marked cardiac remodeling, while overall differences in mitral inflow and annular tissue Doppler velocities during rest and exercise were more associated with age than with training status. The senior participants had lower E/A at rest, overall lower E, e' and s', and greater E/e' compared to the young participants (all values of P < 0.05). The athletes had greater E/A (P = 0.004), but tissue Doppler velocities were not different from those of the controls. CONCLUSIONS: Lifelong endurance running was not found to be associated with major attenuation of the age-related decline in diastolic function at rest or during exercise.

Coronary flow reserve predicts cardiopulmonary fitness in patients with coronary artery disease independently of systolic and diastolic function.

AIMS: Despite revascularization and optimal medical treatment, patients with coronary artery disease (CAD) have reduced exercise capacity. In the absence of coronary artery stenosis, coronary flow reserve (CFR) is a measure of coronary microvascular function, and a marker of future poor outcome in CAD patients. The aim of this study was to examine the relationship among CFR, systolic and diastolic function, peripheral vascular function, and cardiopulmonary fitness in CAD patients. METHODS AND RESULTS: Forty patients with median left ventricular ejection fraction (LVEF) 49 (interquartile 46-55) with documented CAD without significant left anterior descending artery (LAD) stenosis underwent cardiorespiratory exercise test with measurement of VO2 peak, digital measurement of endothelial function and arterial stiffness, and an echocardiography with measurement of LVEF using the biplane Simpson model, mitral early (E) and late (A) inflow velocities, and tissue Doppler diastolic (e') and systolic (s') velocities. Peak coronary flow velocity (CFV) was measured in the LAD using pulse-wave Doppler. CFR was calculated as the ratio between peak CFV at rest and during vasodilator stress. Median CFR was 2.22 (1.90-2.62) and VO2 peak was 21.8 (17.6-25.5). VO2 peak correlated significantly with CFR (r = 0.57, P < 0.001), E/e' (r = -0.35, P = 0.04), and s' (r = 0.41, P = 0.01) and with LVEF (r = 0.35, P = 0.03). CFR remained independently associated with VO2 peak after adjustment for systolic and diastolic function. CONCLUSIONS: Coronary flow reserve measured noninvasively predicts cardiopulmonary fitness independently of resting systolic and diastolic function in CAD patients, indicating that cardiac output during maximal exercise is dependent on the ability of the coronary circulation to adapt to the higher metabolic demands of the myocardium.

Resting, night-time, and 24 h heart rate as markers of cardiovascular risk in middle-aged and elderly men and women with no apparent heart disease.

AIMS: Increased heart rate (HR) is a predictor of all-cause and cardiovascular (CV) mortality. We tested which measure of HR had the strongest prognostic value in a population with no apparent heart disease. METHODS AND RESULTS: Six hundred and fifty-three men and women between the age of 55 and 75 years were included in the Copenhagen Holter Study and underwent 48 h ambulatory electrocardiographic (ECG) monitoring. Resting HR was measured after at least 10 min of rest. Twenty-four-hour HR was derived from the mean time between normal-to-normal RR intervals (MEANNN). Night-time HR was derived from a 15 min sequence between 2:00 and 2:15 a.m. The median follow-up time was 76 months, and an adverse outcome was defined as all-cause mortality and the combined endpoint of CV death, acute myocardial infarction (AMI), and revascularization. All three measures of HR were significantly associated with all-cause mortality, also after adjustment for conventional risk factors. We found an association between all three measures of HR and CV events in analyses adjusted for sex and age. However, when adjusting for CV risk factors, the association with resting HR and 24 h HR disappeared. In a fully adjusted model, only night-time HR remained in the model, hazard ratio = 1.17 (1.05-1.30), P = 0.005. CONCLUSION: In middle-aged subjects with no apparent heart disease, all measures of increased HR were associated with increased mortality and CV risk. However, night-time HR was the only parameter with prognostic importance after multivariable adjustment.

Sources of drug information.

Modern healthcare requires clinicians to navigate through complex drug treatments. This review offers an overview of sources of drug information which can be used for general medication prescription and for challenging patient populations. Key considerations for pregnant or breastfeeding patients, those with renal impairment, and those with liver dysfunction are discussed. We also touch on adverse drug reactions and drug interactions. Finally, information about services from independent regional drug information centers, that can be used by clinicians, are provided.

Reevaluating the role of interferon-beta in psoriasis pathogenesis: A registry-based self-controlled study.

Interferon-beta has been suggested as a trigger of psoriasis, yet a systematic investigation is lacking. This study aimed to assess the risk of developing psoriasis following interferon-beta treatment, utilizing a pharmaco-epidemiological approach to investigate the role of interferon-beta in psoriasis pathogenesis. We included all treatment-naïve patients with multiple sclerosis (MS) in Denmark who initiated interferon-beta treatment for MS from January 1996 to June 2023. These patients were compared to a control cohort of patients with MS treated with other disease-modifying drugs. We compared the incidence rates of psoriasis before and during the treatment. Data for this study were extracted from the Danish MS Registry and integrated with information from other national Danish health registries. Among 7174 patients treated with interferon-beta, the incidence rate of psoriasis post-treatment initiation was slightly higher (2.01 per 1000 person-years) compared to the rate prior to treatment (1.67 per 1000 person-years). This increase did not achieve statistical significance (P = 0.53), with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 0.68-2.13). The control cohort showed an increase in psoriasis incidence post-treatment initiation (3.12 per 1000 person-years) compared to prior (1.11 per 1000 person-years), with an IRR of 2.80 (95% CI 1.36-4.77, P = 0.0038). This registry-based self-controlled study does not support the theory that interferon-beta acts as a trigger for psoriasis development.

Monitoring and treatment of hypercholesterolemia after an atherosclerotic cardiovascular disease event in Denmark from 2015 to 2020.

BACKGROUND AND AIMS: Lowering the blood concentration of low-density lipoprotein cholesterol (LDL-C), is a cornerstone in preventing atherosclerotic cardiovascular disease (ASCVD). Current European guidelines recommends LDL-C < 1.4 mmol/L for secondary prevention in high-risk patients. The aim of this study is to investigate monitoring and treatment of hypercholesterolemia one year after a ASCVD event. METHODS: Danish patients with hypercholesterolemia and an incident ASCVD event from 2015 to 2020 were included in this nationwide cohort study. Patients' LDL-C measurements and lipid-lowering treatment were followed for one year after ASCVD event, or until death or migration. Imputation was used to estimate absolute LDL-values when patients were unmeasured. RESULTS: A total of 139,043 patients were included in the study with a mean follow-up time of 10.4 months. During the one-year period, 120,020 (86%) patients had their LDL-C measured at least once, 83,723 (60%) patients were measured at least twice. During the period one to six months after ASCVD event 25,999 (19%) achieved an LDL-C < 1.4 mmol/L, 93,349 (67%) failed to achieve an LDL-C < 1.4 mmol/L, and 196,950 (14%) had died or migrated. Missing LDL-C values were estimated via imputation. At the end of month twelve, 60,583 (44%) patients were in statin monotherapy, 2926 (2%) were treated with other lipid-lowering treatment, 42,869 (31%) were in no treatment, and 32,665 (23%) had died or migrated. CONCLUSIONS: Many Danish patients are not appropriately followed-up with LDL-C measurements, and a substantial number of patients are not in lipid-lowering treatment one year after an ASCVD event.

Copenhagen study of overweight patients with coronary artery disease undergoing low energy diet or interval training: the randomized CUT-IT trial protocol.

BACKGROUND: Coronary artery disease (CAD) is accountable for more than 7 million deaths each year according to the World Health Organization (WHO). In a European population 80% of patients diagnosed with CAD are overweight and 31% are obese. Physical inactivity and overweight are major risk factors in CAD, thus central strategies in secondary prevention are increased physical activity and weight loss. METHODS/DESIGN: In a randomized controlled trial 70 participants with stable CAD, age 45-75, body mass index 28-40 kg/m2 and no diabetes are randomized (1:1) to 12 weeks of intensive exercise or weight loss both succeeded by a 40-week follow-up. The exercise protocol consist of supervised aerobic interval training (AIT) at 85-90% of VO2peak 3 times weekly for 12 weeks followed by supervised AIT twice weekly for 40 weeks. In the weight loss arm dieticians instruct the participants in a low energy diet (800-1000 kcal/day) for 12 weeks, followed by 40 weeks of weight maintenance combined with supervised AIT twice weekly. The primary endpoint of the study is change in coronary flow reserve after the first 12 weeks' intervention. Secondary endpoints include cardiovascular, metabolic, inflammatory and anthropometric measures. DISCUSSION: The study will compare the short and long-term effects of a protocol consisting of AIT alone or a rapid weight loss followed by AIT. Additionally, it will provide new insight in mechanisms behind the benefits of exercise and weight loss. We wish to contribute to the creation of effective secondary prevention and sustainable rehabilitation strategies in the large population of overweight and obese patients diagnosed with CAD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01724567.

Association between structural and functional treatment outcomes in neovascular age-related macular degeneration.

PURPOSE: The administration frequency of intravitreal anti-vascular endothelial growth factor (anti-VEGF) in neovascular age-related macular degeneration (AMD) have been widely discussed. The primary objective of the study was to explore the association between anatomical outcomes and changes in functional outcome. METHODS: This was a retrospective cohort study of patients with newly diagnosed neovascular AMD with a minimum of 12 months of follow-up. Only one eye per patient was included. Patients were treated according to the observe-and-plan or the pro-re-nata regimen. All patients were regularly examined from the time of diagnosis up to 24 months. The effect of intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelium detachment (PED) at any time point on visual acuity (VA) was tested, as well as the long-term effect and the risk of losing VA. Further, the variability of central retinal thickness (CRT) was calculated for each eyes' individual measures during the observation period, excluding the monthly loading phase. The prognostic effect of each factor on VA was estimated by regression analysis. The primary outcome measure was VA, which was correlated with the presence or absence of fluid, seen as IRF, SRF or PED. RESULTS: A total of 504 treatment naïve eyes from 504 patients was included. The presence of IRF was associated with lower VA at all visits (p < 0.001). However, the presence of SRF or PED was not significantly associated with worse VA at any time point during the observation period. Patients in the upper quartile of CRT variance had a greater loss in VA after 12 and 24 months (p < 0.001). CONCLUSIONS: In this retrospective cohort study, the presence of intraretinal fluid was associated with poorer visual outcome in neovascular AMD patients treated with anti-VEGF, but the presence of subretinal fluid and PEDs was not. This suggests that IRF is worse than subretinal fluid and PEDs for AMD outcomes and therefore requires the most intensive treatment. Further, we found that patients with the highest CRT variability during the study period had poorer visual outcomes after 12 and 24 months, indicating that stringent control of retinal fluid volume fluctuations is important to prevent visual acuity decline over time.

Potential for Treatment Interval Extension in Eyes with nAMD Disease Activity Post Loading Phase in HAWK and HARRIER.

INTRODUCTION: The HAWK and HARRIER studies evaluated the efficacy and safety of brolucizumab versus aflibercept in treatment-naïve eyes with neovascular age-related macular degeneration. Based on the study design, brolucizumab-treated eyes adjusted to a q8w regimen because the presence of disease activity (DA) at the end of the matched loading phase (Week 16) could not subsequently extend to a q12w interval. The aim of this post hoc analysis was to assess subsequent DA in this subgroup to determine the potential for interval extensions during the first year of treatment. METHODS: Pooled data from the brolucizumab 6 mg arms and aflibercept arms of HAWK and HARRIER were included. Presence of DA was determined by the masked investigator based on their assessment of functional and anatomical parameters measured by optical coherence tomography. DA was compared at DA assessments, conducted at Weeks 16, 20, 32, and 44; fluid was also assessed at the primary analysis at Week 48. RESULTS: Fewer brolucizumab- (22.8%) than aflibercept-treated (32.2%) eyes had DA at the first DA assessment at Week 16. In eyes with investigator-identified DA at Week 16, BCVA change from baseline to Week 96 was comparable between treatment arms. Fewer brolucizumab- than aflibercept-treated eyes had DA at each subsequent DA assessment in Year 1: 31.8% vs 39.1% (Week 20), 27.3% vs 43.5% (Week 32), and 17.3% vs 31.2% (Week 44). Fewer eyes treated with brolucizumab than aflibercept had intraretinal and/or subretinal fluid: 35.3% vs 43.5% (Week 20), 55.8% vs 69.6% (Week 32), 30.0% vs 43.1% (Week 44), and 48.6% vs 68.6% (Week 48). CONCLUSION: These findings indicate that, in eyes that still had DA 8 weeks after the final dose of loading phase, brolucizumab-treated eyes had improved fluid resolution and higher potential for treatment interval extension than aflibercept-treated eyes during the first year of treatment.

Insulin resistance and exercise tolerance in heart failure patients: linkage to coronary flow reserve and peripheral vascular function.

BACKGROUND: Insulin resistance has been linked to exercise intolerance in heart failure patients. The aim of this study was to assess the potential role of coronary flow reserve (CFR), endothelial function and arterial stiffness in explaining this linkage. METHODS: 39 patients with LVEF < 35% (median LV ejection fraction (LVEF) 31 (interquartile range (IQ) 26-34), 23/39 of ischemic origin) underwent echocardiography with measurement of CFR. Peak coronary flow velocity (CFV) was measured in the LAD and coronary flow reserve was calculated as the ratio between CFV at rest and during a 2 minutes adenosine infusion. All patients performed a maximal symptom limited exercise test with measurement of peak oxygen uptake (VO(2)peak), digital measurement of endothelial function and arterial stiffness (augmentation index), dual X-ray absorptiometry scan (DEXA) for body composition and insulin sensitivity by a 2 hr hyperinsulinemic (40 mU/min/m(2)) isoglycemic clamp. RESULTS: Fat free mass adjusted insulin sensitivity was significantly correlated to VO(2)peak (r = 0.43, p = 0.007). Median CFR was 1.77 (IQ 1.26-2.42) and was correlated to insulin sensitivity (r 0.43, p = 0.008). CFR (r = 0.48, p = 0.002), and arterial stiffness (r = -0.35, p = 0.04) were correlated to VO(2)peak whereas endothelial function and LVEF were not (all p > 0.15). In multivariable linear regression adjusting for age, CFR remained independently associated with VO2peak (standardized coefficient (SC) 1.98, p = 0.05) whereas insulin sensitivity (SC 1.75, p = 0.09) and arterial stiffness (SC -1.17, p = 0.29) were no longer associated with VO2peak. CONCLUSIONS: The study confirms that insulin resistance is associated with exercise intolerance in heart failure patients and suggests that this is partly through reduced CFR. This is the first study to our knowledge that shows an association between CFR and exercise capacity in heart failure patients and links the relationship between insulin resistance and exercise capacity to CFR.

Exploration of real-world outcomes and treatment patterns in patients treated with anti-vascular endothelial growth factors for neovascular age-related macular degeneration in Sweden.

PURPOSE: To analyse and compare the number and interval of anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD), as well as the visual development in patients followed up for one to three years in clinical practice and during different index periods. METHODS: This observational study included treatment-naïve eyes with nAMD from the Swedish Macula Register that started treatment between 2007 and 2017, stratified by different index periods (2007-2010, 2011-2013, 2014-2015 and 2016-2017) and by follow-up cohorts for each index period of one, two or three years (cohorts 1-3). Their intravitreal anti-VEGF treatment was assessed by number of injections, injection intervals, visual acuity (VA) and near VA change. RESULTS: From the earliest index period 2007-2010 to the latest 2016-2017, the number of injections increased for the comparable follow-up time; 6.2 ± 1.4 versus 8.3 ± 2.0 injections after 1 year of treatment, 4.8 ± 1.6 versus 6.7 ± 2.4 during year 2. The last injection interval was 73 ± 34 days after 1, 71 ± 33 after 2 and 67 ± 32 after 3 years of follow-up for the index period 2014-2015. For the same period, the percentage of eyes with at least two consecutive 12-16 weeks of injection interval over 1-, 2- and 3-year follow-up increased from 5.2%, 15.0%, to 17.5% respectively. Baseline VA for eyes indexed 2016-2017 increased and presented with 62.1 ± 13.4 letters compared with 57.7 ± 13.5 letters in 2007-2010; p < 0.0001. CONCLUSIONS: From the earliest to the latest index periods, the number of injections increased for the comparable follow-up time. Accordingly, baseline VA and near VA and their outcomes improved continuously.

A dataset for buffering delays due to the interaction between the Nagle algorithm and the delayed acknowledgement algorithm in cyber-physical systems communication.

In this article, we provide the research community with a dataset for the buffering delays that data packets experience at the TCP sending side in the realm of Cyber-Physical Systems (CPSs) and IoT. We focus on the buffering that occurs at the sender side due to the the adverse interaction between the Nagle algorithm and the delayed acknowledgement algorithm, which both were originally introduced into TCP to prevent sending out many small-sized packets over the network. These two algorithms are turned on (enabled) by default in most operating systems. The dataset is collected using four real-life operating systems: Windows, Linux, FreeBSD, and QNX (a real-time operating system). In each scenario, there are three separate different (virtual) machines running various operating systems. One machine, or an end-host, acts a data source, another acts as a data sink, and a third acts a network emulator that introduces artificial propagation delays between the source and the destination. To measure buffering delay at the sender side, we record for each sent packet the two time instants: when the packet is first generated at the application layer, and when it is actually sent on the physical network. In each case, 10 different independent experiment replications/runs are executed. Here, we provide the full distribution of all delay samples represented by the cumulative distribution function (CDF), which is expressed mathematically by F X ( x ) = P ( X ≤ x ) , where x is the delay measured in milliseconds, and P is the probability operator. The data exhibited here gives an impression of the amount and scale of the delay occurring at sender-side in TCP. More importantly, the data can be used to investigate the degree these delays affect the performance of cyber-physical systems and IoT or other real-time applications employing TCP.