Are the results of the RATE-AF trial reproducible in daily practice? Clinical outcomes with digoxin vs beta-blocker for heart rate control in permanent atrial fibrillation

Background There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation (AF), in particular those with coexisting heart failure. In the recent RATE-AF trial that included patients with permanent AF and symptoms of heart failure, treatment with low-dose digoxin or bisoprolol did not result in statistically significant difference in quality of life at 6 months. The purpose of the study was to analyse whether the clinical outcomes may differ among unselected patients with permanent AF treated with digoxin or beta-blocker seen in daily practice. Methods All patients with atrial fibrillation (AF) seen in an academic institution were identified in a database. We examined the clinical course of 8962 consecutive patients with AF seen over a 10-year period. The adverse outcomes were investigated during follow-up and we identified the causes of death. Among them 1,787 patients had the RATE-AF criteria of inclusion (permanent AF, age ≥60 and NYHA ≥2), of whom 512 patients (29%) were treated with beta-blocker alone, 425 (24%) were treated with digoxin alone and 237 (13%) were treated with both a beta-blocker and digoxin. Outcomes in patients treated with beta-blocker alone or digoxin alone were compared after 1:1 propensity-score matching. Results After propensity score matching, 270 patients treated with beta-blocker were matched 1:1 with 270 patients treated with digoxin. In these patients (age 79±8 years, CHA2DS2VASc score 4.0±1.3), 125 deaths were recorded during a follow-up of 2.2±2.7 years (median 1.1, interquartile 0.1–3.5 years, yearly rate of death 10.4%) including 72 cardiovascular deaths (yearly rate 6.0%). Major clinical events (all-cause death, myocardial infarction, ischemic stroke or major bleeding) were recorded in 192 patients (yearly rate 19.1%). In this matched analysis, risk was not statistically significant in the 2 groups for all-cause death (HR 0.95, 95% CI 0.67–1.35 for beta-blocker use vs digoxin use), cardiovascular death (HR 1.23, 95% CI 0.77–1.96 for beta-blocker use vs digoxin use) or major clinical events (HR 0.98, 95% CI 0.74–1.31 for beta-blocker use vs digoxin use). Conclusion Our analysis included more patients and had a longer follow-up than in the RATE-AF trial, resulting in a 10-fold higher number of clinical events. We found that among patients with permanent AF and symptoms of HF, there was no statistically significant difference in the risk of all-cause death, cardiovascular mortality and major clinical events between those treated with digoxin or beta-blocker. Concerns regarding the use of digoxin, such as the narrow therapeutic window and drug interactions, were not issues resulting in worse clinically relevant cardiovascular outcomes with the approach used in the current study. FUNDunding Acknowledgement Type of funding sources: None.

Impact of type 2 targeting biologics on acute exacerbations of chronic rhinosinusitis

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are associated with significant morbidity and decreased quality of life. There are sparse data assessing the real-world impact of biologics on AECRS. Objectives: We sought to determine the impact of type 2‐targeting biologics on the frequency of medication use for AECRS episodes. Methods: Antibiotic and/or systemic corticosteroid courses for AECRS were identified in a retrospective study from November 2015 to February 2020, at a single academic health system. The estimated yearly rates for antibiotic and corticosteroid courses were evaluated before and after initiation of type 2 biologics. Results: One-hundred and sixty-five patients with chronic rhinosinusitis (CRS) had received either omalizumab (n = 12), mepolizumab (n = 42), benralizumab (n = 44), dupilumab (n = 61), or reslizumab (n = 6). Seventy percent had CRS with nasal polyps, and 30% had CRS without nasal polyps. All the patients had asthma. When all the biologics were combined, the estimated yearly rate for antibiotics for AECRS decreased from 1.34 (95% confidence interval [CI], 1.12‐1.59) to 0.68 (95% CI, 0.52‐0.88) with biologic use (49% reduction, p < 0.001). Those with frequent AECRS (three or more courses of antibiotics in the 1 year before biologic use) had a larger degree of reduction, with an estimated yearly rate of 4.15 (95% CI, 3.79‐4.55) to 1.58 (95% CI, 1.06‐2.35) with biologic use (n = 27; 62% reduction; p < 0.001). Within the total cohort, the estimated yearly rate for systemic corticosteroids for AECRS decreased from 1.69 (95% CI, 1.42‐2.02) to 0.68 (95% CI, 0.53‐0.88) with biologic use (60% reduction; p < 0.001). Conclusion: Type 2‐targeting biologics reduced medication use for AECRS. This suggested that biologics may be a therapeutic option for patients with frequent AECRS.

Diffusely abnormal white matter converts to T2 lesion volume in the absence of acute inflammation

Diffusely abnormal white matter (DAWM), characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive MS (SPMS). However, little is known about changes of DAWM over time and their relation to focal white matter lesions (FWML). The objectives of this work were: 1) To characterize the longitudinal evolution of FWML, DAWM, and DAWM that transforms into FWML, and 2) To determine whether gadolinium enhancement, known to be associated with the development of new FWML, is also related to DAWM voxels that transform into FWML. Our data included 4220 MRI scans of 689 SPMS participants, followed for 156 weeks and 2677 scans of 686 RRMS participants, followed for 96 weeks. FWML and DAWM were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, DAWM voxels at each visit that transformed into FWML on the last MRI scan as well as their overlap with gadolinium enhancing lesion masks were identified. Our results showed that the average yearly rate of conversion of DAWM-to-FWML was 1.27cc for SPMS and 0.80cc for RRMS. FWML in SPMS participants significantly increased (t=3.9; p=0.0001) while DAWM significantly decreased (t=-4.3 p<0.0001) and the ratio FWML:DAWM increased (t=12.7; p<0.00001). RRMS participants also showed an increase in the FWML:DAWM Ratio (t=6.9; p<0.00001) but without a significant change of the individual volumes. Gadolinium enhancement was associated with 7.3% and 18.7% of focal New T2 lesion formation in the infrequent scans of the RRMS and SPMS cohorts, respectively. In comparison, only 0.1% and 0.0% of DAWM-to-FWML voxels overlapped with gadolinium enhancement. We conclude that DAWM transforms into FWML over time, in both RRMS and SPMS. DAWM appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.

Trends in Adolescent Hip Arthroscopy From the PHIS Database: 2008 to 2018

Background: Previous studies have suggested that hip arthroscopy has been performed with increasing frequency. Few studies have examined this trend in the adolescent population. Purpose: The purpose of this study was to evaluate the trend in the frequency of hip arthroscopy in adolescents standardized by total orthopaedic surgeries in adolescents at pediatric hospitals in the United States. Methods: The Pediatric Health Information System (PHIS) database was queried for patients aged 10 to 19 years who underwent orthopaedic surgery at any of the PHIS-participating hospitals from 2008 to 2018. The subgroup of patients in this age cohort who underwent hip arthroscopy was identified using Current Procedural Terminology (CPT) procedure codes. The yearly rate was expressed as the number of hip arthroscopies per 1000 orthopaedic surgeries. A linear model was used to fit the data and illustrate the relative trend. Results: A total of 432309 orthopaedic surgeries including 9491 hip arthroscopies were performed for patients 10 to 19 years of age. Hip arthroscopies were performed at a yearly rate of 22 per 1000 orthopaedic surgeries. Over the 10-year period, the number of hip arthroscopies increased 6.2-fold, whereas the number of orthopaedic procedures increased 1.6-fold. There was a 3.9-fold increase in hip arthroscopies relative to total orthopaedic surgeries. Conclusion: The number of hip arthroscopic procedures in adolescent patients has increased by 3.9-fold times relative to total orthopaedic surgeries in adolescents over a 10-year span. This finding mirrors the trends in the adult population over similar time periods. This may be due to increasing participation in sports in the adolescent population as well as a better understanding of the diagnosis and treatment of femoroacetabular impingement and other sports-related hip pathologies. [Table: see text][Figure: see text]

Rate of Progression of Aortic Stenosis in Patients With Cancer

Patients with cancer and aortic stenosis (AS) are exposed to several factors that could accelerate the progression of AS. This study aimed to determine the cumulative incidence of AS progression and associated factors in these patients. This retrospective cohort study included patients with cancer, mild or moderate AS and at least two echocardiograms 6 months apart between 1996 and 2016 at MD Anderson Cancer Center. AS progression was defined by an increase in mean gradient of 20 mmHg or peak velocity of 2 m/s by spectral Doppler echocardiography or as requiring aortic valve replacement. Univariate and multivariable Fine-Gray models to account for the competing risk of death were used. One hundred and two patients were included and median follow-up was 7.3 years. Overall, 30 patients (29%) developed AS progression, while 48 (47%) died without it. Yearly rate of mean gradient change was 4.9 ± 3.9 mmHg and yearly rate of peak velocity change was 0.23 ± 0.29 m/s for patients who developed AS progression. In the univariate analysis, coronary artery disease (CAD), dyspnea, prevalent cyclophosphamide and beta-blocker use were associated with AS progression. In multivariable analysis, CAD and prevalent cyclophosphamide use for the time interval of more than 3 years of follow-up remained significantly associated with increased cumulative incidence of AS progression. In conclusion, patients with mild or moderate AS and cancer are more likely to die before having AS progression. AS progression is associated with CAD and prevalent cyclophosphamide use.

Ischemic Stroke in Patients With Sinus Node Disease, Atrial Fibrillation, and Other Cardiac Conditions

Background and Purpose— Atrial fibrillation (AF) is known to increase risk of ischemic stroke (IS), but the risk of IS in isolated sinus node disease (SND) is unclear. We compared the incidence of IS in patients with SND, patients with AF, and in a control population with other cardiac diseases (disease of the circulatory system using the International Classification of Diseases, Tenth Revision ). Methods— This French longitudinal cohort study was based on the national database covering hospital care for the entire population from 2008 to 2015. Results— Of 1 692 157 patients included in the cohort, 100 366 had isolated SND, 1 564 270 had isolated AF, and 27 521 had AF associated with SND. Incidence of IS during follow-up was higher in isolated patients with AF than in AF associated with SND (yearly rate 2.22% versus 2.06%) and in isolated patients with AF than in isolated patients with SND (yearly rate 2.22% versus 1.59%). The incidence of IS was lower in a control population with other cardiac conditions (n=479 108) compared with SND and patients with AF (0.96%/y, 1.59%/y, and 2.22%/y, respectively). After 1:1 propensity score matching, SND was associated with lower incidence of IS compared to AF (hazard ratio, 0.77 [95% CI, 0.73–0.82]) but higher incidence of IS compared to control population (hazard ratio, 1.27 [95%CI, 1.19–1.35]). Conclusions— Patients with SND had a lower risk of thromboembolic events than patients with AF but a higher risk than a control population with other cardiac diseases. Randomized clinical trial in a selected SND population, with, for example, a high CHA 2 DS 2 -VASc score, would be required to determine the value of IS prevention by anticoagulation.

P999Major adverse events with percutaneous left atrial appendage closure in patients with atrial fibrillation in real life setting

Transcatheter left atrial appendage (LAA) closure is an alternative strategy for stroke prevention in atrial fibrillation (AF) patients with an inacceptable risk of bleeding with oral anticoagulation (OAC). A better characterization of major adverse clinical events after LAA closure in daily practice is still needed. Methods We analysed data from all AF patients treated with Watchman or Amplatzer LAA closure according to European guidelines in 8 French cardiology departments. Antithrombotic management was decided for each patient on an individual basis. A Cox regression model was used for multivariable analysis of major adverse events. Yearly rate of ischemic stroke during follow-up was calculated and compared to that expected for a same risk score population. Yearly rate of bleeding was extrapolated from that reported with the HASBLED score. Results A total of 469 consecutive AF patients (299 males, 74.9±8.9 years old, mean CHA2DS2-VASc score 4.5±1.4, HASBLED score 3.7±1.0) received LAA closure from March 2012 to January 2017. There were 272 Watchman devices (58%) and 197 ACP devices (42%) implanted. At discharge, 36% received a single anti platelet therapy (APT), 23% received dual APT, 29% received OAC and no APT, 5% received OAC plus APT and 8% received no antithrombotic therapy. Mean follow up was 11.4 months (median 7, interquartile 3–22 months) during which 70 major adverse events (19 ischemic strokes, 18 major haemorrhages and 33 deaths) were recorded in 69 patients. The annual rate of ischemic stroke was 3.96%, which translates into a 13% relative risk reduction (95% CI −59 to 52%) as compared with the calculated stroke rate for similar CHA2DS2-VASc score after adjustment for exposure to APT and OAC. The annual rate of major bleeding in the study was 3.75%, which corresponds to a 48% relative risk reduction (95% CI 9 to 70%) as compared with the rate that would have been expected based on a comparable HAS-BLED score. Yearly rate of mortality was 7.4% (2.5 to 3 fold higher than in previous randomized trials) and the rate of non-cardiovascular death was 82%. None of the baseline characteristics was predictive of major adverse events, neither in univariate nor in multivariable analysis, which highlights the difficulty in identifying a risk of unfavourable outcome with simple tools. Conclusions AF patients treated with LAA closure may have a lower risk of stroke and bleeding events compared to their theoretical risk. However, our findings indicate that a high rate of major adverse events is observed in these patients during follow-up. This questions the suggested cost-effectiveness of the procedure (with models based on previous trials) for a real-life perspective. A better identification of patients with a relevant benefit of LAA closure is needed among those with long-term anticoagulation contraindication, both for an optimal management of each patient on an individual basis and for a global perspective with limited healthcare resources.

Population decline of the Eurasian Curlew in Akershus (southeastern Norway)

The Eurasian Curlew (Numenius arquata) is a species in decline, classified as near threatened (NT) worldwide, and vulnerable (VU) in Norway. In Akershus county, southeastern Norway, the population of breeding Eurasian Curlews was estimated at 50-60 pairs in 1982. No recent update exists of this population size estimate. In this study, we assessed the population size in 2017 in Akershus, and examined how the population size changed between 1971 and 2017 by using historical observation records of Eurasian Curlews. We estimated that there were 30 territories in Akershus in 2017 and found that the population declined by 47% since 1995 and 77% since 1971. In the period 1995-2017, the yearly rate of decline was 2.8%. We discuss possible reasons for the decline, such as intensive agricultural practices, high nest predation rates, and large-scale threats on the wintering grounds.

STRATEGI PENGEMBANGAN BISNIS PROPERTI UNTUK KAWASAN CENGKARENG BUSINESS CITY

Pertumbuhan besar pembangunan real estate di Jakarta terutama di dekat Bandara Internasional Soekarno-Hatta dan pertumbuhan pesat kondisi ekonomi Indonesia karena program tax amnesty yang diadakan oleh pemerintah, harus meningkatkan peluang bagi perusahaan pengembang real estate lokal dan internasional. Business plan ini akan memberikan informasi dan konsep dasar yang diperlukan oleh ahli strategi bisnis atau investor dalam mengevaluasi kelayakan aspek dan sebagai pedoman dan informasi strategis untuk manajer berikutnya yang mencoba mengembangkan konsep bisnis konstruksi yang sesuai di Cengkareng, Jakarta Barat yang merupakan lokasi yang dekat dengan bandara internasional. Konsep bisnis ini bertujuan untuk menjadi konsep dasar bagi pemasar dan ahli strategi bisnis di Kota Bisnis Cengkareng (CBC) untuk membangun kembali area situs kosong menjadi produk bangunan yang sesuai dan menguntungkan bagi investor dengan memberikan informasi, perhitungan, dan konsep desain yang berguna untuk selanjutnya proyek dalam CBC. Berdasarkan hasil studi kelayakan rencana bisnis, rencana bisnis ini dihitung untuk mencapai hasil yang baik untuk investasi dengan mendapatkan nilai NPV sebesar Rp 219.556.798.184,16, dengan menggunakan asumsi biaya modal 10%. Ia juga berencana untuk mendapatkan nilai IRR 30%, lebih besar dari tingkat tahunan 10%. Ini menunjukkan bahwa investasi untuk business plan ini dapat melebihi tingkat investasi yang ditujukan oleh investor CBC sendiri. The massive growth of real estate development in Jakarta especially in near area Soekarno-Hatta International Airport and rapid growth Indonesia economic condition due to tax amnesty program that held by government , should increase opportunity for the local and international real estate developer company . This business plan will provide the information and basic concept that needed by business strategist or investors in evaluating aspect feasibility and as guidelines and strategic information for next managers who try to develop suitable construction business concept in Cengkareng , Jakarta Barat which is the location itself near with international airport .This business concept aim to become basic concept for the marketers and business strategist in Cengkareng Business City (CBC) to redevelope blank site area into suitable and profitable building product for the investors by providing useful information , calculation , and design concept for next project in CBC . Based on result of businessn plan feasibility study , this business plan is calculated to achieve good results for investment by gaining NPV value of Rp219,556,798,184.16 , by using assumption cost of capital 10% . It also planned to gain IRR value 30 % , it bigger than yearly rate 10% . It shows that the investment for this business plan can exceed the rate of investment that aimed by CBC investors themselves .

Changing Face of Invasive Diagnostic Testing in the Era of Cell-Free DNA

Background Screening for fetal chromosomal anomalies using cell-free DNA (cfDNA) became clinically available in 2012. Since then, it has been widely adopted by providers and pregnant women with or without risk factors for aneuploidy. Concomitantly, the use of invasive diagnostic testing has been steadily declining. Objective To determine the magnitude of decline and changes in indications for invasive prenatal testing over the past 6 years. Study Design This was an institutional review board (IRB) approved retrospective cohort study that included women who were referred to our genetic division for consultation between January 2010 and December 2015 and decided to have invasive testing. The total number of patients choosing either option was determined for each year over the entire period and grouped by following indications: advanced maternal age, abnormal maternal serum screening (MS), abnormal ultrasound finding (US), personal or family history of genetic anomaly (FH), and others. Patients, who were advanced maternal age (AMA), were offered noninvasive prenatal screening or chorionic villus sampling (CVS) or amniocentesis in addition to routine nuchal translucency screening. The proportion of AMA patients choosing each of the three options was determined in a 6-month interval over the entire study period. Statistical analysis included logistic regression and chi-square test. Results While the number of patients receiving genetic counseling at our unit remained unchanged over the study period, the number of invasive procedures declined steadily from 429 amniocentesis (amnio) and 154 CVS in 2010 to 72 amnio and 60 CVS in 2015 (p < 0.001). Over the same period, the distribution of indications for diagnostic testing changed significantly. The proportion of procedures performed due to AMA or MS declined significantly over time (p < 0.001). The proportion of procedures performed for AMA declined at an average yearly rate of 24% (95% CI: 19–29%) and those performed for MS declined at a yearly rate of 13% (95% CI: 6–20%). Over the same period, the proportion of procedures performed due to US, FH, and other indications combined increased (p < 0.001) at an average rate of 45% (95% CI: 36–55%). A total of 5,188 women (61% of the study cohort) had genetic counseling for AMA. The percentage of patients opting for invasive procedures with AMA as the sole indication declined significantly from 38% in 2010 to 2% in 2015 (p < 0.0001) at an average rate of 29% (95% CI: 27–31%) reduction every 6 months. The rate of AMA women opting for cf DNA increased precipitously from 28% in 2012 to 91% in 2015 (p < 0.0001) at an average rate of 66% increase (95% CI: 57–76%) every 6 months. Conclusion The use of invasive procedures to diagnose chromosomal and genetic anomalies has declined over the past years, primarily due to the availability of cfDNA testing for AMA and abnormal serum screening. The new reality is that fewer women opt for invasive procedures and do so primarily following abnormal ultrasound findings or due to a history of chromosomal or genetic anomalies. Given these trends, it is likely that future generations of maternal–fetal medicine (MFM) subspecialists will not have the opportunity to acquire the necessary skills to perform these procedures, when needed.