Citations

Background: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. Methods and Results: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464–1610), and structural heart disease. Conclusions: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01920711.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P <5×10 − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Background Headache disorders comprise the three most prevalent medical disorders globally and contribute almost 20% to the total burden of neurologic illness. Although the experience of a recurrent headache disorder tends to be highly individualized, patient preferences tend to be a low priority in guidelines for the management of patients with headache. Methods In September 2017, the first Global Patient Advocacy Summit was convened, bringing together patients, patient advocates, patient advocacy organizations, healthcare professionals, pharmaceutical manufacturers, scientists, and regulatory agencies to advance issues of importance to patients affected by headache worldwide. Results Presentations and discussion covered multiple issues, such as improving access to appropriate medical care; incorporating the insights of independent patient advocates and advocacy organizations; leveraging the insights, experience and influence of leading health and neurological organizations; and raising awareness of the role of regulatory agencies in disease advocacy. Attendees agreed that it is important to understand and promote the global, regional, and local interests of people with headache disorders, as well as challenge the pervasive stigma associated with headache. They also agreed that those with severe, recurrent, or disabling headache disorders should have reliable access to competent medical care; healthcare professionals should have access to adequate training in Headache Medicine; global benchmarks should be established for accurate diagnosis and the use of evidence-based treatments in patients with headache; and that information is needed about consultation, diagnosis, and treatment of headache, particularly in regard to patient preferences. Conclusion Based on the group’s consensus around these issues, a series of statements was developed, and they are collectively presented herein as the Vancouver Declaration on Global Headache Patient Advocacy 2018.

ABSTRACTLocal, regional, and national registries have played an important role in the development of hip and knee arthroplasty and the treatment of patients with various maladies of these joints. Four arthroplasty registries stand out as leading forces behind the drive to popularize the use of registries and pursue the concept of evidence based medicine. The Mayo registry, started by Mark Coventry, is recognized as the oldest continuing registry for arthroplasty. The Harris Registry at Massachusetts General Hospital, along with the Mayo Registry, has greatly contributed to the advancement of arthroplasty surgery and have served an important role of identifying poorly performing implants and techniques in the United States. The Swedish Knee Arthroplasty Registry is the oldest national registry dedicated to joint arthroplasty and along with the Swedish Hip Arthroplasty Registry have established the infrastructure, analysis and reporting mechanisms, and leadership that has enabled other countries to subsequently develop national registries around the world. As more countries have adopted the concept of national registries, a new area of research is possible by pooling the resources of large registries as is now occurring with the Nordic countries. Several international organizations have been formed to promote future collaboration and develop international standards. The process of globalization of registries is a result of continued efforts over the past 50 years in improving and disseminating the knowledge gained from the early registries. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2319–2330, 2018.

PurposeThe task‐based assessment of image quality using model observers is increasingly used for the assessment of different imaging modalities. However, the performance computation of model observers needs standardization as well as a well‐established trust in its implementation methodology and uncertainty estimation. The purpose of this work was to determine the degree of equivalence of the channelized Hotelling observer performance and uncertainty estimation using an intercomparison exercise.Materials and MethodsImage samples to estimate model observer performance for detection tasks were generated from two‐dimensional CT image slices of a uniform water phantom. A common set of images was sent to participating laboratories to perform and document the following tasks: (a) estimate the detectability index of a well‐defined CHO and its uncertainty in three conditions involving different sized targets all at the same dose, and (b) apply this CHO to an image set where ground truth was unknown to participants (lower image dose). In addition, and on an optional basis, we asked the participating laboratories to (c) estimate the performance of real human observers from a psychophysical experiment of their choice. Each of the 13 participating laboratories was confidentially assigned a participant number and image sets could be downloaded through a secure server. Results were distributed with each participant recognizable by its number and then each laboratory was able to modify their results with justification as model observer calculation are not yet a routine and potentially error prone.ResultsDetectability index increased with signal size for all participants and was very consistent for 6 mm sized target while showing higher variability for 8 and 10 mm sized target. There was one order of magnitude between the lowest and the largest uncertainty estimation.ConclusionsThis intercomparison helped define the state of the art of model observer performance computation and with thirteen participants, reflects openness and trust within the medical imaging community. The performance of a CHO with explicitly defined channels and a relatively large number of test images was consistently estimated by all participants. In contrast, the paper demonstrates that there is no agreement on estimating the variance of detectability in the training and testing setting.

AbstractThe Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the “A, T, N System” (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.

Abstract Introduction. Male breast cancer (male BC) is a rare disease for which disease management is extrapolated from females. IMBC, an international consortium, which previously reported on clinico-pathological aspects, now reports on molecular subgroups revealed by RNA sequencing and their relation to patient outcome. Methods. Tumor samples from the retrospective MALE BC registry diagnosed between 1990-2010 and with pathology and outcome data (relapse-free- (RFS) and overall survival (OS)) were included (n=699). To allow the discovery of prognostic features, we selected, stratified for known risk factors (TN stage, grade, age at diagnose and adjuvant endocrine treatment), from the cohort 152 cases with poor (RFS &lt;= 4 yrs) and good outcome (RFS &gt; 7yrs) evenly distributed. Here, we report RNA sequencing results of the first 73 cases, 38 with poor and 35 with good outcome. RNA sequencing reads were used to generate gene expression values and to report transcripts carrying driver mutations. Unsupervised clustering identified subgroups and within subgroups differentially expressed genes were identified. The reported prognostic male BC subgroups M1 and M2 (Johansson BCR 2012(14):R31) were also annotated. All identified subgroups were related to outcome using logistic regression (p-value using Wald test). Results. Unsupervised clustering revealed 2 main subgroups of which group 1 was enriched for expression of ER target genes, WNT3 and genes from amplicons known for female BC, e.g. 19p13 (CCNE1), 8q24 (MYC), and 11q13 (CCND1). The biology of the smaller group 2 was less defined but TGFβ2 expression was high as were various kallikreins (KLK) including interestingly KLK3 (prostate specific antigen). Other known amplified regions [(8p11 (FGFR1), 20q13 (ZNF217) and 12q15 (MDM2)] and mutated transcripts [PIK3CA (H1047R/L/Q; E542K, E545K, N345K; 16% of cases), TP53 and SF3B1 (K700E) (2% of cases)] were identified. Profound tumor infiltrate gene expression was present in 5% of cases and one third of cases expressed proliferation markers. Except for TP53, none of these latter characteristics were unevenly distributed among the 2 main subgroups. ER and AR were highly correlated, particularly in group 1. The two main groups could be further subdivided. Group 1 comprised 3 subgroups of which subgroup 1a expressed TFF1/3 and NAT1, well-known ER targets, while subgroups 1b and 1c expressed other ER targets,respectively BEX1 and PITX1. HOXC cluster expression differentiated subgroup 1b from 1a and 1c. None of these intrinsic subgroups were, however, related to RFS. The previously reported M2 subgroup, which largely segregated with subclusters 1a and 1b, was associated with a better RFS than the M1 subgroup (OR=2.9; 95%CI 1.1-7.5; p-value=0.03). Conclusions. 1) Intrinsic subtypes of male BC were revealed and their subgrouping is defined by ER associated subsets of genes. 2) The association of the reported M2 subgroup of male BC with longer RFS was validated; 3) Currently identified biological characteristics of male BC may improve future treatments. The full report on 152 cases including a comparison to female BC will be presented at the conference. This research was funded by Breast Cancer Research Foundation Citation Format: Martens JWM, Sieuwerts A, Ponchet C, Smid M, de Weerd V, Slaets L, Piper T, van Deurzen CHM, Schroder CP, Stangle C, Kloosterman W, van Leeuwen-Stok E, Nilsson C, Vermeij J, Peeters S, Goulioti T, Nowaczyk M, Aebi S, Rubio IT, Kelly C, Bayani J, Porter P, Murray M, Hudis C, Middleton L, Korde L, Ruddy K, Winer E, Bogler O, van den Weyngaert D, dal Lago L, Fraser J, Benstead K, van Asperen C, Linderholm B, Hedenfalk I, Tryfonidis K, Giordano S, Bartlett J, Cardoso F. Molecular subtyping of male breast cancer by the International male breast cancer program (IMBC): EORTC 10085/TBCRC 0-29/BIG 2-07/NABCG/BOOG 2009-04 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-12.