Greater Progression Research Articles

Subclinical Atherosclerosis Progression in Low-Risk, Middle-Aged Adults: Carotid Leads Femoral in IMT Increase but Not in Plaque Formation.

Clinical data, risk factors, carotid/femoral intima-media thickness (IMT), and plaque presence were analyzed. Cardiovascular risk factors and scores increased significantly at follow-up. Both carotid and femoral mean IMT increased (p < 0.001). While plaque prevalence rose and was similar in both arteries (carotid: 4.8% to 17.9%, femoral: 3.6% to 17.7%, p < 0.001 for both), the progression of plaque burden was greater in femorals. Notably, the carotid mean IMT demonstrated a faster yearly progression rate compared to the mean femoral IMT. The prevalence of pathological nomogram-based mean IMT right or left was higher in the carotids (52.9% to 78.8%, p < 0.001) compared to femorals (23.2% to 44.7%, p < 0.001), with a significant increase at the end of follow-up in both territories. This study demonstrates significant subclinical atherosclerosis progression in low-risk, middle-aged adults over 5 years. Carotid arteries showed a faster progression rate of mean IMT and a higher prevalence of pathological nomogram-based mean IMT compared to the femoral arteries. However, plaque burden was similar in both territories, with greater progression in femorals. Identifying carotid and femoral atherosclerosis burden may be a valuable tool for risk stratification in this population.

Prevention of Radiographic Progression in Higher-Risk Patients with Rheumatoid Arthritis Using Filgotinib in PhaseIII Studies: Narrative Review of PostHoc Analyses.

Filgotinib is an oral preferential Janus kinase1 inhibitor that demonstrated significant reductions in radiographic progression, with an acceptable tolerability and safety profile, vs placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR; FINCH1) and vs MTX in MTX-naïve patients with RA (FINCH3). International treatment guidelines identify multiple poor prognostic factors (PPFs) associated with worse disease outcomes among patients with RA. However, questions remain both about the clinical utility of considering PPFs and about which PPFs should drive treatment decisions. Additionally, the role of radiographic findings in clinical practice continues to be discussed and to evolve. This review examines radiographic results from posthoc analyses of phase3 trials of filgotinib that examined subgroups with 4PPFs or with baseline estimated rapid radiographic progression (e-RRP). In MTX groups, there were trends toward greater progression among patients with 4PPFs or e-RRP, suggesting these subgroups may comprise a higher-risk population. Results show general consistency for the efficacy of filgotinib 200mg plus MTX vs placebo plus MTX/MTX monotherapy on radiographic assessments, including change from baseline in modified total Sharp score and proportions without radiographic progression, even among MTX-IR or MTX-naïve patients with 4PPFs or e-RRP who may be at higher risk of bone damage. Multivariate analysis identified multiple factors associated with baseline e-RRP status. This summary of the current understanding of benefits associated with filgotinib on radiographic progression and the relevance of baseline factors to these benefits may help inform treatment decisions for patients facing high risk of radiographic progression.

26-LB: Identifying the Risk of Diabetic Retinopathy Progression Using Machine Learning on Ultrawide Field Retinal Images

Estimating the risk of diabetic retinopathy (DR) progression is one of the most important and difficult tasks when caring for individuals with diabetic eye disease. Current DR severity scales have informed clinicians on the progression risk and provided recommendations for follow-up and treatment. The use of artificial intelligence (AI) algorithms may improve in this process. In this study, we developed and validated machine learning (ML) models for DR progression from ultrawide field (UWF) retinal images, which were labeled for baseline DR severity and progression based on clinician review of the images and 3-year longitudinal follow-up using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. This dataset has 8 classes: no DR nonprogression (14.62%), Mild nonproliferative DR (NPDR) progression (10.16%) /nonprogression (10.73%), Moderate NPDR progression (10.1%) /nonprogression (15.85%), Severe NPDR progression (11.27%) /nonprogression (10.68%), and proliferative DR (16.55%). A total of 9970 unique images were split into the train, the validation, and the test datasets based on 60-20-20 proportions. The class imbalance was addressed during model building through data augmentation. The ResNet model fine-tuned on this dataset has a classification test accuracy of 81% and an AUC of 0.967 on the test dataset. The objective of the model is to reduce false negatives, which refers to predicting a class that is less progressive than the true label. The predicted labels for 91% of the images were either correct labels or were the labels with greater progression than the original labels. These findings demonstrate the accuracy and feasibility of using machine learning models for identifying DR progression developed using UWF images. Potentially, the use of machine learning algorithms may further refine the risk of disease progression and personalize screening intervals that may reduce costs and improve vision-related outcomes. Disclosure A. Nigam: None. J. Sun: None. V. Subhash: None. P. S. Silva: Research Support; Optos plc., Optomed, Speaker's Bureau; Novartis, Roche Pharmaceuticals, Bayer Inc.

A Distress-Processing Model for Clients in Suicidal Crisis.

Background: While crisis intervention frameworks have indicated the importance of clients in suicidal crisis better understanding their distress to decrease suicidality, it is unclear how clients in suicidal crisis process their distress. Aims: To develop (Study 1) and validate (Study 2) a sequential distress-processing model for clients in suicidal crisis. Methods: Applying task analysis, Study 1 consisted of three phases, which resulted in a theoretically and empirically informed model. In Study 2, we examined the distress-processing model's validity using a longitudinal design. In both studies, data were online crisis chats with adults in suicidal crisis. Results: In Study 1, we developed a sequential five-stage distress-processing model: (Stage 1) unengaged with distress, (Stage 2) distress awareness, (Stage 3) distress clarity, (Stage 4) distress insight, and (Stage 5) applying distress insight. In Study 2, the model's validity was supported via evidence that (H1) progression through the processing stages was sequential and (H2) clients with good outcomes had greater progression in their processing than clients with poor outcomes. Limitation: Clients who were suicidal but did not disclose their suicidality were not included. Conclusion: Our findings provide a framework for conceptualizing and operationalizing how clients move through suicidal crises, which can facilitate intervention and research developments.

FIVE-YEAR INCIDENCE OF FELLOW EYE NEOVASCULAR INVOLVEMENT IN AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY IN AN ASIAN POPULATION

To assess 5-year cumulative incidence and risk factors of fellow eye involvement in Asian neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy. In a prospective cohort study of Asian nAMD and polypoidal choroidal vasculopathy, the fellow eyes were evaluated for exudation. The 5-year incidence of exudation was compared between nAMD and polypoidal choroidal vasculopathy. A total of 488 patients were studied. The 5-year incidence of exudation in fellow eyes was 16.2% (95% confidence interval: 12.0-20.2). Polypoidal choroidal vasculopathy compared with nAMD in the first eye was associated with lower fellow eye progression (9.8% [95% confidence interval: 5.1-14.3]) vs. 22.9% [95% confidence interval: 15.8-29.3], P < 0.01). Drusen (hazards ratio 2.11 [95% confidence interval: 1.10-4.06]), shallow irregular retinal pigment epithelium elevation (2.86 [1.58-5.18]), and pigment epithelial detachment (3.01 [1.27-7.17]) were associated with greater progression. A combination of soft drusens and subretinal drusenoid deposits, and specific pigment epithelial detachment subtypes (multilobular, and sharp peaked) were associated with progression. Pigment epithelial detachment, shallow irregular retinal pigment epithelium elevation, and new subretinal hyperreflective material occurred at 10.4 ± 4.2 months, 11.1 ± 6.0 months, and 6.9 ± 4.3 months, respectively, before exudation. The 5-year incidence of fellow eye involvement in Asian nAMD is lower than among Caucasians because of a higher polypoidal choroidal vasculopathy prevalence. Drusens, shallow irregular retinal pigment epithelium elevation, and pigment epithelial detachment are risk factors for fellow eye progression.

The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study

We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues. Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months. In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8× 103 mm3). Mean baseline low-dose whole-body computed tomography(excluding head) HO volume was 314.4× 103 mm3; lowest at 2 to <8 years (68.8× 103 mm3) and increasing by age (25-65 years: 575.2× 103 mm3). The mean annualized volume of new HO was 23.6× 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9× 103 and 41.5× 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6× 103 mm3/year). Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.

Coronary artery calcium incidence and changes using direct plaque measurements: The MASALA study

Background and aimsWe aimed to identify predictors of change in direct measures of coronary artery calcium (CAC) volume and density in South Asian participants. MethodsWe used data from participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study with prevalent CAC and direct measures of CAC by serial computed tomography (CT) exams (2010–2013, 2016–2018). We examined the distribution of incident CAC volume and peak density, as well as progression and identified risk factors for progression of change in volume and density in multivariable models. ResultsThe study cohort consisted of 102 participants with incident CAC and 285 with CAC progression. CAC volume and density were highest, and incident CAC was most common in the left anterior descending artery (LAD). The greatest progression in volume was in the right coronary artery and the greatest change in density was in the left main. In linear regression models for CAC progression adjusted for baseline density, volume, risk factors, smoking (β +190.1, p = 0.02), baseline volume (β +0.24 per mm3, p < 0.01), and scan interval (β +0.15 per day, p = 0.01) were associated with change in total volume whereas Lp(a) (β +0.81 per mg/dL, p = 0.03), exercise (β +0.19 per 10 MET-min/week, p = 0.01), and baseline volume (β +0.15 per mm3, p < 0.01) and density (β −0.55 per unit, p < 0.01) were associated with change in total density. ConclusionsIn this South Asian cohort, smoking was associated with CAC volume progression, while Lp(a) and exercise were associated with progression of peak CAC density.

Abstract 102: Effect Of Antihypertensives By Class On Cerebral Small Vessel Disease: A Post-hoc Analysis Of SPRINT-MIND

Introduction: Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, though it is unclear whether this reduction occurs due to blood pressure control or antihypertensive class-specific pleotropic effects. The goal of this study was to investigate the influence of antihypertensive medication class on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. Methods: Using the SPRINT-MIND dataset, we completed a post-hoc analysis of participants who completed a baseline and 4-year follow-up brain MRI with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the MRIs. A percentage of follow-up time participants were prescribed each of the eleven classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between two scans and, to address skew, dichotomized into a top tertile (greatest) accumulation and combined middle and bottom tertiles (slowest) accumulation. Results: Among 448 individuals included in this study, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 years versus 65.7±7.3 years, p&lt;0.001) and systolic blood pressure (128.3±11.0 mmHg versus 126.2±9.4 mmHg, p=0.039). The high had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL for the slowest progressors (p&lt;0.001). Only angiotensin converting enzyme inhibitors (ACE-I) (OR 0.34, 95% CI 0.15-0.75, p=0.008) and dihydropyridine calcium channel blockers (d-CCB) (OR 0.39, 95% CI 0.19-0.81, p=0.012) were independently associated with lower odds of being in the greatest progression grouping. Conclusions: Amongst hypertensive participants in the SPRINT-MIND trial, ACE-I and d-CCB antihypertensive medications were associated with significantly lower odds of being in the highest tertile of WMH progression compared with other antihypertensive classes, independent of blood pressure control.

Not all low grade dysplasia in Barrett's oesophagus is the same: using specific histological criteria in predicting progression to neoplasia.

Barrett's oesophagus with low grade dysplasia (LGD) is a risk factor for progression to high grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC); however, only a subgroup of LGD will progress. We used a combination of specific histological criteria to identify patients with LGD who are more likely to progress to HGD or OAC. LGD slides from 38 patients within the progressor group (PG) and 17 patients from the non-progressor group (NPG) were obtained and reviewed by two expert GI pathologists, to be stratified by the same four specific histological variables identified by Ten Kate etal.: loss of surface maturation, mucin depletion, nuclear enlargement, and increase of mitosis. After review of LGD slides by two expert GI pathologists, 27 suitable patients were identified. Of these 27 patients there was a higher proportion of patients from the PG with all four specific criteria reported, compared to the NPG: 14 (78%) vs 3 (33%) p=0.0394. Patients with all four specific criteria were more likely to progress compared to those who had one or less specific criteria reported (OR 7, 95% CI 1.1848-41.3585, p=0.032). A combination of ≥2 or ≥3 specific histological criteria was not prognostic. Patients with a combination of all four specific histological criteria (loss of surface maturation, mucin depletion, nuclear enlargement, and increase of mitosis) were associated with greater progression from LGD to HGD or OAC in Barrett's oesophagus.

10-Year Follow-Up of Lung Function, Respiratory Symptoms, and Functional Capacity in the COPDGene Study.

Rationale: The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]) study provides a unique cohort to examine these trajectories, and now 10-year follow-up data are available. Objectives: This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers. Methods: We analyzed available longitudinal data for COPDGene participants who did not change smoking status over three visits spanning approximately 10 years of follow-up. Change in postbronchodilator forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ), and 6-minute walk distance (6MWD) from Phase 1 to Phase 3 were examined using linear mixed models. Terms were included in the models to estimate mean progression separately for current and former cigarette smokers. Models were stratified by baseline Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry stages as well as by new 2019 COPDGene classification. Results: The mean age at enrollment of the 9,103 participants in this analysis was 59.8 years (SD = 9.2 yr); 46.4% were women, and 32.6% were African American. In all GOLD COPD groups, including participants with normal spirometry, and all groups categorized by 2019 COPDGene classification, FEV1 decreased, SGRQ increased (indicating higher symptom burden), and 6MWD decreased over the 10-year follow-up period. Current smokers exhibited a greater mean loss of FEV1 over the study period than former smokers for all groups except those with preserved ratio impaired spirometry. For both SGRQ and 6MWD, rates of progression tended to be similar for former and current smokers except for 6MWD in the highest severity groups, in which former smokers had greater progression. However, this could be impacted by some current smokers with faster progression who had quit smoking and were dropped from analyses. Conclusions: Progression in FEV1, SGRQ, and 6MWD overall appears to be slow, and the change over time in groups traditionally characterized as not having disease closely mirrors that of the groups with COPD at all GOLD stages. Current cigarette smokers had greater loss of FEV1 than former smokers, whereas SGRQ and 6MWD changes were more similar between current and former cigarette smokers.

Investigation of association of genetic variant rs3918242 of matrix metalloproteinase-9 with hypertension, myocardial infarction and progression of ventricular dysfunction in Irish Caucasian patients with diabetes: a report from the STOP-HF follow-up programme

BackgroundHypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes. Progression to heart failure is usually preceded by ventricular dysfunction, linked to matrix metalloproteinase (MMP) mediated extracellular matrix changes. We hypothesise that the minor allele of genetic variant rs3918242 in the promoter region of the MMP-9 gene is associated with hypertension and/or myocardial infarction, with resultant progression of dysfunctional cardiac remodelling in patients with diabetes without symptomatic heart failure.MethodsWe genotyped 498 diabetes patients participating in the St Vincent’s Screening TO Prevent Heart Failure (STOP-HF) follow-up programme for the rs3918242 single nucleotide polymorphism and investigated associations with the co-primary endpoints hypertension and/or myocardial infarction using a dominant model. We also evaluated resulting cardiometabolic phenotype and progression of ventricular dysfunction and cardiac structural abnormalities over a median follow-up period of 3.5 years.ResultsThe CT/TT genotype comprised 28.1% of the cohort and was associated with a twofold higher risk of myocardial infarction (17.9% vs 8.4%), a reduction in ejection fraction and greater left ventricular systolic dysfunction progression [adjusted OR = 2.56 (1.09, 6.01), p = 0.026] over a median follow-up of 3.5 years [IQR 2.6, 4.9 years]. Conversely, rs3918242 was not associated with hypertension, blood pressure, pulse pressure or left ventricular mass index at baseline or over follow up.ConclusionsDiabetes patients with the minor T allele of rs3918242 in the STOP-HF follow up programme have greater risk of myocardial infarction, lower ejection fraction and greater progression of left ventricular systolic abnormalities, a precursor to heart failure. These data may support further work on MMP-9 as a biomarker of ventricular dysfunction and the investigation of MMP-9 inhibitors for heart failure prevention in diabetes, particularly in the post-infarction setting.ClinicalTrials.gov Identifier: NCT00921960

Myopia progression varies with age and severity of myopia.

ObjectiveTo investigate annual myopia progression in individuals from South Indian states across different age groups, and its association with age of onset and severity of myopia.MethodsThis retrospective study included the data of 6984 myopes (range: 1–30 years), who visited at least twice to LV Prasad Eye Institute and on whom a standard retinoscopy technique was performed to determine refractive error. Based on spherical equivalent (SE) refractive error, individuals were classified into mild, moderate, high and severe myopic groups. Myopia progression was calculated as difference between SE at 1-year follow-up visit and at baseline. To determine the age-specific myopia progression, individuals were further categorized as myopes who are at least 15 years or younger and those who are above 15.ResultsThe mean annual progression of myopia was influenced by both the age group (p < 0.001) and severity type of myopia (p < 0.001). The overall mean myopia progression ranged from -0.07 ± 0.02 D (standard error) to -0.51 ± 0.02 D across different age groups with maximum change in refractive error noted in children aged 6–10 years and the least in adults aged 26–30 years. Myopia progression was greater in severe myopes, followed by high, moderate, mild myopes and in individuals aged ≤ 15 years compared to those aged >15 years (-0.45 ± 0.01 vs. 0.14 ± 0.01, p < 0.001). Severe myopes alone had similar annual myopia progression rate irrespective of age (i.e ≤15 and >15 years, p = 0.71). Early onset of myopia was associated with high myopia in adulthood.ConclusionThe magnitude of myopia progression in children from South Indian states is comparable to that of Caucasians and Chinese. The greater progression in ‘severe myopes’ across different age groups emphasize the need for regular follow-ups, monitoring axial lengths, and anti-myopia strategies to control myopia progression irrespective of the age and degree of myopia.

Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial

BackgroundIn the GO-VIBRANT trial of intravenous golimumab in psoriatic arthritis (PsA), golimumab significantly inhibited radiographic progression. In post hoc analyses, we evaluated changes in total PsA-modified Sharp/van der Heijde scores (SHS) across levels of composite index-defined disease activity following treatment.MethodsIn this phase-3, double-blind, placebo-controlled trial, 480 bio-naïve patients with active PsA randomly received intravenous golimumab 2 mg/kg (N = 241; week 0, week 4, every 8 weeks [q8w]) or placebo (N = 239; week 0, week 4, week 12, week 20) followed by golimumab (week 24, week 28, q8w) through week 52. Week 24 and week 52 SHS changes in patient subgroups, defined by levels of disease activity as assessed by several composite measures (minimal disease activity [MDA], very low disease activity [VLDA], Psoriatic ArthritiS Disease Activity Score [PASDAS], Disease Activity in Psoriatic Arthritis [DAPsA], Clinical Disease Activity Index [CDAI]), were evaluated post hoc in 474 patients with evaluable radiographic data. Partially (last-observation-carried-forward methodology) and completely (nonresponder methodology) missing data were imputed.ResultsAcross indices, golimumab-treated patients demonstrated less radiographic progression than placebo-treated patients, regardless of disease activity state achieved via golimumab, from week 0 to 24 (e.g., mean changes in PsA-modified SHS were − 0.83 vs. 0.91, respectively, in patients achieving MDA and − 0.05 vs. 1.49, respectively, in those not achieving MDA). Treatment differences observed at week 24 persisted through week 52, despite placebo-randomized patients crossing over to golimumab at week 24 (e.g., mean changes in PsA-modified SHS from week 0 to 52 for golimumab- vs. placebo→golimumab-treated patients achieving MDA were − 1.16 vs. 1.19, respectively) and regardless of whether low disease activity was achieved (0.03 vs. 1.50, respectively, in those not achieving MDA). Consistent patterns were observed for disease activity assessed using VLDA, PASDAS, DAPsA, and CDAI composite endpoints.ConclusionsThe extent of structural damage inhibition afforded by up to 1 year of intravenous golimumab treatment paralleled levels of PsA activity, with greater progression of structural damage observed in patients with sustained higher disease activity. Among patients not achieving low levels of disease activity across several composite indices, golimumab-randomized patients appeared to exhibit far less progression of structural damage than placebo-randomized PsA patients, illustrating a potential disconnect between responses, wherein golimumab can inhibit structural damage independent of clinical effect.Trial registrationClinicalTrials.gov. NCT02181673. Registered 04 July 2014.

Abstract 24: Amyloidogenic V122I Transthyretin Variant is Associated With Progression of Adverse Cardiac Mechanics in Middle-aged African American Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Introduction: Direct-to-consumer testing (e.g. 23andme) reports now include common pathogenic variants in the transthyretin (TTR) gene, such as V122I. TTR cardiac amyloidosis due to V122I is an autosomal dominant disease known to be of variable penetrance in elderly African Americans. However, the association of carrier status for V122I with echocardiographic measures of cardiac mechanics in middle-age African Americans is not known. Hypothesis: Presence of V122I TTR mutation is associated with adverse cardiac mechanics in middle-aged African Americans. Methods: All African Americans from the CARDIA study with imputed genetic data (R 2 = 0.98) and echocardiography at year 25 (Y25) were included. Echo parameters at Y25 and change from Y25 to Y30 were compared between V122I heterozygote carriers and controls using linear regression models. The analysis was adjusted for age, sex, and top 3 principal components of ancestry. Analysis for change from Y25 to Y30 was adjusted for baseline Y25 echo parameters. Results: Of 874 included participants, mean age was 50.2 (3.6) years at Y25. There were 843 controls and 31 carriers for the V122I genotype (3.5% prevalence). There was no difference in age, sex, or clinical characteristics. Carriers of the V122I variant had worse diastolic function as measured by early diastolic tissue Doppler velocity (e’) at Y25 (9.2 [2.1] vs. 10.2 [2.4], p=0.048). From Y25 to Y30, V122I carriers had greater progression of left ventricular (LV) volume and mass as well as greater decline in subclinical LV systolic function as measured by circumferential strain (Table). Conclusions: Prevalence of the carrier status of the V122I genotype in CARDIA is relatively high and consistent with prior studies. Our findings suggest that the V122I mutation may be a unique risk enhancer for heart failure in middle-aged African Americans. Further data are needed for clarity on risk associated with carrier status of V122I and implications for cascade screening given emerging therapies for TTR cardiac amyloidosis.

Arterial Stiffness Accelerates Within 1 Year of the Final Menstrual Period: The SWAN Heart Study.

Menopause may augment age-dependent increases in arterial stiffness, with black women having greater progression in midlife compared with white women. We sought to determine whether and when women experience changes in arterial stiffness relative to the final menstrual period (FMP) and whether these changes differ between black and white midlife women. Approach and Results: We evaluated 339 participants from the SWAN (Study of Women's Health Across the Nation) Heart Ancillary study (Study of Women's Health Across the Nation). Women had ≤2 carotid-femoral pulse-wave velocity (cfPWV) exams over a mean±SD of 2.3±0.5 years of follow-up. Annual percentage changes in cfPWV were estimated in 3 time segments relative to FMP and compared using piecewise linear mixed-effects models. At baseline, women were 51.1±2.8 years of age and 36% black. Annual percentage change (95% CI) in cfPWV varied by time segments: 0.9% (-0.6% to 2.3%) for >1 year before FMP, 7.5% (4.1% to 11.1%) within 1 year of FMP, and -1.0% (-2.8% to 0.8%) for >1 year after FMP. Annual percentage change in cfPWV within 1 year of FMP was significantly greater than the other 2 time segments; P<0.05 for both comparisons. Adjusting for concurrent cardiovascular disease risk factors explained part of the change estimates but did not eliminate the difference. Black women had greater increase in cfPWV compared with white women in the first segment; P for interaction, 0.04. The interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.

Efficiency of the Halliwick concept in the rehabilitation of children with cerebral palsy

Background/Aim: Since 2010, the Halliwick Concept has been applied in the rehabilitation of children with neurological disorders at the Department of Habilitation and Rehabilitation of Children and Youth at the Institute for Physical Medicine and Rehabilitation (IPMR) "Dr Miroslav Zotović" in Banja Luka, the Republic of Srpska, Bosna and Herzegovina. Aim of this study was to analyse results of the implementation of the full Halliwick Concept programme over the period from 1 January 2016 to 1 January 2017 and points to the effectiveness of this type of hydrokinesitherapy. Methods: After analysing 40 patients with different diagnoses of neurological disorders: cerebral palsy (CP), arthrogryposis (AG), Down syndrome (DS), and central nervous system (CNS) injury, only patients with CP were represented due to the homogeneity of the diagnosis and were included in analysis (N = 30). Rehabilitation treatment of patients according to the Halliwick concept was performed, over a period of one year, for 60 minutes once a week. Patients were tested by Swimming with Independent Measurement (SWIM) test, Gross Motor Function Measure (GMFM) and Barthel Index before and after treatment. Results: Considering all patients, before and after the application of the concept of individual Halliwick swimming skills/movement in water, a statistically significant difference was detected by assessing the SWIM test and a highly significant difference was detected by evaluating the Gross motor function measure test of GMFM66, as well as in evaluating the Barthel Index test. Assessment of swimming abilities through the SWIM test showed the least progression was in the ability in Getting out of the water, with the greatest progression in the ability in Breathing control. Conslusion: The Halliwick Concept programme at the Department for the Habilitation and Rehabilitation of Children and Youth, IPMR "Dr Miroslav Zotović" in Banja Luka is effective and the results indicate the need for its application in the rehabilitation of children with CP.

Progression of Carotid Plaque Among Postmenopausal Asymptomatic Women: A Prospective Observational Population-based Follow-up Study

Introduction: The most frequent underlying mechanism of CVD is universal atherosclerotic vascular disease. Atherosclerosis in the carotid arteries (carotid plaque=CP) are often present without symptoms. Despite this, present of CP has previously been shown to predict future CVD events. Data on progression and development of CP over time remains sparse, especially among women. Simultaneous, more strokes are seen in women than men and along an increasing incidence of CVD due to longer life expectancy of women. This study examines the CP progression of screening-detected CP among postmenopausal women and evaluates adherence to the recommended prophylactic medical therapy after screening-detected CP 6 years ago. Methods: Between 2011 and 2013, a combined cardiovascular screening programme including 1474 60 to77 year-old asymptomatic women (attendance rate 74.3%) was conducted. CP was detected in 601 women (40.8%), who all were recommended prophylactic anti-platelet and lipid-lowering therapy. These 601 women were re-invited to a follow-up screening 6 years after the primary screening. The carotid intima media thickness and plaque progression were examined by ultrasonography. CP was measured from leading edge observed in the lumen echo to its most protruding part within the lumen. The anatomic placements described: common carotid arteries, bulb of the common carotid arteries, internal carotid arteries and external carotid arteries. Positive findings resulted in recommendation of prophylactic medical therapy (75 mg acetylsalicylic acid and 20 mg atorvastatin). Self-reported questionnaires regarding current medication were used to determine whether the participants were adherent to the recommendation concerning prophylactic medical therapy from the primary screening. Results: In total, 559 women (38 died and 4 were lost to follow-up) were invited, and 417 (74.6%) participated. The mean follow-up duration was 5.8 years (SD ±0.33; range 5.3 to 6.7 years). A tendency for plaque progression was observed at all investigated anatomical sites. The largest progression (0.66mm) was seen in the left common carotid artery (from 0.39mm to 1.05mm; p=0.000, 95% CI: 0.38-0.93). When stratifying for +/- prophylactic lipid-lowering therapy during the 6-year period, plaque progression was observed in both groups with a greater progression in the non-therapy group (ex: CP internal carotid; progression with lipid lowering therapy 0.37 mm versus 0.77 mm without lipid lowering therapy). No regression of CP was observed. 248 (59.5%) women had been adherent to the recommended lipid-lowering therapy and 247 (59.2%) to anti-platelet therapy. When combining the women already in prophylactic therapy and women accepting therapy after the follow-up screening, lipid-lowering therapy were accepted by 101 women (prophylactic coverage of 83.9%) and Anti-platelet were accepted by 119 women (prophylactic coverage of 87.8%). Conclusion: CP progressed over time in all examined sites in the carotid artery. Stratifying for lipid-lowering therapy between primary screening and follow-up showed a more prominent CP progression in the non-therapy group compared with the lipid-lowering group. Medication adherence to relevant prophylactic therapy 6 years after CP detection was approximately 60% increasing to approximately prophylactic coverage of 85% after re-scanning. This identified hesitation concerning prophylactic medical therapy needs to be addressed in future studies. Disclosure: Nothing to disclose

People With COPD Who Respond to Ground-Based Walking Training Are Characterized by Lower Pre-training Exercise Capacity and Better Lung Function and Have Greater Progression in Walking Training Distance.

To investigate the characteristics that distinguish responders from nonresponders to ground-based walking training (GBWT) in people with chronic obstructive pulmonary disease (COPD). An analysis was undertaken of data collected during a trial of GBWT in people with COPD. Responders to GBWT were defined in 2 ways: (1) improved time on the endurance shuttle walk test of ≥190 sec (criterion A); or (2) improved ability to walk, perceived by the participant to be at least "moderate" (criterion B). Differences in participant characteristics, pre-training exercise capacity, health-related quality of life, and the improvement in the distance walked during the training program were examined between responders and nonresponders. Of the 95 participants randomized to GBWT (age 69 ± 8 yr, forced expiratory volume in 1 sec [FEV1] % predicted = 43% ± 15%), data were available for analysis on 78 and 73 patients by criterion A and criterion B, respectively. According to criterion A, 32 (41%) participants were responders. The odds of being a responder increased with increasing FEV1 % predicted (OR = 1.2; 95% CI, 1.0-1.5, for every 5% increase) and increased with decreasing pre-training incremental shuttle walk distance (OR = 1.4; 95% CI, 1.0-1.8, for every 50-m decrement). According to criterion B, 42 (58%) participants were responders. There were no differences in characteristics or pre-training measures between the responders and nonresponders. For both criteria, responders demonstrated greater change in the distance walked during the training program (P < .05). Responders to GBWT had lower pre-training exercise capacity, had better lung function, and demonstrated greater change in the distance walked during the training program.

The IRX-2 regimen combined with nivolumab in recurrent/metastatic solid tumors: A phase 1b study to evaluate the safety, determine recommended phase 2 dose (RP2D), and investigate the biologic and clinical activity.

TPS2662 Background: IRX-2 is a biologic immunotherapeutic containing a mixture of cytokines including IL-2, IL-1β IL-6, IL-8, TNFα, GM-CSF, and IFN-γ. It is derived from stimulating human PBMCs with phytohemagglutinin. Preclinical studies have shown that IRX-2 enhances dendritic cell maturation, T cell activation, and NK cell stimulation. In a Phase 2 trial of head and neck squamous cell carcinoma (HNSCC) patients, IRX-2 increased immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival. Moreover, it has been shown that the degree of lymphocyte infiltration is an important prognostic factor for treatment with anti- programmed cell death protein 1 (PD-1) monoclonal antibodies. These data provide a compelling rationale for incorporating IRX-2 regimen into anti-PD-1 treatment strategies to increase the level of lymphocyte infiltration in the TME and improve immune response. Methods: This is a phase Ib trial exploring safety and tolerability of IRX-2 regimen in combination with nivolumab. Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections in 2 or 4 lymph node-bearing regions (based on dose level) for 10 days every 3 months. Two dose levels of IRX-2 regimen will be studied. Nivolumab is administered at 240 mg Q2W. Once the RP2D is determined, an additional 88 pts will be enrolled in an expansion phase, for a planned total enrollment of approximately 100 pts. Dose expansion phase will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies. The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. Study Progress: Study is actively accruing. Clinical trial information: NCT03758781.

The Impact of Intracerebral Hemorrhage on the Progression of White Matter Hyperintensity.

Objective: The exact relationship between white matter hyperintensity (WMH) and intracerebral hemorrhage (ICH) after ICH remains unclear. In this retrospective study, we investigated whether patients with ICH had more severe WMH progression.Patients and Methods: A total of 2,951 patients aged ≥40 years with ICH who received brain computed tomography (CT) imaging within 12 h of ICH symptom onset were screened. Ninety patients with two fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) assessments, including 36 patients with Lobar ICH, 40 with basal ganglia region ICH and 14 with ICH at other sites, were included in the final study. We selected 90 age- and gender-matched healthy individuals with two MRI scans as the control group. The WMH volumes at baseline and follow-up were assessed using the FLAIR image by MRICRON and ITK-SNAP software, while the hematoma volumes were calculated based on the CT images using ITK-SNAP software.Results: The annual progression rate of WMH was significantly higher in the ICH group compared with the control group (p < 0.05). Furthermore, WMH progression was associated with the ICH volume. The largest ICH volume (>30 mL) was associated with the highest annual progression rate of WMH (p < 0.05). In contrast, no trend toward an association between ICH location and the annual progression rate of WMH was observed (p > 0.05).Conclusions: Our results showed that ICH patients had more severe WMH progression and that larger ICH volume was related to greater progression of WMH after ICH. These results could provide important prognostic information about patients with ICH.