Risultati per: Low Back Pain: raccomandazioni

Circulation, Volume 150, Issue Suppl_1, Page A4146364-A4146364, November 12, 2024. Background:According to the European Guidelines, “low-risk” pulmonary arterial hypertension (PAH) patients is defined as a risk of death < 5% within a year and represents a treatment-goal. However, the impact of morbidity (e.g. hospitalization and clinical worsening), were not included in this definition.Research Questions:Can REVEAL 2.0 risk score further identify low-risk PAH patients for both morbidity and mortality?Aims:Using the REVEAL 2.0 risk score, to propose a modified definition of “low-risk” to include the risk of both morbidity and mortality at 1- and 3-years, respectively.Methods:A harmonized dataset from 8 PAH randomized controlled trials from the FDA was used for this analysis and REVEAL 2.0 risk score was calculated for each patient. Modified low-risk was a priori defined by “risk of death ≤ 5% at 3-years and risk of clinical worsening ≤10% at 1-year”. Clinical worsening was defined as any of the following: lung transplantation or hospitalization due to PAH worsening, initiation of prostanoids/chronic oxygen, 15% decrease in 6-MWD from baseline, a worsening of NYHA, addition of a new PAH medication.Results:A total of 4,122 PAH patients were included: median age 49 (36, 62) yo, mPAP 50 (40, 60) mmHg, PVR 10 (7, 14) WU, 6MWD 375 (306, 423) m, NTproBNP 884 (230, 3010) pg/mL. Patients with a REVEAL 2.0 risk score ≤ 4 had a 1-year clinical worsening free-survival and 3-year survival rate of 92% and 95% (Figure 1). The 3-years survival was significantly better in patients with a REVEAL 2.0 ≤ 4 compared to 5-6: HR=0.47, 95%CI[0.27-0.84], p=0.01. Compared to patients with REVEAL 2.0 risk score of 5-6 (“classical” low-risk), those with a REVEAL 2.0 risk score ≤ 4 (“refined low-risk”) had a better clinical, biological, hemodynamic presentation, and outcomes (Table 1).Conclusion:This study is the first embedding both morbidity and mortality within the definition of low risk for PAH patients and suggests that PAH patients with REVEAL 2.0 risk score ≤ 4 meet this definition. This definition may be a promising new treatment-goal strategy in future randomized controlled trials but also for daily clinical practice.

Circulation, Volume 150, Issue Suppl_1, Page A4139307-A4139307, November 12, 2024. Introduction:Heart failure (HF) is associated with unique comorbidities and sequelae, which can affect clinical presentation and patient outcomes. This is specifically challenging when patients are evaluated for suspected acute coronary syndrome (ACS). We sought to compare the most important predictors of poor outcomes in patients with and without HF seen in the emergency department (ED) for ACS.Methods:This was a secondary analysis of a prospective observational cohort study of consecutive patients seen for symptoms suggestive of ACS, such as chest pain (CP) and dyspnea, in the EDs of three UPMC-affiliated tertiary care hospitals (NCT04237688, clinicaltrials.gov). Primary outcome was 30-day major adverse cardiac events (MACE), adjudicated by two independent reviewers. Clinical data were collected form charts and we used KNN to impute missing data for features, most of which had less than 12.5% missingness. For features with greater than 12.5% missingness (i.e., BNP, Mg), binary indicators were added to flag missing values. Data were normalized using the Euclidean norm. Two random forest (RF) classifiers were trained using 10-fold cross validation with 71 manually selected features available early in the ED course (i.e., vital signs, labs, past medical history, ECG), and tested on patients with and without known HF. Model performance was evaluated using AUROC, and top features were identified with SHAP values.Results:The sample included 2400 patients (age 59 ± 16 years; 47% female, 41% Black, 15.9% ACS), of whom 438 had HF (age 66 ± 14 years; 45% female, 49% Black, 15.1% ACS). Individuals with HF were more likely to experience MACE (38% vs 23%,p

Circulation, Volume 150, Issue Suppl_1, Page A4134364-A4134364, November 12, 2024. Introduction:Inclisiran, an siRNA, targeting PCSK9 mRNA, reduces LDL-c levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower cardiovascular (CV) events in virtual patients with atherosclerotic cardiovascular disease (ASCVD).Research question:This analysis predicted the potential efficacy of inclisiran on CV outcomes in virtual patients with or without prior ischemic stroke (IS).Methods:The SIRIUS trial was conducted using a calibrated and validated knowledge-based mechanistic computational model of ASCVD applied to a virtual population with LDL-C ≥ 70 mg/dL. Each virtual patient was its own control. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statin with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal IS over 5 years in patients with or without prior IS. Occurrence of fatal and non-fatal (IS) was also individually assessed in time-to-first-event analyses.Results:Among 204,691 virtual SIRIUS ASCVD patients, 39 371 (19%) had prior IS. At 5 years, the predicted mean percentage reduction in LDL-C with inclisiran as compared to placebo was –49.17% and –49.88% in patients with or without prior IS respectively. Patients with prior IS were at higher risk of 3P-MACE than patients without IS both with placebo and inclisiran (17.01% vs 14.41% with placebo and 13.44% vs 10.83% with inclisiran). However, the predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm for both prior IS and no prior IS (HR 0.78 medium uncertainty and 0.74 low uncertainty respectively). Compared to placebo, inclisiran was also predicted to consistently reduce fatal and non-fatal IS in patients with or without prior IS (5.45% vs 7.22%; HR: 0.75 medium uncertainty and 1.87% vs 2.54%; HR: 0.73 medium uncertainty respectively).Conclusion:SIRIUS provides insights into the potential efficacy of inclisiran on CV events suggesting a substantial 3P-MACE and fatal and non-fatal IS reduction in ASCVD patients including those with prior IS, several years before the availability of results from ongoing outcomes trials (ORION-4, VICTORION-2P).

Circulation, Volume 150, Issue Suppl_1, Page A4142085-A4142085, November 12, 2024. Background:Highly precise definition of high-risk features associated with HFpEF may guide targeted treatments and inform biological studies. The aim of this two-step study is to 1) define a high risk HFpEF cluster with unsupervised machine learning approach using cardiac magnetic resonance (CMR), 2) define novel pulmonary vascular mechanics at rest and with exercise in low- vs. high-risk phenotypes. Vascular mechanics defines vessel- and cardiac cycle-specific flow dynamics in pulmonary circulation.Methods:48 HFpEF participants underwent CMR and invasive cardiopulmonary exercise testing. With unsupervised K-means clustering analyses using CMR data, two specific clusters were identified with different survival outcomes at 12-months (mortality and heart failure hospitalizations): HR=5.4 (CI:1.7-17.4), log-rank p

Circulation, Volume 150, Issue Suppl_1, Page A4140363-A4140363, November 12, 2024. Introduction:An estimated 23-85% of adults with chronic heart failure (HF) experience comorbid chronic pain, yet no comprehensive theoretical models have been developed or tested that completely capture the salient variables which affect pain. The aim of this study was to construct a preliminary theoretical model of pain in HF and evaluate the associations between identified variables in the model with pain presence.Methods:In this cross-sectional study, baseline data were obtained from the Cognitive Intervention to Improve Memory in Heart Failure Patients study (MEMOIR-HF) (n = 235). The Biopsychosocial Model of Chronic Pain was adapted for an HF-specific population. The dependent variable was pain presence (yes/no), which was measured using the Health Utilities Index Mark-3 (HUI-3). Independent variables were identified for the model using previous literature and univariate analyses comparing patients with vs. without pain in MEMOIR-HF. Logistic regression was used to test for differences between patients with pain present and not present.Results:Demographics were 45.5% men, 54.5% women, 86.4% White, 13.6% Black, mean age 66.39 (SD 12.04) years. Of 235 patients, 159 (67.66%) reported pain on the HUI-3 items.The variables that were included following univariate analysis and literature review were age, self-reported race and gender, comorbid conditions, sleep disturbances, HF severity, B-type natriuretic peptide, brain-derived neurotrophic factor, body mass index, and depression. Patients with pain were more likely to have worse HF severity (NYHA Class II or III compared with Class I) (Class II: OR 5.09 [1.71 – 15.08], p = .003, Class III: 5.05 [1.73 – 14.71], p = .003), more severe depression (OR 1.14 [1.06 – 1.23], p = .001), and worsened daytime sleepiness (OR 0.90 [0.83 – 0.98], p = .017), see Table 1.Conclusions:We believe this study is one of the first to construct and test a preliminary comprehensive model of pain in HF. Complete characterization of pain in HF is needed before treatments can be improved. Future research is needed to explore variables that were not available in the MEMOIR-HF dataset. More robust pain measures are needed to adequately test all variables.

Circulation, Volume 150, Issue Suppl_1, Page A4139036-A4139036, November 12, 2024. Background:Patients with low-flow low-gradient (LFLG) aortic stenosis (AS) are at risk of worse outcomes following transcatheter aortic valve replacement (TAVR). Flow is known to improve after TAVR, however the clinical and echocardiographic characteristics correlating with flow improvement in patients with LFLG AS are still unclear.Hypothesis:Some baseline and discharge clinical and echocardiographic characteristics correlate with flow improvement in patients with LFLG AS post-TAVR.Aims:The present study sought to explore the clinical and echocardiographic characteristics correlating with flow improvement in patients with LFLG AS post-TAVR.Methods:This is a retrospective cohort of patients >18 years of age who underwent TAVR at Cleveland Clinic between 2016 and 2020. Only patients with aortic valve (AV) area

Circulation, Volume 150, Issue Suppl_1, Page A4144964-A4144964, November 12, 2024. Major adverse cardiovascular (CV) events (MACE) occur in a substantioal percentage of individuals following acute coronary syndromes (ACS), primarily driven by residual vascular inflammation. Anti-inflammatory drugs have improved CV outcomes but their use is limited by significant side-effects. Low-dose interleukin 2 (IL2) increases regulatory T (Treg) cells, which are powerful endogenous regulators of the immune response, and could provide a new, targeted anti-inflammatory strategy in high-risk ACS patients. In IVORY, we hypothesised that treatment with low-dose IL2 would reduce arterial inflammation measured by18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), compared to placebo. In IVORY FINALE we hypothesised that low dose IL2 could reduce MACE compared to placebo at follow up (up to 5 years.)IVORY was a double-blind, placebo-controlled, Phase IIb trial randomising ACS patients with high-sensitivity CRP levels ≧ 2mg/L to receive either 1.5×106IU IL2 or placebo (1:1). Dosing consisted of a daily induction (5 days) and a weekly maintenance phase (7 weeks).18F-FDG-PET/CT imaging of the ascending aorta and carotid arteries was performed before and after treatment. The primary outcome was the difference in the mean maximum target-to-background ratio (TBRmax) in the index vessel on follow-up imaging between the groups.60 patients (IL2:placebo, n=31:29) completed the trial. Arterial inflammation in the index vessel was lower at the end of treatment in the IL2 group than in placebo (TBRmax = -0.171[-7.7%], 95% CI -0.308 to -0.034, p=0.015)[Fig1]. In more inflamed areas with a mean TBRmax ≧ 2 (active slices), the difference between the groups was greater (-0.185 [-8.3%], P=0.009, 95% CI -0.323 to -0.0478). Overall, the additive treatment effect of low-dose IL2 was greater at higher baseline inflammation [Fig 2]. Low-dose IL2 significantly increased circulating Tregs compared to placebo (p

Circulation, Volume 150, Issue Suppl_1, Page A4138733-A4138733, November 12, 2024. Introduction:Identifying low-voltage areas (LVAs) within left atrium (LA) is crucial for predicting atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). Animal studies have shown that the parasympathetic neurotransmitter vasoactive intestinal peptide (VIP) affects atrial electrophysiological remodeling.Hypothesis:Thus, we hypothesized that elevated serum VIP levels might contribute to the development of LVAs and that serum VIP concentrations could serve as a biomarker for LVA presence in AF patients.Aims:The aim of this study is to investigate the relationship between the blood levels of VIP and the presence of LVAs in AF patients with electroanatomical mapping (EAM).Methods:We conducted an observational, prospective cross-sectional study on AF patients undergoing PVI between 2021 and 2023. Blood samples for VIP were collected before atrial septal puncture, and EAM was performed using CARTO 3® before PVI. VIP concentrations were measured using an enzyme-linked immunosorbent assay kit. Patients were divided into two groups based on LVA presence (≥5% or

Circulation, Volume 150, Issue Suppl_1, Page A4147691-A4147691, November 12, 2024. Background:The prognosis of patients with paradoxical low flow, low gradient, severe aortic stenosis (LFLGAS) is variable, necessitating improved risk stratification. Although this entity is more common in women, the impact of sex on outcomes remains unclear. Energy loss index (ELI), which accounts for aortic root size in estimating the severity of aortic valve stenosis, may enhance risk prediction in LFLGAS. This study aims to investigate sex-based ELI prognostic value in patients with paradoxical LFLGAS.Methods:This study analyzed clinical, echocardiographic, and outcome data collected in 294 patients with paradoxical LFLGAS, with AVA

Circulation, Volume 150, Issue Suppl_1, Page A4136136-A4136136, November 12, 2024. Background:The optimal clinical management and timing of intervention are less well defined in paradoxical low-flow, low-gradient severe aortic stenosis (PLFLG AS). Left ventricular global longitudinal strain (LV-GLS) has been shown to predict outcomes in high flow severe AS, but there is lack of data in patients with PLFLG AS. Given the exaggerated LV hypertrophy and remodeling pattern in PLFLG AS, LV-GLS may be a mechanistic imaging marker for worse outcomes.Hypothesis:In patients with PLFLG AS, LV-GLS is associated with adverse clinical outcomes by detecting subclinical myocardial fibrosis resulting from myocardial remodeling due to LV pressure overload.Methods:We examined patients with PLFLG AS defined as AVA

Circulation, Volume 150, Issue Suppl_1, Page A4141389-A4141389, November 12, 2024. Introduction:Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure (HF) in the US today. Our prior work revealed low albumin at first hospitalization for HF exacerbation with underlying HFpEF to be an independent predictor of all-cause mortality in a small cohort of patients. We now sought to confirm our earlier findings across a larger and more diverse patient population.Methods:Seven thousand, eight hundred and forty patients had a first admission to Mayo Clinic for HF exacerbation with an echo-confirmed left ventricular ejection fraction >50% between 2010 and 2020. Patient baseline demographics, co-morbidities, admission laboratory values, echocardiographic parameters, discharge medications, and outcomes were obtained from chart abstraction. To validate our previous model, patients were grouped based on the number of risk factors as previously defined: age >80 years, serum albumin level

Circulation, Volume 150, Issue Suppl_1, Page A4120657-A4120657, November 12, 2024. Introduction:Early prehospital chest pain assessment improves acute coronary syndrome (ACS) outcomes and can reduce unnecessary Emergency Room (ER) visits but requires medical personnel and electrocardiographic (ECG) equipment.Objective:To evaluate the feasibility of a personal credit-card sized chest pain self-assessment device (HeartBeam, Santa Clara, CA, USA) in diagnosing ACS.Methods:ACS risk was estimated by serial likelihood ratio analysis of 3 components: pre-existing coronary heart disease (CHD) risk (pre-calculated based on pooled ASCVD equation), chest pain characteristics (interactive proprietary questionnaire), and integrated near-orthogonal 3-lead self-recorded vectorcardiogram (VCG) with optional comparison to baseline using portable handheld HeartBeam recorder. Final ACS risk was graded High/Intermediate/Low by the cloud-based proprietary algorithm. High risk was considered positive for ACS.Results:184 ER patients with chest pain (Age 57 +/- 7years, 90 Male, 43 (23%) ACS) comprised learning (n=96) and test (n=88) sets. ACS sensitivity was 28/28 (100%) in learning and 15/16 (94%) in test set with specificity of 43% and 42% respectively. In the subset of patients with pain-free portable VCG recorded 9 months later used as a “reverse baseline” (n=110) sensitivity was 17/17 (100%) and 11/12 (92%), specificity 54% and 58% in learning and test set, respectively (p >0.1 with no baseline). Single patient missed by the analysis had known coronary disease with usual anginal episode resulting in minor troponin leak. In “reverse baseline” analysis 41/110 (37%) patients were classified as Low risk compared to 18/184 (10%) without baseline (p0.1 with HeartBeam device).Conclusion:HeartBeam chest pain self-assessment device provides accurate ACS detection comparable to expert ER physicians using 12 lead ECG. The presence of baseline recording reduces the number of false positive results. If confirmed in larger studies, it can be used to facilitate outpatient chest pain assessment and triage by remote physicians and patients themselves.

Circulation, Volume 150, Issue Suppl_1, Page A4142690-A4142690, November 12, 2024. Introduction:Given the well-documented benefits of yoga on the cardiovascular system and improvement of exercise tolerance and quality of life, the American Heart Association recently recommended yoga as a safe and well-tolerated adjunctive therapy for patients with heart failure (HF). However, most studies have focused on testing yoga with moderate levels of physical movement, leaving a gap in our understanding of the potential benefits of yoga with low levels of physical movement.The specific aims of this pilot study were to explore the potential benefits of yoga with low levels of physical exercise movement, combined with longer deep breathing and meditation, on the psychological and physical health outcomes of patients with HF.Methods:Yoga was delivered using tele-health to patients with HF at home. Outpatients with HF (N=17) were randomly assigned to either the intervention (n=11) or the control (n=6) groups using a 2:1 ratio. The intervention group participated in twice-weekly live-streamed yoga sessions over a 12-week period led by nurse yoga instructors. Outcome measures included depressive symptoms (Patient Health Questionnaire-9), anxiety (Hospital Anxiety Index), sleep quality (Pittsburgh Sleep Quality Index), perceived control (Control Attitude Scale-Revised), sit-stand test, and length of activity measured with an ActiGraph watch worn for 7 days. Paired t-tests were conducted to examine the differences in outcomes over time.Results:For the intervention group, there was a significant improvement in global sleep quality (8.8 vs. 6.0, p= 0.4 respectively), with a significant increase in sleep duration (3.0 vs 0.6, P

Circulation, Volume 150, Issue Suppl_1, Page A4138757-A4138757, November 12, 2024. Background:Optimizing lipid-lowering therapy (LLT) use is foundational to reduce atherosclerotic cardiovascular disease (ASCVD) risk, especially among patients who have already experienced an ASCVD event. This study aimed to evaluate the patterns of LLT intensification and LDL-C testing within 12 months following an ASCVD event in US patients.Methods:Adults who experienced an ASCVD event (acute coronary syndrome, coronary revascularization, stable angina, ischemic stroke, transient ischemic attack, or peripheral arterial disease) between January 1, 2016 and December 31, 2022 in the IQVIA Longitudinal Access and Adjudication Data were included. The first instance of LLT intensification after the event was defined as an increase from a low-moderate to high intensity statin, or the initiation of statins, ezetimibe, PCSK9i, or bempedoic acid in addition to a baseline LLT regimen that did not include these medications. Baseline medication use was defined during 6 months before the ASCVD event.Results:Among 6,028,573 patients who had an eligible ASCVD event (mean age: 63.6 years, 51.5% male), 53.9% were not taking any LLT and 43.2% were taking statins only (low-moderate intensity: 26.7%; high intensity: 16.4%) during baseline. Within 1, 3, and 12 months after the event, 16.3%, 21.3%, and 30.0% of patients intensified LLT, respectively. Among patients who intensified LLT within 12 months (n= 1,820,246), the most commonly observed intensification was from no LLT use at baseline to low-moderate (29.0%) or high-intensity statins (43.5%), followed by intensification from low-moderate to high-intensity statins (20.3%). LDL-C values at baseline were available in a subset of 10.7% of patients, with the median being 95 mg/dL (78.9% ≥70 mg/dL). LDL-C values were observed in 17.7% of patients within 12 months after the ASCVD event, with the median being 84 mg/dL (68.3% ≥70 mg/dL).Conclusions:Within 12 months after an ASCVD event, only about one-third of patients intensified LLT and two-thirds did not achieve guideline-recommended LDL-C levels. The results highlight a missed opportunity to reduce recurrent ASCVD events. Future effort is warranted to address the clinical inertia that may be contributing to this unmet need.

Circulation, Volume 150, Issue Suppl_1, Page A4128599-A4128599, November 12, 2024. Background:Inferior vena cava (IVC) filters are commonly implanted in patients with venous thromboembolism (VTE) who are unable to receive anticoagulation, to protect against clot migration to the heart. With prolonged implantation, IVC filters are associated with complications: device fracture, migration, penetration into adjacent organs and worsened VTE. Two Federal Drug Administration advisories and multi-society guidelines have emphasized the importance of timely retrieval but national retrieval rates remain low (= 18 years was identified in the 2016-2020 inpatient and outpatient 100% limited data set Medicare files using claims codes. Hospital information for the implanting facility was cross-linked from the American Hospital Association and Healthcare Cost Report Information System files, including identifying information, teaching status, census location, operating margin and % uncompensated care. IVC filter retrieval rates and time to retrieval from implantation was calculated. Bayesian hospital profiling methods were used to quantify 1-year retrieval rate for all U.S. facilities, adjusting for patient factors – demographics, diagnostic indications and comorbidities.Results:Among Medicare beneficiaries, there were 140,481 IVC Filter implantations across 2,850 facilities. Excluding patients who died within 90 days of implantation (25.7%), retrieval rates at 3 months, 1 year and anytime were 7.9%, 18.7% and 20.0% respectively. IVC Filter retrieval within 1 year varied significantly at the facility-level, from 0-100%.Focusing on facilities with at least 13 IVC filter implantations each year (top 25%ile volume), 1-year retrieval ranged from 0 to 74.5%. Higher 1-year retrieval was seen among higher implantation volume (12.4% bottom quartile, 20.5% top quartile), teaching (21.1% teaching vs. 16.9% nonteaching) and non-safety net (21.1% low uncompensated care, 15.0% high uncompensated care) hospitals. Retrieval rates did not vary significantly by hospital operating margin or rurality.Conclusion(s):There is low overall IVC filter retrieval in the United States with large underlying facility-level variation. Focused examination of high-performing facilities could yield insights on how to improve device retrieval nationally.

Circulation, Volume 150, Issue Suppl_1, Page A4139930-A4139930, November 12, 2024. Introduction:Despite a rigorous screening process, including cardiac catheterization, a subset of single right ventricle (SRV) patients demonstrate suboptimal short-term outcomes after the Fontan operation. The goal of this study was to perform a comprehensive assessment of diastolic function in pre-Fontan SRV patients using invasive reference-standard measures and determine their associations with post-Fontan outcomes.Methods:Children 2-6 years old with SRV physiology undergoing pre-Fontan heart catheterization were recruited prospectively. SRV patients were divided into those who had an optimal or suboptimal outcome. A suboptimal outcome was defined as length of stay ≥14 days or heart transplant/cardiac death in first year after Fontan. Patients with hemodynamically insignificant patent ductus arteriosus referred for catheterization closure were recruited as controls. Patients underwent pressure-volume loop analysis using reference-standard methods. The measure of ventricular stiffness, β, was obtained via preload reduction. Cardiac magnetic resonance imaging for extracellular volume (ECV) and serum draws for matrix metalloproteinase (MMP) activity were performed.Results:Of 19 SRV patients, 9 (47%) had a suboptimal outcome. 15 controls were included. Demographic and catheterizations are shown in Table 1. Echocardiographic and MRI data are shown in Table 2. Patients with suboptimal outcomes had lower ventricular stiffness, lower ECV, and lower MMP-2 compared to patients with optimal outcomes (Figure 1). Patients with suboptimal outcomes had similar stiffness to biventricular controls. Patients with optimal outcome had less total fluid in the first 24 hours than the suboptimal group (1107 (IQR 953, 1303) vs. 1482 (IQR 1305, 1598) mL, p = 0.03). The only invasive measure that had an association with suboptimal outcome was β, p=0.038.Conclusion:SRV patients with suboptimal outcome after Fontan had lower ventricular stiffness compared to patients with optimal outcome. Lower stiffness led to an increased need for fluid resuscitation and higher chest tube output after Fontan. The usual response in chronically increased RV afterload is for the RV to hypertrophy and stiffen over time in order to maintain cardiac output. This is not seen in low SRV stiffness patients and may represent a maladaptive extracellular matrix response to chronic afterload elevation. This novel phenotype that may have important clinical implications and requires further study.