Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

To examine factors accounting for differences in hyoid motion during obstructive breathing events amongst obstructive sleep apnea (OSA) patients. This was a prospective cohort study from June 2022 to October 2022. Patients with OSA undergoing evaluation for PAP alternative therapies with drug-induced sleep endoscopy with positive airway pressure titration (DISE-PAP). All patients underwent DISE-PAP and concurrent hyoid-focused ultrasound. DISE-PAP enabled measurement of airway physiology (flow, respiratory effort) and airway collapsibility (pharyngeal opening pressure, PhOP). Hyoid-ultrasound enabled hyoid bone movement during obstructive breathing. Respiratory effort was measured using a retro-epiglottic pressure-sensitive catheter. Hyoid position was measured using a standardized, awake, CT protocol. Regression analyses adjusted for age, race, sex, and BMI were performed to associate indices of respiratory effort and CT data with hyoid motion. On average, the 26 patients in this cohort were older (63.9 ± 10.5 years), male (69

People with depression often underutilize mental health care. This study was conceived as a first step toward a clinical decision support tool that helps identify patients who are at higher risk of underutilizing care. The primary goals were to (a) describe treatment utilization patterns, early termination, and return to care; (b) identify factors associated with early termination of treatment; and (c) evaluate the accuracy of regression models to predict early termination. These goals were evaluated in a retrospective cohort analysis of 108,457 U.S. veterans who received care from the Veterans Health Administration between 2001 and 2021. Our final sample was 16.5% female with an average age of 34.5. Veterans were included if they had a depression diagnosis, a positive depression screen, and received general health care services at least a year before and after their depression diagnosis. Using treatment quality guidelines, the threshold for treatment underutilization was defined as receiving fewer than four psychotherapy sessions or less than 84 days of antidepressants. Over one fifth of veterans (21.6%) received less than the minimally recommended care for depression. The odds of underutilizing treatment increased with lack of Veterans Administration benefits, male gender, racial/ethnic minority status, and having received mental health treatment in the past (adjusted OR > 1.1). Posttraumatic stress disorder comorbidity correlated with increased depression treatment utilization (adjusted OR < .9). Models with demographic and clinical information from medical records performed modestly in classifying patients who underutilized depression treatment (area under the curve = 0.595, 95% CI [0.588, 0.603]). Most veterans in this cohort received at least the minimum recommended treatment for depression. To improve the prediction of underutilization, patient factors associated with treatment underutilization likely need to be supplemented by additional clinical information.

Abstract Background Depression is prevalent among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans, yet rates of Veteran mental health care utilization remain modest. The current study examined: factors in electronic health records (EHR) associated with lack of treatment initiation and treatment delay; the accuracy of regression and machine learning models to predict initiation of treatment. Methods We obtained data from the VA Corporate Data Warehouse (CDW). EHR data were extracted for 127,423 Veterans who deployed to Iraq/Afghanistan after 9/11 with a positive depression screen and a first depression diagnosis between 2001 and 2021. We also obtained 12-month pre-diagnosis and post-diagnosis patient data. Retrospective cohort analysis was employed to test if predictors can reliably differentiate patients who initiated, delayed, or received no mental health treatment associated with their depression diagnosis. Results 108,457 Veterans with depression, initiated depression-related care (55,492 Veterans delayed treatment beyond one month). Those who were male, without VA disability benefits, with a mild depression diagnosis, and had a history of psychotherapy were less likely to initiate treatment. Among those who initiated care, those with single and mild depression episodes at baseline, with either PTSD or who lacked comorbidities were more likely to delay treatment for depression. A history of mental health treatment, of an anxiety disorder, and a positive depression screen were each related to faster treatment initiation. Classification of patients was modest (ROC AUC = 0.59 95%CI = 0.586–0.602; machine learning F-measure = 0.46). Conclusions Having VA disability benefits was the strongest predictor of treatment initiation after a depression diagnosis and a history of mental health treatment was the strongest predictor of delayed initiation of treatment. The complexity of the relationship between VA benefits and history of mental health care with treatment initiation after a depression diagnosis is further discussed. Modest classification accuracy with currently known predictors suggests the need to identify additional predictors of successful depression management.

Introduction The VA estimates that over 750,000 veterans are diagnosed with dementia as of 2010 and that an additional 420,000 will develop the disease between 2010-2020. There has been a 166% increase in enrollment of veterans who have Alzheimer's dementia over the last decade. The experience of health outcomes in Vietnam era women veterans has been less understood due to the very small population size, but learning from their outcomes is essential to understand risks for future women serving in combat scenarios. Methods A case description will be summarized of an older woman veteran referred for geriatric psychiatry consultation by a local behavioral intervention team (VA BRO team). The case demonstrated onset of dementia with symptoms of agitation and erratic driving. The case will be reviewed in context of the Vietnam era women's study and other studies demonstrating health outcomes and mortality data suggesting motor vehicle accident as a feature of women veteran health outcomes. Results The case report illustrates poor outcomes that may be unique to women veterans including a risk for lower mental health stability, which may lead to unstable behaviors in dementia. Data will be reviewed that show PTSD in women veterans may be associated with lower health functioning, and greater disability. Findings will also be noted that mortality data show a higher than population rate of motor vehicle accident mortality among women Vietnam Veterans relative to their counterparts in the general population. More recent studies have shown that women with TBI, PTSD, and depression had a significant increase in risk of developing dementia with multiple factors increasing risk up to 2-fold. Conclusions Women Veterans may have unique characteristics, social settings and health factors that impact dementia outcomes. Exposure by women in combat zones has increased dramatically in later Veteran cohorts (e.g., OEF-OIF), consequently data from the Vietnam era Veteran studies may help us understand and plan for future dementia care for female veterans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT (P < .001), with no evidence of a difference from 2D CE US (P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US (P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

Blood-brain barrier (BBB) leakage is a marker of vascular cognitive impairment and dementia (VCID). The advance of in vivo imaging enabled us to quantify the degree of BBB transfer rates in VCID patients. However, a consensus has not been reached on the role of BBB in the differential diagnosis of VCI subtypes. The objective of this work was to use neuroinflammatory and in vivo imaging data on BBB health to identify clusters of VCID patients with distinct underlying pathologies. Patients included were on average 61 (SD = 15.94, M/F = 27/34) years old. The MRI data were collected by using a 1.5 Tesla Siemens Sonata scanner. Pixel-by-pixel BBB transfer rate (Ki) was calculated using Patlak compartmental analysis on dynamic contrast-enhanced T1 maps. The mean BBB transfer rate was calculated for the brain section above the ventricular zone (sampled by six consecutive slices). MR Spectroscopy was used to investigate N-Acetylaspartate (NAA), Creatine (Cr), and Choline (Cho) levels. Moreover, Active MMP3 data were used in patients clustering. Thirty-eight patients enrolled in the study have all data for three entities; NAA, mean Ki, and active MMP3 used for clustering. A multi-parametric model-based classification method was used to blindly classify VCID data based on Ki, NAA, and active MMPs. BBB leakage increased by age, which is more pronounced in patients diagnosed with cognitive impairment when compared with 17 controls, r2 = 0.060, P = 0.021. Statistical classifiers identified three clusters in VCID patients. Identified VCID clusters are similar to the distinction that was made on this VCID cohort based on the clinical scores and psychological entities that we have published earlier. The results suggest that a statistical combination of imaging and inflammatory attributes renders a tool to blindly separate VCID patients into distinct groups that may have different underlying pathology.

INTRODUCTION:The significance of hyoid dynamics in OSA pathophysiology remains unclear. Drug-induced sleep endoscopy (DISE) is often used for evaluating patients intolerant to positive airway pressure (PAP) therapy. We performed DISE with concurrent hyoid-focused ultrasonography to quantify hyoid dynamics during obstructive and non-obstructive breathing. METHODS:A cross-sectional analysis from a prospective cohort of patients undergoing DISE with PAP titration (DISE-PAP) and hyoid-focused ultrasound was conducted. Hyoid ultrasound was performed during obstructive breathing, and non-obstructive breathing after PAP administration. Motion was quantified by generating displacement curves based on echo-tracking hyoid movement. The image analysis protocol for quantifying hyoid displacement was performed independently by two researchers, and reliability of measures was assessed. Univariate and multivariate regressions were performed for various clinical data and hyoid displacement during obstructive breathing. RESULTS:Twenty patients met inclusion criteria. On average, the cohort was male (75%), elderly (65.9 ± 10 years), overweight (29.3 ± 3.99 kg/m2 ), and with moderate-to-severe OSA (29.3 ± 12.5 events/h). Mean hyoid displacement during obstructive breathing was 5.81 mm (±3.48). In all patients, hyoid displacement decreased after PAP administration (-3.94 mm [95% CI: -5.10, -2.78]; p < 0.0001). Inter-rater reliability for measures of hyoid displacement was excellent. After multivariate regression, hyoid displacement at baseline was associated with higher AHI (β [95% CI] = 0.18 [0.03, 0.33], p = 0.020). CONCLUSION:During DISE, hyoid displacement is greater during obstructive breathing with significant variability amongst patients. Further, these ultrasonographic measurements had excellent intra- and inter-rater reliability. Additional, larger studies are needed to understand contributors to hyoid mobility. LEVEL OF EVIDENCE:4 Laryngoscope, 133:3221-3227, 2023.

This symposium addresses a critical need to grow the field of geriatric expertise by creating multiple learning options that reach clinicians at all phases of practice. The AAGP Strategic Planning meeting of September 2019 articulated several future goals including 1) Develop our own competency-based certificate program and 2) Offering a pathway to clinical expertise for clinicians (Tampi R, et al 2020). The strategic plan also strongly emphasized partnerships with like-minded organizations. This symposium highlights the success of the AMDA Certified Medical Director (CMD) Program. Dr Meenakshi Patel will discuss how AMDA developed the certification; she will review the core curriculum, the development of the initial certification and the subsequent recertification procedures. She will also discuss the advantages of the certification for other providers (e.g., PCPs, NPs). Discussion will address how new geriatric certification programs may supplement training conducted in traditional post-graduate settings and allow for critical workforce growth. Association-based certifications permit inclusivity for providers who are not able to avail themselves of post-graduate fellowships but wish to gain geriatric expertise. The value of “clinical pathways” to expertise will be discussed and stakeholders will be invited to explore ways for the AAGP to help create more diverse learning pathways in geriatric psychiatry

Machine learning models are increasingly being used in healthcare settings. If integrity of the data used to build these models is impacted by cybersecurity attacks, the results of these predictive models become questionable. To assess the risks associated with false data injections in provider progress notes, and to evaluate the potential of exploiting variance in predictions of text mining methods at detecting such data integrity issues. A simulation of false data injection scenarios was conducted on a set of provider notes. Common statistical text mining (STM) methods were used to assess the mental health severity of patients described in the falsified notes. The simulation experiment focused on 1) assessing the overall classification stability across the different types of false data injections, 2) identifying the classification algorithms that are robust against these attacks, and 3) evaluating the potential of STM methods at signaling data integrity issues. A simulation experiment using a training dataset of 96 severe psychiatric provider notes, 337 non-severe notes revealed that the performance of classification models drops with false data injection attacks. The accuracy of single models such as support vector machines and decision trees significantly dropped (average drop of 16.41%) by injection of a sole screening template. Ensemble models such as bagging and boosting were robust against sole screening template injections with an average drop of the accuracy level by about 0.513%. The performance of all models dropped significantly when false data exceeded 50% of the size of the note. While STM methods can be useful at assessing the severity of the mental health conditions expressed in provider notes, the performance of such models can drop significantly with false data injections. Traditionally, such non-robust behavior of STM models is undesirable. Counter-intuitively, we show here that such a lack of robustness can be leveraged to generate signals of malicious false data injections into EHR systems. Hence prediction variance of these models can potentially be used to signal data integrity issues.

This symposium addresses a critical need in geriatric psychiatry staffing shortages. The Department of Veterans Affairs is increasingly catering to aging veterans with complex medical and emotional problems. Unfortunately, there is a critical shortage of geriatric psychiatry expertise. The COVID-19 pandemic has further amplified the need for geriatric psychiatry services particularly in rural areas. In an effort to extend the valuable and too-often-scarce resource of geriatric psychiatry expertise, the National Telemental Health Center launched a new consultation service, Ask the Expert program in Geriatric Psychiatry, earlier this year. A team of VA Geriatric Psychiatrists were made available to answer general questions that VA clinicians may have about psychiatric care of older Veterans with potentially complex and interacting psychiatric, medical, neurocognitive, and behavioral care needs. The program aimed to provide a response within 7 days. Providers from the field were encouraged not share any Protected Health Information (PHI) in your questions. The service was not intended to make case-specific clinical recommendations, review patient health records, or respond to psychiatric emergencies.

Background Affective characteristics are associated with depression severity, course, and prognosis. Patients’ affect captured by clinicians during sessions may provide a rich source of information that more naturally aligns with the depression course and patient-desired depression outcomes. Objective In this paper, we propose an information extraction vocabulary used to pilot the feasibility and reliability of identifying clinician-recorded patient affective states in clinical notes from electronic health records. Methods Affect and mood were annotated in 147 clinical notes of 109 patients by 2 independent coders across 3 pilots. Intercoder discrepancies were settled by a third coder. This reference annotation set was used to test a proof-of-concept natural language processing (NLP) system using a named entity recognition approach. Results Concepts were frequently addressed in templated format and free text in clinical notes. Annotated data demonstrated that affective characteristics were identified in 87.8% (129/147) of the notes, while mood was identified in 97.3% (143/147) of the notes. The intercoder reliability was consistently good across the pilots (interannotator agreement [IAA] >70%). The final NLP system showed good reliability with the final reference annotation set (mood IAA=85.8%; affect IAA=80.9%). Conclusions Affect and mood can be reliably identified in clinician reports and are good targets for NLP. We discuss several next steps to expand on this proof of concept and the value of this research for depression clinical research.

The pathological cascades associated with the development of Alzheimer’s disease (AD) amyloid pathology, tau pathology, vascular insufficiency, metabolic disturbances and oxidative stress – have a common element – acidosis. T1rho (spin lattice relaxation time in the rotating frame) MRI is a pH sensitive measure with higher values associated with greater neuropathological burden. Methods—Twenty-seven participants (13M,14F, 55 – 90 years) across the cognitive spectrum (17 healthy controls (HC), 7 mild cognitive impairment (MCI), 3 mild Alzheimer’s disease (AD)) underwent neuropsychological testing, MR imaging (T1-weighted and T1rho (spin lattice relaxation time in the rotating frame)) and PET imaging ([11C]PIB for amyloid burden (N=26), and [18F]fluorodeoxyglucose for cerebral glucose metabolism (N=12)). The relationships between global T1rho values and the neuropsychological, demographic and imaging measures were explored. Results—Global mean and median T1rho were positively associated with age. After controlling for age, higher global T1rho was associated with poorer cognitive function, poorer memory function (immediate and delayed memory scores)), higher amyloid burden, and more abnormal cerebral glucose metabolism. Regional T1rho values, when controlled for age, significantly differed between cognitively normal and impaired groups for select frontal, cingulate and parietal regions. Conclusion—Higher T1rho values were associated with greater cognitive impairment and pathological burden. T1rho, a biomarker that varies according to a feature common to each of 1A portion of this work has previously been presented in abstract form at the following meetings: Ponto LL, Schultz SK, Jacob M, Menda Y, Wemmie J, Magnotta VA. Brain pH and Alzheimer’s Disease. SNMMI Annual Meeting 2014, St. Louis, Missouri. June 7 – 11, 2014, # 192. Journal of Nuclear Medicine, 2014 (May); 55(Supplement 1): 192. Ponto LLB, Schultz SK, Menda Y, Arndt S, Magnotta VA. Alzheimer’s pathology and the pH-sensitive marker T1rho MRI. SNMMI Annual Meeting 2016, San Diego, California, June 11 – 15, 2016, abstract #129, Monday, June 13, 2016. Journal of Nuclear Medicine. 2016; 57(Suppl 2): 67P. http://edition.pagesuite-professional.co.uk/launch.aspx?eid=6104d3d1–717b-4ddd-a317b29a5d29272f Corresponding author: Laura L. Boles Ponto, Ph.D., Professor, PET Imaging Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa 52242, laura-ponto@uiowa.edu, 319-356-1857 (tel), 319-353-6512 (fax). HHS Public Access Author manuscript J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2021 December 30. Published in final edited form as: J Neuropsychiatry Clin Neurosci. 2020 ; 32(4): 352–361. doi:10.1176/appi.neuropsych.19100221. A uhor M anscript

OBJECTIVES:Hepatic venous pressure gradient (HVPG) is considered the standard in quantifying portal hypertension, but can be unreliable in dialysis patients. A noninvasive ultrasound technique, subharmonic-aided pressure estimation (SHAPE), may be a valuable surrogate of these pressure estimates. This study compared SHAPE and HVPG with pathology findings for fibrosis in dialysis patients.METHODS:This was a subgroup study from an IRB-approved trial that included 20 patients on dialysis undergoing SHAPE examinations of portal and hepatic veins using a modified Logiq 9 scanner (GE, Waukesha, WI), during infusion of Sonazoid (GE Healthcare, Oslo, Norway). SHAPE was compared to HVPG and pathology findings using the Ludwig-Batts scoring system for fibrosis. Logistic regression, ROC analysis, and t-tests were used to compare HVPG and SHAPE with pathological findings of fibrosis.RESULTS:Of 20 cases, 5 had HVPG values corresponding to subclinical and clinical portal hypertension (≥6 and ≥10 mmHg, respectively) while 15 had normal HVPG values (≤5 mmHg). SHAPE and HVPG correlated moderately (r = 0.45; P = .047). SHAPE showed a trend toward correlating with fibrosis (r = 0.42; P = .068), while HVPG did not (r = 0.18; P = .45). SHAPE could differentiate between mild (stage 0-1) and moderate to severe (stage 2-4) fibrosis (-10.4 ± 4.9 dB versus -5.4 ± 3.2 dB; P = .035), HVPG could not (3.0 ± 0.6 mmHg versus 4.8 ± 0.7 mmHg; P = .30). ROC curves showed a diagnostic accuracy for SHAPE of 80%, while HVPG reached 76%.CONCLUSION:Liver fibrosis staging in dialysis patients evaluated for portal hypertension appears to be more accurately predicted by SHAPE than by HVPG; albeit in a small sample size.