Hepatitis C virus in people with serious mental illness: an analysis of the care cascade at a tertiary health service with a pilot 'identify and treat' strategy.

BACKGROUND: People with serious mental illness (SMI) are underserved from a hepatitis C virus (HCV) screening and treatment perspective. AIMS: To examine the HCV care cascade in people with SMI and to pilot a supported HCV treatment integration programme. METHODS: HCV prevalence was retrospectively analysed from 4492 consecutive individuals admitted to a tertiary hospital mental health service between January 2017 and December 2018. Subcohort analysis of screening patterns and predictors of seropositive infection was performed. Referral pathways and community care integration were analysed for HCV-positive individuals, and a prospective community-based 'identify and treat' HCV programme was assessed. RESULTS: Screening for HCV had been performed in 18.6% (835/4492) of the cohort. Seroprevalence was 4.6% (207/4492). HCV seropositivity was associated with age >40 years (odds ratio (OR) = 9.30; confidence interval (CI) 3.69-23.45; P < 0.01), injecting drug use (OR = 24.26; CI 8.99-65.43; P < 0.01) and previous incarceration (OR = 12.26; CI 4.51-33.31; P < 0.01). In a cohort of treatment-eligible individuals, 43.3% (90/208) had neither been referred to specialist services or general practitioners for HCV management. Amongst those referred to specialist services, 64.7% (57/88) did not attend scheduled follow up, and 48.3% (15/31) of attendees were lost to follow up. Through an intensified community access programme, 10 people were successfully treated for HCV, although 22 could not be engaged. CONCLUSION: People with SMI are underserved by traditional models of HCV healthcare. Intensified community-based support can partially bolster the treatment cascade, although investment in innovative screening and management strategies are required to achieve healthcare parity.

Visualization and Analysis of Multidimensional Cardiovascular Magnetic Resonance Imaging: Challenges and Opportunities.

Recent advances in magnetic resonance imaging are enabling the efficient creation of high-dimensional, multiparametric images, containing a wealth of potential information about the structure and function of many organs, including the cardiovascular system. However, the sizes of these rich data sets are so large that they are outstripping our ability to adequately visualize and analyze them, thus limiting their clinical impact. While there are some intrinsic limitations of human perception and of conventional display devices which hamper our ability to effectively use these data, newer computational methods for handling the data may aid our ability to extract and visualize the salient components of these high-dimensional data sets.

Determinants of Hepatitis C Virus Prevalence in People With Serious Mental Illness: A Systematic Review and Meta-Analysis.

Objective: To perform a meta-analysis of hepatitis C virus (HCV) prevalence in people with serious mental illness (SMI) and to systematically review barriers to care with the contention that both individual complications and HCV community transmission can be reduced with enhanced health care strategies.Data Sources: PubMed, Scopus, Embase, CINAHL, and Web of Science were searched for articles published in English between April 21, 1989, and July 1, 2020. The terms Hepatitis C Virus, HCV, HCV seroprevalence, and HCV prevalence were cross-referenced with serious mental illness, severe mental illness, psychiatric illness, mental illness, and psychiatric patients.Study Selection: We identified 230 titles after removing duplicates. The final analysis included 36 publications drawn from prospective and large retrospective cohort studies that cross-sectionally screened for HCV in people with SMI ≥ 18 years of age.Data Extraction: Pooled HCV prevalence was analyzed, with random effects modeling due to significant attributable study heterogeneity. Demographic data and HCV risk factors were subanalyzed. Qualitative and semiqualitative data relating to control cohort prevalence and the HCV care cascade were also extracted.Results: The pooled HCV prevalence was 8.0% (95% CI, 6.0%-9.0%). Subanalysis of prospective studies (n = 9,015 individuals) demonstrated a similar prevalence, 8.0% (CI, 5.0%-11.0%), to retrospective studies (n = 289,247), 8.0% (CI, 6.0%-10.0%). HCV was 3.0- to 11.3-fold higher in people with SMI relative to controls. Semiqualitative analysis of seropositive cases showed that (1) 20.0%-58.1% did not have an identified HCV risk factor; (2) 12.5%-100% of cases were not previously known to have HCV; and (3) the majority, 57.0%-96.6%, of people with SMI were receptive to HCV screening.Conclusions: People with SMI have high HCV seroprevalence and should be recognized as a priority group for HCV screening and health care access.

Very Delayed Acute Hepatitis after Pembrolizumab Therapy for Advanced Malignancy: How Long Should We Watch?

Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.

Hepatitis E Infection With Acute Liver Failure.

A 21-year-old man from India presented with acute hepatitis associated with a 1-week history of abdominal pain, pruritus, and dark urine. Over a 7-day admission, the patient's acute hepatitis evolved into acute liver failure with low-grade encephalopathy, markedly elevated transaminases, bilirubin, and impaired hepatic synthetic function. He was eventually diagnosed with acute hepatitis E virus (HEV) and was transitioned to supportive management. Acute HEV is a rare cause of acute liver failure. Hence, this case highlights the importance of early consideration of HEV in all patients with acute hepatitis who have originated from endemic regions.

Validation of an automated system for detecting ineffective triggering asynchronies during mechanical ventilation: a retrospective study.

We compare the sensitivity and specificity of clinician visual waveform analysis against an automated system's waveform analysis in detecting ineffective triggering in mechanically ventilated intensive care unit patients when compared against a reference label set based upon analysis of respiratory muscle activity. Electrical activity of the diaphragm or esophageal/transdiaphragmatic pressure waveforms were available to a single clinician for the generation of a reference label set indicating the ground truth, that is, presence or absence of ineffective triggering, on a breath-by-breath basis. Pressure and flow versus time tracings were made available to (i) a group of three clinicians; and (ii) the automated Syncron-E™ system capable of detecting patient-ventilator asynchrony in real-time, in order to obtain breath-by-breath labels indicating the presence or absence of ineffective triggering. The clinicians and the automated system did not have access to other waveforms such as electrical activity of the diaphragm or esophageal/transdiaphragmatic pressure. In total, 926 breaths were analyzed across the seven patients. Specificity for clinicians and the automated system were high (99.3% for clinician and 98.5% for the automated system). The automated system had a significantly higher sensitivity (83.2%) compared to clinicians (41.1%). Ineffective triggering detected by the automated system, which has access only to airway pressure and flow versus time tracings, is in substantial agreement with a reference detection derived from analysis of invasively measured patient effort waveforms.

Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension.

Vascular calcification leads to increased large artery stiffness. Matrix gla-protein (MGP) is a vitamin K-dependent protein that inhibits arterial calcification. Aldosterone promotes vascular calcification and stiffness, but the relationships between aldosterone, MGP, and arterial stiffness are unknown. We studied 199 adults (predominantly older men) with hypertension. We assessed the relationship between levels of dephospho-uncarboxylated MGP (dp-ucMGP), aldosterone, and carotid-femoral pulse wave velocity (CF-PWV) using standard regression and mediation analyses. Plasma aldosterone was measured in a subgroup of subjects (n = 106). Aldosterone was strongly associated with dp-ucMGP (standardized ß = 0.50, P < .001), which was independent of potential confounders (ß = 0.37, P < .001). Levels of dp-ucMGP were significantly associated with CF-PWV (ß = 0.30; P < .001), which persisted after adjustment for potential confounders (ß = 0.25; P = .004). Plasma aldosterone was also significantly associated with CF-PWV (standardized ß = 0.21; P = .035). However, in a model that included aldosterone and dp-ucMGP, only the latter was associated with CF-PWV. Mediation analyses demonstrated a significant dp-ucMGP-mediated effect of aldosterone on CF-PWV, without a significant direct (dp-ucMGP independent) effect. Our study demonstrates a novel independent association between high aldosterone levels and dp-ucMGP, suggesting that aldosterone may influence the MGP pathway. This relationship appears to underlie the previously documented relationship between aldosterone and increased arterial stiffness.

Replicating human expertise of mechanical ventilation waveform analysis in detecting patient-ventilator cycling asynchrony using machine learning.

BACKGROUND: - Acute respiratory failure is one of the most common problems encountered in intensive care units (ICU) and mechanical ventilation is the mainstay of supportive therapy for such patients. A mismatch between ventilator delivery and patient demand is referred to as patient-ventilator asynchrony (PVA). An important hurdle in addressing PVA is the lack of a reliable framework for continuously and automatically monitoring the patient and detecting various types of PVA. METHODS: - The problem of replicating human expertise of waveform analysis for detecting cycling asynchrony (i.e., delayed termination, premature termination, or none) was investigated in a pilot study involving 11 patients in the ICU under invasive mechanical ventilation. A machine learning framework is used to detect cycling asynchrony based on waveform analysis. RESULTS: - A panel of five experts with experience in PVA evaluated a total of 1377 breath cycles from 11 mechanically ventilated critical care patients. The majority vote was used to label each breath cycle according to cycling asynchrony type. The proposed framework accurately detected the presence or absence of cycling asynchrony with sensitivity (specificity) of 89% (99%), 94% (98%), and 97% (93%) for delayed termination, premature termination, and no cycling asynchrony, respectively. The system showed strong agreement with human experts as reflected by the kappa coefficients of 0.90, 0.91, and 0.90 for delayed termination, premature termination, and no cycling asynchrony, respectively. CONCLUSIONS: - The pilot study establishes the feasibility of using a machine learning framework to provide waveform analysis equivalent to an expert human.

Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in Hypertension.

BACKGROUND: Late systolic load has been shown to cause diastolic dysfunction in animal models. Although the systolic loading sequence of the ventricular myocardium likely affects its coupling with the left atrium (LA), this issue has not been investigated in humans. We aimed to assess the relationship between the myocardial loading sequence and LA function in human hypertension. METHODS AND RESULTS: We studied 260 subjects with hypertension and 19 normotensive age- and sex-matched controls. Time-resolved central pressure and left ventricular geometry were measured with carotid tonometry and cardiac magnetic resonance imaging, respectively, for computation of time-resolved ejection-phase myocardial wall stress (MWS). The ratio of late/early ejection-phase MWS time integrals was computed as an index of late systolic myocardial load. Atrial mechanics were measured with cine-steady-state free-precession magnetic resonance imaging using feature-tracking algorithms. Compared with normotensive controls, hypertensive participants demonstrated increased late/early ejection-phase MWS and reduced LA function. Greater levels of late/early ejection-phase MWS were associated with reduced LA conduit, reservoir, and booster pump LA function. In models that included early and late ejection-phase MWS as independent correlates of LA function, late systolic MWS was associated with lower, whereas early systolic MWS was associated with greater LA function, indicating an effect of the relative loading sequence (late versus early MWS) on LA function. These relationships persisted after adjustment for multiple potential confounders. CONCLUSIONS: A myocardial loading sequence characterized by prominent late systolic MWS was independently associated with atrial dysfunction. In the context of available experimental data, our findings support the deleterious effects of late systolic loading on ventricular-atrial coupling.

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction.

AIMS: To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We assessed carotid and aortic pressure-flow relations non-invasively before and after the administration of 0.4 mg of sublingual nitroglycerin (n = 26), and in a separate sub-study, in response to 12.9 mmoL of inorganic nitrate (n = 16). Nitroglycerin did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic: -0.09; P = 0.01; 2nd harmonic: -0.045, P = 0.16; 3rd harmonic: +0.087; P = 0.05), but produced profound vasodilatation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs. 120.5 mmHg; P = 0.011) and a marked reduction in carotid bed vascular resistance (19 580 vs. 13 078 dynes · s/cm5 ; P = 0.001) and carotid characteristic impedance (3440 vs. 1923 dynes · s/cm5 ; P = 0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first three harmonics (change in real part of reflection coefficient, 1st harmonic: -0.12; P = 0.03; 2nd harmonic: -0.11, P = 0.01; 3rd harmonic: -0.087; P = 0.09) and did not reduce blood pressure, carotid bed vascular resistance, or carotid characteristic impedance (P = NS). CONCLUSIONS: Nitroglycerin produces marked vasodilatation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike nitroglycerin, it does so without significant hypotension or cerebrovascular dilatation. These haemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF.

Beta-Blocker Use Is Associated With Impaired Left Atrial Function in Hypertension.

BACKGROUND: Impaired left atrial (LA) mechanical function is present in hypertension and likely contributes to various complications, including atrial arrhythmias, stroke, and heart failure. Various antihypertensive drug classes exert differential effects on central hemodynamics and left ventricular function. However, little is known about their effects on LA function. METHODS AND RESULTS: We studied 212 subjects with hypertension and without heart failure or atrial fibrillation. LA strain was measured from cine steady-state free-precession cardiac MRI images using feature-tracking algorithms. In multivariable models adjusted for age, sex, race, body mass index, blood pressure, diabetes mellitus, LA volume, left ventricular mass, and left ventricular ejection fraction, beta-blocker use was associated with a lower total longitudinal strain (standardized ß=-0.21; P=0.008), and lower LA expansion index (standardized ß=-0.30; P<0.001), indicating impaired LA reservoir function. Beta-blocker use was also associated with a lower positive strain (standardized ß=-0.19; P=0.012) and early diastolic strain rate (standardized ß=0.15; P=0.039), indicating impaired LA conduit function. Finally, beta-blocker use was associated with a lower (less negative) late-diastolic strain (standardized ß=0.15; P=0.049), strain rate (standardized ß=0.18; P=0.019), and a lower active LA emptying fraction (standardized ß=-0.27; P<0.001), indicating impaired booster pump function. Use of other antihypertensive agents was not associated with LA function. CONCLUSIONS: Beta-blocker use is significantly associated with impaired LA function in hypertension. This association could underlie the increased risk of atrial fibrillation and stroke seen with the use of beta-blockers (as opposed to other antihypertensive agents) demonstrated in recent trials.

Aging is Associated With an Earlier Arrival of Reflected Waves Without a Distal Shift in Reflection Sites.

BACKGROUND: Despite pronounced increases in central pulse wave velocity (PWV) with aging, reflected wave transit time (RWTT), traditionally defined as the timing of the inflection point (TINF) in the central pressure waveform, does not appreciably decrease, leading to the controversial proposition of a "distal-shift" of reflection sites. TINF, however, is exceptionally prone to measurement error and is also affected by ejection pattern and not only by wave reflection. We assessed whether RWTT, assessed by advanced pressure-flow analysis, demonstrates the expected decline with aging. METHODS AND RESULTS: We studied a sample of unselected adults without cardiovascular disease (n=48; median age 48 years) and a clinical population of older adults with suspected/established cardiovascular disease (n=164; 61 years). We measured central pressure and flow with carotid tonometry and phase-contrast MRI, respectively. We assessed RWTT using wave-separation analysis (RWTTWSA) and partially distributed tube-load (TL) modeling (RWTTTL). Consistent with previous reports, TINF did not appreciably decrease with age despite pronounced increases in PWV in both populations. However, aging was associated with pronounced decreases in RWTTWSA (general population -15.0 ms/decade, P<0.001; clinical population -9.07 ms/decade, P=0.003) and RWTTTL (general -15.8 ms/decade, P<0.001; clinical -11.8 ms/decade, P<0.001). There was no evidence of an increased effective reflecting distance by either method. TINF was shown to reliably represent RWTT only under highly unrealistic assumptions about input impedance. CONCLUSIONS: RWTT declines with age in parallel with increased PWV, with earlier effects of wave reflections and without a distal shift in reflecting sites. These findings have important implications for our understanding of the role of wave reflections with aging.

Misinterpretation of the Determinants of Elevated Forward Wave Amplitude Inflates the Role of the Proximal Aorta.

BACKGROUND: The hemodynamic basis for increased pulse pressure (PP) with aging remains controversial. The classic paradigm attributes a predominant role to increased pulse wave velocity (PWV) and premature wave reflections (WRs). A controversial new paradigm proposes increased forward pressure wave amplitude (FWA), attributed to proximal aortic characteristic impedance (Zc), as the predominant factor, with minor contributions from WRs. Based on theoretical considerations, we hypothesized that (rectified) WRs drive the increase in FWA, and that the forward pressure wave does not depend solely on the interaction between flow and Zc (QZc product). METHODS AND RESULTS: We performed 3 substudies: (1) open-chest anesthetized dog experiments (n=5); (2) asymmetric T-tube model-based study; and (3) human study in a diverse clinical population (n=193). Animal experiments demonstrated that FWA corresponds to peak QZc only when WRs are minimal. As WRs increased, FWA was systematically greater than QZc and peaked well after peak flow, analogous to late-systolic peaking of pressure attributable to WRs. T-tube modeling confirmed that increased/premature WRs resulted in increased FWA. Magnitude and timing of WRs explained 80.8% and 74.3% of the variability in the difference between FWA and peak QZc in dog and human substudies, respectively. CONCLUSIONS: Only in cases of minimal reflections does FWA primarily reveal the interaction between peak aortic flow and proximal aortic diameter/stiffness. FWA is strongly dependent on rectified reflections. If interpreted out of context with the hemodynamic principles of its derivation, the FWA paradigm inappropriately amplifies the role of the proximal aorta in elevation of FWA and PP.