Clonal haematopoiesis and risk of chronic liver disease.

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH.

BACKGROUND & AIMS: MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. METHODS: A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed. RESULTS: Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53). CONCLUSIONS: These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention. IMPACT AND IMPLICATIONS: There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. CLINICAL TRIAL NUMBER(S): NCT02443116, NCT03976401, NCT03551522.

Quantitative MRI for Monitoring Metabolic Dysfunction-Associated Steatotic Liver Disease: A Test-Retest Repeatability Study.

BACKGROUND: Quantitative magnetic resonance imaging metrics iron-corrected T1 (cT1) and liver fat from proton density fat-fraction (PDFF) are both commonly used as noninvasive biomarkers for metabolic dysfunction-associated steatohepatitis (MASH); however, their repeatability in this population has rarely been characterized. PURPOSE: To quantify the variability of cT1 and liver fat fraction from PDFF in patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. STUDY TYPE: Prospective, single center. POPULATION: Twenty-one participants (female = 11, mean age 53 ± 24 years) with biopsy-confirmed MASLD, including 6 with MASH and fibrosis ≥2. FIELD STRENGTH/SEQUENCE: 3 T; T1 and T2* mapping for the generation of cT1 (shMOLLI: CardioMaps and 2D MDE, T1map-FIESTA and LMS MOST: StarMap, 2D Multi-Echo FSPGR) and magnitude-only PDFF sequence for liver fat quantification (LMS IDEAL: StarMap, 2D Multi-Echo FSPGR). ASSESSMENT: T1 mapping and PDFF scans were performed twice on the same day for all participants (N = 21), with an additional scan 2-4 weeks later for MASH patients with fibrosis ≥2 (N = 6). Whole liver segmentation masks were generated semi-automatically and average pixel counts within these masks were used for the calculation of cT1 and liver fat fraction. STATISTICAL TESTS: Bland-Altman analysis for repeatability coefficient (RC) and 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC). RESULTS: Same-day RC was 32.1 msec (95% LOA: -36.6 to 24.2 msec) for cT1 and 0.6% (95% LOA: -0.5% to 0.7%) for liver fat fraction; the ICCs were 0.98 (0.96-0.99) and 1.0, respectively. Short-term RC was 65.2 msec (95% LOA: -63.8 to 76.5 msec) for cT1 and 2.6% (95% LOA: -2.8% to 3.1%) for liver fat fraction. DATA CONCLUSION: In participants with MASLD and MASH, cT1 and liver fat fraction measurements show excellent test-retest repeatability, supporting their use in monitoring MASLD and MASH. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

NAFLD and NASH biomarker qualification in the LITMUS consortium - Lessons learned.

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Sharing knowledge of such interactions with the scientific community is of paramount importance to increase the chances of qualification of relevant biomarkers that may accelerate drug development, and thereby help patients, across disease indications. A qualified biomarker enables a decision to be made that all understand and support in a common framework.

Liver disease is a significant risk factor for cardiovascular outcomes - A UK Biobank study.

BACKGROUND & AIMS: Chronic liver disease (CLD) is associated with increased cardiovascular disease (CVD) risk. We investigated whether early signs of liver disease (measured by iron-corrected T1-mapping [cT1]) were associated with an increased risk of major CVD events. METHODS: Liver disease activity (cT1) and fat (proton density fat fraction [PDFF]) were measured using LiverMultiScan® between January 2016 and February 2020 in the UK Biobank imaging sub-study. Using multivariable Cox regression, we explored associations between liver cT1 (MRI) and primary CVD (coronary artery disease, atrial fibrillation [AF], embolism/vascular events, heart failure [HF] and stroke), and CVD hospitalisation and all-cause mortality. Liver blood biomarkers, general metabolism biomarkers, and demographics were also included. Subgroup analysis was conducted in those without metabolic syndrome (defined as at least three of: a large waist, high triglycerides, low high-density lipoprotein cholesterol, increased systolic blood pressure, or elevated haemoglobin A1c). RESULTS: A total of 33,616 participants (mean age 65 years, mean BMI 26 kg/m2, mean haemoglobin A1c 35 mmol/mol) had complete MRI liver data with linked clinical outcomes (median time to major CVD event onset: 1.4 years [range: 0.002-5.1]; follow-up: 2.5 years [range: 1.1-5.2]). Liver disease activity (cT1), but not liver fat (PDFF), was associated with higher risk of any major CVD event (hazard ratio 1.14; 95% CI 1.03-1.26; p = 0.008), AF (1.30; 1.12-1.51; p <0.001); HF (1.30; 1.09-1.56; p= 0.004); CVD hospitalisation (1.27; 1.18-1.37; p <0.001) and all-cause mortality (1.19; 1.02-1.38; p = 0.026). FIB-4 index was associated with HF (1.06; 1.01-1.10; p = 0.007). Risk of CVD hospitalisation was independently associated with cT1 in individuals without metabolic syndrome (1.26; 1.13-1.4; p <0.001). CONCLUSION: Liver disease activity, by cT1, was independently associated with a higher risk of incident CVD and all-cause mortality, independent of pre-existing metabolic syndrome, liver fibrosis or fat. IMPACT AND IMPLICATIONS: Chronic liver disease (CLD) is associated with a twofold greater incidence of cardiovascular disease. Our work shows that early liver disease on iron-corrected T1 mapping was associated with a higher risk of major cardiovascular disease (14%), cardiovascular disease hospitalisation (27%) and all-cause mortality (19%). These findings highlight the prognostic relevance of a comprehensive evaluation of liver health in populations at risk of CVD and/or CLD, even in the absence of clinical manifestations or metabolic syndrome, when there is an opportunity to modify/address risk factors and prevent disease progression. As such, they are relevant to patients, carers, clinicians, and policymakers.

Clinical Utility of Magnetic Resonance Imaging Biomarkers for Identifying Nonalcoholic Steatohepatitis Patients at High Risk of Progression: A Multicenter Pooled Data and Meta-Analysis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence worldwide. NAFLD is associated with excess risk of all-cause mortality, and its progression to nonalcoholic steatohepatitis (NASH) and fibrosis accounts for a growing proportion of cirrhosis and hepatocellular cancer and thus is a leading cause of liver transplant worldwide. Noninvasive precise methods to identify patients with NASH and NASH with significant disease activity and fibrosis are crucial when the disease is still modifiable. The aim of this study was to examine the clinical utility of corrected T1 (cT1) vs magnetic resonance imaging (MRI) liver fat for identification of NASH participants with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage (F) ≥2 (high-risk NASH). METHODS: Data from five clinical studies (n = 543) with participants suspected of NAFLD were pooled or used for individual participant data meta-analysis. The diagnostic accuracy of the MRI biomarkers to stratify NASH patients was determined using the area under the receiver operating characteristic curve (AUROC). RESULTS: A stepwise increase in cT1 and MRI liver fat with increased NAFLD severity was shown, and cT1 was significantly higher in participants with high-risk NASH. The diagnostic accuracy (AUROC) of cT1 to identify patients with NASH was 0.78 (95% CI, 0.74-0.82), for liver fat was 0.78 (95% CI, 0.73-0.82), and when combined with MRI liver fat was 0.82 (95% CI, 0.78-0.85). The diagnostic accuracy of cT1 to identify patients with high-risk NASH was good (AUROC = 0.78; 95% CI, 0.74-0.82), was superior to MRI liver fat (AUROC = 0.69; 95% CI, 0.64-0.74), and was not substantially improved by combining it with MRI liver fat (AUROC = 0.79; 95% CI, 0.75-0.83). The meta-analysis showed similar performance to the pooled analysis for these biomarkers. CONCLUSIONS: This study shows that quantitative MRI-derived biomarkers cT1 and liver fat are suitable for identifying patients with NASH, and cT1 is a better noninvasive technology than liver fat to identify NASH patients at greatest risk of disease progression. Therefore, MRI cT1 and liver fat have important clinical utility to help guide the appropriate use of interventions in NAFLD and NASH clinical care pathways.

Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. METHODS: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. RESULTS: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). CONCLUSIONS: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

Dual-task walking and automaticity after Stroke: Insights from a secondary analysis and imaging sub-study of a randomised controlled trial.

OBJECTIVE: To test the extent to which initial walking speed influences dual-task performance after walking intervention, hypothesising that slow walking speed affects automatic gait control, limiting executive resource availability. DESIGN: A secondary analysis of a trial of dual-task (DT) and single-task (ST) walking interventions comparing those with good (walking speed ⩾0.8 m s-1, n = 21) and limited (walking speed <0.79 m s-1, n = 24) capacity at baseline. SETTING: Community. SUBJECTS: Adults six-months post stroke with walking impairment. INTERVENTIONS: Twenty sessions of 30 minutes treadmill walking over 10 weeks with (DT) or without (ST) cognitive distraction. Good and limited groups were formed regardless of intervention received. MAIN MEASURES: A two-minute walk with (DT) and without (ST) a cognitive distraction assessed walking. fNIRS measured prefrontal cortex activation during treadmill walking with (DT) and without (ST) Stroop and planning tasks and an fMRI sub-study used ankle-dorsiflexion to simulate walking. RESULTS: ST walking improved in both groups (∆baseline: Good = 8.9 ± 13.4 m, limited = 5.3±8.9 m, Group × time = P < 0.151) but only the good walkers improved DT walking (∆baseline: Good = 10.4 ± 13.9 m, limited = 1.3 ± 7.7 m, Group × time = P < 0.025). fNIRS indicated increased ispilesional prefrontal cortex activation during DT walking following intervention (P = 0.021). fMRI revealed greater DT cost activation for limited walkers, and increased resting state connectivity of contralesional M1 with cortical areas associated with conscious gait control at baseline. After the intervention, resting state connectivity between ipsilesional M1 and bilateral superior parietal lobe, involved in integrating sensory and motor signals, increased in the good walkers compared with limited walkers. CONCLUSION: In individual who walk slowly it may be difficult to improve dual-task walking ability.Registration: ISRCTN50586966.

Prognostic value of multiparametric magnetic resonance imaging, transient elastography and blood-based fibrosis markers in patients with chronic liver disease.

BACKGROUND & AIMS: Liver cT1 , liver T1 , transient elastography (TE) and blood-based biomarkers have independently been shown to predict clinical outcomes but have not been directly compared in a single cohort of patients. Our aim was to compare these tests' prognostic value in a cohort of patients with compensated chronic liver disease. METHODS: Patients with unselected compensated liver disease aetiologies had baseline assessments and were followed up for development of clinical outcomes, blinded to the imaging results. The prognostic value of non-invasive liver tests at prespecified thresholds was assessed for a combined clinical endpoint comprising ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation and mortality. RESULTS: One hundred and ninety-seven patients (61% male) with median age of 54 years were followed up for 693 patient-years (median (IQR) 43 (26-58) months). The main diagnoses were NAFLD (41%), viral hepatitis (VH, 25%) and alcohol-related liver disease (ArLD; 14%). During follow-up 14 new clinical events, and 11 deaths occurred. Clinical outcomes were predicted by liver cT1  > 825ms with HR 9.9 (95% CI: 1.29-76.4, P = .007), TE > 8kPa with HR 7.8 (95% CI: 0.97-62.3, P = .02) and FIB-4 > 1.45 with HR 4.09 (95% CI: 0.90-18.4, P = .05). In analysis taking into account technical failure and unreliability, liver cT1  > 825 ms could predict clinical outcomes (P = .03), but TE > 8kPa could not (P = .4). CONCLUSIONS: We provide further evidence that liver cT1 , TE and serum-based biomarkers can predict clinical outcomes, but when taking into account technical failure/unreliability, TE cut-offs perform worse than those of cT1 and blood biomarkers.

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought.

Assessing the performance of AI-assisted technicians in liver segmentation, Couinaud division, and lesion detection: a pilot study.

BACKGROUND: In patients with primary and secondary liver cancer, the number and sizes of lesions, their locations within the Couinaud segments, and the volume and health status of the future liver remnant are key for informing treatment planning. Currently this is performed manually, generally by trained radiologists, who are seeing an inexorable growth in their workload. Integrating artificial intelligence (AI) and non-radiologist personnel into the workflow potentially addresses the increasing workload without sacrificing accuracy. This study evaluated the accuracy of non-radiologist technicians in liver cancer imaging compared with radiologists, both assisted by AI. METHODS: Non-contrast T1-weighted MRI data from 18 colorectal liver metastasis patients were analyzed using an AI-enabled decision support tool that enables non-radiology trained technicians to perform key liver measurements. Three non-radiologist, experienced operators and three radiologists performed whole liver segmentation, Couinaud segment segmentation, and the detection and measurements of lesions aided by AI-generated delineations. Agreement between radiologists and non-radiologists was assessed using the intraclass correlation coefficient (ICC). Two additional radiologists adjudicated any lesion detection discrepancies. RESULTS: Whole liver volume showed high levels of agreement between the non-radiologist and radiologist groups (ICC = 0.99). The Couinaud segment volumetry ICC range was 0.77-0.96. Both groups identified the same 41 lesions. As well, the non-radiologist group identified seven more structures which were also confirmed as lesions by the adjudicators. Lesion diameter categorization agreement was 90%, Couinaud localization 91.9%. Within-group variability was comparable for lesion measurements. CONCLUSION: With AI assistance, non-radiologist experienced operators showed good agreement with radiologists for quantifying whole liver volume, Couinaud segment volume, and the detection and measurement of lesions in patients with known liver cancer. This AI-assisted non-radiologist approach has potential to reduce the stress on radiologists without compromising accuracy.

Judicial Threats to Olmstead and the Americans With Disabilities Act.

The authors examine the U.S. Supreme Court decision in Olmstead v L.C. ex rel. Zimring and related Supreme Court rulings that could raise questions about the Americans With Disabilities Act's guarantee of care in integrated settings and about which governmental entity's interpretation should be respected when deciding whether a state has met its integration obligation. After reviewing statutes, administrative regulations, and judicial decisions, the authors conclude that Olmstead's integration mandate will likely stand, but actions should be taken to codify the rule in federal and state statutes so that governmental agencies will continue to have the authority to ensure compliance with the mandate.

Association of sex hormones and sex hormone-binding globulin with liver fat in men and women: an observational and Mendelian randomization study.

Background: Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses. Methods: The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies. Results: In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (ß = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (ß = -0.36, 95% CI: -0.61, -0.12). Conclusion: Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation.

Multi-organ impairment and long COVID: a 1-year prospective, longitudinal cohort study.

OBJECTIVES: To determine the prevalence of organ impairment in long COVID patients at 6 and 12 months after initial symptoms and to explore links to clinical presentation. DESIGN: Prospective cohort study. PARTICIPANTS: Individuals. METHODS: In individuals recovered from acute COVID-19, we assessed symptoms, health status, and multi-organ tissue characterisation and function. SETTING: Two non-acute healthcare settings (Oxford and London). Physiological and biochemical investigations were performed at baseline on all individuals, and those with organ impairment were reassessed. MAIN OUTCOME MEASURES: Primary outcome was prevalence of single- and multi-organ impairment at 6 and 12 months post COVID-19. RESULTS: A total of 536 individuals (mean age 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post COVID-19); 331 (62%) with organ impairment or incidental findings had follow-up, with reduced symptom burden from baseline (median number of symptoms 10 and 3, at 6 and 12 months, respectively). Extreme breathlessness (38% and 30%), cognitive dysfunction (48% and 38%) and poor health-related quality of life (EQ-5D-5L < 0.7; 57% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single-organ impairment. Single- and multi-organ impairment were present in 69% and 23% at baseline, persisting in 59% and 27% at follow-up, respectively. CONCLUSIONS: Organ impairment persisted in 59% of 331 individuals followed up at 1 year post COVID-19, with implications for symptoms, quality of life and longer-term health, signalling the need for prevention and integrated care of long COVID.Trial Registration: ClinicalTrials.gov Identifier: NCT04369807.

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study.

Research question: Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonist d-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials. Methods: 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.gov identifier: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mg d-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between d-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety. Results: No difference between d-cycloserine and placebo groups was observed across the primary or secondary outcome measures. d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Conclusion: Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of d-cycloserine would not be worthwhile.

Cardiac abnormalities in Long COVID 1-year post-SARS-CoV-2 infection.

BACKGROUND: Long COVID is associated with multiple symptoms and impairment in multiple organs. Cross-sectional studies have reported cardiac impairment to varying degrees by varying methodologies. Using cardiac MR (CMR), we investigated a 12-month trajectory of abnormalities in Long COVID. OBJECTIVES: To investigate cardiac abnormalities 1-year post-SARS-CoV-2 infection. METHODS: 534 individuals with Long COVID underwent CMR (T1/T2 mapping, cardiac mass, volumes, function and strain) and multiorgan MRI at 6 months (IQR 4.3-7.3) since first post-COVID-19 symptoms. 330 were rescanned at 12.6 (IQR 11.4-14.2) months if abnormal baseline findings were reported. Symptoms, questionnaires and blood samples were collected at both time points. CMR abnormalities were defined as ≥1 of low left or right ventricular ejection fraction (LVEF), high left or right ventricular end diastolic volume, low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in ≥3 cardiac segments. Significant change over time was reported by comparison with 92 healthy controls. RESULTS: Technical success of multiorgan and CMR assessment in non-acute settings was 99.1% and 99.6% at baseline, and 98.3% and 98.8% at follow-up. Of individuals with Long COVID, 102/534 (19%) had CMR abnormalities at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing CMR abnormalities at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms or clinical outcomes. At baseline, low LVEF was associated with persistent CMR abnormality, abnormal GLS associated with low quality of life and abnormal T1 in at least three segments was associated with better clinical outcomes at 12 months. CONCLUSION: CMR abnormalities (left entricular or right ventricular dysfunction/dilatation and/or abnormal T1mapping), occurred in one in five individuals with Long COVID at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers could not identify CMR abnormalities in Long COVID. TRIAL REGISTRATION NUMBER: NCT04369807.

Technology-Enabled, Evidence-Driven, and Patient-Centered: The Way Forward for Regulating Software as a Medical Device.

Artificial intelligence (AI) is a broad discipline that aims to understand and design systems that display properties of intelligence. Machine learning (ML) is a subset of AI that describes how algorithms and models can assist computer systems in progressively improving their performance. In health care, an increasingly common application of AI/ML is software as a medical device (SaMD), which has the intention to diagnose, treat, cure, mitigate, or prevent disease. AI/ML includes either "locked" or "continuous learning" algorithms. Locked algorithms consistently provide the same output for a particular input. Conversely, continuous learning algorithms, in their infancy in terms of SaMD, modify in real-time based on incoming real-world data, without controlled software version releases. This continuous learning has the potential to better handle local population characteristics, but with the risk of reinforcing existing structural biases. Continuous learning algorithms pose the greatest regulatory complexity, requiring seemingly continuous oversight in the form of special controls to ensure ongoing safety and effectiveness. We describe the challenges of continuous learning algorithms, then highlight the new evidence standards and frameworks under development, and discuss the need for stakeholder engagement. The paper concludes with 2 key steps that regulators need to address in order to optimize and realize the benefits of SaMD: first, international standards and guiding principles addressing the uniqueness of SaMD with a continuous learning algorithm are required and second, throughout the product life cycle and appropriate to the SaMD risk classification, there needs to be continuous communication between regulators, developers, and SaMD end users to ensure vigilance and an accurate understanding of the technology.

Multi-organ imaging demonstrates the heart-brain-liver axis in UK Biobank participants.

Medical imaging provides numerous insights into the subclinical changes that precede serious diseases such as heart disease and dementia. However, most imaging research either describes a single organ system or draws on clinical cohorts with small sample sizes. In this study, we use state-of-the-art multi-organ magnetic resonance imaging phenotypes to investigate cross-sectional relationships across the heart-brain-liver axis in 30,444 UK Biobank participants. Despite controlling for an extensive range of demographic and clinical covariates, we find significant associations between imaging-derived phenotypes of the heart (left ventricular structure, function and aortic distensibility), brain (brain volumes, white matter hyperintensities and white matter microstructure), and liver (liver fat, liver iron and fibroinflammation). Simultaneous three-organ modelling identifies differentially important pathways across the heart-brain-liver axis with evidence of both direct and indirect associations. This study describes a potentially cumulative burden of multiple-organ dysfunction and provides essential insight into multi-organ disease prevention.

Quantitative magnetic resonance imaging to aid clinical decision making in autoimmune hepatitis.

Background: In autoimmune hepatitis (AIH), clinical practice and treatment guidelines frequently diverge as a reflection of disease heterogeneity and challenges in achieving standardised care. We sought to explore the utility of multiparametric (mp) MR in patients with AIH, and the impact of this technology on physicians' decision making and intended patient management. Methods: 82 AIH patients, recruited from two sites between June and November 2019 as part of an observational cohort study, underwent non-contrast MRI alongside their standard clinical investigations. Correlations between iron-corrected T1 (cT1) and other markers of disease were investigated alongside the utility of imaging markers to risk stratify patients in biochemical remission. The impact of mpMR on clinical decision making was evaluated using pairwise t-tests. The discriminatory ability of the imaging markers was assessed using area under the receiver operating characteristic curves (AUCs). Findings: cT1 had a significant impact on clinician intended patient management (p<0.0001). cT1 correlated with ALT (p = 0.0005), AST (p<0.001), IgG (p = 0.0005), and liver stiffness (p<0.0001). Patients in deep biochemical remission (N = 11; AST/ALT <50% upper limit of normal [ULN] and IgG <12 g/L) had low cT1, while 7/34 in normal biochemical remission (AST/ALT between 50 and 100% of ULN) had high cT1 and were at risk of disease flare. cT1 measures of disease heterogeneity, ALP and bilirubin made the best predictor of those not in biochemical remission (AUC:0.85). Interpretation: This study investigates the impact of mpMR results on intended clinical management in a real world setting. Findings showed that mpMR demonstrated a significant impact on clinical management of AIH and has the potential to inform patient risk stratification. Funding: This paper presents independent research supported by the Innovate UK grant (104,915).