Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

OBJECTIVE: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis. DESIGN: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model. RESULTS: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature. CONCLUSIONS: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.

Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.

Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs.

Reward Value Revealed by Auction in Rhesus Monkeys.

Economic choice is thought to involve the elicitation of the subjective values of the choice options. Thus far, value estimation in animals has relied on stochastic choices between multiple options presented in repeated trials and expressed from averages of dozens of trials. However, subjective reward valuations are made moment-to-moment and do not always require alternative options; their consequences are usually felt immediately. Here, we describe a Becker-DeGroot-Marschak (BDM) auction-like mechanism that provides more direct and simple valuations with immediate consequences. The BDM encourages agents to truthfully reveal their true subjective value in individual choices ("incentive compatibility"). Male monkeys reliably placed well-ranked BDM bids for up to five juice volumes while paying from a water budget. The bids closely approximated the average subjective values estimated with conventional binary choices (BCs), thus demonstrating procedural invariance and aligning with the wealth of knowledge acquired with these less direct estimation methods. The feasibility of BDM bidding in monkeys paves the way for an analysis of subjective neuronal value signals in single trials rather than from averages; the feasibility also bridges the gap to the increasingly used BDM method in human neuroeconomics.SIGNIFICANCE STATEMENT The subjective economic value of rewards cannot be measured directly but must be inferred from observable behavior. Until now, the estimation method in animals was rather complex and required comparison between several choice options during repeated choices; thus, such methods did not respect the imminence of the outcome from individual choices. However, human economic research has developed a simple auction-like procedure that can reveal in a direct and immediate manner the true subjective value in individual choices [Becker-DeGroot-Marschak (BDM) mechanism]. The current study implemented this mechanism in rhesus monkeys and demonstrates its usefulness for eliciting meaningful value estimates of liquid rewards. The mechanism allows future neurophysiological assessment of subjective reward value signals in single trials of controlled animal tasks.

Clinical and biological markers predictive of treatment response associated with metastatic pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) offers limited benefits, but survival outcomes vary. Reliable predictive response biomarkers to guide patient management are lacking. METHODS: Patient performance status, tumour burden (determined by the presence or absence of liver metastases), plasma protein biomarkers (CA19-9, albumin, C-reactive protein and neutrophils) and circulating tumour DNA (ctDNA) were assessed in 146 patients with metastatic PDAC prior to starting either concomitant or sequential nab-paclitaxel + gemcitabine chemotherapy in the SIEGE randomised prospective clinical trial, as well as during the first 8 weeks of treatment. Correlations were made with objective response, death within 1 year and overall survival (OS). RESULTS: Initial poor patient performance status, presence of liver metastases and detectable mutKRAS ctDNA all correlated with worse OS after adjusting for the different biomarkers of interest. Objective response at 8 weeks also correlated with OS (P = 0.026). Plasma biomarkers measured during treatment and prior to the first response assessment identified ≥10% decrease in albumin at 4 weeks predicted for worse OS (HR 4.75, 95% CI 1.43-16.94, P = 0.012), while any association of longitudinal evaluation of mutKRAS ctDNA with OS was unclear (ß = 0.024, P = 0.057). CONCLUSIONS: Readily measurable patient variables can aid the prediction of outcomes from combination chemotherapy used to treat metastatic PDAC. The role of mutKRAS ctDNA as a tool to guide treatment warrants further exploration. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

The Impact of Ferric Derisomaltose on Cardiovascular and Noncardiovascular Events in Patients With Anemia, Iron Deficiency, and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: In some countries, intravenous ferric derisomaltose (FDI) is only licensed for treating iron deficiency with anemia. Accordingly, we investigated the effects of intravenous FDI in a subgroup of patients with anemia in the IRONMAN (Effectiveness of Intravenous (IV) Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency) trial. METHOD AND RESULTS: IRONMAN enrolled patients with heart failure, a left ventricular ejection fraction of ≤45%, and iron deficiency (ferritin <100 µg/L or transferrin saturation of <20%), 771 (68%) of whom had anemia (hemoglobin <12 g/dL for women and <13 g/dL for men). Patients were randomized, open label, to FDI (n = 397) or usual care (n = 374) and followed for a median of 2.6 years. The primary end point, recurrent hospitalization for heart failure and cardiovascular death, occurred less frequently for those assigned to FDI (rate ratio 0.78, 95% confidence interval 0.61-1.01; P = .063). First event analysis for cardiovascular death or hospitalization for heart failure, less affected by the coronavirus disease 2019 pandemic, gave similar results (hazard ratio 0.77, 95% confidence interval 0.62-0.96; P = .022). Patients randomized to FDI reported a better Minnesota Living with Heart Failure quality of life, for overall (P = .013) and physical domain (P = .00093) scores at 4 months. CONCLUSIONS: In patients with iron deficiency anemia and heart failure with reduced left ventricular ejection fraction, intravenous FDI improves quality of life and may decrease cardiovascular events.

Whole-Brain Magnetic Resonance Spectroscopy Reveals Distinct Alterations in Neurometabolic Profile in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. OBJECTIVE: The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopic imaging (wbMRSI). METHODS: Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). RESULTS: In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. CONCLUSIONS: In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An acute increase in Left Atrial volume and left ventricular filling pressure during Adenosine administered myocardial hyperaemia: CMR First-Pass Perfusion Study.

OBJECTIVE: To investigate whether left atrial (LA) volume and left ventricular filling pressure (LVFP) assessed by cardiovascular magnetic resonance (CMR) change during adenosine delivered myocardial hyperaemia as part of a first-pass stress perfusion study. METHODS AND RESULTS: We enrolled 33 patients who had stress CMR. These patients had a baseline four-chamber cine and stress four-chamber cine, which was done at peak myocardial hyperaemic state after administering adenosine. The left and right atria were segmented in the end ventricular diastolic and systolic phases. Short-axis cine stack was segmented for ventricular functional assessment. At peak hyperaemic state, left atrial end ventricular systolic volume just before mitral valve opening increased significantly from baseline in all (91 ± 35ml vs. 81 ± 33ml, P = 0.0002), in males only (99 ± 35ml vs. 88 ± 33ml, P = 0.002) and females only (70 ± 26ml vs. 62 ± 22ml, P = 0.02). The right atrial end ventricular systolic volume increased less significantly from baseline (68 ± 21ml vs. 63 ± 20ml, P = 0.0448). CMR-derived LVFP (equivalent to pulmonary capillary wedge pressure) increased significantly at the peak hyperaemic state in all (15.1 ± 2.9mmHg vs. 14.4 ± 2.8mmHg, P = 0.0002), females only (12.9 ± 2.1mmHg vs. 12.3 ± 1.9mmHg, P = 0.029) and males only (15.9 ± 2.8mmHg vs. 15.2 ± 2.7mmHg, P = 0.002) cohorts. CONCLUSION: Left atrial volume assessment by CMR can measure acute and dynamic changes in preloading conditions on the left ventricle. During adenosine administered first-pass perfusion CMR, left atrial volume and LVFP rise significantly.

ICP during head movement: significance of the venous system.

BACKGROUND: It is thought that the internal jugular veins (IJV) are the primary route for cranial venous outflow in supine position and the vertebral venous plexus when upright. Previous studies have noted a greater increase in intracranial pressure (ICP) when subjects turn their head in one direction compared to the other, but no clear cause had been investigated. We hypothesised that in the supine position, head turning and consequently obstructing the IJV draining the dominant transverse sinus (TVS) would lead to a greater rise in ICP compared to turning to the non-dominant side. METHODS: A prospective study in a large-volume neurosurgical centre. Patients undergoing continuous ICP monitoring as part of their standard clinical management were recruited. Immediate ICP was measured in different head positions (neutral, rotated to the right and left) when supine, seated, and standing. TVS dominance was established by consultant radiologist report on venous imaging. RESULTS: Twenty patients were included in the study, with a median age of 44 years. Venous system measurements revealed 85% right-sided vs 15% left-sided dominance. Immediate ICP rose more when head turning from neutral to the dominant TVS (21.93mmHg ± 4.39) vs non-dominant side (16.66mmHg ± 2.71) (p= <0.0001). There was no significant relationship in the sitting (6.08mmHg ± 3.86 vs 4.79mmHg ± 3.81, p = 0.13) or standing positions (8.74mmHg ± 4.30 vs 6.76mmHg ± 4.14, p =0.07). CONCLUSION: This study has provided further evidence that the transverse venous sinus to internal jugular system pathway is the likely primary venous drainage when supine; and quantified its effect when head turning on ICP. It may guide patient-specific nursing care and advice.

Drop metastasis from the extradural to the intradural space in spinal Ewing's sarcoma - a novel case report.

Spinal Ewing's Sarcoma is a rare tumour predominantly affecting children and adolescents. We describe the case of an 18-year-old male patient who first presented with a primary extradural cervical Ewing's sarcoma tumour, and 5 years later had a recurrence with thoracolumbar and lumbosacral intradural extramedullary Ewing's sarcoma tumours. Both presentations were successfully treated by surgical resection and adjuvant chemo- and radiotherapy, and he remains disease-free at 12 months follow-up. This is the first reported case of seeding of tumour from an extradural primary Ewing's sarcoma to intradural metastases. Total surgical resection of his initial cervical tumour, performed at another centre, was complicated by a dural tear and CSF leak. Thus, we propose that isolated drop metastasis via CSF fistula is the most likely mechanism for tumour spread in this case. Thus, clinicians may wish to counsel patients on the possibility of such spread if a CSF leak is encountered, and potentially increase the frequency of imaging surveillance of the whole spine in this context.

Optimising trajectory planning for stereotactic brain tumour biopsy using artificial intelligence: a systematic review of the literature.

PURPOSE: Despite advances in technology, stereotactic brain tumour biopsy remains challenging due to the risk of injury to critical structures. Indeed, choosing the correct trajectory remains essential to patient safety. Artificial intelligence can be used to perform automated trajectory planning. We present a systematic review of automated trajectory planning algorithms for stereotactic brain tumour biopsies. METHODS: A PRISMA adherent systematic review was conducted. Databases were searched using keyword combinations of 'artificial intelligence', 'trajectory planning' and 'brain tumours'. Studies reporting applications of artificial intelligence (AI) to trajectory planning for brain tumour biopsy were included. RESULTS: All eight studies were in the earliest stage of the IDEAL-D development framework. Trajectory plans were compared through a variety of surrogate markers of safety, of which the minimum distance to blood vessels was the most common. Five studies compared manual to automated planning strategies and favoured automation in all cases. However, this comes with a significant risk of bias. CONCLUSIONS: This systematic review reveals the need for IDEAL-D Stage 1 research into automated trajectory planning for brain tumour biopsy. Future studies should establish the congruence between expected risk of algorithms and the ground truth through comparisons to real world outcomes.

The potential role of diffusion weighted imaging in the diagnosis of early carotid and vertebral artery dissection.

PURPOSE: To investigate the role of the diffusion weighted imaging (DWI) in the acute dissection of internal carotid artery (ICA) and vertebral artery (VA) and assessing the length of intramural hematoma (IMH), caused by dissection. METHODS: We analyzed 28 patients presenting with a dissection of the ICA and/or VA with respect to the presence of high signal intensity areas on DWI suggestive of dissection and 20 control subjects without arterial dissection, some with and some without atherosclerotic lesions. ICA or VA dissection was defined by clinical and imaging, computed tomography angiography (CTA), MR angiography (MRA), and digital subtraction angiography (DSA) findings. The length of DWI hyperintensity was compared to length of the occlusion or stenosis on the angiographic examination. RESULTS: In 28 patients, 30 dissected arteries were analyzed. Time intervals from the onset of the first clinical symptoms to the radiological evaluation ranged from 1.5 h to 42 days. In 28 (93%) of the dissections, a high signal intensity of the affected artery was present on DWI. The measurement of the dissection length on DWI compared to DSA showed a mean deviation of 2.7 mm and a standard deviation of 3.7 mm. CONCLUSION: DWI is a highly sensitive and valuable pulse sequence for the detection of dissected cervical arteries even in the first hours after symptom onset. In contrast to CTA and MRA, DWI can be a potential tool for a reliable measurement of the dissection length.

SARS-COV-2 vaccine responses in renal patient populations.

BACKGROUND: Dialysis patients and immunosuppressed renal patients are at increased risk of COVID-19 and were excluded from vaccine trials. We conducted a prospective multicentre study to assess SARS-CoV-2 vaccine antibody responses in dialysis patients and renal transplant recipients, and patients receiving immunosuppression for autoimmune disease. METHODS: Patients were recruited from three UK centres (ethics:20/EM/0180) and compared to healthy controls (ethics:17/EE/0025). SARS-CoV-2 IgG antibodies to spike protein were measured using a multiplex Luminex assay, after first and second doses of Pfizer BioNTech BNT162b2(Pfizer) or Oxford-AstraZeneca ChAdOx1nCoV-19(AZ) vaccine. RESULTS: Six hundred ninety-two patients were included (260 dialysis, 209 transplant, 223 autoimmune disease (prior rituximab 128(57%)) and 144 healthy controls. 299(43%) patients received Pfizer vaccine and 379(55%) received AZ. Following two vaccine doses, positive responses occurred in 96% dialysis, 52% transplant, 70% autoimmune patients and 100% of healthy controls. In dialysis patients, higher antibody responses were observed with the Pfizer vaccination. Predictors of poor antibody response were triple immunosuppression (adjusted odds ratio [aOR]0.016;95%CI0.002-0.13;p < 0.001) and mycophenolate mofetil (MMF) (aOR0.2;95%CI 0.1-0.42;p < 0.001) in transplant patients; rituximab within 12 months in autoimmune patients (aOR0.29;95%CI 0.008-0.096;p < 0.001) and patients receiving immunosuppression with eGFR 15-29 ml/min (aOR0.031;95%CI 0.11-0.84;p = 0.021). Lower antibody responses were associated with a higher chance of a breakthrough infection. CONCLUSIONS: Amongst dialysis, kidney transplant and autoimmune populations SARS-CoV-2 vaccine antibody responses are reduced compared to healthy controls. A reduced response to vaccination was associated with rituximab, MMF, triple immunosuppression CKD stage 4. Vaccine responses increased after the second dose, suggesting low-responder groups should be prioritised for repeated vaccination. Greater antibody responses were observed with the mRNA Pfizer vaccine compared to adenovirus AZ vaccine in dialysis patients suggesting that Pfizer SARS-CoV-2 vaccine should be the preferred vaccine choice in this sub-group.

The effect of protein and essential amino acid supplementation on muscle strength and performance in patients with chronic heart failure: a systematic review.

PURPOSE: Critically low skeletal muscle mass and strength, observed in 20% of people with chronic heart failure (CHF), reduces functional capacity, quality of life (QoL) and survival. Protein and essential amino acid (EAA) supplementation could be a viable treatment strategy to prevent declines in muscle strength and performance, and subsequently improve QoL and survival. This systematic review (PROSPERO: CRD42018103649) aimed to assess the effect of dietary protein and/or EAA supplementation on muscle strength and performance in people with CHF. METHODS: Searches of PubMed, MEDLINE and Embase identified studies that reported changes in strength or muscle performance following protein and/or EAA supplementation in patients with CHF. Following PRISMA guidelines and using predefined inclusion/exclusion criteria relating to participants, intervention, control, outcome and study design, two reviewers independently screened titles, abstracts and full manuscripts for eligibility. Risk of bias was assessed using Cochrane Risk of Bias Tool (RCTs) or Mixed Methods Appraisal Tool (cohort studies). Data were extracted for analysis using predefined criteria. RESULTS: Five randomised controlled trials (RCT) and one cohort study met our inclusion criteria. All RCTs had a high risk of bias. The methodological quality of the cohort study was moderate. Heterogeneity of extracted data prevented meta-analyses, qualitative synthesis was therefore performed. Data from 167 patients with CHF suggest that protein and/or EAA supplementation does not improve strength, but may increase six-minute walk test distance, muscle mass and QoL. CONCLUSIONS: The limited quality of the studies makes firm conclusions difficult, however protein and/or EAA supplementation may improve important outcome measures related to sarcopenia. High-quality randomised controlled studies are needed.

Left ventricular blood flow kinetic energy after myocardial infarction - insights from 4D flow cardiovascular magnetic resonance.

BACKGROUND: Myocardial infarction (MI) leads to complex changes in left ventricular (LV) haemodynamics that are linked to clinical outcomes. We hypothesize that LV blood flow kinetic energy (KE) is altered in MI and is associated with LV function and infarct characteristics. This study aimed to investigate the intra-cavity LV blood flow KE in controls and MI patients, using cardiovascular magnetic resonance (CMR) four-dimensional (4D) flow assessment. METHODS: Forty-eight patients with MI (acute-22; chronic-26) and 20 age/gender-matched healthy controls underwent CMR which included cines and whole-heart 4D flow. Patients also received late gadolinium enhancement imaging for infarct assessment. LV blood flow KE parameters were indexed to LV end-diastolic volume and include: averaged LV, minimal, systolic, diastolic, peak E-wave and peak A-wave KEiEDV. In addition, we investigated the in-plane proportion of LV KE (%) and the time difference (TD) to peak E-wave KE propagation from base to mid-ventricle was computed. Association of LV blood flow KE parameters to LV function and infarct size were investigated in all groups. RESULTS: LV KEiEDV was higher in controls than in MI patients (8.5 ± 3 µJ/ml versus 6.5 ± 3 µJ/ml, P = 0.02). Additionally, systolic, minimal and diastolic peak E-wave KEiEDV were lower in MI (P < 0.05). In logistic-regression analysis, systolic KEiEDV (Beta = - 0.24, P < 0.01) demonstrated the strongest association with the presence of MI. In multiple-regression analysis, infarct size was most strongly associated with in-plane KE (r = 0.5, Beta = 1.1, P < 0.01). In patients with preserved LV ejection fraction (EF), minimal and in-plane KEiEDV were reduced (P < 0.05) and time difference to peak E-wave KE propagation during diastole increased (P < 0.05) when compared to controls with normal EF. CONCLUSIONS: Reduction in LV systolic function results in reduction in systolic flow KEiEDV. Infarct size is independently associated with the proportion of in-plane LV KE. Degree of LV impairment is associated with TD of peak E-wave KE. In patient with preserved EF post MI, LV blood flow KE mapping demonstrated significant changes in the in-plane KE, the minimal KEiEDV and the TD. These three blood flow KE parameters may offer novel methods to identify and describe this patient population.

Cost-Effectiveness Analysis of Natriuretic Peptide Testing and Specialist Management in Patients with Suspected Acute Heart Failure.

OBJECTIVES: To determine the cost-effectiveness of natriuretic peptide (NP) testing and specialist outreach in patients with acute heart failure (AHF) residing off the cardiology ward. METHODS: We used a Markov model to estimate costs and quality-adjusted life-years (QALYs) for patients presenting to hospital with suspected AHF. We examined diagnostic workup with and without the NP test in suspected new cases, and we examined the impact of specialist heart failure outreach in all suspected cases. Inputs for the model were derived from systematic reviews, the UK national heart failure audit, randomized controlled trials, expert consensus from a National Institute for Health and Care Excellence guideline development group, and a national online survey. The main benefit from specialist care (cardiology ward and specialist outreach) was the increased likelihood of discharge on disease-modifying drugs for people with left ventricular systolic dysfunction, which improve mortality and reduce re-admissions due to worsened heart failure (associated with lower utility). Costs included diagnostic investigations, admissions, pharmacological therapy, and follow-up heart failure care. RESULTS: NP testing and specialist outreach are both higher cost, higher QALY, cost-effective strategies (incremental cost-effectiveness ratios of £11,656 and £2,883 per QALY gained, respectively). Combining NP and specialist outreach is the most cost-effective strategy. This result was robust to both univariate deterministic and probabilistic sensitivity analyses. CONCLUSIONS: NP testing for the diagnostic workup of new suspected AHF is cost-effective. The use of specialist heart failure outreach for inpatients with AHF residing off the cardiology ward is cost-effective. Both interventions will help improve outcomes for this high-risk group.

Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression.

Lytic replication of the human gamma herpes virus Epstein-Barr virus (EBV) is an essential prerequisite for the spread of the virus. Differential regulation of a limited number of cellular genes has been reported in B-cells during the viral lytic replication cycle. We asked whether a viral bZIP transcription factor, Zta (BZLF1, ZEBRA, EB1), drives some of these changes. Using genome-wide chromatin immunoprecipitation coupled to next-generation DNA sequencing (ChIP-seq) we established a map of Zta interactions across the human genome. Using sensitive transcriptome analyses we identified 2263 cellular genes whose expression is significantly changed during the EBV lytic replication cycle. Zta binds 278 of the regulated genes and the distribution of binding sites shows that Zta binds mostly to sites that are distal to transcription start sites. This differs from the prevailing view that Zta activates viral genes by binding exclusively at promoter elements. We show that a synthetic Zta binding element confers Zta regulation at a distance and that distal Zta binding sites from cellular genes can confer Zta-mediated regulation on a heterologous promoter. This leads us to propose that Zta directly reprograms the expression of cellular genes through distal elements.

An abrupt bleeding of the anteriorly- displaced sigmoid sinus: a rare complication of myringoplasty.

BACKGROUND: The location of the sigmoid sinus within the mastoid cavity is quite variable. An anteriorly- displaced vertical segment of the sigmoid sinus constitutes an uncommon but dangerous anatomical variation that surgeons rarely encounter during surgery. In this variation, the sigmoid sinus lays underneath a very thin bony flap, which makes it easily damaged. Thus, an abrupt fatal bleeding might occur. Despite the many hypotheses about its origin (Chronic otitis media, hypopneumatization, etc.), the pathogenesis of this variation is still not completely understood. CASE PRESENTATION: We present a case where the vertical segment of the left sigmoid sinus was encountered just underneath a one- millimeter bony flap in the posterior wall of the external auditory canal during an attempted myringoplasty. CONCLUSION: Anatomical variations of the sigmoid sinus are not uncommon, and the otolaryngologist should be aware of such variations to prevent unpleasant, intra- operative surprises.

Tolvaptan for Heart Failure, Systematic Review and Meta-Analysis of Trials.

The vasopressin type 2 receptor antagonist tolvaptan (TLV) is available to treat congestion in patients with heart failure. However, there is paucity of evidence guiding its use, and lack of evidence of its long-term efficacy. Our objectives are to perform a systematic review of studies examining the effects of TLV in patients with heart failure; and a quantitative meta-analysis comparing primary and secondary outcomes between TLV and placebo. Only double-blinded randomized controlled trials, with no restriction on the language or the time of publication, were included. Our main outcome measures were all-cause mortality, change in body weight, change in urine volume, and change in serum sodium. Extracted summary estimates included mean difference and SD for change in body weight, change in urine volume and change in serum sodium levels, and hazard ratio with 95% confidence interval for all-cause mortality. We found 8 double-blinded randomized controlled trials, seven of which were included in this meta-analysis. Assessment of risk of bias was conducted by investigating random sequence generation, allocation concealment, blinding, completeness of outcome data, and potential for selective reporting. We found no evidence of significant bias. TLV showed benefits in reducing body weight, increasing urine volume, and increasing serum sodium. No reduction in mortality was detected. However, the subgroup of patients with hyponatremia might have better mortality outcome with TLV. TLV seemed to be safe, as it did not cause worsening of the renal function or hypotension. In conclusion, a meta-analysis of the published literature suggests short-term benefits of TLV. However, the impact on mortality is inconclusive.