Time for a change to clozapine haematological monitoring.

OBJECTIVES: This paper critiques the haematological monitoring guidelines for clozapine. It describes the history of clozapine, as well as the pathophysiology and epidemiology of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA). The paper appraises the extant literature on mandatory clozapine haematological monitoring. CONCLUSION: Contemporary Australian protocols for clozapine haematological monitoring are not consistent with the current evidence base. CIN and CIA are rare occurrences, and the associated risk of death is low. Potential modifications to existing guidelines include changing neutrophil thresholds for patients with benign ethnic neutropenia and reducing the frequency or removing haematological monitoring after two years of clozapine treatment.

Spontaneous Extrusion of a Conjunctivolith Containing Herpes Virus Confirmed by Electron Microscopy and Energy Dispersive Spectroscopy.

: This report describes the spontaneous extrusion from between the eyelids of a presumed conjunctivolith in a patient with resolving severe herpes zoster ophthalmicus. A 57-year-old man presented for ophthalmologic assessment and management due to severe left herpes zoster ophthalmicus. At one subsequent ophthalmologic assessment, a conjunctivolith spontaneously egressed the lateral commissure of the OS when the lateral fornix was inspected. The conjunctivolith was retrieved from the floor of the consulting room. Electron microscopic analysis and energy dispersive spectroscopy was undertaken to determine its composition. Scanning electron microscopy showed that the conjunctivolith was composed of carbon, calcium, and oxygen. Transmission electron microscopy diagnosed Herpes virus within the conjunctivolith. Conjunctivoliths, or possible lacrimal gland stones, are a very rare phenomenon, and their etiology is currently unclear. In this case, there was likely to have been an association between herpes zoster ophthalmicus and the conjunctivolith.

In silico evaluation of Philippine Natural Products against SARS-CoV-2 Main Protease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is a novel strain of coronavirus first reported in December 2019 which rapidly spread throughout the world and was subsequently declared a pandemic by the World Health Organization (WHO) in March 2020. Although vaccines, as well as treatments, have been rapidly developed and deployed, these are still spread thin, especially in the developing world. There is also a continuing threat of the emergence of mutated variants which may not be as responsive to available vaccines and drugs. Accessible and affordable sources of antiviral drugs against SARS-CoV-2 offer wider options for the clinical treatment of populations at risk for severe COVID-19. Using in silico methods, this study identified potential inhibitors against the SARS-CoV-2 main protease (Mpro), the protease directly responsible for the activation of the viral replication enzyme, from a consolidated database of 1516 Philippine natural products. Molecular docking experiments, along with in silico ADME predictions, determined top ligands from this database with the highest potential inhibitory effects against Mpro. Molecular dynamic trajectories of the apo and diosmetin-7-O-b-D-glucopyranoside (DG) in complex with the protein predicted potential mechanisms of action for the ligand-by separating the Cys145-His41 catalytic dyad and by influencing the protein network through key intra-signaling residues within the Mpro binding site. These findings show the inhibitory potential of DG against the SARS-CoV-2 Mpro, and further validation is recommended through in vitro or in vivo experimentation.

Second-look Surgery for Appendiceal High Grade and Colorectal Cancers Following Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND/AIM: Up to a third of patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) of appendiceal or colorectal origin receive a stoma during primary surgery. Stoma reversal provides an opportunity for second-look surgery. PATIENTS AND METHODS: We performed a retrospective analysis of prospectively collected data of patients with colorectal cancer (CRC) or high-grade appendiceal cancer (AC) from 2006 to 2021 from our database. A total of 34 consecutive stoma closure patients with no evidence of preoperative disease recurrence (tumor markers and CT scans) were compared with 141 consecutive re-do CRS/HIPEC patients with known recurrence. RESULTS: Eleven patients (32.4%) were identified to have peritoneal recurrence at stoma closure. Time between first and second CRS was 12 months (4 to 64.2) in the stoma closure group vs. 24.6 months (5.8 to 119.8) in the re-do group, while median peritoneal cancer index (PCI) was 4 (3 to 6) vs. 8 (1 to 39), respectively (p=0.0143). CONCLUSION: Second-look laparotomy during stoma closure identified unexpected PC in 32.4% of our patients with significantly lower PCI than planned re-do operations.

A systematic review of the associations, mediators and moderators of life satisfaction, positive affect and happiness in near-centenarians and centenarians.

OBJECTIVE: Results from studies investigating life satisfaction, positive affect and happiness of near-centenarians (95+) and centenarians are inconsistent. This is the first systematic review to summarise the extant literature on the subjective well-being of this unique age group. METHOD: Seven electronic databases (PubMed, MEDLINE, EMBASE, PsycINFO, CINAHL, Web of Science and the Cochrane database for systematic reviews) were systematically searched. Subjective well-being was defined as life satisfaction, positive affect and happiness. A narrative synthesis of relevant articles was undertaken. RESULTS: Of 28 studies eligible for inclusion in this review, 20 predominantly examined life satisfaction, 11 positive affect and 4 happiness. Sex and other demographic variables were not significant predictors of subjective well-being. In contrast, greater perceived health was significantly associated with higher levels of life satisfaction and positive affect. Fatigue and visual impairment were significantly correlated with lower levels of life satisfaction and positive affect. However, there was considerable heterogeneity in the findings on physical, cognitive and social associations, mediators and moderators. CONCLUSION: The large discrepancy of results in the literature may be explained by methodological differences between studies. Centenarian research needs a clearer definition of life satisfaction, positive affect and happiness as their operationalisation is inconsistent. An international consortium of centenarian studies could facilitate cross-cultural comparisons on subjective well-being. Future research should be directed towards interventions that promote subjective well-being in the oldest-old.

Plasma Tenascin-C: a prognostic biomarker in heart failure with preserved ejection fraction.

INTRODUCTION: Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes. MATERIALS AND METHODS: Prospective, observational study of 172 age- and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation. RESULTS: Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8-17.3] vs (11.1 [8.9-12.9] ng/ml, p < 0.0001). Tenascin-C correlated positively with markers of clinical severity (NYHA, E/E', BNP) and plasma biomarkers reflecting interstitial fibrosis (ST-2, Galectin-3, GDF-15, TIMP-1, TIMP-4, MMP-2, MMP-3, MMP-7, MMP-8), cardiomyocyte stress (BNP, NTpro-ANP), inflammation (MPO, hs-CRP, TNFR-1, IL6) and renal dysfunction (urea, cystatin-C, NGAL); p < 0.05 for all. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305-2.360; p < 0.0001) and indexed extracellular volume (HR 1.465, CI 1.019-2.106; p = 0.039) were independently associated with adverse outcomes. CONCLUSIONS: In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. Trial registration: ClinicalTrials.gov: NCT03050593.

Characterizing heart failure with preserved and reduced ejection fraction: An imaging and plasma biomarker approach.

INTRODUCTION: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls. MATERIALS AND METHODS: Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization. RESULTS: Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784). CONCLUSIONS: HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.

Left atrial ejection fraction and outcomes in heart failure with preserved ejection fraction.

The aim of this study was to determine whether left atrial ejection fraction (LAEF) quantified with cardiovascular magnetic resonance (CMR) was different between heart failure with preserved ejection fraction (HFpEF) and controls, and its relation to prognosis. As part of our single-centre, prospective, observational study, 188 subjects (HFpEF n = 140, controls n = 48) underwent phenotyping with contrast-enhanced CMR, transthoracic echocardiography, blood sampling and six-minute walk testing. LAEF was calculated using the biplane method. Atrial fibrillation (AF) was present in 43 (31%) of HFpEF subjects. Overall, LAEF (%) was lower in HFpEF patients inclusive of AF (32 ± 16) or those in sinus rhythm alone (41 ± 12) compared to controls (51 ± 11), p < 0.0001. LAEF correlated inversely with maximal and minimal left atrial volumes indexed (r = - 0.602, r = - 0.762), and plasma N-terminal pro-atrial natriuretic peptide (r = - 0.367); p < 0.0001. During median follow-up (1429 days), there were 67 composite events of all-cause death or hospitalization for heart failure (22 deaths, 45 HF hospitalizations) in HFpEF. Lower LAEF (below median) was associated with an increased risk of composite endpoints (Log-Rank: all p = 0.028; sinus p = 0.036). In multivariable Cox regression analysis, LAEF (adjusted hazard ratio [HR] 0.767, 95% confidence interval [CI] 0.591-0.996; p = 0.047) and indexed extracellular volume (HR 1.422, CI 1.015-1.992; p = 0.041) were the only parameters that remained significant when added to a base prognostic model comprising age, prior HF hospitalization, diastolic blood pressure, lung disease, NYHA, six-minute-walk-test-distance, haemoglobin, creatinine and B-type natriuretic peptide. CMR-derived LAEF is lower in HFpEF compared to healthy controls and is a strong prognostic biomarker.

Differential left ventricular and left atrial remodelling in heart failure with preserved ejection fraction patients with and without diabetes.

BACKGROUND: Attempts to characterize cardiac structure in heart failure with preserved ejection fraction (HFpEF) in people with type 2 diabetes (T2D) have yielded inconsistent findings. We aimed to determine whether patients with HFpEF and T2D have a distinct pattern of cardiac remodelling compared with those without diabetes and whether remodelling was related to circulating markers of inflammation and fibrosis and clinical outcomes. METHODS: We recruited 140 patients with HFpEF (75 with T2D and 65 without). Participants underwent comprehensive cardiovascular phenotyping, including echocardiography, cardiac magnetic resonance imaging and plasma biomarker profiling. RESULTS: Patients with T2D were younger (age 70 ± 9 versus 75 ± 9y, p = 0.002), with evidence of more left ventricular (LV) concentric remodelling (LV mass/volume ratio 0.72 ± 0.15 versus 0.62 ± 0.16, p = 0.024) and smaller indexed left atrial (LA) volumes (maximal LA volume index 48 ± 20 versus 59 ± 29 ml/m2, p = 0.004) than those without diabetes. Plasma biomarkers of inflammation and extracellular matrix remodelling were elevated in those with T2D. Overall, there were 45 hospitalizations for HF and 22 deaths over a median follow-up period of 47 months [interquartile range (IQR) 38-54]. There was no difference in the primary composite endpoint of hospitalization for HF and mortality between groups. On multivariable Cox regression analysis, age, prior HF hospitalization, history of pulmonary disease and LV mass/volume were independent predictors of the primary endpoint. CONCLUSIONS: Patients with HFpEF and T2D have increased concentric LV remodelling, smaller LA volumes and evidence of increased systemic inflammation compared with those without diabetes. This suggests the underlying pathophysiology for the development of HFpEF is different in patients with and without T2D. CLINICALTRIALSGOV IDENTIFIER: NCT03050593.

The prevalence and predictors of anxiety and depression in near-centenarians and centenarians: a systematic review.

BACKGROUND: Current research on the psychological health of near-centenarians (95-99 years old) and centenarians remains limited. Existing studies have mainly characterized their physical, cognitive, and social health. Results on the anxiety and depression of near-centenarians and centenarians (more than 95 years old) have been mixed with some studies, finding higher rates of anxiety and depression among those older than 95 years and others reporting no difference in rates compared with younger age groups. This study aims to synthesize the existing literature on the prevalence and predictors of anxiety and depression in near-centenarians and centenarians. METHOD: A systematic review was conducted using Ovid Medline, Embase, PsycINFO, CINAHL, SCOPUS, and the Cochrane database. Common and conflicting findings among the literature were examined. RESULTS: Thirty-eight studies met the inclusion criteria. Six studies examined the prevalence and predictors of anxiety, and 37 studies investigated the prevalence and predictors of depression. Five studies examined both anxiety and depression in the same sample. Prevalence data on anxiety and depression varied significantly, as did comparisons with rates in younger populations. Findings on predictors of anxiety and depression were contradictory. CONCLUSION: There is a large degree of heterogeneity among studies of centenarians' psychological status. Findings conflict on the prevalence and predictors of anxiety and depression and rates compared with younger age groups. Variation in findings may result from the different inclusion criteria, sampling methods, and measurement tools. Better harmonization of centenarian study methodologies may improve consistency of findings to aid in developing clinical interventions.

The psychological health of 207 near-centenarians (95-99) and centenarians from the Sydney Centenarian Study.

OBJECTIVE: While near-centenarians (95-99) and centenarians are the fastest growing sectors of the population in many countries, few studies have investigated their psychological health. We aimed to compare levels of psychological distress and life satisfaction in individuals aged 95 or above (95+) with younger age groups and identify the factors associated with psychological distress and life satisfaction in near-centenarians and centenarians. METHODS: We assessed the physical, cognitive, social and psychological health of 207 participants aged 95+ in the Sydney Centenarian Study. Psychological distress and life satisfaction were rated on the Kessler Psychological Distress Scale (K10) and Satisfaction with Life Scale, respectively. Cross-sectional univariate comparisons were performed with participants aged 70-90 years from the Sydney Memory and Ageing Study. Factors associated with psychological distress and life satisfaction among Sydney Centenarian Study participants were examined using multiple regression analyses. RESULTS: In Sydney Centenarian Study and Memory and Ageing Study, mean K10 scores were 15.3 (±5.9) and 13.4 (±3.6), and clinical levels of psychological distress (K10 ⩾ 20) were 19% and 7%, respectively. Sydney Centenarian Study participants demonstrated significantly higher levels and rates of psychological distress (t = 3.869, p < 0.001; χ2 = 27.331, p < 0.001). In Sydney Centenarian Study, more psychotropic medications and having fewer relatives and friends were associated with higher psychological distress. Sydney Centenarian Study participants reported significantly higher levels of life satisfaction than Memory and Ageing Study participants, mean scores 6.0 (±1.5) and 5.6 (±1.3); t = 5.835, p < 0.001. Lower Mini-Mental State Examination scores and having fewer relatives and friends were associated with lower life satisfaction in Sydney Centenarian Study. CONCLUSION: Despite showing higher levels of psychological distress in the prior 4 weeks than younger age groups, near-centenarians and centenarians remained highly satisfied with their overall lives. The identification of risk and protective factors for psychological distress and life satisfaction provides opportunities for interventions to maintain good psychological health in this vulnerable population.

Relationship Between Focal and Diffuse Fibrosis Assessed by CMR and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

OBJECTIVES: This study sought to assess the presence and extent of focal and diffuse fibrosis in heart failure in patients with preserved ejection fraction (HFpEF) compared to asymptomatic control subjects, and the relationship of fibrosis to clinical outcome. BACKGROUND: Myocardial fibrosis has been implicated in the pathophysiology of HFpEF. METHODS: In this prospective, observational study, 140 subjects of similar age and sex (HFpEF: n = 96; control subjects: n = 44; 73 ± 8 years of age; 49% males) underwent cardiac magnetic resonance imaging. Late gadolinium-enhanced (LGE) imaging and T1 mapping to calculate myocardial extracellular volume indexed to body surface area (iECV) were used to assess fibrosis. RESULTS: Patients with HFpEF had more concentric remodeling and worse diastolic function. Focal fibrosis was more frequent in HFpEF subjects (overall: n = 49; infarction: n = 17; nonischemic cases: n = 36; mixed patterns: n = 4) than in control subjects (overall: n = 3). Diffuse fibrosis was also greater in HFpEF subjects than control subjects (iECV: 13.7 ± 4.4 ml/m2 versus 10.9 ± 2.8 ml/m2; p < 0.0001). During median follow-up (1,429 days), there were 42 composite events (14 deaths; 28 heart failure hospitalizations) in cases of HFpEF. Myocardial infarction revealed on LGE imaging was a predictor of outcomes on univariate analysis only. With multivariate analysis, iECV (hazard ratio [HR]: 1.689; 95% confidence interval [CI]: 1.141 to 2.501; p = 0.009) was an independent predictor of outcome along with mitral peak velocity of early filling (E)-to-early diastolic mitral annular velocity (E') (E/E') ratio (HR: 1.716; 95% CI: 1.191 to 2.472; p = 0.004) and prior HF hospitalization (HR: 2.537; 95% CI: 1.090 to 5.902; p = 0.031). iECV was also significantly associated with ventricular/left atrial remodeling and renal dysfunction: right ventricular end-diastolic volume indexed (r = 0.456; p < 0.0001), left ventricular mass/volume (r = 0.348; p = 0.001), maximal left atrial volume indexed (r = 0. 269; p = 0.009), and creatinine (r = 0.271; p = 0.009). CONCLUSIONS: Both focal and diffuse myocardial fibrosis are more prevalent in HFpEF subjects than in control subjects of similar age and sex. iECV significantly correlates with indices of ventricular/left atrial remodeling and renal dysfunction and is an independent predictor of adverse outcome in HFpEF. (Developing Imaging And plasMa biOmarkers iN Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593).

Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in heart failure with preserved ejection fraction - implications for clinical trials.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a poorly characterized condition. We aimed to phenotype patients with HFpEF using multiparametric stress cardiovascular magnetic resonance imaging (CMR) and to assess the relationship to clinical outcomes. METHODS: One hundred and fifty four patients (51% male, mean age 72 ± 10 years) with a diagnosis of HFpEF underwent transthoracic echocardiography and CMR during a single study visit. The CMR protocol comprised cine, stress/rest perfusion and late gadolinium enhancement imaging on a 3T scanner. Follow-up outcome data (death and heart failure hospitalization) were captured after a minimum of 6 months. RESULTS: CMR detected previously undiagnosed pathology in 42 patients (27%), who had similar baseline characteristics to those without a new diagnosis. These diagnoses consisted of: coronary artery disease (n = 20, including 14 with 'silent' infarction), microvascular dysfunction (n = 11), probable or definite hypertrophic cardiomyopathy (n = 10) and constrictive pericarditis (n = 5). Four patients had dual pathology. During follow-up (median 623 days), patients with a new CMR diagnosis were at higher risk of adverse outcome for the composite endpoint (log rank test: p = 0.047). In multivariate Cox proportional hazards analysis, a new CMR diagnosis was the strongest independent predictor of adverse outcome (hazard ratio: 1.92; 95% CI: 1.07 to 3.45; p = 0.03). CONCLUSIONS: CMR diagnosed new significant pathology in 27% of patients with HFpEF. These patients were at increased risk of death and heart failure hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03050593 . Retrospectively registered; Date of registration: February 06, 2017.

Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance.

An increasingly powerful approach for studying brain circuits relies on targeting genetically encoded sensors and effectors to specific cell types. However, current approaches for this are still limited in functionality and specificity. Here we utilize several intersectional strategies to generate multiple transgenic mouse lines expressing high levels of novel genetic tools with high specificity. We developed driver and double reporter mouse lines and viral vectors using the Cre/Flp and Cre/Dre double recombinase systems and established a new, retargetable genomic locus, TIGRE, which allowed the generation of a large set of Cre/tTA-dependent reporter lines expressing fluorescent proteins, genetically encoded calcium, voltage, or glutamate indicators, and optogenetic effectors, all at substantially higher levels than before. High functionality was shown in example mouse lines for GCaMP6, YCX2.60, VSFP Butterfly 1.2, and Jaws. These novel transgenic lines greatly expand the ability to monitor and manipulate neuronal activities with increased specificity.

Calculated plasma volume status and prognosis in chronic heart failure.

AIMS: Plasma volume (PV) expansion hallmarks worsening chronic heart failure (CHF) but no non-invasive means of quantifying volume status exists. Because weight and haematocrit are related to PV, they can be used to calculate relative PV status (PVS). We tested the validity and prognostic utility of calculated PVS in CHF patients. METHODS AND RESULTS: First, we evaluated the agreement between calculated actual PV (aPV) and aPV levels measured using (125)Iodine-human serum albumin. Second, we derived PVS as: [(calculated aPV - ideal PV)/ideal PV] × 100%. Third, we assessed the prognostic implications of PVS in 5002 patients from the Valsartan in Heart Failure Trial (Val-HeFT), and validated this in another 246 routine CHF outpatients. On analysis, calculated and measured aPV values correlated significantly in 119 normal subjects and 30 CHF patients. In the Val-HeFT cohort, mean (+SD) PVS was -9 ± 8% and related to volume biomarkers such as brain natriuretic peptide (BNP). Over 2 years, 977 (20%) patients died. Plasma volume status was associated with death and first morbid events in a 'J-shaped' fashion with the highest risk seen with a PVS > -4%. Stratification into PVS quartiles confirmed that a PVS > -4% was associated with increased mortality (unadjusted hazard ratio 1.65, 95% confidence interval 1.44-1.88, χ(2) = 54, P < 0.001) even after adjusting for 22 variables, including brain natriuretic peptide. These results were mirrored in the validation cohort. CONCLUSIONS: Relative PVS calculated from simple clinical indices reflects the degree to which patients have deviated from their ideal PV and independently relates to outcomes. The utility of PVS-driven CHF management needs further evaluation.

Serum albumin changes and multivariate dynamic risk modelling in chronic heart failure.

BACKGROUND: We examined the prognostic utility of rate of change in serum albumin over time in chronic heart failure (CHF), as well as the utility of multivariate dynamic risk modelling. METHODS AND RESULTS: The survival implication of ∆albumin was analysed in 232 systolic CHF patients and validated in 212 patients. A multivariate dynamic risk score predicated on the rate of change in 6 simple indices including albumin was calculated and related to mortality. In derivation patients, 50 (22%) deaths occurred over 13 months. Greater rates of decline in albumin related to higher mortality (HR 0.55, 95% CI 0.41-0.73, P<0.0001) independently, incrementally and more accurately than other covariates including baseline albumin. A rate of attenuation >0.4 g/dL/month optimally forecasted death and was associated with a 5-fold escalated risk of mortality (HR 5.13, 95% CI 2.92-9.00, P<0.0001). Similar results were seen in the validation cohort. On multivariate dynamic risk modelling, survival at 1-year worsened with higher scores-a score ≥ 3 was associated with a 12-fold greater risk of death than a score of 0, a 6-fold higher risk of death than a score of 1, and a 4-fold enhanced risk of mortality than a score of 2. CONCLUSION: Attenuations in serum albumin over time relate to increased mortality in CHF, and a risk model predicated on the rate of change in 6 simple indices can identify patients at a 12-fold enhanced risk of death over the coming year.

Expansion of the red cell distribution width and evolving iron deficiency as predictors of poor outcome in chronic heart failure.

BACKGROUND: An elevated red cell distribution width (RDW) and iron deficiency (ID) at baseline predict enhanced mortality in chronic heart failure (CHF), but little is known about the prognostic implications of their temporal trends. We sought to determine the survival implications of temporal changes in RDW and evolving ID in patients with CHF. METHODS: The relation between red cell indices on first consultation and over time with mortality in 274 stable patients with systolic CHF was analysed. The combination of a rising RDW with a falling mean cell volume (MCV) over time defined evolving ID. RESULTS: Over a median 12 month period, 51% and 23% of patients had a rise in RDW and evolving ID, respectively. After a median follow-up of 27 months, 60 (22%) patients died. A rising RDW predicted enhanced all-cause mortality (unadjusted HR for 1% per week rise 9.27, 95% CI 3.58 to 24.00, P<0.0001) independently and incrementally to baseline RDW, with an absolute increase >0.02% per week optimally predictive. Evolving ID also related to higher rates of mortality (HR 2.78, 95% CI 1.64 to 4.73, P<0.001) and was prognostically worse than a rising RDW alone (P<0.005). Patients with evolving ID who maintained their Hb levels over time had a 2-fold greater risk of death than those whose Hb levels declined without evolving ID. CONCLUSIONS: An expanding RDW and evolving iron deficiency over time predict an amplified risk of death in CHF and should be utilised for risk stratification and/or therapeutically targeted to potentially improve outcomes.

Simultaneous two-photon calcium imaging at different depths with spatiotemporal multiplexing.

In vivo two-photon calcium imaging would benefit from the use of multiple excitation beams to increase scanning speed, signal-to-noise ratio and field of view or to image different axial planes simultaneously. Using spatiotemporal multiplexing we circumvented light-scattering ambiguity inherent to deep-tissue multifocal two-photon microscopy. We demonstrate calcium imaging at multiple axial planes in the intact mouse brain to monitor network activity of ensembles of cortical neurons in three spatial dimensions.

High field cardiac magnetic resonance imaging--current and future perspectives.

Potential advantages of high field cardiac magnetic resonance imaging include superior signal-to-noise ratio, image contrast and spectral separation. These might be used to improve spatial and/or temporal resolution and imaging speed. However, high field imaging presents new challenges to the operator, including increased magnetic field heterogeneity, susceptibility, artefacts and higher specific absorption rate. Recently, studies have reported on the clinical utility of cardiac magnetic resonance imaging at 3 Tesla in the assessment of myocardial function, perfusion and viability, and coronary arteries. The results of these clinical studies are reviewed, as well as emerging applications in myocardial tagging and cardiac spectroscopy.

Reliability and validity of the Euthanasia Attitude Scale (EAS) for Hong Kong medical doctors.

This study aimed to examine the reliability and validity of the Euthanasia Attitude Scale (EAS) in Hong Kong medical doctors. A total of 107 medical doctors (61.7% men) participated in a survey at clinical settings in 2008. The 21-item EAS was used to assess their attitudes toward euthanasia. The mean (standard deviation) and median of the EAS were 63.60 (60.31) and 63.00. Total EAS scores correlated well with ''Ethical Considerations,'' ''Practical Considerations,'' and ''Treasuring Life'' (Spearman rho =.37-.96, P < .001) but not ''Naturalistic Beliefs.'' The construct validity of the 3-factor model was appropriate (Kaiser-Meyer-Olkin [KMO] value = 0.90) and showed high internal consistency (Cronbach alpha =.79-.92). Euthanasia Attitude Scale may be a reliable and valid measure for assessing the attitudes toward euthanasia in medical professionals.