Are non-invasive estimations of plasma volume an accurate measure of congestion in patients with chronic heart failure?

AIMS: We report associations between different formulae for estimating plasma volume status (PVS) and clinical and ultrasound markers of congestion in patients with chronic heart failure (CHF) enrolled in the Hull Lifelab registry. METHODS AND RESULTS: Cohort 1 comprised patients with data on signs and symptoms at initial evaluation (n = 3505). Cohort 2 included patients with ultrasound assessment of congestion [lung B-line count, inferior vena cava (IVC) diameter, jugular vein distensibility (JVD) ratio] (N = 341). Two formulae for PVS were used: (a) Hakim (HPVS) and (b) Duarte (DPVS). Results were compared with clinical and ultrasound markers of congestion. Outcomes assessed were mortality and the composite of heart failure (HF) hospitalisation and all-cause mortality. In cohort 1, HPVS was associated with mortality [hazard ratio (HR) per unitary increase = 1.02 (1.01-1.03); P < 0.001]. In cohort 2, HPVS was associated with B-line count (HR) = 1.05 [95% confidence interval (CI) (1.01-1.08); P = 0.02] and DPVS with the composite outcome [HR = 1.26 (1.01-1.58); P = 0.04]. HPVS and DPVS were strongly related to haemoglobin concentration and HPVS to weight. After multivariable analysis, there were no strong or consistent associations between PVS and measures of congestion, severity of symptoms, or outcome. By contrast, log[NTproBNP] was strongly associated with all three. CONCLUSION: Amongst patients with CHF, HPVS and DPVS are not strongly or consistently associated with clinical or ultrasound evidence of congestion, nor clinical outcomes after multivariable adjustment. They appear only to be surrogates of the variables from which they are calculated with no intrinsic clinical utility.

Re-defining iron deficiency in patients with heart failure.

INTRODUCTION: Iron deficiency (ID) is common in patients with chronic heart failure (CHF) and is associated with worse symptoms and prognosis regardless of whether anemia is also present. However, randomized controlled trials (RCT) of intravenous (IV) iron in patients with CHF have produced inconsistent results. This review considers the past, present, and future of defining and treating ID in patients with CHF. AREAS COVERED: The current guideline definition of ID is a serum ferritin <100 µg/L or serum ferritin 100-299 µg/L and transferrin saturation (TSAT) <20% derived from trials of IV iron in patients with end-stage renal failure. Ferritin synthesis and secretion is promoted by inflammatory cytokines which are raised in patients with CHF; thus, using ferritin to define iron deficiency in patients with CHF may be flawed. Observational data suggest that the current definition of iron deficiency in CHF does not identify a high-risk population. EXPERT OPINION: Alternative indicators of ID such as low serum iron concentrations or TSAT may better identify patients with ID who are at greater risk of adverse outcome and thus, possibly, more likely to benefit from IV iron.

Osteoanabolic therapy for osteoporosis in women.

Therapy to activate bone formation is required to reverse and restore the damaged bone architecture found in women with postmenopausal osteoporosis. The osteoanabolic drugs include teriparatide, which has been available for several years, and abaloparatide and romosozumab, novel osteoanabolic drugs that have become available more recently. By stimulating bone formation, these drugs produce greater increases in bone mass and bone strength, and they do so more quickly compared to the commonly used anti-remodeling (also called antiresorptive) drugs such as bisphosphonates. In head-to-head trials, teriparatide and romosozumab reduce fracture risk more effectively than do oral bisphosphonates in women with osteoporosis and high fracture risk. Osteoanabolic drugs have little role in the prevention of bone loss during early menopause, but they have an important place in the treatment of women at very high risk of fracture or who remain at high fracture risk after a course of bisphosphonate therapy. Primarily because of the high cost of the drugs, these therapies are initiated by specialists rather than primary-care physicians in most countries. This review will present the evidence for efficacy and safety of these drugs so that clinicians may discern their appropriate use when caring for postmenopausal women with osteoporosis.

Hypochloraemia following admission to hospital with heart failure is common and associated with an increased risk of readmission or death: a report from OPERA-HF.

AIMS: Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK. METHODS AND RESULTS: Hypochloraemia (<96 mmol/L), hyponatraemia (<135 mmol/L), and metabolic alkalosis (bicarbonate >32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan-Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272-1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15-1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04-1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14-1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion. CONCLUSION: Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.

Effect of frailty on treatment, hospitalisation and death in patients with chronic heart failure.

BACKGROUND: Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. The natural history of frail patients with CHF is unknown. METHODS: Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median age 76 years, median NT-proBNP 1156 ng/L) attending a routine follow-up visit. Those with CFS > 4 were classified as frail. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. RESULTS: 206 patients (44%) were frail. Of 291 patients with HF with reduced ejection fraction (HeFREF), those who were frail (N = 117; 40%) were less likely to receive optimal treatment, with many not receiving a renin-angiotensin-aldosterone system inhibitor (frail: 25% vs. non-frail: 4%), a beta-blocker (16% vs. 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). By 1 year, there were 56 deaths and 322 hospitalisations, of which 25 (45%) and 198 (61%), respectively, were due to non-cardiovascular (non-CV) causes. Most deaths (N = 46, 82%) and hospitalisations (N = 215, 67%) occurred in frail patients. Amongst frail patients, 43% of deaths and 64% of hospitalisations were for non-CV causes; 58% of cardiovascular (CV) deaths were due to advancing HF. Among non-frail patients, 50% of deaths and 57% of hospitalisations were for non-CV causes; all CV deaths were due to advancing HF. CONCLUSION: Frailty in patients with HeFREF is associated with sub-optimal medical treatment. Frail patients are more likely to die or be admitted to hospital, but whether frail or not, many events are non-CV.

Routine exercise-based cardiac rehabilitation does not increase aerobic fitness: A CARE CR study.

BACKGROUND: Recent evidence suggests that routine exercise-based cardiac rehabilitation (CR) may not lead to a substantial increase in estimated peak oxygen uptake (V̇O2peak). This could reduce the potential benefits of CR and explain why CR no longer improves patient survival in recent studies. We aimed to determine whether routine exercise-based CR increases V̇O2peak using gold-standard maximal cardiopulmonary exercise testing (CPET), and to quantify the exercise training stimulus which might be insufficient in patients undertaking CR. METHODS: We studied the effects of a routine, twice weekly, exercise-based CR programme for eight weeks (intervention group) compared with abstention from supervised exercise training (control group) in patients with coronary heart disease. The primary outcome was V̇O2peak measured using CPET. We also measured changes in body composition using dual X-ray absorptiometry, carotid intima-media thickness, hs-CRP and N-terminal pro B-type natriuretic peptide at baseline, 10 weeks and 12 months. We also calculated the Calibre 5-year all-cause mortality risk score. RESULTS: Seventy patients (age 63.1 SD10.0 years; BMI 29.2 SD4.0 kg·m-2; 86% male) were recruited (n = 48 intervention; n = 22 controls). The mean aerobic exercise training duration was 23 min per training session, and the mean exercise training intensity was 45.9% of heart rate reserve. V̇O2peak was 23·3 ml·kg-1·min-1 at baseline, and there were no changes in V̇O2peak between groups at any time point. The intervention had no effect on any of the secondary endpoints. CONCLUSION: Routine CR does not lead to an increase in V̇O2peak and is unlikely to improve long-term physiological outcomes.

Telemonitoring in subjects with newly diagnosed heart failure with reduced ejection fraction: From clinical research to everyday practice.

INTRODUCTION: Heart failure is increasingly common, and characterised by frequent admissions to hospital. To try and reduce the risk of hospitalisation, techniques such as telemonitoring (TM) may have a role. We wanted to determine if TM in patients with newly diagnosed heart failure and ejection fraction <40% reduces the risk of readmission or death from any cause in a 'real-world' setting. METHODS: This is a retrospective study of 124 patients (78.2% male; 68.6 ± 12.6 years) who underwent TM and 345 patients (68.5% male; 70.2 ± 10.7 years) who underwent the usual care (UC). The TM group were assessed daily by body weight, blood pressure and heart rate using electronic devices with automatic transfer of data to an online database. Follow-up was 12 months. RESULTS: Death from any cause occurred in 8.1% of the TM group and 19% of the UC group ( p = 0.002). There was no difference between the two groups in all-cause hospitalisation, either in the number of subjects hospitalised ( p = 0.7) or in the number of admissions per patient ( p = 0.6). There was no difference in the number of heart-failure-related readmissions per person between the two groups ( p = 0.5), but the number of days in hospital per person was higher in the UC group ( p = 0.03). Also, there were a significantly greater number of days alive and out of hospital for the patients in the TM group compared with the UC group ( p = 0.0001). DISCUSSION: TM is associated with lower any-cause mortality and also has the potential to reduce the number of days lost to hospitalisation and death.

Mode of presentation and mortality amongst patients hospitalized with heart failure? A report from the First Euro Heart Failure Survey.

BACKGROUND: Heart failure is heterogeneous in aetiology, pathophysiology, and presentation. Despite this diversity, clinical trials of patients hospitalized for HF deal with this problem as a single entity, which may be one reason for repeated failures. METHODS: The first EuroHeart Failure Survey screened consecutive deaths and discharges of patients with suspected heart failure during 2000-2001. Patients were sorted into seven mutually exclusive hierarchical presentations: (1) with cardiac arrest/ventricular arrhythmia; (2) with acute coronary syndrome; (3) with rapid atrial fibrillation; (4) with acute breathlessness; (5) with other symptoms/signs such as peripheral oedema; (6) with stable symptoms; and (7) others in whom the contribution of HF to admission was not clear. RESULTS: The 10,701 patients enrolled were classified into the above seven presentations as follows: 260 (2%), 560 (5%), 799 (8%), 2479 (24%), 1040 (10%), 703 (7%), and 4691 (45%) for which index-admission mortality was 26%, 20%, 10%, 8%, 6%, 6%, and 4%, respectively. Compared to those in group 7, the hazard ratios for death during the index admission were 4.9 (p ≤ 0.001), 4.0 (p < 0.001), 2.2 (p < 0.001), 2.1 (p < 0.001), 1.4 (p < 0.04) and 1.4 (p = 0.04), respectively. These differences were no longer statistically significant by 12 weeks. CONCLUSION: There is great diversity in the presentation of heart failure that is associated with very different short-term outcomes. Only a minority of hospitalizations associated with suspected heart failure are associated with acute breathlessness. This should be taken into account in the design of future clinical trials.

Added value of frailty and social support in predicting risk of 30-day unplanned re-admission or death for patients with heart failure: An analysis from OPERA-HF.

BACKGROUND: Models for predicting the outcome of patients hospitalized for heart failure (HF) rarely take a holistic view. We assessed the ability of measures of frailty and social support in addition to demographic, clinical, imaging and laboratory variables to predict short-term outcome for patients discharged after a hospitalization for HF. METHODS: OPERA-HF is a prospective observational cohort, enrolling patients hospitalized for HF in a single center in Hull, UK. Variables were combined in a logistic regression model after multiple imputation of missing data to predict the composite outcome of death or readmission at 30 days. Comparisons were made to a model using clinical variables alone. The discriminative performance of each model was internally validated with bootstrap re-sampling. RESULTS: 1094 patients were included (mean age 77 [interquartile range 68-83] years; 40% women; 56% with moderate to severe left ventricular systolic dysfunction) of whom 213 (19%) had an unplanned re-admission and 60 (5%) died within 30 days. For the composite outcome, a model containing clinical variables alone had an area under the receiver-operating characteristic curve (AUC) of 0.68 [95% CI 0.64-0.72]. Adding marital status, support from family and measures of physical frailty increased the AUC (p < 0.05) to 0.70 [95% CI 0.66-0.74]. CONCLUSIONS: Measures of physical frailty and social support improve prediction of 30-day outcome after an admission for HF but predicting near-term events remains imperfect. Further external validation and improvement of the model is required.

Dynamic risk stratification using serial measurements of plasma concentrations of natriuretic peptides in patients with heart failure.

BACKGROUND: Prognostic models for patients with chronic heart failure are generally based on a single assessment but treatment is often given with the intention of changing risk; re- evaluation of risk is an important aspect of care. The prognostic value of serial measurements of natriuretic peptides for the assessment of changes in risk is uncertain. AIMS: To evaluate the prognostic value of serial measurements of plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP) during follow-up of out-patients with chronic heart failure (CHF). METHODS: Patients diagnosed with CHF between 2001 and 2014 at a single out-patient clinic serving a local community were included in this analysis. NT-proBNP was measured at the initial visit and serially during follow-up. Only patients who had one or more measurements of NT-proBNP after baseline, at 4, 12 and/or 24 months were included. RESULTS: At baseline, amongst 1998 patients enrolled, the median age was 73 (IQR: 64-79) years, 70% were men, 31% were in NYHA class III/IV, and 77% had NT-proBNP >400 pg/mL. Median follow-up was 4.8 (IQR: 2.5-8.6) years. Serial measurements of NT-proBNP improved prediction of all-cause mortality at 3 years (c- statistic = 0.71) compared with using baseline data only (c-statistic = 0.67; p < 0.001) but a model using only the most recent NT-proBNP had an even higher c-statistic (0.72; p < 0.001). Similar results were obtained based on long-term prediction of mortality using all available follow-up data. CONCLUSIONS: Serial measurement of NT-proBNP in patients with CHF improves prediction of all-cause mortality. However, using the most recent value of NT-proBNP has similar predictive power as using serial measurements.

Estimated peak functional capacity: an accurate method for assessing change in peak oxygen consumption after cardiac rehabilitation?

OBJECTIVE: Cardiopulmonary exercise testing (CPET) is the 'gold standard' method of determining VO2peak . When CPET is unavailable, VO2peak may be estimated from treadmill or cycle ergometer workloads and expressed as estimated metabolic equivalents (METs). Cardiac rehabilitation (CR) programmes use estimated VO2peak (METs) to report changes in cardiorespiratory fitness (CRF). However, the accuracy of determining changes in VO2peak based on estimated functional capacity is not known. METHODS: A total of 27 patients with coronary heart disease (88·9% male; age 59·5 ± 10·0 years, body mass index 29·6 ± 3·8 kg m-2 ) performed maximal CPET before and after an exercise-based CR intervention. VO2peak was directly determined using ventilatory gas exchange data and was also estimated using the American College of Sports Medicine (ACSM) leg cycling equation. Agreement between changes in directly determined VO2peak and estimated VO2peak was evaluated using Bland-Altman limits of agreement (LoA) and intraclass correlation coefficients. RESULTS: Directly determined VO2peak did not increase following CR (0·5 ml kg-1 min-1 (2·7%); P = 0·332). Estimated VO2peak increased significantly (0·4 METs; 1·4 ml kg-1  min-1 ; 6·7%; P = 0·006). The mean bias for estimated VO2peak versus directly determined VO2peak was 0·7 ml kg-1  min-1 (LoA -4·7 to 5·9 ml  kg-1  min-1 ). Aerobic efficiency (ΔVO2 /ΔWR slope) was significantly associated with estimated VO2peak measurement error. CONCLUSION: Change in estimated VO2peak derived from the ACSM leg cycling equation is not an accurate surrogate for directly determined changes in VO2peak . Our findings show poor agreement between estimates of VO2peak and directly determined VO2peak . Applying estimates of VO2peak to determine CRF change may over-estimate the efficacy of CR and lead to a different interpretation of study findings.

Effects of human recombinant growth hormone on exercise capacity, cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency.

Objective Epidemiological studies suggest that adult-onset growth hormone deficiency (AGHD) might increase the risk of death from cardiovascular causes. Methods This was a 6-month double-blind, placebo-controlled, randomised, cross-over trial followed by a 6-month open-label phase. Seventeen patients with AGHD received either recombinant human growth hormone (rGH) (0.4 mg injection daily) or placebo for 12 weeks, underwent washout for 2 weeks, and were then crossed over to the alternative treatment for a further 12 weeks. Cardiac magnetic resonance imaging, echocardiography, and cardiopulmonary exercise testing were performed at baseline, 12 weeks, 26 weeks, and the end of the open phase (12 months). The results were compared with those of 16 age- and sex-matched control subjects. Results At baseline, patients with AGHD had a significantly higher systolic blood pressure, ejection fraction, and left ventricular mass than the control group, even when corrected for body surface area. Treatment with rGH normalised the insulin-like growth factor 1 concentration without an effect on exercise capacity, cardiac structure, or cardiac function. Conclusion Administration of rGH therapy for 6 to 9 months failed to normalise the functional and structural cardiac differences observed in patients with AGHD when compared with a control group.

Prognostic value of simple frailty and malnutrition screening tools in patients with acute heart failure due to left ventricular systolic dysfunction.

BACKGROUND: Frailty and malnutrition are common in patients with heart failure (HF), and are associated with adverse outcomes. We studied the prognostic value of three malnutrition and three frailty indices in patients admitted acutely to hospital with HF. METHODS: 265 consecutive patients [62% males, median age 80 (interquartile range (IQR): 72-86) years, median NTproBNP 3633 (IQR: 2025-6407) ng/l] admitted with HF between 2013 and 2014 were enrolled. Patients were screened for frailty using the Derby frailty index (DFI), acute frailty network (AFN) frailty criteria, and clinical frailty scale (CFS) and for malnutrition using the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score and prognostic nutritional index (PNI). RESULTS: According to the CFS (> 4), DFI, and AFN, 53, 50, and 53% were frail, respectively. According to the GNRI (≤ 98), CONUT score (> 4), and PNI (≤ 38), 46, 46, and 42% patients were malnourished, respectively. During a median follow-up of 598 days (IQR 319-807 days), 113 patients died. One year mortality was 1% for those who were neither frail nor malnourished; 15% for those who were either malnourished or frail; and 65% for those who were both malnourished and frail. Amongst the malnutrition scores, PNI, and amongst the frailty scores, CFS increased model performance most compared with base model. A final model, including CFS and PNI, increased c-statistic for mortality prediction from 0.68 to 0.84. CONCLUSION: Worsening frailty and malnutrition indices are strongly related to worse outcome in patients hospitalised with HF.

Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis.

BACKGROUND: Preterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48 hours of rescue tocolysis improves neonatal outcome is unproven. OBJECTIVES: To evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA). SEARCH STRATEGY: We searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour. SELECTION CRITERIA: We selected trials including pregnant women between 24 and 36(6/7)  weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48 hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment. DATA COLLECTION AND ANALYSIS: The primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed. MAIN RESULTS: Six randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n = 390 for nifedipine; n = 397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR 1.36; 95% confidence interval, 95% CI 0.35-5.33), intraventricular haemorrhage (IVH) ≥ grade II (RR 0.65; 95% CI 0.16-2.67), necrotising enterocolitis (NEC) (RR 1.15; 95% CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR 0.98; 95% CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR 0.74; 95% CI 0.55-1.01). CONCLUSION: Maintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice. TWEETABLE ABSTRACT: Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation.

Depression as an independent prognostic factor for all-cause mortality after a hospital admission for worsening heart failure.

BACKGROUND: Depression is associated with increased mortality amongst patients with chronic heart failure (HF). Whether depression is an independent predictor of outcome in patients admitted for worsening of HF is unclear. METHODS: OPERA-HF is an observational study enrolling patients hospitalized with worsening HF. Depression was assessed by the Hospital Anxiety and Depression Scale (HADS-D) questionnaire. Comorbidity was assessed by the Charlson Comorbidity Index (CCI). Kaplan-Meier and Cox regression analyses were used to estimate the association between depression and all-cause mortality. RESULTS: Of 242 patients who completed the HADS-D questionnaire, 153, 54 and 35 patients had no (score 0-7), mild (score 8-10) or moderate-to-severe (score 11-21) depression, respectively. During follow-up, 35 patients died, with a median time follow-up of 360days amongst survivors (interquartile range, IQR 217-574days). In univariable analysis, moderate-to-severe depression was associated with an increased risk of death (HR: 4.9; 95% CI: 2.3 to 10.2; P<0.001) compared to no depression. Moderate-to-severe depression also predicted all-cause mortality after controlling for age, CCI score, NYHA class IV, NT-proBNP and treatment with mineralocorticoid receptor antagonist, beta-blocker and diuretics (HR: 3.0; 95% CI: 1.3 to 7.0; P<0.05). CONCLUSIONS: Depression is strongly associated with an adverse outcome in the year following discharge after an admission to hospital for worsening HF. The association is only partly explained by the severity of HF or comorbidity. Further research is required to demonstrate whether recognition and treatment of depression improves patient outcomes.

Telemonitoring predicts in advance heart failure admissions.

BACKGROUND: Heart failure (HF) is increasingly common and characterised by frequent admissions to hospital. To reduce the risk of HF hospitalisation (HFH), approaches as telemonitoring (TM) have been introduced. This study aimed to develop an algorithm for detecting patients at high risk of HFH, using daily collected physiological data (blood pressure, heart rate, weight) by non-invasive TM. METHODS: The analysis was based on home-TM data collected from a single centre as part of HF care. The prediction of HFH was considered as a signal processing and classification problem. Signal processing aimed to transform the signals to enhance the information relevant to HFH. We attempted to construct an algorithm that could identify such patterns and classify them as abnormal by assessing the predictive value of each of the monitored signals and their combinations using analysis of vectors (e.g. vectors of raw signal values, vectors of signals obtained by Multi-Resolution Analysis). RESULTS: The best predictive results were achieved with the combined used of weight and diastolic BP. The highest predictive performance was achieved using 8-day TM data (area under the receiver operator characteristic curve (AUC) 0.82±0.02). Prediction based on 4-day TM data was slightly less accurate with an AUC of 0.77±0.01. CONCLUSION: We have found that using an algorithm based on weight and diastolic blood pressure measured over 8days predicts heart failure admissions with a high degree of accuracy. The value of such an algorithm should be tested in clinical trials.

Integrin α1ß1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling.

OBJECTIVE: To investigate the role of integrin α1ß1 in the progression of post-traumatic osteoarthritis (PTOA), and elucidate the contribution of epidermal growth factor receptor (EGFR) signalling to the mechanism by which integrin α1ß1 might control PTOA. We hypothesised that integrin α1ß1 plays a protective role in the course of PTOA and that the effect of PTOA (e.g., synovitis, loss of cartilage and growth of osteophytes) would be exacerbated in mice lacking integrin α1ß1 at every time point post destabilisation of medial meniscus (DMM). METHODS: DMM or sham surgery was performed on integrin α1-null and wild type (WT) mice and the progression of PTOA analysed at 2, 4, 8 and 12 weeks post-surgery (PS) using micro-computed tomography (microCT), histology, and immunohistochemistry. In addition, the effects of EGFR blockade were examined by treating the mice with the EGFR inhibitor erlotinib. RESULTS: Integrin α1-null female, but not male, mice showed earlier cartilage degradation post DMM surgery compared to WT controls. Furthermore, erlotinib treatment resulted in significantly less cartilage damage in integrin α1-null but not WT mice. Independent of genotype, erlotinib treatment significantly mitigated the effects of PTOA on many tissues of female mice including meniscal and fabella bone volume, subchondral bone thickness and density and cartilage degradation. In contrast, reduced EGFR signalling had little effect on signs of PTOA in male mice. CONCLUSION: Integrin α1ß1 protects against PTOA-induced cartilage degradation in female mice partially via the reduction of EGFR signalling. Furthermore, reduction of EGFR signalling protects against the development of PTOA in female, but not male mice.

Effects of yohimbine and drug cues on impulsivity and attention in cocaine-dependent men and women and sex-matched controls.

BACKGROUND: Deficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. METHODS: In a double-blind placebo controlled cross-over study, cocaine-dependent men (n=12), cocaine-dependent women (n=27), control men (n=31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors' Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session RESULTS: Healthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0-1.3), χ(2)1=2.0, p=0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI)=0.6 (0.4-0.8), χ(2)1=8.6, p=0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)=7.2 (3.6-14.7), χ(2)1=30.1, p<0.001]. Cocaine-dependent women exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354 ± 13 vs. Male 415 ± 14; t89=2.6, p=0.012]. CONCLUSIONS: These data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals.

Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury.

We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9 months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our combat-exposed veterans.