Large Treatment Trials Research Articles

Endovascular Treatment for Cerebral Venous Thrombosis: Applying Lessons Learned from Clinical Trials of Endovascular Treatment in Acute Arterial Ischemic Stroke.

Cerebral venous thrombosis (CVT) is a rare but severely disabling form of stroke. Acute treatment mainly consists of medical management, since there is no robust evidence suggesting the benefit of endovascular treatment for CVT. Given the relative lack of data to guide acute treatment decision-making, CVT treatment decisions are mostly made on a case-by-case basis. In some ways, the current status quo of endovascular treatment for CVT resembles the state of endovascular treatment for acute ischemic stroke before the wave of major positive large vessel occlusion endovascular treatment trials in 2015. The current state of evidence with regard to endovascular CVT treatment is summarized, parallels to acute ischemic stroke are drawn, and it is discussed how the lessons learned from the evolution of acute ischemic stroke endovascular treatment (EVT) trials could be applied to designing a trial of endovascular treatment for CVT. The review ends by outlining possible scenarios for the future of endovascular CVT treatment. CVT is a serious disease, affecting young patients and their families, and harbors a considerable social and economic burden. Working toward high-level evidence for the best possible treatment strategy and exploring a possible role for EVT to improve outcomes in CVT needs to remain a high priority in stroke research.

The experience of re-infection among people who inject drugs successfully treated for hepatitis C

IntroductionHighly effective direct-acting antiviral (DAA) agents have changed the landscape of hepatitis C virus infection (HCV) treatment and have become more available to people who inject drugs (PWID) over the past several years. Although many achieve a sustained virologic response (SVR), a small proportion will become re-infected. This study examined experiences of re-infection among participants in Project HERO, a large multi-site treatment trial designed to test alternative treatment delivery models for DAAs. MethodsStudy staff conducted qualitative interviews with twenty-three HERO participants who experienced reinfection following successful treatment for HCV. Interviews focused on life circumstances and experiences with treatment/re-infection. We conducted a thematic analysis, followed by a narrative analysis. ResultsParticipants described challenging life circumstances. The initial experience of cure was joyful, leading participants to feel that they had escaped a defiled, stigmatized identity. Re-infection was very painful. Feelings of shame were common. Participants with fully developed narratives of re-infection described both a strong emotional response as well as a plan for avoiding re-infection during retreatment. Participants who lack such stories showed signs of hopelessness and apathy. ConclusionThough the promise of personal transformation through SVR may be motivating for patients, clinicians should be cautious about how they describe the “cure” when educating patients about HCV treatment. Patients should be encouraged to avoid stigmatizing, dichotomizing language of the self, including terms such as “dirty” and “clean.” In acknowledging the benefits of HCV cure, clinicians should emphasize that re-infection does not mean failed treatment; and that current treatment guidelines support retreatment of re-infected PWID.

OR18-05 Thyroid Hormone Use and Survival among Older Adults - Longitudinal Analysis of the Baltimore Longitudinal Study of Aging (BLSA)

: Introduction: Thyrotropin (TSH) levels on average are higher and vary more widely among older adults.1 Large meta-analyses and treatment trials for isolated elevated TSH in older adults did not demonstrate harm from no treatment or benefit from treatment in this population.2 Isolated, elevated TSH can result from adaptations to aging, rather than primary thyroid disease, suggesting that thyroid hormone treatment could actually cause harm.3 Objective:To determine if there is a survival effect from thyroid hormone treatment in adults aged 65+. Methodology:Thyroid functional status and thyroid hormone exposure were analyzed for 1,258 participants of the BLSA aged 65+ through death or end of follow up. We analyzed exposures by visit and also compared survival between individuals with consistently elevated, euthyroid or low TSH both on and off of therapy.Incident rate ratios (IRR) were calculated using time-dependent Poisson regression models. Covariates included age, sex, race, walking index (measure of physical function), self-rated health (SF-12), body mass index (BMI), smoking and comorbidity score. Results: Average follow-up was 9 years, with 169 deaths over the study period. The cohort comprised 49.5% women, with average age in the study being 78 years (SD ±8.2). Thyroid hormone use trended towards harm analyzed at each visit with an IRR=1.40 (95% CI 0.93–2.12) after adjusting for other covariates. Among ‘treated-to-target’versus euthyroid individuals, thyroid hormone use was associated with a significantly increased mortality rate with an IRR=1.80 (95% CI 1.09–2.96) in multivariable analysis. Conclusion: Thyroid hormone replacement among older adults,even when treated-to-target, is associated with a significantly increased mortality risk compared to euthyroid individuals with no history of thyroid hormone exposure. This suggests that treating isolated elevated TSH when changes are aging adaptations rather than primary thyroid disease could adversely affect health by altering key homeostatic adaptation. We recommend clinicians consider the underlying physiology of aging and employ age specific reference ranges when deciding on treatment for elevated TSH in older adults.4

Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial

Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN. Double-blind, randomized, placebo-controlled, phase 2 clinical trial. Participants had IgAN(proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m2) and were receiving optimized RAAS inhibitor therapy. Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months. The primary outcome was percentage change in proteinuria between baseline and 6 months. 60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m2; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (-48.4% [IQR,-64.2%,-30.5%] vs 10.0% [IQR,-38.7%, 30.6%]; P<0.001, respectively). At 6 months, median proteinuria level was significantly lower in the HCQ group than in the placebo group (0.9 [IQR, 0.6, 1.0] g/d vs 1.9 [IQR, 0.9, 2.6] g/d; P=0.002, respectively). No serious adverse events were recorded during the study in either study group. The short treatment period and lack ofpostwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety. HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials. This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund. Registered at ClinicalTrials.gov with study number NCT02942381.

The association of atrial fibrillation and dementia incidence: a meta-analysis of prospective cohort studies.

ObjectivesTo assess and synthesize the prospective cohort studies published so far on the association between atrial fibrillation (AF) and dementia incidence.MethodsWe searched PubMed, Web of Science, and the Cochrane Library for potential studies published in English previous to April 2018. Two independent reviewers screened the search results for prospective cohort studies reporting the association between AF and dementia incidence in patients with normal cognitive function at baseline and not suffering from an acute stroke. The Newcastle-Ottawa Scale was adopted to evaluate the quality of the included studies. The pooled hazard ratio (HR) of AF for dementia was calculated with the Comprehensive Meta-Analysis software, version 2. Heterogeneity and publication bias were assessed with the I2 test and funnel plot, respectively.ResultsWe finally identified 11 prospective cohort studies covering 112,876 patients. All the included studies reported an adjusted HR obtained in multiple Cox regression models. The qualities of the included studies ranged from moderate to high. In pooled analysis with a fixed-effects model, AF was independently associated with dementia incidence (HR = 1.34, 95% CI: 1.24–1.44). Subgroup analysis of studies considering anticoagulation as an important confounding factor achieved a similar result. Based on the I2 test and funnel plot, we did not detect obvious heterogeneity and publication bias in our study. Meta-regression on age did not find significant results.ConclusionsThe results of our meta-analysis further confirmed that AF was an independent risk factor for dementia in patients with normal baseline cognitive function not suffering from acute stroke. Screening for dementia in AF patients and including dementia as an independent outcome in large AF treatment trials is warranted.

AEROBIC BIOLOGICAL TREATABILITY STUDIES ON LANDFILL LEACHATE WITH NITRIFICATION AND DENITRIFICATION

Large pilot-scale treatment trials have examined the treatment of a leachate typical of those found at many closed landfill sites, containing approximately 200mg/l of ammoniacal-N. At such sites, treatment of these leachates with nitrification of ammoniacal-N alone, will not allow discharges of treated leachate to be made into sensitive surface watercourses, because of concerns about nitrate-N. The trials therefore included denitrification processes, by modification of an SBR process configuration, using the waste product glycerol, widely available as a by-product from the production of biodiesel, as the carbon source for denitrification. Initially a nitrification-only Stage 1 treatment trial treated strong, methanogenic leachate containing 2000mg/l of ammoniacal-N and 4000mg/l COD, completely nitrifying all ammoniacal-N to nitrate-N. Following the successful treatment of strong leachate through nitrification, the innovative combined nitrification and denitrification treatment system was constructed. Stage 2 of the treatability trial used this newly designed system to incorporate both aeration and anoxic phases within a single reactor; enabling full nitrification and denitrification of weaker leachate from a closed landfill, containing 150mg/l ammoniacal-N and 200mg/l COD. In particular, the development of an innovative, stable, robust and relatively simple combined nitrification and denitrification process will have wide application at many closed landfill sites, where a reliable and robust treatment process is required, whilst full denitrification of nitrate-N is essential if treated leachate is to be discharged locally into small watercourses. The relative simplicity of the new process, in a single tank, with readily-automated operation and few chemical additions, means that it can be used at remote closed landfills, to produce high quality effluents suitable for discharge into many surface watercourses.

Treatment in myositis.

As with the treatment of many immune-mediated diseases, managing myositis encompasses diverse factors, which present a challenge to the physician caring for these patients. The idiopathic inflammatory myopathies (IIMs, also known as myositis), are fundamentally heterogeneous; many contributory immunological perturbations are involved in the pathogenesis of myositis, leading to varying clinical phenotypic presentations. Targeting any one or several of these deleterious pathways with a therapeutic agent might seem reasonable, but the desired response is not uniformly predictable. The presence of many serious extramuscular manifestations, such as severe skin rash, interstitial lung disease and arthritis, complicates the management of myositis. Myositis is rare, and very few large treatment trial results are available to guide clinicians. Outcome measures to effectively gauge treatment responses have been available for only a few years, and response criteria that incorporate critical core set measures continue to evolve. Nevertheless, a multitude of immunosuppressive and immunomodulatory agents are available to clinicians managing myositis, and the emergence of biologic agents targeting potential pathogenic pathways offers hope for mitigating or curing this enigmatic group of diseases. Paradigm shifts in the nonpharmacological approach to treat myositis have also occurred as more aggressive exercise regimens have shown benefit in patients, even those with active disease.

Viability of the World Health Organization quality of life measure to assess changes in quality of life following treatment for alcohol use disorder.

Quality of life is an outcome often examined in treatment research contexts such as biomedical trials, but has been studied less often in alcohol use disorder (AUD) treatment. The importance of considering QoL in substance use treatment research has recently been voiced, and measures of QoL have been administered in large AUD treatment trials. Yet, the viability of popular QoL measures has never been evaluated in AUD treatment samples. Accordingly, the present manuscript describes a psychometric examination of and prospective changes in the World Health Organization Quality of Life measure (WHOQOL-BREF) in a large sample (N=1383) of patients with AUD recruited for the COMBINE Study. Specifically, we examined the construct validity (via confirmatory factor analyses), measurement invariance across time, internal consistency reliability, convergent validity, and effect sizes of post-treatment changes in the WHOQOL-BREF. Confirmatory factor analyses of the WHOQOL-BREF provided acceptable fit to the current data and this model was invariant across time. Internal consistency reliability was excellent (α>.9) for the full WHOQOL-BREF for each timepoint; the WHOQOL-BREF had good convergent validity, and medium effect size improvements were found in the full COMBINE sample across time. These findings suggest that the WHOQOL-BREF is an appropriate measure to use in samples with AUD, that the WHOQOL-BREF scores may be examined over time (e.g., from pre- to post-treatment), and the WHOQOL-BREF may be used to assess improvements in quality of life in AUD research.

The scientific impact and value of large, NCI-sponsored randomized phase III cancer prevention trials.

1541 Background: The cooperative cancer research groups of the National Cancer Institute’s National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of prevention for cancer. An important question for funding agencies is whether the conduct of large prevention trials provides strong scientific return on investment. Methods: We used study data from a single NCI-sponsored cooperative group (SWOG) over a 20-year period (1990-2009, inclusive). During this time, SWOG conducted two large prevention trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin E Cancer Prevention Trial) and numerous treatment trials. Scientific impact for prevention and treatment trials was examined using citation analysis. Average annual citation counts were compared using t-tests. Scientific impact was also assessed as a function of trial costs. Results: Twenty-six treatment trials with 16,391 patients and two prevention trials with 54,415 patients were examined. The mean annual citation rate for primary articles was higher for prevention trials compared to treatment trials (173.6 vs. 41.7, p = .003). For both primary and secondary article publications, mean annual citations for articles associated with prevention trials were also higher (557.2 vs. 67.6, p &lt; .0001). Large prevention trials were estimated to provide 70% greater scientific impact on a cost-adjusted basis. Conclusions: Based on these criteria, the scientific impact of large phase III cancer prevention trials was very high in absolute terms and after accounting for trial costs. For appropriate scientific questions, large prevention trials provide a strong scientific return on investment for federal funding agencies.

Conditional moving linear regression: Modeling the recruitment process for ALLHAT

ABSTRACTEffective recruitment is a prerequisite for successful execution of a clinical trial. ALLHAT, a large hypertension treatment trial (N = 42,418), provided an opportunity to evaluate adaptive modeling of recruitment processes using conditional moving linear regression. Our statistical modeling of recruitment, comparing Brownian and fractional Brownian motion, indicates that fractional Brownian motion combined with moving linear regression is better than classic Brownian motion in terms of higher conditional probability of achieving a global recruitment goal in 4-week ahead projections. Further research is needed to evaluate how recruitment modeling can assist clinical trialists in planning and executing clinical trials.

Chronic kidney disease-associated pruritus: impact on quality of life and current management challenges.

Chronic kidney disease-associated pruritus (CKD-aP) is a distressing, often overlooked condition in patients with CKD and end-stage renal disease. It affects ~40% of patients with end-stage renal disease and has been associated with poor quality of life, poor sleep, depression, and mortality. Prevalence estimates vary based on the instruments used to diagnose CKD-aP, and standardized diagnostic instruments are sorely needed. Treatment studies have often yielded conflicting results. This is likely related to studies that are limited by small sample size, flawed designs, and nonstandardized diagnostic instruments. Several large well-designed treatment trials have recently been completed and may soon influence CKD-aP management.

Developing an Integrated Image Bank and Metadata for Large-scale Research in Cerebrovascular Disease: Our Experience from the Stroke Image Bank Project

A framework for building an infrastructure that semantically integrates, archives and reuses data for various research purposes in human brain imaging remains critical. In particular, problems of aligning technical, clinical and professional systems in order to facilitate data sharing are a recurring issue in brain imaging. However, large samples of well characterised images with detailed metadata are increasingly needed. This paper outlines the experience of the NeuroGrid Stroke Exemplar and further work in the Brain Research Imaging Centre and Stroke Trials Unit in developing an infrastructure that facilitates the linkage, archiving and reuse of imaging data from stroke patients for large scale clinical and epidemiological studies. We examined data from 12 past stroke projects carried out over the past two decades in our centre and two large trials with 329 centres. We assessed previously published schemas and those developed specifically for large multicentre ischaemic and haemorrhagic stroke treatment trials. We then developed our own harmonised and integrated schema and database with a web-based interface system, aiming to be flexible and adaptable to future trials and observational studies. We then linked image and meta-data from 3079 patients acquired in stroke research in one centre in a 14 year period (1996 – 2010) with prospective central hospital health statistics to obtain long term follow-up. Our integrated database includes 3079 subjects and over 550 federated and searchable data items including imaging details, medical history and examination, stroke and laboratory details, which maps to large multicentre stroke trials with imaging data from over 10,000 patients from 30 countries. The central linkage identified 879 of 3079 patients had died, 525 had recurrent strokes and 291 developed dementia during up to a 19 year period (range=0 -19; median=9.04; IQR=12.17) of follow-up, demonstrating its utility. The core metadata schema, has benefited from extensive development in large clinical trials. Further trials’ data can now be added. It provides an opportunity to crosslink and reuse data for a range of large scale stroke brain imaging clinical and research purposes including developing data analytics models for research into common brain diseases and their consequences.

Mechanisms underlying increased mortality risk in patients with heart failure and reduced ejection fraction randomly assigned to adaptive servoventilation in the SERVE-HF study: results of a secondary multistate modelling analysis

A large randomised treatment trial (SERVE-HF) showed that treatment of central sleep apnoea with adaptive servoventilation in patients with heart failure and reduced ejection fraction (HFREF) increased mortality, although the analysis of the composite primary endpoint (time to first event of death from any cause, life-saving cardiovascular intervention, or unplanned hospital admission for worsening heart failure) was neutral. This secondary multistate modelling analysis of SERVE-HF data investigated associations between adaptive servoventilation and individual components of the primary endpoint to try to better understand the mechanisms underlying the observed increased mortality. In SERVE-HF, participants were randomly assigned to receive either optimum medical treatment for heart failure alone (control group), or in combination with adaptive servoventilation. We analysed individual components of the primary SERVE-HF endpoint separately in a multistate model, with and without three covariates suggested for effect modification (implantable cardioverter defibrillator at baseline, left ventricular ejection fraction [LVEF], and proportion of Cheyne-Stokes Respiration [CSR]). The SERVE-HF study is registered with ClinicalTrials.gov, number NCT00733343. Univariate analysis showed an increased risk of both cardiovascular death without previous hospital admission (hazard ratio [HR] 2·59, 95% CI 1·54-4·37, p<0·001) and cardiovascular death after a life-saving event (1·57, 1·01-2·44, p=0·045) in the group receiving adaptive servoventilation versus the control group. Adjusted analysis showed that the increased risk attributed to adaptive servoventilation of cardiovascular death without previous hospital admission for worsening heart failure varied with LVEF and that the risk attributed to adaptive servoventilation of hospital admission for worsening heart failure varied with LVEF and CSR. In patients with LVEF less than or equal to 30%, use of adaptive servoventilation markedly increased the risk of cardiovascular death without previous hospital admission (HR 5·21, 95% CI 2·11-12·89, p=0·026). Adaptive servoventilation is associated with an increased risk of cardiovascular death in patients with heart failure and reduced ejection fraction (LVEF ≤45%) treated for predominant central sleep apnoea. This multistate modelling analysis shows that this risk is increased for cardiovascular death in patients not previously admitted to hospital, presumably due to sudden death, and in patients with poor left ventricular function. ResMed.

Cumulative Proportion of Responders Analysis (CPRA) as a Tool to Assess Treatment Outcome in Alcohol Clinical Trials

Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment. All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy. Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various definitions of a positive response.

Quality of life as a primary endpoint in ovarian cancer trials

Multimodal treatment of patients with advanced ovarian cancer consists of radical debulking surgery and a combination of platinum and taxane chemotherapy. Although this approach is highly effective and potentially curative, most women will relapse, which can be treated effectively but is rarely cured. 1 du Bois A Reuss A Pujade-Lauraine E Harter P Ray-Coquard I Pfisterer J Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer. 2009; 115: 1234-1244 Crossref PubMed Scopus (1037) Google Scholar In this context, quality of life is an important outcome measure. Unfortunately, few detailed analyses of quality of life have been done in large first-line treatment trials for ovarian cancer: primary publications traditionally focus on efficacy data and, typically, only outline results of quality of life are presented. Detailed description of health-related quality of life could help clinicians and patients with respect to making informed treatment decisions. 2 Luckett T King M Butow P Friedlander M Paris T Assessing health-related quality of life in gynecologic oncology: a systematic review of questionnaires and their ability to detect clinically important differences and change. Int J Gynecol Cancer. 2010; 20: 664-684 Crossref PubMed Scopus (47) Google Scholar Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trialA weekly regimen of carboplatin and paclitaxel might be a reasonable option for first-line treatment of women with advanced ovarian cancer. Full-Text PDF

Is BP Lowering During Acute Intracerebral Hemorrhage Safe?

One of the most devastating consequences of hypertension is stroke resulting from brain hemorrhage. These acute situations generate some of the highest blood pressure (BP) readings. Despite impressive levels of BP, we are often reluctant to treat these patients with BPlowering drugs for three reasons. First is the concern that the area around the hemorrhage, called the penumbra, is in jeopardy of ischemia, and BP reduction might tip it more towards ischemia and extend the consequences of the stroke. Second, thrombolytic therapy, which requires a systolic BP <185 mm Hg to be given safely, is not an issue since that would worsen this presentation. Finally, there simply wasn’t evidence to demonstrate benefit in this situation until recently, when the pilot study Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT), which assessed the effectiveness of early intensive BP-lowering targeting lower systolic BP (SBP) levels of <140 mm Hg in patients with acute intracerebral hemorrhage (ICH), showed less growth in the size of the brain hematoma at 72 hours in patients assigned to a lower (<140 mm Hg) compared with a higher (<180 mm Hg) in-hospital BP goal. Building on this original study, the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2) was recently conducted. INTERACT2 was a large multicenter international prospective randomized open treatment trial. Patients with spontaneous acute ICH within the previous 6 hours were randomized to receive either intensive treatment to lower BP to a target SBP of <140 mm Hg within 1 hour vs guideline-recommended treatment of SBP <180 mm Hg. The BP level was maintained for the next 7 days after randomization. The agents used to lower BP were left to the discretion of the treating physician. The main outcome at 90 days was death or major disability using a Rankin scale, where a score of 0 indicates no symptoms/disabilities, 5 indicates severe disability, and 6 indicates death. A prespecified ordinal analysis of a modified Rankin score was also performed. The analysis showed a 13% improvement in the modified Rankin score with intensive treatment (odds ratio for greater disability, 0.87; 95% confidence interval, 0.77–1.00; P=.04). Rate of mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. Episodes of severe hypotension were similar in both groups and occurred in <1% of participants. The difference in hematoma growth between groups was not significant. What this says to us is that (1) it appears to be safe to lower the systolic BP within about 6 hours of an ICH, and (2) there may be a small benefit to doing so in terms of symptoms and disabilities following stroke, bearing in mind that many (two thirds) of the participants were Chinese and that the main drug used was urapidil (an a1 adrenoceptor and serotonin blocker), which is not available in the United States. It will be important to frame INTERACT2 findings in the light of the ongoing trial being conducted in the United States—Antihypertensive Treatment of Acute Cerebral Hemorrhage Trial II (ATACH)—which will compare treating the SBP to <140 mm Hg vs <180 mm Hg in patients with acute ICH using nicardipine as the agent of choice to lower BP. Some patience will be needed as the results are expected in 2016. In the meantime, there is some encouragement that managing high systolic pressures in the presence of an acute brain hemorrhage does not cause harm and may have some benefit.

C‐reactive protein versus erythrocyte sedimentation rate, white blood cell count and alkaline phosphatase in diagnosing bacteraemia in bone and joint infections

Bacteraemia is common in childhood acute bone and joint infections and demands urgent treatment. Blood C-reactive protein (CRP), erythrocyte sedimentation rate and white blood cell count (WBC) are well known and established markers in these infections. Instead, no information is available on serum alkaline phosphatase whose concentration is known to increase in septic conditions. In our large prospective treatment trial comprising of 265 children with acute culture-positive bone or joint infection, all these laboratory indices were monitored on admission to hospital. The predictive value to detect bacteraemia was assessed for each of these four indices. In all, 59% of the patients showed bacteraemia. CRP was significantly (P < 0.05) higher among bacteraemic patients, whereas erythrocyte sedimentation rate, white blood cell count and alkaline phosphatase were not. The area under receiver operator characteristic curve for CRP was 0.588 (CI95% 0.524-0.649) and the significance level P (Area = 0.5) was <0.05. None of the markers could reliably diagnose bacteraemia. CRP alone was significantly higher among bacteraemic patients.

Commonly asked questions: thrombolytic therapy in the management of acute stroke

Questions about thrombolytic management arise frequently, often with the intent of ascertaining safety and efficacy in specific situations. Thrombolytic therapy is generally safe, even if a nonruptured intracranial aneurysm is present. The risk of cardiac rupture with tamponade is low, except for the first 7 weeks following myocardial infarction. Over this duration, there is an increased risk of intravenous thrombolytic therapy in specific patient groups. Stroke infrequently occurs during cardiac catheterization. Its infrequent occurrence has limited large treatment trials. Basilar artery occlusion management will be reviewed. Thrombolytic therapy is generally safe in the context of pre-existing cerebral microhemorrhages and cervical artery dissections. Additionally, the role of multimodal penumbral imaging in planning stroke therapy will be reviewed.

Alzheimer's Disease, Oestrogen and Mitochondria: an Ambiguous Relationship

Hormonal deficit in post-menopausal women has been proposed to be one risk factor in Alzheimer's disease (AD) since two thirds of AD patients are women. However, large treatment trials showed negative effects of long-term treatment with oestrogens in older women. Thus, oestrogen treatment after menopause is still under debate, and several hypotheses trying to explain the failure in outcome are under discussion. Concurrently, it was shown that amyloid-beta (Aβ) peptide, the main constituent of senile plaques, as well as abnormally hyperphosphorylated tau protein, the main component of neurofibrillary tangles, can modulate the level of neurosteroids which notably represent neuroactive steroids synthetized within the nervous system, independently of peripheral endocrine glands. In this review, we summarize the role of neurosteroids especially that of oestrogen in AD and discuss their potentially neuroprotective effects with specific regard to the role of oestrogens on the maintenance and function of mitochondria, important organelles which are highly vulnerable to Aβ- and tau-induced toxicity. We also discuss the role of Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme able to bind Aβ peptide thereby modifying mitochondrial function as well as oestradiol levels suggesting possible modes of interaction between the three, and the potential therapeutic implication of inhibiting Aβ–ABAD interaction.

The question of primary lipid nephrotoxicity

Half a century ago, Bagdade [1] reported hypertriglyceridaemia in haemodialysis patients. Since then, the serum lipoprotein patterns of the various forms of kidney disease have been amply documented. In patients with reduced kidney function, this pattern is characterized by increases in triglycerides, apolipoprotein CIII and remnant particles as well as decreases in high-density lipoprotein (HDL) cholesterol and apolipoprotein A1. Low-density lipoprotein (LDL) cholesterol and apolipoprotein B are generally reported to be similar to those of healthy individuals. This pattern, largely explained by delayed removal of triglyceride-rich lipoproteins and disturbed synthesis of apolipoproteins in the liver, is full-blown in end-stage renal disease but changes can be detected early in chronic kidney disease [2, 3]. The focus of lipoprotein research in nephrology has changed. Small studies, documenting and searching for pathophysiological mechanisms of dyslipoproteinaemia, have been replaced by large treatment trials and risk estimations with regard to cardiovascular disease and kidney function. This development is rational; the prevalence of chronic kidney disease is steadily increasing worldwide; there are many indications that dyslipoproteinaemia accelerates the progress of chronic kidney disease, and the cardiovascular risk is manifold in patients with reduced kidney function, increasing early in that process [4]. The entry of the statins has radically changed the treatment scene, even though the impact of lipid-modifying treatment in chronic kidney disease has not been fully elucidated.