Incidence, complications and risk factors for severe falls in patients on maintenance haemodialysis.

BACKGROUND: Falls have been insufficiently studied in patients on maintenance haemodialysis (MHD). This study assessed the incidence and complications of severe falls and the ability of risk factors, including the Performance-Oriented Mobility Assessment (POMA) test, to predict them in this population. METHODS: All patients on MHD from our centre were asked to participate in this survey. POMA test and a record of risk factors for falls were obtained at baseline. Severe falls, as defined by an admission in an emergency ward, were documented prospectively. RESULTS: Eighty-four patients (median age 69.5 years, minimum 26 years, maximum 85 years) were enrolled. Predialytic POMA scores were low (median 20, minimum 5, maximum 26). After a mean follow-up of 20.6 months (142.2 patient-years), 31 severe falls were recorded in 24 patients (28.6%; incidence 0.22 per patient-year) and complicated by fractures in 54.8% of severe falls. In univariate analysis, age, a past history of falls, malnutrition, depression, but not POMA score, were associated with severe falls. A POMA score of >21 had a negative predictive value of 82%. CONCLUSIONS: Severe falls were common in MHD patients in this study and resulted in fractures in >50% of the cases. They were associated with ageing, a past history of falls, malnutrition and depression. Although there was a trend towards a lower POMA score in fallers as compared to non-fallers, the POMA score was not an independent predictor of severe falls in this study. These data may help to stratify the patient's risk of falling in order to target programmes to prevent falls in this population.

Dominant TNF-α(+) Mycobacterium tuberculosis-specific CD4(+) T cell responses discriminate between latent infection and active disease.

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4(+) T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4(+) T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4(+) T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

Association of major and minor ECG abnormalities with coronary heart disease events.

CONTEXT: In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle-aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction. OBJECTIVE: To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997-1998 and 2006-2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events. MAIN OUTCOME MEASURE: Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization). RESULTS: At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02-1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20-1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%-19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32%-2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33-3.02; and HR, 1.66; 95% CI, 1.18-2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, -0.4% to 11.8%). CONCLUSIONS: Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors.

Hippocampal atrophy predicts conversion to dementia after STN-DBS in Parkinson's disease.

BACKGROUND: Hippocampal atrophy (HA) is a known predictor of dementia in Alzheimer's disease. HA has been found in advanced Parkinson's disease (PD), but no predicting value has been demonstrated yet. The identification of such a predictor in candidates for subthalamic deep brain stimulation (STN-DBS) would be of value. Our objective was to compare preoperative hippocampal volumes (HV) between PD patients who subsequently converted to dementia (PDD) after STN-DBS and those who did not (PDnD). METHODS: From a cohort of 70 consecutive STN-DBS treated PD patients, 14 converted to dementia over 25.6+/-20.2 months (PDD). They were compared to 14 matched controls (PDnD) who did not convert to dementia after 43.9+/-11.7 months. On the preoperative 3D MPRAGE MRI images, HV and total brain volumes (TBV) were measured by a blinded investigator using manual and automatic segmentation respectively. RESULTS: PDD had smaller preoperative HV than PDnD (1.95+/-0.29 ml; 2.28+/-0.33 ml; p<0.01). This difference reinforced after normalization for TBV (3.28+/-0.48, 3.93+/-0.60; p<0.01). Every 0.1 ml decrease of HV increased the likelihood to develop dementia by 24.6%. A large overlap was found between PD and PDnD HVs, precluding the identification of a cut-off score. CONCLUSIONS: As in Alzheimer's disease, HA may be a predictor of the conversion to dementia in PD. This preoperative predictor suggests that the development of dementia after STN-DBS is related to the disease progression, rather then the procedure. Further studies are needed to define a cut-off score for HA, in order to affine its predictive value for an individual patient.

Selective in vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 cardiac magnetic resonance.

BACKGROUND: The goal of this study was to characterize the performance of fluorine-19 ((19)F) cardiac magnetic resonance (CMR) for the specific detection of inflammatory cells in a mouse model of myocarditis. Intravenously administered perfluorocarbons are taken up by infiltrating inflammatory cells and can be detected by (19)F-CMR. (19)F-labeled cells should, therefore, generate an exclusive signal at the inflamed regions within the myocardium. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in BALB/c mice. After intravenous injection of 2×200 µL of a perfluorocarbon on day 19 and 20 (n=9) after immunization, in vivo (19)F-CMR was performed at the peak of myocardial inflammation (day 21). In 5 additional animals, perfluorocarbon combined with FITC (fluorescein isothiocyanate) was administered for postmortem immunofluorescence and flow-cytometry analyses. Control experiments were performed in 9 animals. In vivo (19)F-CMR detected myocardial inflammation in all experimental autoimmune myocarditis-positive animals. Its resolution was sufficient to identify even small inflammatory foci, that is, at the surface of the right ventricle. Postmortem immunohistochemistry and flow cytometry confirmed the presence of perfluorocarbon in macrophages, dendritic cells, and granulocytes, but not in lymphocytes. The myocardial volume of elevated (19)F signal (rs=0.96; P<0.001), the (19)F signal-to-noise ratio (rs=0.92; P<0.001), and the (19)F signal integral (rs=0.96; P<0.001) at day 21 correlated with the histological myocarditis severity score. CONCLUSIONS: In vivo (19)F-CMR was successfully used to visualize the inflammation specifically and robustly in experimental autoimmune myocarditis, and thus allowed for an unprecedented insight into the involvement of inflammatory cells in the disease process.

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program.

Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

MGMT methylation status: the advent of stratified therapy in glioblastoma?

Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming available using new tools such as gene arrays, proteomics, and molecular imaging, will take us to an era where more targeted and effective treatments may be implemented. A first step towards the design of such therapies is the identification of relevant molecular mechanisms driving the aggressive biological behavior of glioblastoma. The accumulation of diverse aberrations in regulatory processes enables tumor cells to bypass the effects of most classical therapies available. Molecular alterations underlying such mechanisms comprise aberrations on the genetic level, such as point mutations of distinct genes, or amplifications and deletions, while others result from epigenetic modifications such as aberrant methylation of CpG islands in the regulatory sequence of genes. Epigenetic silencing of the MGMT gene encoding a DNA repair enzyme was recently found to be of predictive value in a randomized clinical trial for newly diagnosed glioblastoma testing the addition of the alkylating agent temozolomide to standard radiotherapy. Determination of the methylation status of the MGMT promoter may become the first molecular diagnostic tool to identify patients most likely to respond that will allow individually tailored therapy in glioblastoma. To date, the test for the MGMT-methylation status is the only tool available that may direct the choice for alkylating agents in glioblastoma patients, but many others may hopefully become part of an arsenal to stratify patients to respective targeted therapies within the next years.

Imagerie et arthrose [Imaging in osteoarthritis].

Plain radiography remains useful for the diagnosis of osteoarthritis, even if it is not always essential. It is moreover poorly correlated with symptoms, as it reflects rather the accumulation of damage then active processes. Similarly, it is a poor indicator of the progression of osteoarthritis. Modem imaging, particularly MRI, has allowed us to understand better the evolving processes, demonstrating a good correlation with symptoms and a better predictive value of clinical course. It has gradually replaced standard radiography in the study because it directly demonstrates sequelae and the active processes in all the structures of the joint. It remains clinically indicated only to exclude an alternative diagnosis or to determine a possible complication of osteoarthritis.

Persistent association of nailfold capillaroscopy changes and skin involvement over thirty-six months with duration of untreated disease in patients with juvenile dermatomyositis.

OBJECTIVE: To determine the association of changes on nailfold capillaroscopy with clinical findings and genotype in children with juvenile dermatomyositis (DM), in order to identify potential differences in disease course over 36 months. METHODS: At diagnosis of juvenile DM in 61 children prior to the initiation of treatment, tumor necrosis factor alpha (TNFalpha) -308 allele and DQA1*0501 status was determined, juvenile DM Disease Activity Scores (DAS) were obtained, and nailfold capillaroscopy was performed. The disease course was monitored for 36 months. Variations within and between patients were assessed by regression analysis. RESULTS: At diagnosis, shorter duration of untreated disease (P = 0.05) and a lower juvenile DM skin DAS (P = 0.035) were associated with a unicyclic disease course. Over 36 months, end-row loop (ERL) regeneration was associated with lower skin DAS (P &lt; 0.001) but not muscle DAS (P = 0.98); ERL regeneration and decreased bushy loops were associated with a shorter duration of untreated disease (P = 0.04 for both). At 36 months, increased ERL regeneration (P = 0.007) and improvement of skin DAS (P &lt; 0.001) and muscle DAS (P = 0.025) were associated with a unicyclic disease course. CONCLUSION: Early treatment of juvenile DM may lead to a unicyclic disease course. The non-unicyclic disease course usually involves continuing skin manifestations with persistent nailfold capillaroscopy changes. The correlation of nailfold capillaroscopy results with cutaneous but not with musculoskeletal signs of juvenile DM over a 36-month period suggests that the cutaneous and muscle vasculopathies have different pathophysiologic mechanisms. These findings indicate that efforts to identify the optimal treatment of cutaneous features in juvenile DM require greater attention.

INTERMED predicts non-return to work in an occupational rehabilitation setting for individuals with orthopaedic trauma-part 2

Introduction.- The model presented in part I (19 predictors) had good predictive values for non-return to work 2 years after vocational rehabilitation for orthopaedic trauma. However, the number of predictors is high for the detection of patients at risk in a clinic. For example, the INTERMED for itself consists of 20 questions and needs 20 minutes to be filled in. For this reason, the aim of this study was to compare the predictive value of different models for the prediction of non-return to work.Patients and methods.- In this longitudinal prospective study, the cohort consisted of 2156 included inpatients with orthopaedic trauma attending a rehabilitation hospital after a work, traffic, sport or leisure related injury. Two years after discharge, 1502 patients returned a questionnaire regarding return to work. We compared the area under the receiver-operator-characteristics curve (ROC) between different models: INTERMED total score, the 4 partial INTERMED scores, the items of the most predictive partial score; with or without confounders.Results.- The ROC for the total score of the INTERMED plus the five confounders of the of the part one (qualified work, speaking French, lesion of upper extremity, education and age) was 0.72. The sole partial INTERMED score to predict return to work was the social sub score. The ROC for the five items of the latter sub score of the INTERMED was 0.69. The ROC for the five items of the social subscale of the INTERMED combined with five predictors was 0.73. This was significantly better than the use of only the five items from INTERMED alone (delta 0.034; 95% CI 0.017 to .050). The model presented in part I (INTERMED total score plus 18 predictors) was not significantly better than the five items INTERMED social score plus five confounders.Discussion.- The use of a model with ten variables (INTERMED social five items plus five confounders) has good predictive value to detect patients not returning to work after vocational rehabilitation after orthopaedic trauma. The parsimony of this model facilitates its use in a clinic for the detection of patients at risk.

Chemoradiotherapy in malignant glioma: standard of care and future directions.

Glioma has been considered resistant to chemotherapy and radiation. Recently, concomitant and adjuvant chemoradiotherapy with temozolomide has become the standard treatment for newly diagnosed glioblastoma. Conversely (neo-)adjuvant PCV (procarbazine, lomustine, vincristine) failed to improve survival in the more chemoresponsive tumor entities of anaplastic oligoastrocytoma and oligodendroglioma. Preclinical investigations suggest synergism or additivity of radiotherapy and temozolomide in glioma cell lines. Although the relative contribution of the concomitant and the adjuvant chemotherapy, respectively, cannot be assessed, the early introduction of chemotherapy and the simultaneous administration with radiotherapy appear to be key for the improvement of outcome. Epigenetic inactivation of the DNA repair enzyme methylguanine methyltransferase (MGMT) seems to be the strongest predictive marker for outcome in patients treated with alkylating agent chemotherapy. Patients whose tumors do not have MGMT promoter methylation are less likely to benefit from the addition of temozolomide chemotherapy and require alternative treatment strategies. The predictive value of MGMT gene promoter methylation is being validated in ongoing trials aiming at overcoming this resistance by a dose-dense continuous temozolomide administration or in combination with MGMT inhibitors. Understanding of molecular mechanisms allows for rational targeting of specific pathways of repair, signaling, and angiogenesis. The addition of tyrosine kinase inhibitors vatalanib (PTK787) and vandetinib (ZD6474), the integrin inhibitor cilengitide, the monoclonal antibodies bevacizumab and cetuximab, the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and the protein kinase C inhibitor enzastaurin, among other agents, are in clinical investigation, building on the established chemoradiotherapy regimen for newly diagnosed glioblastoma.

Hémorragie digestive haute: utilité des scores pronostiques [Upper gastrointestinal bleeding: usefulness of prognostic scores].

Upper gastrointestinal bleeding is a potentially serious event, usually requiring urgent endoscopic treatment. Better stratification of the risk of complication or death could optimize management and improve patient outcomes, while ensuring adequate resource allocation. Several prognostic scores have been developed, in order to identify high risk patients, who require immediate treatment, and patients at low risk for whom endoscopy may be delayed. An ideal prognostic score should be accurate, simple, reproducible, and prospectively validated in different populations. Published scores meet these requirements only partially, and thus can only be used as part of an integrative diagnostic and therapeutic process.

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.

BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (nâeuro0/00=âeuro0/00543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (Pâeuro0/00=âeuro0/00.77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (Pâeuro0/00=âeuro0/00.45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (Pâeuro0/00<âeuro0/00.0001) and OS (Pâeuro0/00=âeuro0/00.001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

Can MRI replace CT in evaluating semicircular canal dehiscence?

BACKGROUND AND PURPOSE: Patients with symptoms of semicircular canal dehiscence often undergo both CT and MR imaging. We assessed whether FIESTA can replace temporal bone CT in evaluating patients for SC dehiscence. MATERIALS AND METHODS: We retrospectively reviewed 112 consecutive patients (224 ears) with vestibulocochlear symptoms who underwent concurrent MR imaging and CT of the temporal bones between 2007 and 2009. MR imaging protocol included a FIESTA sequence covering the temporal bone (axial 0.8-mm section thickness, 0.4-mm spacing, coronal/oblique reformations; 41 patients at 1.5T, 71 patients at 3T). CT was performed on a 64-row multidetector row scanner (0.625-mm axial acquisition, with coronal/oblique reformations). Both ears of each patient were evaluated for dehiscence of the superior and posterior semicircular canals in consensual fashion by 2 neuroradiologists. Analysis of the FIESTA sequence and reformations was performed first for the MR imaging evaluation. CT evaluation was performed at least 2 weeks after the MR imaging review, resulting in a blinded comparison of CT with MR imaging. CT was used as the reference standard to evaluate the MR imaging results. RESULTS: For SSC dehiscence, MR imaging sensitivity was 100%, specificity was 96.5%, positive predictive value was 61.1%, and negative predictive value was 100% in comparison with CT. For PSC dehiscence, MR imaging sensitivity was 100%, specificity was 99.1%, positive predictive value was 33.3%, and negative predictive value was 100% in comparison with CT. CONCLUSIONS: MR imaging, with a sensitivity and negative predictive value of 100%, conclusively excludes SSC or PSC dehiscence. Negative findings on MR imaging preclude the need for CT to detect SC dehiscence. Only patients with positive findings on MR imaging should undergo CT evaluation.

Nontraumatic subarachnoid hemorrhage management: evaluation with reduced iodine volume at CT angiography.

PURPOSE: To evaluate the technical quality and the diagnostic performance of a protocol with use of low volumes of contrast medium (25 mL) at 64-detector spiral computed tomography (CT) in the diagnosis and management of adult, nontraumatic subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: This study was performed outside the United States and was approved by the institutional review board. Intracranial CT angiography was performed in 73 consecutive patients with nontraumatic SAH diagnosed at nonenhanced CT. Image quality was evaluated by two observers using two criteria: degree of arterial enhancement and venous contamination. The two independent readers evaluated diagnostic performance (lesion detection and correct therapeutic decision-making process) by using rotational angiographic findings as the standard of reference. Sensitivity, specificity, and positive and negative predictive values were calculated for patients who underwent CT angiography and three-dimensional rotational angiography. The intraclass correlation coefficient was calculated to assess interobserver concordance concerning aneurysm measurements and therapeutic management. RESULTS: All aneurysms were detected, either ruptured or unruptured. Arterial opacification was excellent in 62 cases (85%), and venous contamination was absent or minor in 61 cases (84%). In 95% of cases, CT angiographic findings allowed optimal therapeutic management. The intraclass correlation coefficient ranged between 0.93 and 0.95, indicating excellent interobserver agreement. CONCLUSION: With only 25 mL of iodinated contrast medium focused on the arterial phase, 64-detector CT angiography allowed satisfactory diagnostic and therapeutic management of nontraumatic SAH.