Evaluation of a Single Dose of Ferric Carboxymaltose in Fatigued, Iron-Deficient Women - PREFER a Randomized, Placebo-Controlled Study

BACKGROUND: Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue. METHODS: Fatigued women (Piper Fatigue Scale [PFS] score ≥5) with iron deficiency (ferritin <50 µg/L and transferrin saturation <20%, or ferritin <15 µg/L) and normal or borderline hemoglobin (≥115 g/L) were enrolled in 21 sites in Austria, Germany, Sweden and Switzerland, blinded to the study drug and randomized (computer-generated randomization sequence) to a single FCM (1000 mg iron) or saline (placebo) infusion. Primary endpoint was the proportion of patients with reduced fatigue (≥1 point decrease in PFS score from baseline to Day 56). RESULTS: The full analysis included 290 women (FCM 144, placebo 146). Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68, 95%CI 1.05-2.70; p = 0.03). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients (p<0.001). At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM. 'Power of attention' improved better in FCM-treated patients with ferritin <15 µg/L. Treatment-emergent adverse events (placebo 114, FCM 209; most frequently headache, nasopharyngitis, pyrexia and nausea) were mainly mild or moderate. CONCLUSION: A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women's health, and a normal iron status should be maintained independent of hemoglobin levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT01110356.

Effectiveness of olive oil for the prevention of pressure ulcers caused in immobilized patients within the scope of primary health care: study protocol for a randomized controlled trial.

BACKGROUND Pressure ulcers are considered an important issue, mainly affecting immobilized older patients. These pressure ulcers increase the care burden for the professional health service staff as well as pharmaceutical expenditure. There are a number of studies on the effectiveness of different products used for the prevention of pressure ulcers; however, most of these studies were carried out at a hospital level, basically using hyperoxygenated fatty acids (HOFA). There are no studies focused specifically on the use of olive-oil-based products and therefore this research is intended to find the most cost-effective treatment and achieve an alternative treatment. METHODS/DESIGN The main objective is to assess the effectiveness of olive oil, comparing it with HOFA, to treat immobilized patients at home who are at risk of pressure ulcers. As a secondary objective, the cost-effectiveness balance of this new application with regard to the HOFA will be assessed. The study is designed as a noninferiority, triple-blinded, parallel, multi-center, randomized clinical trial. The scope of the study is the population attending primary health centers in Andalucía (Spain) in the regional areas of Malaga, Granada, Seville, and Cadiz. Immobilized patients at risk of pressure ulcers will be targeted. The target group will be treated by application of an olive-oil-based formula whereas the control group will be treated by application of HOFA to the control group. The follow-up period will be 16 weeks. The main variable will be the presence of pressure ulcers in the patient. Secondary variables include sociodemographic and clinical information, caregiver information, and whether technical support exists. Statistical analysis will include the Kolmogorov-Smirnov test, symmetry and kurtosis analysis, bivariate analysis using the Student's t and chi-squared tests as well as the Wilcoxon and the Man-Whitney U tests, ANOVA and multivariate logistic regression analysis. DISCUSSION The regular use of olive-oil-based formulas should be effective in preventing pressure ulcers in immobilized patients, thus leading to a more cost-effective product and an alternative treatment. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01595347.

Polymorphism at a sex-linked transcription cofactor in European tree frogs (Hyla arborea): Sex-antagonistic selection or neutral processes?

Nascent sex chromosomes offer a unique opportunity to investigate the evolutionary fate of genesrecently trapped in non-recombining segments. A housekeeping gene (MED15) was recently shown to lie on the nascent sex-chromosomes of the European tree frog (Hyla arborea), with different alleles fixed on the X and the Y chromosomes. Here we document a polymorphism (glutamine deletion) in the X copy of the gene, and use population surveys and experimental crosses to test whether this polymorphism is neutral or maintained by sex-antagonistic selection. Tadpoles from parents of known genotypes revealed significant discrepancies from Mendelian inheritance, suggesting possible sex-antagonistic effects under laboratory conditions. Quantitatively, however, these effects did not meet the conditions for polymorphism maintenance. Furthermore, field estimates of female genotypic frequencies did not differ from Hardy-Weinberg equilibrium and allelic frequencies on the X chromosome did not differ between sexes. In conclusion, although sex antagonistic effects cannot be excluded given the laboratory conditions, the X-linked polymorphism under study appears neutral in the wild. Alternatively, sex-antagonistic selection might still account for the fixation of a male specific allele on the Y chromosome.

Deficits in executive and memory processes in delusional disorder: a case-control study

OBJECTIVE Delusional disorder has been traditionally considered a psychotic syndrome that does not evolve to cognitive deterioration. However, to date, very little empirical research has been done to explore cognitive executive components and memory processes in Delusional Disorder patients. This study will investigate whether patients with delusional disorder are intact in both executive function components (such as flexibility, impulsivity and updating components) and memory processes (such as immediate, short term and long term recall, learning and recognition). METHODS A large sample of patients with delusional disorder (n = 86) and a group of healthy controls (n = 343) were compared with regard to their performance in a broad battery of neuropsychological tests including Trail Making Test, Wisconsin Card Sorting Test, Colour-Word Stroop Test, and Complutense Verbal Learning Test (TAVEC). RESULTS When compared to controls, cases of delusional disorder showed a significantly poorer performance in most cognitive tests. Thus, we demonstrate deficits in flexibility, impulsivity and updating components of executive functions as well as in memory processes. These findings held significant after taking into account sex, age, educational level and premorbid IQ. CONCLUSIONS Our results do not support the traditional notion of patients with delusional disorder being cognitively intact.

Telehealth system (e-CUIDATE) to improve quality of life in breast cancer survivors: rationale and study protocol for a randomized clinical trial.

BACKGROUND Breast cancer survivors suffer physical impairment after oncology treatment. This impairment reduces quality of life (QoL) and increase the prevalence of handicaps associated to unhealthy lifestyle (for example, decreased aerobic capacity and strength, weight gain, and fatigue). Recent work has shown that exercise adapted to individual characteristics of patients is related to improved overall and disease-free survival. Nowadays, technological support using telerehabilitation systems is a promising strategy with great advantage of a quick and efficient contact with the health professional. It is not known the role of telerehabilitation through therapeutic exercise as a support tool to implement an active lifestyle which has been shown as an effective resource to improve fitness and reduce musculoskeletal disorders of these women. METHODS / DESIGN This study will use a two-arm, assessor blinded, parallel randomized controlled trial design. People will be eligible if: their diagnosis is of stages I, II, or IIIA breast cancer; they are without chronic disease or orthopedic issues that would interfere with ability to participate in a physical activity program; they had access to the Internet and basic knowledge of computer use or living with a relative who has this knowledge; they had completed adjuvant therapy except for hormone therapy and not have a history of cancer recurrence; and they have an interest in improving lifestyle. Participants will be randomized into e-CUIDATE or usual care groups. E-CUIDATE give participants access to a range of contents: planning exercise arranged in series with breathing exercises, mobility, strength, and stretching. All of these exercises will be assigned to women in the telerehabilitation group according to perceived needs. The control group will be asked to maintain their usual routine. Study endpoints will be assessed after 8 weeks (immediate effects) and after 6 months. The primary outcome will be QoL measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version 3.0 and breast module called The European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality of Life questionnaire. The secondary outcomes: pain (algometry, Visual Analogue Scale, Brief Pain Inventory short form); body composition; physical measurement (abdominal test, handgrip strength, back muscle strength, and multiple sit-to-stand test); cardiorespiratory fitness (International Fitness Scale, 6-minute walk test, International Physical Activity Questionnaire-Short Form); fatigue (Piper Fatigue Scale and Borg Fatigue Scale); anxiety and depression (Hospital Anxiety and Depression Scale); cognitive function (Trail Making Test and Auditory Consonant Trigram); accelerometry; lymphedema; and anthropometric perimeters. DISCUSSION This study investigates the feasibility and effectiveness of a telerehabilitation system during adjuvant treatment of patients with breast cancer. If this treatment option is effective, telehealth systems could offer a choice of supportive care to cancer patients during the survivorship phase. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01801527.

Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

A temporal hierarchy for conspecific vocalization discrimination in humans.

Introduction: Discrimination of species-specific vocalizations is fundamental for survival and social interactions. Its unique behavioral relevance has encouraged the identification of circumscribed brain regions exhibiting selective responses (Belin et al., 2004), while the role of network dynamics has received less attention. Those studies that have examined the brain dynamics of vocalization discrimination leave unresolved the timing and the inter-relationship between general categorization, attention, and speech-related processes (Levy et al., 2001, 2003; Charest et al., 2009). Given these discrepancies and the presence of several confounding factors, electrical neuroimaging analyses were applied to auditory evoked-potential (AEPs) to acoustically and psychophysically controlled non-verbal human and animal vocalizations. This revealed which region(s) exhibit voice-sensitive responses and in which sequence. Methods: Subjects (N=10) performed a living vs. man-made 'oddball' auditory discrimination task, such that on a given block of trials 'target' stimuli occurred 10% of the time. Stimuli were complex, meaningful sounds of 500ms duration. There were 120 different sound files in total, 60 of which represented sounds of living objects and 60 man-made objects. The stimuli that were the focus of the present investigation were restricted to those of living objects within blocks where no response was required. These stimuli were further sorted between human non-verbal vocalizations and animal vocalizations. They were also controlled in terms of their spectrograms and formant distributions. Continuous 64-channel EEG was acquired through Neuroscan Synamps referenced to the nose, band-pass filtered 0.05-200Hz, and digitized at 1000Hz. Peri-stimulus epochs of continuous EEG (-100ms to 900ms) were visually inspected for artifacts, 40Hz low-passed filtered and baseline corrected using the pre-stimulus period . Averages were computed from each subject separately. AEPs in response to animal and human vocalizations were analyzed with respect to differences of Global Field Power (GFP) and with respect to changes of the voltage configurations at the scalp (reviewed in Murray et al., 2008). The former provides a measure of the strength of the electric field irrespective of topographic differences; the latter identifies changes in spatial configurations of the underlying sources independently of the response strength. In addition, we utilized the local auto-regressive average distributed linear inverse solution (LAURA; Grave de Peralta Menendez et al., 2001) to visualize and statistically contrast the likely underlying sources of effects identified in the preceding analysis steps. Results: We found differential activity in response to human vocalizations over three periods in the post-stimulus interval, and this response was always stronger than that to animal vocalizations. The first differential response (169-219ms) was a consequence of a modulation in strength of a common brain network localized into the right superior temporal sulcus (STS; Brodmann's Area (BA) 22) and extending into the superior temporal gyrus (STG; BA 41). A second difference (291-357ms) also followed from strength modulations of a common network with statistical differences localized to the left inferior precentral and prefrontal gyrus (BA 6/45). These two first strength modulations correlated (Spearman's rho(8)=0.770; p=0.009) indicative of functional coupling between temporally segregated stages of vocalization discrimination. A third difference (389-667ms) followed from strength and topographic modulations and was localized to the left superior frontal gyrus (BA10) although this third difference did not reach our spatial criterion of 12 continuous voxels. Conclusions: We show that voice discrimination unfolds over multiple temporal stages, involving a wide network of brain regions. The initial stages of vocalization discrimination are based on modulations in response strength within a common brain network with no evidence for a voice-selective module. The latency of this effect parallels that of face discrimination (Bentin et al., 2007), supporting the possibility that voice and face processes can mutually inform one another. Putative underlying sources (localized in the right STS; BA 22) are consistent with prior hemodynamic imaging evidence in humans (Belin et al., 2004). Our effect over the 291-357ms post-stimulus period overlaps the 'voice-specific-response' reported by Levy et al. (Levy et al., 2001) and the estimated underlying sources (left BA6/45) were in agreement with previous findings in humans (Fecteau et al., 2005). These results challenge the idea that circumscribed and selective areas subserve con-specific vocalization processing.

Hidratos de carbono: actualización de su papel en la diabetes mellitus y la enfermedad metabólica.

BACKGROUND: There is a prevalence of diabetes mellitus (DM), unknown DM and stress hyperglycemia among hospital patients, and the nutritional treatment is a key part of care, where carbohydrates (CH) intake is a controversial issue. There is also a discussion on the increase of prevalence for DM, obesity and metabolic disease with refined CH or sugar. OBJECTIVES: This review examines the recommendations from different scientific societies about the percentage of CH in the total calorie intake of the diabetic patient, the CH value in the glycemic index and glycemic load, the new CH included in enteral formulae and the association of refined CH with the high prevalence of DM and metabolic disease. METHODS: Systematic review of literature using the electronic scientific databases Pubmed, Science Direct, Scielo, Scopus and Medline. CONCLUSIONS: Scientific societies are flexible about the CH intake in the diet of diabetic patients, suggesting to customize it according to each metabolic profile. Using the glycemic index and glycemic load can provide an extra benefit in the postprandial glycemic control. The new diabetes-specific enteral formulae, with fructooligosaccharides, resistant maltodextrins and fructose-free show efficacy in improving the glycemic control, although more controlled and long-term studies are needed. There is still some controversy about the links between sugar intake and DM, obesity and metabolic disease, although this relationship would be more linked to an increase of the total calorie intake than to a specific nutrient. .

High levels of Bifidobacteria are associated with increased levels of anthocyanin microbial metabolites: a randomized clinical trial.

The health benefits associated with the consumption of polyphenol-rich foods have been studied in depth, however, the full mechanism of action remains unknown. One of the proposed mechanisms is through microbiota interaction. In the present study, we aimed to explore the relationship between changes in fecal microbiota and changes in urinary phenolic metabolites after wine interventions. Nine participants followed a randomized, crossover, controlled interventional trial. After the washout period, they received red wine, dealcoholized red wine or gin for 20 days each. Polyphenol metabolites (n > 60) in urine were identified and quantified by UPLC-MS/MS and the microbial content of fecal samples was quantified by real-time quantitative PCR. Interventions with both red wine and dealcoholized red wine increased the fecal concentration of Bifidobacterium, Enterococcus and Eggerthella lenta, compared to gin intervention and baseline. When participants were categorized in tertiles of changes in fecal bacteria, those in the highest tertile of Bifidobacteria had higher urinary concentration changes in syringic acid, p-coumaric acid, 4-hydroxybenzoic acid and homovanillic acid (all anthocyanin metabolites) than those in tertile 1 (P < 0.05, all). In addition, changes of Bifidobacteria correlated positively with changes of these metabolites (r = 0.5-0.7, P < 0.05, all). Finally, the 68.5% changes in Bifidobacteria can be predicted by syringic acid and 4-hydroxybenzoic acid changes. This study confirms the important role of polyphenols as bacterial substrates and their modulatory capacity as an important field in the research of new products with prebiotic and probiotic characteristics for the food industry.

Comparative review of vertebroplasty and kyphoplasty.

The aim of this review is to compare the effectiveness of percutaneous vertebroplasty and kyphoplasty to treat pain and improve functional outcome from vertebral fractures secondary to osteoporosis and tumor conditions. In 2009, two open randomized controlled trials published in the New England Journal of Medicine questioned the value of vertebroplasty in treating vertebral compression fractures. Nevertheless, the practice of physicians treating these conditions has barely changed. The objective of this review is to try to clarify the most important issues, based on our own experience and the reported evidence about both techniques, and to guide towards the most appropriate choice of treatment of vertebral fractures, although many questions still remain unanswered.

Prevention of major depression in complex medically ill patients: preliminary results from a randomized, controlled trial.

BACKGROUND: Depression is highly prevalent in patients with physical illness and is associated with a diminished quality of life and poorer medical outcomes. OBJECTIVE: The authors evaluated whether a multifaceted intervention conducted by a psychiatric consultation-liaison nurse could reduce the incidence of major depression in rheumatology inpatients and diabetes outpatients with a high level of case complexity. METHOD: Of 247 randomized patients, the authors identified 100 patients with a high level of case complexity at baseline and without major depression (65 rheumatology and 35 diabetes patients). Patients were randomized to usual care (N=53) or to a nurse-led intervention (N=47). Main outcomes were the incidence of major depression and severity of depressive symptoms during a 1-year follow-up, based on quarterly assessments with standardized psychiatric interviews. RESULTS: The incidence of major depression was 63% in usual-care patients and 36% in the intervention group. Effects of intervention on depressive symptoms were observed in outpatients with diabetes but not in rheumatology inpatients. CONCLUSION: These preliminary results based on subgroup analysis suggest that a multifaceted nurse-led intervention may prevent the occurrence of major depression in complex medically ill patients and reduce depressive symptoms in diabetes outpatients.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

CAC controlled services sharing a link with connectionless data services in an ATM network: a performance evaluation study

In the B-ISDN there is a provision for four classes of services, all of them supported by a single transport network (the ATM network). Three of these services, the connected oriented (CO) ones, permit connection access control (CAC) but the fourth, the connectionless oriented (CLO) one, does not. Therefore, when CLO service and CO services have to share the same ATM link, a conflict may arise. This is because a bandwidth allocation to obtain maximum statistical gain can damage the contracted ATM quality of service (QOS); and vice versa, in order to guarantee the contracted QOS, the statistical gain have to be sacrificed. The paper presents a performance evaluation study of the influence of the CLO service on a CO service (a circuit emulation service or a variable bit-rate service) when sharing the same link