Longitudinal analysis of patterns and predictors of changes in self-reported adherence to antiretroviral therapy: Swiss HIV Cohort Study.

BACKGROUND: Adherence to combination antiretroviral therapy (cART) is a dynamic process, however, changes in adherence behavior over time are insufficiently understood. METHODS: Data on self-reported missed doses of cART was collected every 6 months in Swiss HIV Cohort Study participants. We identified behavioral groups associated with specific cART adherence patterns using trajectory analyses. Repeated measures logistic regression identified predictors of changes in adherence between consecutive visits. RESULTS: Six thousand seven hundred nine individuals completed 49,071 adherence questionnaires [median 8 (interquartile range: 5-10)] during a median follow-up time of 4.5 years (interquartile range: 2.4-5.1). Individuals were clustered into 4 adherence groups: good (51.8%), worsening (17.4%), improving (17.6%), and poor adherence (13.2%). Independent predictors of worsening adherence were younger age, basic education, loss of a roommate, starting intravenous drug use, increasing alcohol intake, depression, longer time with HIV, onset of lipodystrophy, and changing care provider. Independent predictors of improvements in adherence were regimen simplification, changing class of cART, less time on cART, and starting comedications. CONCLUSIONS: Treatment, behavioral changes, and life events influence patterns of drug intake in HIV patients. Clinical care providers should routinely monitor factors related to worsening adherence and intervene early to reduce the risk of treatment failure and drug resistance.

Self-reported alcohol consumption and its association with adherence and outcome of antiretroviral therapy in the Swiss HIV Cohort Study.

BACKGROUND: Alcohol consumption leading to morbidity and mortality affects HIV-infected individuals. Here, we aimed to study self-reported alcohol consumption and to determine its association with adherence to antiretroviral therapy (ART) and HIV surrogate markers. METHODS: Cross-sectional data on daily alcohol consumption from August 2005 to August 2007 were analysed and categorized according to the World Health Organization definition (light, moderate or severe health risk). Multivariate logistic regression models and Pearson's chi(2) statistics were used to test the influence of alcohol use on endpoints. RESULTS: Of 6,323 individuals, 52.3% consumed alcohol less than once a week in the past 6 months. Alcohol intake was deemed light in 39.9%, moderate in 5.0% and severe in 2.8%. Higher alcohol consumption was significantly associated with older age, less education, injection drug use, being in a drug maintenance programme, psychiatric treatment, hepatitis C virus coinfection and with a longer time since diagnosis of HIV. Lower alcohol consumption was found in males, non-Caucasians, individuals currently on ART and those with more ART experience. In patients on ART (n=4,519), missed doses and alcohol consumption were positively correlated (P<0.001). Severe alcohol consumers, who were pretreated with ART, were more often off treatment despite having CD4+ T-cell count <200 cells/microl; however, severe alcohol consumption per se did not delay starting ART. In treated individuals, alcohol consumption was not associated with worse HIV surrogate markers. CONCLUSIONS: Higher alcohol consumption in HIV-infected individuals was associated with several psychosocial and demographic factors, non-adherence to ART and, in pretreated individuals, being off treatment despite low CD4+ T-cell counts.

OnabotulinumtoxinA and multiple sclerosis.

Lower urinary tract dysfunction is present in two of three patients with multiple sclerosis five years after the diagnosis. Most frequent symptoms are related to neurogenic detrusor overactivity, often associated with detrusor-sphincter dyssynergia. From the end of the 1990s, there is growing evidence that neurogenic detrusor overactivity can be effectively managed by intradetrusorial injections of botulinum toxin type A. This treatment has shown, in different randomised placebo-controlled trials, to be safe and effective on clinical and urodynamic parameters with significant improvement in quality of life. The median duration of effect is in mean nine months. The vast majority of studies have been conducted with onabotulinumtoxinA. The dose of onabotulinumtoxinA commonly used to treat neurogenic detrusor overactivity in patients with multiple sclerosis is 200 UI, even if in selected patients lower doses can be preferred. To be considered eligible for treatment, all patients should accept and be instructed to perform clean intermittent self-catheterisation, since the risk of increased post-void residual volume and/or urinary retention after injection is high, especially with 200 UI of onabotulinumtoxinA. However, quality of life and patient satisfaction seem not to be affected by the need of intermittent catheterisation. The risk of urinary infection after the procedure is to be kept in mind, mainly in patients with multiple sclerosis, so that adequate antibiotic prophylaxis is highly recommended.

Real-Time implementation of a blind authentication method using self-synchronous speech watermarking

A blind speech watermarking scheme that meets hard real-time deadlines is presented and implemented. In addition, one of the key issues in these block-oriented watermarking techniques is to preserve the synchronization. Namely, to recover the exact position of each block in the mark extract process. In fact, the presented scheme can be split up into two distinguished parts, the synchronization and the information mark methods. The former is embedded into the time domain and it is fast enough to be run meeting real-time requirements. The latter contains the authentication information and it is embedded into the wavelet domain. The synchronization and information mark techniques are both tunable in order to allow a con gurable method. Thus, capacity, transparency and robustness can be con gured depending on the needs. It makes the scheme useful for professional applications, such telephony authentication or even sending information throw radio applications.

Bioconjugated lanthanide luminescent helicates as multilabels for lab-on-a-chip detection of cancer biomarkers.

The lanthanide binuclear helicate [Eu(2)(L(C2(CO(2)H)))(3)] is coupled to avidin to yield a luminescent bioconjugate EuB1 (Q = 9.3%, tau((5)D(0)) = 2.17 ms). MALDI/TOF mass spectrometry confirms the covalent binding of the Eu chelate and UV-visible spectroscopy allows one to determine a luminophore/protein ratio equal to 3.2. Bio-affinity assays involving the recognition of a mucin-like protein expressed on human breast cancer MCF-7 cells by a biotinylated monoclonal antibody 5D10 to which EuB1 is attached via avidin-biotin coupling demonstrate that (i) avidin activity is little affected by the coupling reaction and (ii) detection limits obtained by time-resolved (TR) luminescence with EuB1 and a commercial Eu-avidin conjugate are one order of magnitude lower than those of an organic conjugate (FITC-streptavidin). In the second part of the paper, conditions for growing MCF-7 cells in 100-200 microm wide microchannels engraved in PDMS are established; we demonstrate that EuB1 can be applied as effectively on this lab-on-a-chip device for the detection of tumour-associated antigens as on MCF-7 cells grown in normal culture vials. In order to exploit the versatility of the ligand used for self-assembling [Ln(2)(L(C2(CO(2)H)))(3)] helicates, which sensitizes the luminescence of both Eu(III) and Tb(III) ions, a dual on-chip assay is proposed in which estrogen receptors (ERs) and human epidermal growth factor receptors (Her2/neu) can be simultaneously detected on human breast cancer tissue sections. The Ln helicates are coupled to two secondary antibodies: ERs are visualized by red-emitting EuB4 using goat anti-mouse IgG and Her2/neu receptors by green-emitting TbB5 using goat anti-rabbit IgG. The fact that the assay is more than 6 times faster and requires 5 times less reactants than conventional immunohistochemical assays provides essential advantages over conventional immunohistochemistry for future clinical biomarker detection.

Low intensity vs. self-guided internet-delivered psychotherapy for major depression: a multicenter, controlled, randomized study.

BACKGROUND Major depression will become the second most important cause of disability in 2020. Computerized cognitive-behaviour therapy could be an efficacious and cost-effective option for its treatment. No studies on cost-effectiveness of low intensity vs self-guided psychotherapy has been carried out. The aim of this study is to assess the efficacy of low intensity vs self-guided psychotherapy for major depression in the Spanish health system. METHODS The study is made up of 3 phases: 1.- Development of a computerized cognitive-behaviour therapy for depression tailored to Spanish health system. 2.- Multicenter controlled, randomized study: A sample (N=450 patients) with mild/moderate depression recruited in primary care. They should have internet availability at home, not receive any previous psychological treatment, and not suffer from any other severe somatic or psychological disorder. They will be allocated to one of 3 treatments: a) Low intensity Internet-delivered psychotherapy + improved treatment as usual (ITAU) by GP, b) Self-guided Internet-delivered psychotherapy + ITAU or c) ITAU. Patients will be diagnosed with MINI psychiatric interview. Main outcome variable will be Beck Depression Inventory. It will be also administered EuroQol 5D (quality of life) and Client Service Receipt Inventory (consume of health and social services). Patients will be assessed at baseline, 3 and 12 months. An intention to treat and a per protocol analysis will be performed. DISCUSSION The comparisons between low intensity and self-guided are infrequent, and also a comparative economic evaluation between them and compared with usual treatment in primary. The strength of the study is that it is a multicenter, randomized, controlled trial of low intensity and self-guided Internet-delivered psychotherapy for depression in primary care, being the treatment completely integrated in primary care setting. TRIAL REGISTRATION Clinical Trials NCT01611818.

Positional scanning-synthetic peptide library-based analysis of self- and pathogen-derived peptide cross-reactivity with tumor-reactive Melan-A-specific CTL.

Synthetic combinatorial peptide libraries in positional scanning format (PS-SCL) have recently emerged as a useful tool for the analysis of T cell recognition. This includes identification of potentially cross-reactive sequences of self or pathogen origin that could be relevant for the understanding of TCR repertoire selection and maintenance, as well as of the cross-reactive potential of Ag-specific immune responses. In this study, we have analyzed the recognition of sequences retrieved by using a biometric analysis of the data generated by screening a PS-SCL with a tumor-reactive CTL clone specific for an immunodominant peptide from the melanocyte differentiation and tumor-associated Ag Melan-A. We found that 39% of the retrieved peptides were recognized by the CTL clone used for PS-SCL screening. The proportion of peptides recognized was higher among those with both high predicted affinity for the HLA-A2 molecule and high predicted stimulatory score. Interestingly, up to 94% of the retrieved peptides were cross-recognized by other Melan-A-specific CTL. Cross-recognition was at least partially focused, as some peptides were cross-recognized by the majority of CTL. Importantly, stimulation of PBMC from melanoma patients with the most frequently recognized peptides elicited the expansion of heterogeneous CD8(+) T cell populations, one fraction of which cross-recognized Melan-A. Together, these results underline the high predictive value of PS-SCL for the identification of sequences cross-recognized by Ag-specific T cells.

Effectiveness of two interventions based on improving patient-practitioner communication on diabetes self-management in patients with low educational level: study protocol of a clustered randomized trial in primary care.

BACKGROUND In the last decades the presence of social inequalities in diabetes care has been observed in multiple countries, including Spain. These inequalities have been at least partially attributed to differences in diabetes self-management behaviours. Communication problems during medical consultations occur more frequently to patients with a lower educational level. The purpose of this cluster randomized trial is to determine whether an intervention implemented in a General Surgery, based in improving patient-provider communication, results in a better diabetes self-management in patients with lower educational level. A secondary objective is to assess whether telephone reinforcement enhances the effect of such intervention. We report the design and implementation of this on-going study. METHODS/DESIGN The study is being conducted in a General Practice located in a deprived neighbourhood of Granada, Spain. Diabetic patients 18 years old or older with a low educational level and inadequate glycaemic control (HbA1c > 7%) were recruited. General Practitioners (GPs) were randomised to three groups: intervention A, intervention B and control group. GPs allocated to intervention groups A and B received training in communication skills and are providing graphic feedback about glycosylated haemoglobin levels. Patients whose GPs were allocated to group B are additionally receiving telephone reinforcement whereas patients from the control group are receiving usual care. The described interventions are being conducted during 7 consecutive medical visits which are scheduled every three months. The main outcome measure will be HbA1c; blood pressure, lipidemia, body mass index and waist circumference will be considered as secondary outcome measures. Statistical analysis to evaluate the effectiveness of the interventions will include multilevel regression analysis with three hierarchical levels: medical visit level, patient level and GP level. DISCUSSION The results of this study will provide new knowledge about possible strategies to promote a better diabetes self-management in a particularly vulnerable group. If effective, this low cost intervention will have the potential to be easily incorporated into routine clinical practice, contributing to decrease health inequalities in diabetic patients. TRIAL REGISTRATION Clinical Trials U.S. National Institutes of Health, NCT01849731.

Quantization of energy and writhe in self-repelling knots

Probably the most natural energy functional to be considered for knotted strings is that given by electrostatic repulsion. In the absence of counter-charges, a charged, knotted string evolving along the energy gradient of electrostatic repulsion would progressively tighten its knotted domain into a point on a perfectly circular string. However, in the presence of charge screening self-repelling knotted strings can be stabilized. It is known that energy functionals in which repulsive forces between repelling charges grow inversely proportionally to the third or higher power of their relative distance stabilize self-repelling knots. Especially interesting is the case of the third power since the repulsive energy becomes scale invariant and does not change upon Mobius transformations (reflections in spheres) of knotted trajectories. We observe here that knots minimizing their repulsive Mobius energy show quantization of the energy and writhe (measure of chirality) within several tested families of knots.

CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma.

Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.