Using the costs of drug therapy to screen patients for a community pharmacy-based medication review program

Objectives: To measure the positive predictive value (PPV) of the cost of drug therapy (threshold = 2000 Swiss francs [CHF], US$1440, <euro>1360) as a screening criterion for identifying patients who may benefit from medication review (MR). To describe identified drug-related problems (DRPs) and expense problems (EPs), and to estimate potential savings if all recommendations were accepted. Setting Five voluntary Swiss community pharmacies. Methods: Of 12,680 patients, 592 (4.7%) had drug therapy costs exceeding 2000 CHF over a six-month period from July 1 to December 31, 2002. This threshold limit was set to identify high-risk patients for DRPs and EPs. Three pharmacists consecutively conducted a medication review based on the pharmaceutical charts of 125 sampled patients who met the inclusion criterion. Main outcome measure: The PPV of a threshold of 2000 CHF for identifying patients who might benefit from a MR: true positives were patients with at least one DRP, while false positives were patients with no DRP. Results: The selection based on this criterion had a PPV of 86% for detecting patients with at least one DRP and 95% if EPs were also considered. There was a mean of 2.64 (SD = 2.20) DRPs per patient and a mean of 2.14 (SD = 1.39) EPs per patient. Of these patients, 90% were over 65 years old or were treated with at least five chronic medications, two common criteria for identifying patients at risk of DRPs. The main types of DRPs were drug-drug interactions, compliance problems and duplicate drugs. Mean daily drug cost per patient was CHF 14.87 (US$10.70, <euro>10.10). A potential savings of CHF 1.67 (US$1.20, <euro>1.14) per day (11%) was estimated if all recommendations to solve DRPs and EPs suggested herein were implemented. Conclusion: Further studies should investigate whether the potential benefit of medication reviews in preventing DRPs and containing costs in this patient group can be confirmed in a real practice environment. [Authors]

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.

The neurobiological basis of prefrontal cortex impairment in the phencyclidine model of schizophrenia : convergent reduction of synaptic glutamate release, energy metabolism and cognitive performance

RÉSUMÉ : Le traitement répété à la phencyclidine (PCP), un bloqueur du récepteur NMDA (NMDAR), reproduit chez les rongeurs une partie de la symptomatologie typique de la schizophrénie. Le blocage prolongé du NMDAR par la PCP mime une hypofunction du NMDAR, une des principales altérations supposées exister dans les cerveaux des patients schizophréniques. Le but de notre étude était d'examiner les conséquences neurochimiques, métaboliques et fonctionnelles du traitement répété à la phencyclidine in vivo, au niveau du cortex préfrontal (cpf), une région cérébrale qui joue un rôle dans les déficits cognitifs observés chez les patients schizophréniques. Pour répondre à cette question, les rats ou les souris ont reçu chaque jour une injection soit de PCP (5 mg/kg), soit de solution saline, pendant 7 ou 14 jours. Les animaux ont ensuite été sacrifiés au moins 24 heures après le dernier traitement. Des tranches aiguës du cpf ont été préparées rapidement, puis stimulées avec une concentration élevée de KCI, de manière à induire une libération de glutamate à partir des terminaisons synaptiques excitatrices. Les résultats montrent que les tranches du cpf des animaux traités à la PCP ont libéré une quantité de glutamate significativement inférieure par rapport à celles des animaux contrôle. Ce déficit de libération a persisté 72 heures après la fin du traitement, tandis qu'il n'était pas observé dans le cortex visuel primaire, une autre région corticale. En outre, le traitement avec des antipsychotiques, l'halopéridol ou l'olanzapine, a supprimé le déficit induit par la PCP. Le même déficit de libération a été remarqué sur des synaptosomes obtenus à partir du cpf des animaux traités à la phenryclidine. Cette observation indique que la PCP induit une modification plastique adaptative du mécanisme qui contrôle la libération du glutamate dans les terminaisons synaptiques. Nous avons découvert que cette modification implique la sous-régulation d'un NMDAR présynaptique, qui serait doué d'un rôle d'autorécepteur stimulateur de la libération du glutamate. Grâce à des tests comportementaux conduits en parallèle et réalisés pour évaluer la fonctionnalité du cpf, nous avons observé chez les souris traitées à la PCP une flexibilité comportementale réduite lors d'un test de discrimination de stimuli visuels/tactiles. Le déficit cognitif était encore présent 4 jours après la dernière administration de PCP. La technique de l'autoradiographie quantitative du [14C]2-deoxyglucose a permis d'associer ce déficit à une réduction de l'activité métabolique cérébrale pendant le déroulement du test, particulièrement au niveau du cpf. Dans l'ensemble, nos résultats suggèrent que le blocage prolongé du NMDAR lors de l'administration répétée de PCP produit un déficit de libération du glutamate au niveau des terminaisons synaptiques excitatrices du cpf. Un tel déficit pourrait être provoqué par la sousrégulation d'un NMDAR présynaptique, qui aurait une fonction de stimulateur de libération; la transmission excitatrice du cpf s'en trouverait dans ce cas réduite. Ce résultat est en ligne avec l'activité métabolique et fonctionnelle réduite du cpf et l'observation de déficits cognitifs induits lors de l'administration de la PCP. ABSTRACT : Sub-chronic treatment with phencyclidine (PCP), an NMDA receptor (NMDAR) channel blocker, reproduces in rodents part of the symptomatology associated to schizophrenia in humans. Prolonged pharmacological blockade of NMDAR with PCP mimics NMDAR hypofunction, one of the main alterations thought to take place in the brains of schizophrenics. Our study was aimed at investigating the neurochemical, metabolic and behavioral consequences of repeated PCP administration in vivo, focusing on the functioning of the prefrontal cortex (pfc), a brain region highly relevant for the cognitive deficits observed in schizophrenic patients. Rats or mice received a daily administration of either PCP (5 mg/kg) or saline for 7 or 14 days. At least 24 hours after the last treatment the animals were sacrificed. Acute slices of the pfc were quickly prepared and challenged with high KCl to induce synaptic glutamate release. Pfc slices from PCP-treated animals released significantly less glutamate than slices from salinetreated animals. The deficit persisted 72 hours after the end of the treatment, while it was not observed in another cortical region: the primary visual cortex. Interestingly, treatment with antipsychotic drugs, either haloperidol or olanzapine, reverted the glutamate release defect induced by PCP treatment. The same release defect was observed in synaptosomes prepared from the pfc of PCP-treated animals, indicating that PCP induces a plastic adaptive change in the mechanism controlling glutamate release in the glutamatergic terminals. We discovered that such change most likely involves the down-regulation of a newly identified, pre-synaptic NMDAR with stimulatory auto-receptor function on glutamate release. In parallel sets of behavioral experiments challenging pfc function, mice sub-chronically treated with PCP displayed reduced behavioral flexibility (reversal learning) in a visual/tactile-cued discrimination task. The cognitive deficit was still evident 4 days after the last PCP administration and was associated to reduced brain metabolic activity during the performance of the behavioral task, notably in the pfc, as determined by [14C]2-deoxyglucose quantitative autoradiography. Clverall, our findings suggest that prolonged NMDAR blockade by repeated PCP administration results in a defect of glutamate release from excitatory afferents in the pfc, possibly ascribed to down-regulation of apre-synaptic stimulatory NMDAR. Deficient excitatory neurotransmission in the pfc is consistent with the reduced metabolic and functional activation of this area and the observed PCP-induced cognitive deficits.

CNS safety at 48-week of switching to ATV/r plus 3TC or two nucleos(t)ides in HIV-suppressed patients on stable ART: the SALT neurocognitive sub-study.

INTRODUCTION Due to their low CNS penetrance, there are concerns about the capacity of non-conventional PI-based ART (monotherapy and dual therapies) to preserve neurocognitive performance (NP). METHODS We evaluated the NP change of aviremic participants of the SALT clinical trial (1) switching therapy to dual therapy (DT: ATV/r+3TC) or triple therapy (TT: ATV/r+2NRTI) who agreed to perform an NP assessment (NPZ-5) at baseline and W48. Neurocognitive impairment and NP were assessed using AAN-2007 criteria (2) and global deficit scores (GDS) (3). Neurocognitive change (GDS change: W48 - baseline) and the effect of DT on NP evolution crude and adjusted by significant confounders were determined using ANCOVA. RESULTS A total of 158 patients were included (Table 1). They had shorter times because HIV diagnosis, ART initiation and HIV-suppression and their virologic outcome at W48 by snapshot was higher (79.1% vs 72.7%; p=0.04) compared to the 128 patients not included in the sub-study. By AAN-2007 criteria, 51 patients in each ART group (68% vs 63%) were neurocognitively impaired at baseline (p=0.61). Forty-seven patients were not reassessed at W48: 30 lost of follow-up (16 DT-14 TT) and 17 had non-evaluable data (6 DT-11 TT). Patients retested were more likely to be men (78.9% vs 61.4%) and had neurological cofounders (9.6% vs 0%) than patients non-retested. At W48, 3 out of 16 (5.7%) patients on DT and 6 out of 21 (10.5%) on TT who were non-impaired at baseline became impaired (p=0.49) while 10 out of 37 (18.9%) on DT and 7 out of 36 (12.3%) on TT who were neurocognitively impaired at baseline became non-impaired (p=0.44). Mean GDS changes (95% CI) were: Overall -0.2 (-0.3 to -0.04): DT -0.26 (-0.4 to -0.07) and TT -0.08 (-0.2 to 0.07). NP was similar between DT and TT (0.15). This absence of differences was also observed in all cognitive tests. Effect of DT: -0.16 [-0.38 to 0.06]) (r(2)=0.16) on NP evolution was similar to TT (reference), even after adjusting (DT: -0.11 [-0.33 to 0.1], TT: reference) by significant confounders (geographical origin, previous ATV use and CD4 cell count) (r(2)=0.25). CONCLUSIONS NP stability was observed after 48 weeks of follow up in the majority of patients whether DT or TT was used to maintain HIV-suppression. Incidence rates of NP impairment or NP impairment recovery were also similar between DT and TT.

Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy.

INTRODUCTION Chronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies. MATERIALS AND METHODS Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. RESULTS 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference -16.3 [CI 95%: -31.4, -1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference -21.8 [-38.0, -5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. CONCLUSIONS In virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.

TRAF1/C5 but not PTPRC variants are potential predictors of rheumatoid arthritis response to anti-tumor necrosis factor therapy.

BACKGROUND The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. METHODS We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. RESULTS No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. CONCLUSION This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response.

Faut-il traiter les dyslipidémies chez les personnes âgées et très âgées. [Should we treat dyslipidemia in the elderly and the oldest old?].

Therapy of dyslipidemia in the elderly and the oldest old remains controversial. Several studies have shown benefits of statins on secondary prevention of cardiovascular disease in older adults up to 80 years, but data remain scarce after that age. Fewer studies have assessed the impact of statins in primary prevention in the elderly. Most studies have not included adults older than 75 years, and absolute risk reduction is far lower compared to secondary prevention. Use of statins for primary prevention in this age group should be based on individual decision, taking into account patient's functional and cognitive status, comorbidities and other therapies to avoid drugs interactions, with the help of shared-decision making.