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.

Molecular testing for fragile X: analysis of 5062 tests from 1105 fragile X families--performed in 12 clinical laboratories in Spain.

Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.

Lipid changes in HIV-patients switching to the coformulated single tablet FTC/RPV/TDF (Eviplera®). Efficacy and safety analysis. GeSida Study 8114.

INTRODUCTION Rilpivirine (RPV) has a better lipid profile than efavirenz (EFV) in naïve patients (1). Switching to RPV may be convenient for many patients, while maintaining a good immunovirological control (2). The aim of this study was to analyze lipid changes in HIV-patients at 24 weeks after switching to Eviplera® (emtricitabine/RPV/tenofovir disoproxil fumarate [FTC/RPV/TDF]). MATERIALS AND METHODS Retrospective, multicentre study of a cohort of asymptomatic HIV-patients who switched from a regimen based on 2 nucleoside reverse transcriptase inhibitors (NRTI)+protease inhibitor (PI)/non nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir boosted PI monotherapy to Eviplera® during February-December, 2013; all had undetectable HIV viral load for ≥3 months prior to switching. Patients with previous failures on antiretroviral therapy (ART) including TDF and/or FTC/3TC, with genotype tests showing resistance to components of Eviplera®, or who had changed the third drug of the ART during the study period were excluded. Changes in lipid profile and cardiovascular risk (CVR), and efficacy and safety at 24 weeks were analyzed. RESULTS Among 305 patients included in the study, 298 were analyzed (7 cases were excluded due to lack of data). Men 81.2%, mean age 44.5 years, 75.8% of HIV sexually transmitted. 233 (78.2%) patients switched from a regimen based on 2 NRTI+NNRTI (90.5% EFV/FTC/TDF). The most frequent reasons for switching were central nervous system (CNS) adverse events (31.0%), convenience (27.6%) and metabolic disorders (23.2%). At this time, 293 patients have reached 24 weeks: 281 (95.9%) have continued Eviplera®, 6 stopped it (3 adverse events, 2 virologic failures, 1 discontinuation) and 6 have been lost to follow up. Lipid profiles of 283 cases were available at 24 weeks and mean (mg/dL) baseline vs 24 weeks are: total cholesterol (193 vs 169; p=0.0001), HDL-c (49 vs 45; p=0.0001), LDL-c (114 vs 103; p=0.001), tryglycerides (158 vs 115; p=0.0001), total cholesterol to HDL-c ratio (4.2 vs 4.1; p=0.3). CVR decreased (8.7 vs 7.5%; p= 0.0001). CD4 counts were similar to baseline (653 vs 674 cells/µL; p=0.08), and 274 (96.8%) patients maintained viral suppression. CONCLUSIONS At 24 weeks after switching to Eviplera®, lipid profile and CVR improved while maintaining a good immunovirological control. Most subjects switched to Eviplera® from a regimen based on NNRTI, mainly EFV/FTC/TDF. CNS adverse events, convenience and metabolic disorders were the most frequent reasons for switching.

Truncated robust distance for clinical laboratory safety data monitoring and assessment.

Laboratory safety data are routinely collected in clinical studies for safety monitoring and assessment. We have developed a truncated robust multivariate outlier detection method for identifying subjects with clinically relevant abnormal laboratory measurements. The proposed method can be applied to historical clinical data to establish a multivariate decision boundary that can then be used for future clinical trial laboratory safety data monitoring and assessment. Simulations demonstrate that the proposed method has the ability to detect relevant outliers while automatically excluding irrelevant outliers. Two examples from actual clinical studies are used to illustrate the use of this method for identifying clinically relevant outliers.

The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study.

BACKGROUND: European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. METHODS: The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members. RESULTS: Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. CONCLUSIONS: Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry.

Empirical approaches to inequality of opportunity: principles, measures, and evidence

We put together the different conceptual issues involved in measuring inequality of opportunity, discuss how these concepts have been translated into computable measures, and point out the problems and choices researchers face when implementing these measures. Our analysis identifies and suggests several new possibilities to measure inequality of opportunity. The approaches are illustrated with a selective survey of the empirical literature on income inequality of opportunity.

Randomised controlled study in the primary healthcare sector to investigate the effectiveness and safety of auriculotherapy for the treatment of uncomplicated chronic rachialgia: a study protocol.

BACKGROUND Uncomplicated chronic rachialgia is a highly prevalent complaint, and one for which therapeutic results are contradictory. The aim of the present study is to evaluate the effectiveness and safety of treatment with auriculopressure, in the primary healthcare sector, carried out by trained healthcare professionals via a 30-hour course. METHODS/DESIGN The design consists of a multi-centre randomized controlled trial, with placebo, with two parallel groups, and including an economic evaluation. Patients with chronic uncomplicated rachialgia, whose GP is considering referral for auriculopressure sensory stimulation, are eligible for inclusion. Sampling will be by consecutive selection, and randomised allocation to one of the two study arms will be determined using a centralised method, following a 1:1 plan (true auriculopressure; placebo auriculopressure). The implants (true and placebo) will be replaced once weekly, and the treatment will have a duration of 8 weeks. The primary outcome measure will be the change in pain intensity, measured on a visual analogue scale (VAS) of 100 mm, at 9 weeks after beginning the treatment. A follow up study will be performed at 6 months after beginning treatment. An assessment will also be made of the changes measured in the Spanish version of the McGill Pain Questionnaire, of the changes in the Lattinen test, and of the changes in quality of life (SF-12). Also planned is an analysis of cost-effectiveness and also, if necessary, a cost-benefit analysis. DISCUSSION This study will contribute to developing evidence on the use of auriculotherapy using Semen vaccariae [wang bu liu xing] for the treatment of uncomplicated chronic rachialgia. TRIAL REGISTRATION Current Controlled Trials ISRCTN01897462.

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

BACKGROUND Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. METHODS This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. RESULTS Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6 %) patients were male, 64 (48.1 %) had pancreatic NET, 23 (17.3 %) had ECOG PS ≥2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery of the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 % (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. CONCLUSIONS The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.

A Clinical Decision Support using a Terminology Server to improve Patient Safety.

Clinical Decision Support Systems (CDSS) are software applications that support clinicians in making healthcare decisions providing relevant information for individual patients about their specific conditions. The lack of integration between CDSS and Electronic Health Record (EHR) has been identified as a significant barrier to CDSS development and adoption. Andalusia Healthcare Public System (AHPS) provides an interoperable health information infrastructure based on a Service Oriented Architecture (SOA) that eases CDSS implementation. This paper details the deployment of a CDSS jointly with the deployment of a Terminology Server (TS) within the AHPS infrastructure. It also explains a case study about the application of decision support to thromboembolism patients and its potential impact on improving patient safety. We will apply the inSPECt tool proposal to evaluate the appropriateness of alerts in this scenario.

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

BACKGROUND Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN A phase II randomized, double-blind pilot clinical trial. SCOPE male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).

Adaptation of AHRQ patient safety indicators for use in ICD-10 administrative data by an international consortium.

Objective: The Agency for Healthcare Research and Quality (AHRQ) developed Patient Safety Indicators (PSIs) for use with ICD-9-CM data. Many countries have adopted ICD-10 for coding hospital diagnoses. We conducted this study to develop an internationally harmonized ICD-10 coding algorithm for the AHRQ PSIs. Methods: The AHRQ PSI Version 2.1 has been translated into ICD-10-AM (Australian Modification), and PSI Version 3.0a has been independently translated into ICD-10-GM (German Modification). We converted these two country-specific coding algorithms into ICD-10-WHO (World Health Organization version) and combined them to form one master list. Members of an international expert panel-including physicians, professional medical coders, disease classification specialists, health services researchers, epidemiologists, and users of the PSI-independently evaluated this master list and rated each code as either "include," "exclude," or "uncertain," following the AHRQ PSI definitions. After summarizing the independent rating results, we held a face-to-face meeting to discuss codes for which there was no unanimous consensus and newly proposed codes. A modified Delphi method was employed to generate a final ICD-10 WHO coding list. Results: Of 20 PSIs, 15 that were based mainly on diagnosis codes were selected for translation. At the meeting, panelists discussed 794 codes for which consensus had not been achieved and 2,541 additional codes that were proposed by individual panelists for consideration prior to the meeting. Three documents were generated: a PSI ICD-10-WHO version-coding list, a list of issues for consideration on certain AHRQ PSIs and ICD-9-CM codes, and a recommendation to WHO to improve specification of some disease classifications. Conclusion: An ICD-10-WHO PSI coding list has been developed and structured in a manner similar to the AHRQ manual. Although face validity of the list has been ensured through a rigorous expert panel assessment, its true validity and applicability should be assessed internationally.

Evaluation of two HbA1c point-of-care analyzers.

BACKGROUND Measurement of HbA1c is the most important parameter to assess glycemic control in diabetic patients. Different point-of-care devices for HbA1c are available. The aim of this study was to evaluate two point-of-care testing (POCT) analyzers (DCA Vantage from Siemens and Afinion from Axis-Shield). We studied the bias and precision as well as interference from carbamylated hemoglobin. METHODS Bias of the POCT analyzers was obtained by measuring 53 blood samples from diabetic patients with a wide range of HbA1c, 4%-14% (20-130 mmol/mol), and comparing the results with those obtained by the laboratory method: HPLC HA 8160 Menarini. Precision was performed by 20 successive determinations of two samples with low 4.2% (22 mmol/mol) and high 9.5% (80 mmol/mol) HbA1c values. The possible interference from carbamylated hemoglobin was studied using 25 samples from patients with chronic renal failure. RESULTS The means of the differences between measurements performed by each POCT analyzer and the laboratory method (95% confidence interval) were: 0.28% (p<0.005) (0.10-0.44) for DCA and 0.27% (p<0.001) (0.19-0.35) for Afinion. Correlation coefficients were: r=0.973 for DCA, and r=0.991 for Afinion. The mean bias observed by using samples from chronic renal failure patients were 0.2 (range -0.4, 0.4) for DCA and 0.2 (-0.2, 0.5) for Afinion. Imprecision results were: CV=3.1% (high HbA1c) and 2.97% (low HbA1c) for DCA, CV=1.95% (high HbA1c) and 2.66% (low HbA1c) for Afinion. CONCLUSIONS Both POCT analyzers for HbA1c show good correlation with the laboratory method and acceptable precision.

Adaptation au codage CIM-10 de 15 indicateurs de la sécurité des patients proposés par l'Agence étasunienne pour la recherche et la qualité des soins de santé (AHRQ) [ICD-10 adaptation of 15 Agency for Healthcare Research and Quality patient safety indicators].

BACKGROUND: In the United States, the Agency for Healthcare Research and Quality (AHRQ) has developed 20 Patient Safety Indicators (PSIs) to measure the occurrence of hospital adverse events from medico-administrative data coded according to the ninth revision of the international classification of disease (ICD-9-CM). The adaptation of these PSIs to the WHO version of ICD-10 was carried out by an international consortium. METHODS: Two independent teams transcoded ICD-9-CM diagnosis codes proposed by the AHRQ into ICD-10-WHO. Using a Delphi process, experts from six countries evaluated each code independently, stating whether it was "included", "excluded" or "uncertain". During a two-day meeting, the experts then discussed the codes that had not obtained a consensus, and the additional codes proposed. RESULTS: Fifteen PSIs were adapted. Among the 2569 proposed diagnosis codes, 1775 were unanimously adopted straightaway. The 794 remaining codes and 2541 additional codes were discussed. Three documents were prepared: (1) a list of ICD-10-WHO codes for the 15 adapted PSIs; (2) recommendations to the AHRQ for the improvement of the nosological frame and the coding of PSI with ICD-9-CM; (3) recommendations to the WHO to improve ICD-10. CONCLUSIONS: This work allows international comparisons of PSIs among the countries using ICD-10. Nevertheless, these PSIs must still be evaluated further before being broadly used.

Safety and efficacy in gamma knife radiosurgery for trigeminal neuralgia due to megadolichbasilar artery compression: a prospective series of 29 consecutive patients

Purpose: To analyse prospectively the long-term results of Gamma Knife surgery (GKS) in patients with trigeminal neuralgia secondary to megadolichobasilar artery (MBA). Methods: Between December 1992 and November 2010, 33 consecutive patients presenting with ITN secondary to MBA were operated by GKS and followed prospectively in Timone University Hospital. The follow up is at least of 1 year in 29 patients. The median age was 74.90 years (range 51 to 90). The GKS typically was performed using MR and CT imaging guidance and a single 4 mm isocenter. The median of the prescription dose (at the 100%) was 90 Gy (range 80 to 90). The target was placed on the cisternal portion of the Vth nerve. Clinical and dosimetric parameters were analyzed. GKS was the first surgical procedure in 23 patients (79.31%). Results: The median follow- up period was 46.12 months (range 12.95 to 157.93). All the 29 patients (100%) were initially pain free in a median time of 13.5 days (range 0 to 240). The probability of remaining pain free at 0.5, 1, 2 years was 93.1%, 79.3% and 75.7% respectively, reaching at this time the flat part of the curve. Seven patients (24.13%) experienced a recurrence with a median delay of 10.75 months (range 3.77 to 12.62). The actuarial rate of recurrence was not higher than in our population with essential TN although atypical pain was associated with a much higher risk of recurrence (HR= 6.92, p= 0.0117). The hypoesthesia actuarial rates at 0.5 years was 4.3% and at 1 year reach 13% and remains stable till 12 years with a median delay of onset of 7 (5, 12) months. Female patients had a statistically much lower probability of developing a facial numbness (p of 0.03). No patient reported a bothersome hypoesthesia. Conclusion: Retrogaserian, high dose GKS, turned out to be very safe with only 13.04% hypoesthesia, which was never disabling (0%), while achieving high quality pain control. The majority of the patients demonstrated a prolonged effect of radiosurgery in absence of any trigeminal nerve disturbance.