Impact of prolonged antihypertensive duration of action on predicted clinical outcomes in imperfectly adherent patients: comparison of aliskiren, irbesartan and ramipril.

Background: Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses. Aim:To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk. Method:For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%). Results:Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients). Conclusion:To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection: Determinants and Outcomes.

BACKGROUND Current guidelines give recommendations for preferred combination antiretroviral therapy (cART). We investigated factors influencing the choice of initial cART in clinical practice and its outcome. METHODS We analyzed treatment-naive adults with human immunodeficiency virus (HIV) infection participating in the Swiss HIV Cohort Study and starting cART from January 1, 2005, through December 31, 2009. The primary end point was the choice of the initial antiretroviral regimen. Secondary end points were virologic suppression, the increase in CD4 cell counts from baseline, and treatment modification within 12 months after starting treatment. RESULTS A total of 1957 patients were analyzed. Tenofovir-emtricitabine (TDF-FTC)-efavirenz was the most frequently prescribed cART (29.9%), followed by TDF-FTC-lopinavir/r (16.9%), TDF-FTC-atazanavir/r (12.9%), zidovudine-lamivudine (ZDV-3TC)-lopinavir/r (12.8%), and abacavir/lamivudine (ABC-3TC)-efavirenz (5.7%). Differences in prescription were noted among different Swiss HIV Cohort Study sites (P < .001). In multivariate analysis, compared with TDF-FTC-efavirenz, starting TDF-FTC-lopinavir/r was associated with prior AIDS (relative risk ratio, 2.78; 95% CI, 1.78-4.35), HIV-RNA greater than 100 000 copies/mL (1.53; 1.07-2.18), and CD4 greater than 350 cells/μL (1.67; 1.04-2.70); TDF-FTC-atazanavir/r with a depressive disorder (1.77; 1.04-3.01), HIV-RNA greater than 100 000 copies/mL (1.54; 1.05-2.25), and an opiate substitution program (2.76; 1.09-7.00); and ZDV-3TC-lopinavir/r with female sex (3.89; 2.39-6.31) and CD4 cell counts greater than 350 cells/μL (4.50; 2.58-7.86). At 12 months, 1715 patients (87.6%) achieved viral load less than 50 copies/mL and CD4 cell counts increased by a median (interquartile range) of 173 (89-269) cells/μL. Virologic suppression was more likely with TDF-FTC-efavirenz, and CD4 increase was higher with ZDV-3TC-lopinavir/r. No differences in outcome were observed among Swiss HIV Cohort Study sites. CONCLUSIONS Large differences in prescription but not in outcome were observed among study sites. A trend toward individualized cART was noted suggesting that initial cART is significantly influenced by physician's preference and patient characteristics. Our study highlights the need for evidence-based data for determining the best initial regimen for different HIV-infected persons.

De la recommandation d'un dépistage à son (non) implantation: le cas de l'anévrisme de l'aorte abdominale. [From guidelines for screening to their (poor) implementation: the case of the abdominal aortic aneurysm].

Suite à des essais cliniques randomisés démontrant l'efficacité du dépistage de l'anévrisme de l'aorte abdominale (AAA) par échographie, plusieurs recommandations ont été publiées dans de nombreux pays en faveur du dépistage dans une partie de la population générale. De plus, au-delà de la rupture aortique, le dépistage d'un petit AAA semble être une bonne occasion d'appliquer les stratégies de prévention secondaire, permettant une amélioration globale du pronostic cardiovasculaire du patient. Ces recommandations sont cependant peu suivies; les campagnes de dépistage systématique sont rares, laissant la responsabilité du dépistage au médecin généraliste. Cet article se propose de discuter les raisons de la non-implantation du dépistage de l'AAA. [Abstract] Following the evidence of benefits of ultrasound screening for abdominal aorta aneurysms (AAA), several guidelines support this screening in population. Beyond the prompt diagnosis of AAA prior to its rupture of grim vital prognosis, small AAA can beconsidered as a prognostic marker for cardiovascular diseases (CVD). Yet, its detection is an opportunity for secondary prevention to reduce CVD mortality. Despite, these guidelines are poorly applied: systematic screening campaigns are infrequent, making the screening of family physicians responsibility. While the major benefit from this screening strategy is to reduce AAA-related death (but only trivial effect on long-term total mortality), this explains only partially the lack of guidelines implementation. The reasons of the poor implementation of these guidelines are discussed herein.

Computer-generated reminders delivered on paper to healthcare professionals; effects on professional practice and health care outcomes.

BACKGROUND: Clinical practice does not always reflect best practice and evidence, partly because of unconscious acts of omission, information overload, or inaccessible information. Reminders may help clinicians overcome these problems by prompting the doctor to recall information that they already know or would be expected to know and by providing information or guidance in a more accessible and relevant format, at a particularly appropriate time. OBJECTIVES: To evaluate the effects of reminders automatically generated through a computerized system and delivered on paper to healthcare professionals on processes of care (related to healthcare professionals' practice) and outcomes of care (related to patients' health condition). SEARCH METHODS: For this update the EPOC Trials Search Co-ordinator searched the following databases between June 11-19, 2012: The Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Library (Economics, Methods, and Health Technology Assessment sections), Issue 6, 2012; MEDLINE, OVID (1946- ), Daily Update, and In-process; EMBASE, Ovid (1947- ); CINAHL, EbscoHost (1980- ); EPOC Specialised Register, Reference Manager, and INSPEC, Engineering Village. The authors reviewed reference lists of related reviews and studies.  SELECTION CRITERIA: We included individual or cluster-randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) that evaluated the impact of computer-generated reminders delivered on paper to healthcare professionals on processes and/or outcomes of care. DATA COLLECTION AND ANALYSIS: Review authors working in pairs independently screened studies for eligibility and abstracted data. We contacted authors to obtain important missing information for studies that were published within the last 10 years. For each study, we extracted the primary outcome when it was defined or calculated the median effect size across all reported outcomes. We then calculated the median absolute improvement and interquartile range (IQR) in process adherence across included studies using the primary outcome or median outcome as representative outcome. MAIN RESULTS: In the 32 included studies, computer-generated reminders delivered on paper to healthcare professionals achieved moderate improvement in professional practices, with a median improvement of processes of care of 7.0% (IQR: 3.9% to 16.4%). Implementing reminders alone improved care by 11.2% (IQR 6.5% to 19.6%) compared with usual care, while implementing reminders in addition to another intervention improved care by 4.0% only (IQR 3.0% to 6.0%) compared with the other intervention. The quality of evidence for these comparisons was rated as moderate according to the GRADE approach. Two reminder features were associated with larger effect sizes: providing space on the reminder for provider to enter a response (median 13.7% versus 4.3% for no response, P value = 0.01) and providing an explanation of the content or advice on the reminder (median 12.0% versus 4.2% for no explanation, P value = 0.02). Median improvement in processes of care also differed according to the behaviour the reminder targeted: for instance, reminders to vaccinate improved processes of care by 13.1% (IQR 12.2% to 20.7%) compared with other targeted behaviours. In the only study that had sufficient power to detect a clinically significant effect on outcomes of care, reminders were not associated with significant improvements. AUTHORS' CONCLUSIONS: There is moderate quality evidence that computer-generated reminders delivered on paper to healthcare professionals achieve moderate improvement in process of care. Two characteristics emerged as significant predictors of improvement: providing space on the reminder for a response from the clinician and providing an explanation of the reminder's content or advice. The heterogeneity of the reminder interventions included in this review also suggests that reminders can improve care in various settings under various conditions.

Rethinking ovarian cancer: recommendations for improving outcomes.

There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.

Valganciclovir to prevent or treat cytomegalovirus disease in organ transplantation.

Cytomegalovirus (CMV) is generally considered the most significant pathogen to infect patients following organ transplantation. Significant improvements have been achieved in the management of CMV disease over recent years, especially since the introduction of oral drugs such as oral ganciclovir followed by valganciclovir (VGC), a prodrug of ganciclovir with enhanced bioavailability. Several randomized controlled trials have shown that VGC is an efficacious and convenient oral drug to prevent or treat CMV disease in solid-organ transplant recipients. In this article, we discuss the clinical and pharmacological experience with the use of VGC for the management of CMV in solid-organ transplant recipients. Finally, novel strategies to further reduce the incidence of CMV disease after transplantation are also reviewed.

Treatment of drug-eluting stent restenosis: an emerging challenge.

Drug eluting stent (DES) restenosis has emerged as a significant clinical entity owing to the increasing use of DES in complex lesions and patients. However, to date, there is a paucity of studies that have addressed the management of DES restenosis and the resulting outcome, leaving the interventional cardiologist with a therapeutic dilemma. The purpose of this paper is therefore to provide a concise review of available data's dealing with the treatment of DES restenosis, including the outcome of patients treated for DES restenosis, the prognostic importance of the angiographic pattern and the available therapeutic modalities.

Ruling out coronary heart disease in primary care: external validation of a clinical prediction rule.

BACKGROUND: The Marburg Heart Score (MHS) aims to assist GPs in safely ruling out coronary heart disease (CHD) in patients presenting with chest pain, and to guide management decisions. AIM: To investigate the diagnostic accuracy of the MHS in an independent sample and to evaluate the generalisability to new patients. DESIGN AND SETTING: Cross-sectional diagnostic study with delayed-type reference standard in general practice in Hesse, Germany. METHOD: Fifty-six German GPs recruited 844 males and females aged ≥ 35 years, presenting between July 2009 and February 2010 with chest pain. Baseline data included the items of the MHS. Data on the subsequent course of chest pain, investigations, hospitalisations, and medication were collected over 6 months and were reviewed by an independent expert panel. CHD was the reference condition. Measures of diagnostic accuracy included the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, likelihood ratios, and predictive values. RESULTS: The AUC was 0.84 (95% confidence interval [CI] = 0.80 to 0.88). For a cut-off value of 3, the MHS showed a sensitivity of 89.1% (95% CI = 81.1% to 94.0%), a specificity of 63.5% (95% CI = 60.0% to 66.9%), a positive predictive value of 23.3% (95% CI = 19.2% to 28.0%), and a negative predictive value of 97.9% (95% CI = 96.2% to 98.9%). CONCLUSION: Considering the diagnostic accuracy of the MHS, its generalisability, and ease of application, its use in clinical practice is recommended.

Adoption of the Healthy Heart Kit by Alberta family physicians

OBJECTIVE: The Healthy Heart Kit (HHK) is a risk management and patient education kit for the prevention of cardiovascular disease (CVD) and the promotion of CV health. There are currently no published data examining predictors of HHK use by physicians. The main objective of this study was to examine the association between physicians' characteristics (socio-demographic, cognitive, and behavioural) and the use of the HHK. METHODS: All registered family physicians in Alberta (n=3068) were invited to participate in the "Healthy Heart Kit" Study. Consenting physicians (n=153) received the Kit and were requested to use it for two months. At the end of this period, a questionnaire collected data on the frequency of Kit use by physicians, as well as socio-demographic, cognitive, and behavioural variables pertaining to the physicians. RESULTS: The questionnaire was returned by 115 physicians (follow-up rate = 75%). On a scale ranging from 0 to 100, the mean score of Kit use was 61 [SD=26]. A multiple linear regression showed that "agreement with the Kit" and the degree of "confidence in using the Kit" was strongly associated with Kit use, explaining 46% of the variability for Kit use. Time since graduation was inversely associated with Kit use, and a trend was observed for smaller practices to be associated with lower use. CONCLUSION: Given these findings, future research and practice should explore innovative strategies to gain initial agreement among physicians to employ such clinical tools. Participation of older physicians and solo-practitioners in this process should be emphasized.

Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary international expert panel (EPACT II)

Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.

The emergence of forensic nursing and advanced nursing practice in Switzerland: an innovative case study consultation.

BACKGROUND AND METHODS: The objectives of this article were to systematically describe and examine the novel roles and responsibilities assumed by nurses in a forensic consultation for victims of violence at a University Hospital in French-speaking Switzerland. Utilizing a case study methodology, information was collected from two main sources: (a) discussion groups with nurses and forensic pathologists and (b) a review of procedures and protocols. Following a critical content analysis, the roles and responsibilities of the forensic nurses were described and compared with the seven core competencies of advanced nursing practice as outlined by Hamric, Spross, and Hanson (2009). RESULTS: Advanced nursing practice competencies noted in the analysis included "direct clinical practice," "coaching and guidance," and "collaboration." The role of the nurse in terms of "consultation," "leadership," "ethics," and "research" was less evident in the analysis. DISCUSSION AND CONCLUSION: New forms of nursing are indeed practiced in the forensic clinical setting, and our findings suggest that nursing practice in this domain is following the footprints of an advanced nursing practice model. Further reflections are required to determine whether the role of the forensic nurse in Switzerland should be developed as a clinical nurse specialist or that of a nurse practitioner.

Improvement of cardiovascular risk prediction: time to review current knowledge, debates, and fundamentals on how to assess test characteristics.

Cardiovascular risk assessment might be improved with the addition of emerging, new tests derived from atherosclerosis imaging, laboratory tests or functional tests. This article reviews relative risk, odds ratios, receiver-operating curves, posttest risk calculations based on likelihood ratios, the net reclassification improvement and integrated discrimination. This serves to determine whether a new test has an added clinical value on top of conventional risk testing and how this can be verified statistically. Two clinically meaningful examples serve to illustrate novel approaches. This work serves as a review and basic work for the development of new guidelines on cardiovascular risk prediction, taking into account emerging tests, to be proposed by members of the 'Taskforce on Vascular Risk Prediction' under the auspices of the Working Group 'Swiss Atherosclerosis' of the Swiss Society of Cardiology in the future.

The role of stereotactic ablative radiotherapy in oncological and non-oncological clinical settings: highlights from the 7th Meeting of AIRO - Young Members Working Group (AIRO Giovani).

Stereotactic ablative radiotherapy is a modern cancer treatment strategy able to deliver highly focused radiation in one or a few fractions with a radical intent in several clinical settings. Young radiation oncologists need a constant and tailored update in this context to improve patient care in daily clinical practice. A recent meeting of AIRO Giovani (AIRO - Young Members Working Group) was specifically addressed to this topic, presenting state-of-the-art knowledge, based on the latest evidence in this field. Highlights of the congress are summarized and presented in this report, including thorough contributions of the speakers dealing with the role of stereotactic ablative radiotherapy in both oncological and non-oncological diseases, divided according to anatomical and clinical scenarios: intra-cranial settings (brain malignant primary tumors, metastases, benign tumors and functional disorders) and extra-cranial indications (lung primary tumors and metastases, thoracic re-irradiation, liver, lymph node and bone metastases, prostate cancer). With literature data discussed during the congress as a background, stereotactic ablative radiotherapy has proved to be a consolidated treatment approach in specific oncological and non-oncological scenarios, as well as a promising option in other clinical settings, requiring a further prospective validation in the near future. We herein present an updated overview of stereotactic ablative radiotherapy use in the clinic.

Sensitive bioassay for determination of fluconazole concentrations in plasma using a Candida albicans mutant hypersusceptible to azoles.

The antifungal agent fluconazole (FLC) is widely used in clinical practice. Monitoring FLC levels is useful in complicated clinical settings and in experimental infection models. A bioassay using Candida pseudotropicalis, a simple and cost-effective method, is validated only for FLC levels ranging from 5 to 40 mg/liter. An extension of the analytical range is needed to cover most yeast MICs. A new bioassay in RPMI agar containing methylene blue was developed using C. albicans DSY1024, a mutant rendered hypersusceptible to FLC constructed by the deletion of the multidrug efflux transporter genes CDR1, CDR2, CaMDR1, and FLU1. Reproducible standard curves were obtained with FLC concentrations in plasma ranging from 1 to 100 mg/liter (quadratic regression coefficient &gt; 0.997). The absolute sensitivity was 0.026 microg of FLC. The method was internally validated according to current guidelines for analytical method validation. Both accuracy and precision lied in the required +/-15% range. FLC levels measured by bioassay and by high-performance liquid chromatography (HPLC) performed with 62 plasma samples from humans and rats showed a strong correlation (coefficients, 0.979 and 0.995, respectively; percent deviations of bioassay from HPLC values, 0.44% +/- 15.31% and 2.66% +/- 7.54%, respectively). In summary, this newly developed bioassay is sensitive, simple, rapid, and inexpensive. It allows nonspecialized laboratories to determine FLC levels in plasma to within the clinically relevant concentration range and represents a useful tool for experimental treatment models.

Cross-cultural clinical competence and post-graduate teaching: any impact(s) on doctors?

Context: Cross-cultural clinical competence (CCC) requires a mixtureof "knowledge" (K), "attitude" (A) and "skills" (S), in order to develop theability to give quality care to patients of different cultures. Theseattributes allow, while providing medical care, consideration of thepatient's medical, social, cultural and language needs. The LausanneUniversity Medical Policlinic (PMU) provides approximately 30000consultations per year to migrant patients and over the past five yearshas implemented a training course on CCC that focuses on trialogue,stereotypes and administrative procedures for the healthcare ofmigrants.Method: A quantitative survey of 18 new residents, was carried outusing a validated questionnaire, the "Multicultural AssessmentQuestionnaire" (the MAQ, 16 questions on K, A and S) to evaluate theimpact of CCC training. The questionnaire was distributed before theCCC course (J-1), three days after (J+3) and three months later (J+90).A descriptive univariate analysis of the difference in MAQ scoresbetween the times J-1 - J+3 and J-1 - J+90 was made. Three FocusGroups were conducted, at three months, to explore residents' thoughtsabout the course.Results: A significant increase was observed in global performancedeclared by residents. Following the intervention, the score of the MAQincreased from 31.4 points to 38.0 points at three days (p = 0.004) andto 37.7 points at three months (p = 0.003). This increase was mostnoticeable in the field of acquiring K: total score J-1: 118, J+3: 189,J+90: 190 (difference J-1 - J+3 and J-1 - J+90: p <0.005). There was nosignificant difference in acquiring A (J-1: 222, J+3: 228, J+90: 229), andS increases in a significant way at first (J-1: 222, J+3: 265, J-1 - J+3:p = 0.035), then comes back to the start value (J+90: 217). The residentswere interested by the course which they felt provides useful informationfor clinical practice. They had a great number of expectations in varyingfields (medical anthropology, cultural differences, epidemiology, etc.),hoping a "ready-made" solution for the approach of migrant patients.Conclusions: A unique training of CCC at the post-graduate level,upgraded K, and to a lesser extent A and S, for these 18 residents. Theywere interest and they had many expectations. Subsequent coursesshould consolidate these acquisitions. Future study should demonstratethe impact on patients' clinical outcome.