Between manualized treatments and principle-guided psychotherapy: illustration in the case of Caroline

My case study of "Caroline"-a 26 year old presenting with depression, PTSD symptoms, and a history of sexual abuse as a teenager-represents a "third way" between (1) a strict adherence to a manualized treatment, and (2) a principle-guided therapy, in which the therapy follows particular theoretical concepts, but depends on the therapist's clinical judgement to flexibly apply them to the individual case. Specifically, in my therapy with Caroline (Kramer, 2009), I employed Foa and Rothbaum's (1998) cognitive-behavioral, "Prolonged Exposure" (PE) manual for PTSD, but deviated from it in certain ways based upon my evaluation of Caroline's individualized goals and reactions using Grawe and Caspar's "Plan Analysis," which is a cross-theoretical model for assessment and treatment planning. In their commentaries on my case study of Caroline, Caspar (2009) and Haldimann-Balli (see Appendix in Kramer, 2009) support my use of this third way. On the other hand, the other commentators-Muller (2009) and Hembree and Brinen (2009)-critique my handling of the case, arguing that strict adherence to the Foa and Rothbaum manual would have resulted in a more cost-effective therapy. In this article, I respond to the important issues raised by the four commentators.

Latent tuberculosis: which test in which situation?

Detection of latent tuberculosis infection (LTBI) is a cost-effective procedure in patients at high risk of developing tuberculosis later and who could benefit from preventive treatment. The commonest situation where screening is indicated is the search for infected contacts of an index case with pulmonary tuberculosis. As a screening procedure the current tendency is to replace the time-honoured tuberculin skin test by one of the new blood tests measuring the release of interferon gamma by sensitised T lymphocytes after stimulation by specific peptides from M. tuberculosis. The main advantage of the new tests is the absence of interference with BCG and non-tuberculous mycobacteria, which confers high specificity on the test. This allows a more selective choice of persons for whom preventive treatment is indicated. Some controversial issues remain, such as sensitivity in children and immunocompromised subjects, the predictive value of the blood test and interpretation of possible changes in test results over time. The technical aspects required for performance of the tests must be considered.

Country actions to meet UN commitments on non-communicable diseases: a stepwise approach.

Strong leadership from heads of state is needed to meet national commitments to the UN political declaration on non-communicable diseases (NCDs) and to achieve the goal of a 25% reduction in premature NCD mortality by 2025 (the 25 by 25 goal). A simple, phased, national response to the political declaration is suggested, with three key steps: planning, implementation, and accountability. Planning entails mobilisation of a multisectoral response to develop and support the national action plan, and to build human, financial, and regulatory capacity for change. Implementation of a few priority and feasible cost-effective interventions for the prevention and treatment of NCDs will achieve the 25 by 25 goal and will need only few additional financial resources. Accountability incorporates three dimensions: monitoring of progress, reviewing of progress, and appropriate responses to accelerate progress. A national NCD commission or equivalent, which is independent of government, is needed to ensure that all relevant stakeholders are held accountable for the UN commitments to NCDs.

A fast automated screening method for the detection of blood transfusion in sports.

Currently, there is no simple direct screening method for the misuse of blood transfusions in sports. In this study, we investigated whether the measurement of iron in EDTA-plasma can serve as biomarker for such purpose. Our results revealed an increase of the plasma iron level up to 25-fold 6 h after blood re-infusion. The variable remained elevated 10-fold one day after the procedure. A specificity of 100% and a sensitivity of 93% were obtained with a proposed threshold at 45 µg/dL of plasma iron. Therefore, our test could be used as a simple, cost effective biomarker for the screening for blood transfusion misuse in sports. Copyright © 2014 John Wiley & Sons, Ltd.

Multiplex targeted high-throughput sequencing for Mendelian cardiac disorders.

Mendelian cardiomyopathies and arrhythmias are characterized by an important genetic heterogeneity, rendering Sanger sequencing very laborious and expensive. As a proof of concept, we explored multiplex targeted high-throughput sequencing (HTS) as a fast and cost-efficient diagnostic method for individuals suffering from Mendelian cardiac disorders. We designed a DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing. Two patients had familial hypertrophic cardiomyopathy (HCM) and two patients suffered from long QT syndrome (LQTS). In patient 1 with HCM, we identified two known pathogenic missense variants in the two most frequently mutated sarcomeric genes MYH7 and MYBPC. In patient 2 with HCM, a known acceptor splice site variant in MYBPC3 was found. In patient 3 with LQTS, two missense variants in the genes SCN5A and KCNQ were identified. Finally, in patient 4 with LQTS a known missense variant was found in MYBPC3, which is usually mutated in patients with cardiomyopathy. Our results showed that multiplex targeted HTS works as an efficient and cost-effective tool for molecular diagnosis of heterogeneous disorders in clinical practice and offers new insights in the pathogenesis of these complex diseases.

Medical and pharmacological direct costs of a 9-week smoking cessation programme.

Background: Medical and pharmacological direct costs of cigarette smoking cessation programmes are not covered by health insurance in several countries despite documented cost-effectiveness. Design: prospective cost identification study of a 9-week programme in Switzerland. Methods: A total of 481 smokers were followed-up for 9 weeks. Socio-demographic characteristics, number of outpatient visits, dosage and frequency of use of nicotine replacement therapy (NRT) as well as date of relapse were prospectively collected. Individual cost of care until relapse or programme end as well as cost per week of follow-up were computed. Comparisons were carried out between the groups with or without relapse at the end of the programme. Results: Of the 209 men and 272 women included, 347 patients (72%) finished the programme. Among them, 240 patients (70%) succeeded in quitting and 107 patients (30%) relapsed. As compared with the group relapsing by the end of the programme, the group succeeding in quitting was more often living in a couple (68% vs. 55%, p = 0.029). Their mean weekly costs of visits were higher (CHF 81.2 ± 6.1 vs. 78.4 ± 7.6, p = 0.001), while their mean weekly costs for NRT were similar (CHF 24.2 ± 12.6 vs. 25.4 ± 15.9, p = 0.711). Mean total costs per week were similar (CHF 105.4 ± 15.4 vs. 103.8 ± 19.4, p = 0.252). More intensive NRT at week 4 increased the probability not to relapse at the end of the programme. Conclusions: Over 9 weeks, medical and pharmacological costs of stopping smoking are low. Good medical and social support as well as adequate NRT seem to play a role in successful quitting.

Beneficial effects of combinatorial micronutrition on body fat and atherosclerosis in mice.

AIMS: More than two billion people worldwide are deficient in key micronutrients. Single micronutrients have been used at high doses to prevent and treat dietary insufficiencies. Yet the impact of combinations of micronutrients in small doses aiming to improve lipid disorders and the corresponding metabolic pathways remains incompletely understood. Thus, we investigated whether a combination of micronutrients would reduce fat accumulation and atherosclerosis in mice. METHODS AND RESULTS: Lipoprotein receptor-null mice fed with an original combination of micronutrients incorporated into the daily chow showed reduced weight gain, body fat, plasma triglycerides, and increased oxygen consumption. These effects were achieved through enhanced lipid utilization and reduced lipid accumulation in metabolic organs and were mediated, in part, by the nuclear receptor PPARα. Moreover, the micronutrients partially prevented atherogenesis when administered early in life to apolipoprotein E-null mice. When the micronutrient treatment was started before conception, the anti-atherosclerotic effect was stronger in the progeny. This finding correlated with decreased post-prandial triglyceridaemia and vascular inflammation, two major atherogenic factors. CONCLUSION: Our data indicate beneficial effects of a combination of micronutritients on body weight gain, hypertriglyceridaemia, liver steatosis, and atherosclerosis in mice, and thus our findings suggest a novel cost-effective combinatorial micronutrient-based strategy worthy of being tested in humans.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (&lt; 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Comparable effectiveness from organised and opportunistic mammography screening in Switzerland

Effectiveness of organised (service) and opportunistic mammography screening in Switzerland was evaluated for thefirst time, based on internationally recognised prognostic indicators. Effectiveness by screening type (organised vs opportunistic screening) and detection modality (screened / unscreened women) was examined for 3 cantons (Vaud, Valais, Geneva) with organised programmes. Comparisons of prognostic profile were drawn with 2 regions (St-Gall/Appenzell and Ticino) uncovered by service screening, of low and high prevalence of opportunistic screening, respectively. Opportunistic and organised screening yielded little difference in breast cancerprognostic profile. Both screening types led to substantial stage shifting.Breast cancer prognostic indicators were systematically more favourable in cantons covered by a programme. In regions without a screening programme, the higher the prevalence of opportunistic screening, the better the prognostic profile. Organised screening appeared as effectiveas opportunistic screening in Switzerland. The favourable influence of mammography screening on stage distribution augurs a screen-attributable decline ofbreast cancer mortality. Extension of organised mammography screening to the whole of Switzerland can be expected to further improve breast cancer prognosis in a cost-effective way.

Personality traits, behavioral and psychological symptoms and cognitive decline in patients at an early stage of Alzheimer's disease

The aim of this doctoral thesis was to study personality characteristics of patients at an early stage of Alzheimer's disease (AD), and more specifically to describe personality and its changes over time, and to explore its possible links with psychological and symptoms (BPS) and cognitive level. The results were compared to those of a group of participants without cognitive disorder through three empirical studies. In the first study, the findings showed significant personality changes that follow a specific trend in the clinical group. The profil of personality changes showed an increase in Neuroticism and a decrease in Extraversion, Openess to experiences, and Conscientiousness over time. The second study highlighted that personality and BPS occur early in the cours of AD. Recognizing them as possible precoce signs of neurodegeneration may prove to be a key factor for early detection and intervention. In the third study, a significant association between personality changes and cognitive status was observed in the patients with incipient AD. Thus, changes in Neuroticism and Conscientiousness were linked with cognitive deterioration, whereas decreased Openness to experiences and Conscientiousness over time predicted loss of independence in daily functioning. Other well-known factors such as age, education level or civil status were taken into account to predict cognitive decline. The three studies suggested five important implications: (1) cost-effective screening should take into account premorbid and specific personality changes; (2) psycho-educative interventions should provide information on the possible personality changes and BPS that may occur at the beginning of the disease; (3) using personality traits alongside other variables in the future studies on prevention might help to better understand AD's etiology; (4) individual treatment plans (psychotherapeutic, social, and pharmacological) might be adapted to the specific changes in personality profiles; (5) more researches are needed to study the impact of social-cultural and lifestyle variables on the development of AD.

A microarray-based system for the simultaneous analysis of single nucleotide polymorphisms in human genes involved in the metabolism of anti-malarial drugs

Background: In order to provide a cost-effective tool to analyse pharmacogenetic markers in malaria treatment, DNA microarray technology was compared with sequencing of polymerase chain reaction (PCR) fragments to detect single nucleotide polymorphisms (SNPs) in a larger number of samples. Methods: The microarray was developed to affordably generate SNP data of genes encoding the human cytochrome P450 enzyme family (CYP) and N-acetyltransferase-2 (NAT2) involved in antimalarial drug metabolisms and with known polymorphisms, i.e. CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NAT2. Results: For some SNPs, i.e. CYP2A6*2, CYP2B6*5, CYP2C8*3, CYP2C9*3/*5, CYP2C19*3, CYP2D6*4 and NAT2*6/*7/*14, agreement between both techniques ranged from substantial to almost perfect (kappa index between 0.61 and 1.00), whilst for other SNPs a large variability from slight to substantial agreement (kappa index between 0.39 and 1.00) was found, e. g. CYP2D6*17 (2850C>T), CYP3A4*1B and CYP3A5*3. Conclusion: The major limit of the microarray technology for this purpose was lack of robustness and with a large number of missing data or with incorrect specificity.

Mapping HIV/STI behavioural surveillance in Europe.

BACKGROUND: Used in conjunction with biological surveillance, behavioural surveillance provides data allowing for a more precise definition of HIV/STI prevention strategies. In 2008, mapping of behavioural surveillance in EU/EFTA countries was performed on behalf of the European Centre for Disease prevention and Control. METHOD: Nine questionnaires were sent to all 31 member States and EEE/EFTA countries requesting data on the overall behavioural and second generation surveillance system and on surveillance in the general population, youth, men having sex with men (MSM), injecting drug users (IDU), sex workers (SW), migrants, people living with HIV/AIDS (PLWHA), and sexually transmitted infection (STI) clinics patients. Requested data included information on system organisation (e.g. sustainability, funding, institutionalisation), topics covered in surveys and main indicators. RESULTS: Twenty-eight of the 31 countries contacted supplied data. Sixteen countries reported an established behavioural surveillance system, and 13 a second generation surveillance system (combination of biological surveillance of HIV/AIDS and STI with behavioural surveillance). There were wide differences as regards the year of survey initiation, number of populations surveyed, data collection methods used, organisation of surveillance and coordination with biological surveillance. The populations most regularly surveyed are the general population, youth, MSM and IDU. SW, patients of STI clinics and PLWHA are surveyed less regularly and in only a small number of countries, and few countries have undertaken behavioural surveys among migrant or ethnic minorities populations. In many cases, the identification of populations with risk behaviour and the selection of populations to be included in a BS system have not been formally conducted, or are incomplete. Topics most frequently covered are similar across countries, although many different indicators are used. In most countries, sustainability of surveillance systems is not assured. CONCLUSION: Although many European countries have established behavioural surveillance systems, there is little harmonisation as regards the methods and indicators adopted. The main challenge now faced is to build and maintain organised and functional behavioural and second generation surveillance systems across Europe, to increase collaboration, to promote robust, sustainable and cost-effective data collection methods, and to harmonise indicators.

Solution scanning as a key policy tool: identifying management interventions to help maintain and enhance regulating ecosystem services

The major task of policy makers and practitioners when confronted with a resource management problem is to decide on the potential solution(s) to adopt from a range of available options. However, this process is unlikely to be successful and cost effective without access to an independently verified and comprehensive available list of options. There is currently burgeoning interest in ecosystem services and quantitative assessments of their importance and value. Recognition of the value of ecosystem services to human well-being represents an increasingly important argument for protecting and restoring the natural environment, alongside the moral and ethical justifications for conservation. As well as understanding the benefits of ecosystem services, it is also important to synthesize the practical interventions that are capable of maintaining and/or enhancing these services. Apart from pest regulation, pollination, and global climate regulation, this type of exercise has attracted relatively little attention. Through a systematic consultation exercise, we identify a candidate list of 296 possible interventions across the main regulating services of air quality regulation, climate regulation, water flow regulation, erosion regulation, water purification and waste treatment, disease regulation, pest regulation, pollination and natural hazard regulation. The range of interventions differs greatly between habitats and services depending upon the ease of manipulation and the level of research intensity. Some interventions have the potential to deliver benefits across a range of regulating services, especially those that reduce soil loss and maintain forest cover. Synthesis and applications: Solution scanning is important for questioning existing knowledge and identifying the range of options available to researchers and practitioners, as well as serving as the necessary basis for assessing cost effectiveness and guiding implementation strategies. We recommend that it become a routine part of decision making in all environmental policy areas.

Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe.

Since its introduction to the market in 1985, mefloquine has been used for malaria chemoprophylaxis by more than 35 million travellers. In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. Some malaria prevention advisors question the scientific basis for the restrictions and suggest that this cost-effective, anti-malarial drug will be displaced as a first-line anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children are left without a suitable alternative chemoprophylaxis. This commentary looks at the current position of mefloquine prescribing and the rationale of the new EMA recommendations and restrictions. It also describes the new recommendations for malaria prophylaxis that have been adapted by Switzerland, Germany, Austria and Italy where chemoprophylaxis use is restricted to high-risk malaria-endemic areas.