Adolescent survivors of childhood cancer: are they vulnerable for psychological distress?

OBJECTIVES: We aimed to (i) evaluate psychological distress in adolescent survivors of childhood cancer and compare them to siblings and a norm population; (ii) compare the severity of distress of distressed survivors and siblings with that of psychotherapy patients; and (iii) determine risk factors for psychological distress in survivors. METHODS: We sent a questionnaire to all childhood cancer survivors aged <16 years when diagnosed, who had survived ≥ 5 years and were aged 16-19 years at the time of study. Our control groups were same-aged siblings, a norm population, and psychotherapy patients. Psychological distress was measured with the Brief Symptom Inventory-18 (BSI-18) assessing somatization, depression, anxiety, and a global severity index (GSI). Participants with a T-score ≥ 57 were defined as distressed. We used logistic regression to determine risk factors. RESULTS: We evaluated the BSI-18 in 407 survivors and 102 siblings. Fifty-two survivors (13%) and 11 siblings (11%) had scores above the distress threshold (T ≥ 57). Distressed survivors scored significantly higher in somatization (p=0.027) and GSI (p=0.016) than distressed siblings, and also scored higher in somatization (p ≤ 0.001) and anxiety (p=0.002) than psychotherapy patients. In the multivariable regression, psychological distress was associated with female sex, self-reported late effects, and low perceived parental support. CONCLUSIONS: The majority of survivors did not report psychological distress. However, the severity of distress of distressed survivors exceeded that of distressed siblings and psychotherapy patients. Systematic psychological follow-up can help to identify survivors at risk and support them during the challenging period of adolescence.

Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey.

BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines. RESULTS: Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey-Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: 26 Week Data of the FACTS II Survey.

BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6 and 26 were completed by gastroenterologists in hospitals and private practices. RESULTS: Sixty patients (38F/22M) were included, 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of Harvey Bradshaw Index (HBI) was observed under CZP therapy (12.24.9 at week 0 vs 6.34.7 at week 6 and 6.75.3 at week 26, both P <0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36% respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behaviour, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

Telmisartan: a different angiotensin II receptor blocker protecting a different population?

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET()) showed that the angiotensin II receptor blocker (ARB) telmisartan was as protective as the reference-standard ramipril in a broad cross-section of patients at increased cardiovascular risk, but was better tolerated. Telmisartan has a unique profile among ARBs, with a high affinity for the angiotensin II type 1 receptor, a long duration of receptor binding, a high lipophilicity and a long plasma half life. This leads to sustained and powerful blood pressure lowering when compared with the first marketed ARBs, such as losartan and valsartan. Some pharmacological properties of telmisartan clearly distinguish it from other members of the ARB class and may contribute to the clinical effects seen with telmisartan. A class effect for ARBs cannot be assumed. To date, telmisartan is the only ARB that has been shown to reduce cardiovascular risk in at-risk cardiovascular patients.

The natural history of type II odontoid fractures in the elderly population. A retrospective study over a 14 years period.

Odontoid fractures are the most common cervical fractures in the adult population. They represent 9 to 18 % of all cervical fractures and the type II is the most common. The incidence of neurologic deficits (ND) in odontoid fractures varies between 3 to 25%. A recent study showed that patients with ND had a mortality rate increased by 4.72 times and a complication rate higher of 1.18 times. The most common complication in patients with ND was respiratory distress8. Surprisingly, although type II odontoid fractures are frequent cervical fractures, their natural history has been poorly described. Surgery for odontoid fractures is well described. However, there are so far guidelines based on class II and class III evidence only regarding indications for surgery and regarding surgical techniques. The class II guidelines recommend to consider surgical stabilization and fusion for type II odontoid in patients over 50 years of age. The class III recommendations are to first manage non-displaced odontoid type II fracture with external immobilization and that translation of 5mm or more is associated with a high rate of non- union with the conservative treatment and should be treated surgically.

Restriction site-associated DNA sequencing, genotyping error estimation and de novo assembly optimization for population genetic inference.

Restriction site-associated DNA sequencing (RADseq) provides researchers with the ability to record genetic polymorphism across thousands of loci for nonmodel organisms, potentially revolutionizing the field of molecular ecology. However, as with other genotyping methods, RADseq is prone to a number of sources of error that may have consequential effects for population genetic inferences, and these have received only limited attention in terms of the estimation and reporting of genotyping error rates. Here we use individual sample replicates, under the expectation of identical genotypes, to quantify genotyping error in the absence of a reference genome. We then use sample replicates to (i) optimize de novo assembly parameters within the program Stacks, by minimizing error and maximizing the retrieval of informative loci; and (ii) quantify error rates for loci, alleles and single-nucleotide polymorphisms. As an empirical example, we use a double-digest RAD data set of a nonmodel plant species, Berberis alpina, collected from high-altitude mountains in Mexico.

Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.

OBJECTIVE: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. DESIGN: A randomized, observer-blind, controlled trial (NCT00707967). METHODS: HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. RESULTS: Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. CONCLUSION: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2.

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.

Colonoscopy is the preferred colorectal cancer screening method in a population-based program.

BACKGROUND AND STUDY AIMS: Various screening methods for colorectal cancer (CRC) are promoted by professional societies; however, few data are available about the factors that determine patient participation in screening, which is crucial to the success of population-based programs. This study aimed (i) to identify factors that determine acceptance of screening and preference of screening method, and (ii) to evaluate procedure success, detection of colorectal neoplasia, and patient satisfaction with screening colonoscopy. PATIENTS AND METHODS: Following a public awareness campaign, the population aged 50 - 80 years was offered CRC screening in the form of annual fecal occult blood tests, flexible sigmoidoscopy, a combination of both, or colonoscopy. RESULTS: 2731 asymptomatic persons (12.0 % of the target population) registered with and were eligible to take part in the screening program. Access to information and a positive attitude to screening were major determinants of participation. Colonoscopy was the method preferred by 74.8 % of participants. Advanced colorectal neoplasia was present in 8.5 %; its prevalence was higher in males and increased with age. Significant complications occurred in 0.5 % of those undergoing colonoscopy and were associated with polypectomy or sedation. Most patients were satisfied with colonoscopy and over 90 % would choose it again for CRC screening. CONCLUSIONS: In this population-based study, only a small proportion of the target population underwent CRC screening despite an extensive information campaign. Colonoscopy was the preferred method and was safe. The determinants of participation in screening and preference of screening method, together with the distribution of colorectal neoplasia in different demographic categories, provide a rationale for improving screening procedures.

Restriction site-associated DNA sequencing, genotyping error estimation and de novo assembly optimization for population genetic inference.

Restriction site-associated DNA sequencing (RADseq) provides researchers with the ability to record genetic polymorphism across thousands of loci for nonmodel organisms, potentially revolutionizing the field of molecular ecology. However, as with other genotyping methods, RADseq is prone to a number of sources of error that may have consequential effects for population genetic inferences, and these have received only limited attention in terms of the estimation and reporting of genotyping error rates. Here we use individual sample replicates, under the expectation of identical genotypes, to quantify genotyping error in the absence of a reference genome. We then use sample replicates to (i) optimize de novo assembly parameters within the program Stacks, by minimizing error and maximizing the retrieval of informative loci; and (ii) quantify error rates for loci, alleles and single-nucleotide polymorphisms. As an empirical example, we use a double-digest RAD data set of a nonmodel plant species, Berberis alpina, collected from high-altitude mountains in Mexico.

THE USE OF SIMULATIONS IN EVOLUTIONARY POPULATION GENETICS: APPLICATIONS ON HUMANS, OWLS AND VIRTUAL ORGANISMS

Summary (in English) Computer simulations provide a practical way to address scientific questions that would be otherwise intractable. In evolutionary biology, and in population genetics in particular, the investigation of evolutionary processes frequently involves the implementation of complex models, making simulations a particularly valuable tool in the area. In this thesis work, I explored three questions involving the geographical range expansion of populations, taking advantage of spatially explicit simulations coupled with approximate Bayesian computation. First, the neutral evolutionary history of the human spread around the world was investigated, leading to a surprisingly simple model: A straightforward diffusion process of migrations from east Africa throughout a world map with homogeneous landmasses replicated to very large extent the complex patterns observed in real human populations, suggesting a more continuous (as opposed to structured) view of the distribution of modern human genetic diversity, which may play a better role as a base model for further studies. Second, the postglacial evolution of the European barn owl, with the formation of a remarkable coat-color cline, was inspected with two rounds of simulations: (i) determine the demographic background history and (ii) test the probability of a phenotypic cline, like the one observed in the natural populations, to appear without natural selection. We verified that the modern barn owl population originated from a single Iberian refugium and that they formed their color cline, not due to neutral evolution, but with the necessary participation of selection. The third and last part of this thesis refers to a simulation-only study inspired by the barn owl case above. In this chapter, we showed that selection is, indeed, effective during range expansions and that it leaves a distinguished signature, which can then be used to detect and measure natural selection in range-expanding populations. Résumé (en français) Les simulations fournissent un moyen pratique pour répondre à des questions scientifiques qui seraient inabordable autrement. En génétique des populations, l'étude des processus évolutifs implique souvent la mise en oeuvre de modèles complexes, et les simulations sont un outil particulièrement précieux dans ce domaine. Dans cette thèse, j'ai exploré trois questions en utilisant des simulations spatialement explicites dans un cadre de calculs Bayésiens approximés (approximate Bayesian computation : ABC). Tout d'abord, l'histoire de la colonisation humaine mondiale et de l'évolution de parties neutres du génome a été étudiée grâce à un modèle étonnement simple. Un processus de diffusion des migrants de l'Afrique orientale à travers un monde avec des masses terrestres homogènes a reproduit, dans une très large mesure, les signatures génétiques complexes observées dans les populations humaines réelles. Un tel modèle continu (opposé à un modèle structuré en populations) pourrait être très utile comme modèle de base dans l'étude de génétique humaine à l'avenir. Deuxièmement, l'évolution postglaciaire d'un gradient de couleur chez l'Effraie des clocher (Tyto alba) Européenne, a été examiné avec deux séries de simulations pour : (i) déterminer l'histoire démographique de base et (ii) tester la probabilité qu'un gradient phénotypique, tel qu'observé dans les populations naturelles puisse apparaître sans sélection naturelle. Nous avons montré que la population actuelle des chouettes est sortie d'un unique refuge ibérique et que le gradient de couleur ne peux pas s'être formé de manière neutre (sans l'action de la sélection naturelle). La troisième partie de cette thèse se réfère à une étude par simulations inspirée par l'étude de l'Effraie. Dans ce dernier chapitre, nous avons montré que la sélection est, en effet, aussi efficace dans les cas d'expansion d'aire de distribution et qu'elle laisse une signature unique, qui peut être utilisée pour la détecter et estimer sa force.

Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study.

BACKGROUND: Socioeconomic adversity in early life has been hypothesized to "program" a vulnerable phenotype with exaggerated inflammatory responses, so increasing the risk of developing type 2 diabetes in adulthood. The aim of this study is to test this hypothesis by assessing the extent to which the association between lifecourse socioeconomic status and type 2 diabetes incidence is explained by chronic inflammation. METHODS AND FINDINGS: We use data from the British Whitehall II study, a prospective occupational cohort of adults established in 1985. The inflammatory markers C-reactive protein and interleukin-6 were measured repeatedly and type 2 diabetes incidence (new cases) was monitored over an 18-year follow-up (from 1991-1993 until 2007-2009). Our analytical sample consisted of 6,387 non-diabetic participants (1,818 women), of whom 731 (207 women) developed type 2 diabetes over the follow-up. Cumulative exposure to low socioeconomic status from childhood to middle age was associated with an increased risk of developing type 2 diabetes in adulthood (hazard ratio [HR] = 1.96, 95% confidence interval: 1.48-2.58 for low cumulative lifecourse socioeconomic score and HR = 1.55, 95% confidence interval: 1.26-1.91 for low-low socioeconomic trajectory). 25% of the excess risk associated with cumulative socioeconomic adversity across the lifecourse and 32% of the excess risk associated with low-low socioeconomic trajectory was attributable to chronically elevated inflammation (95% confidence intervals 16%-58%). CONCLUSIONS: In the present study, chronic inflammation explained a substantial part of the association between lifecourse socioeconomic disadvantage and type 2 diabetes. Further studies should be performed to confirm these findings in population-based samples, as the Whitehall II cohort is not representative of the general population, and to examine the extent to which social inequalities attributable to chronic inflammation are reversible. Please see later in the article for the Editors' Summary.

Seroepidemiology of Herpes Simplex virus type 1 and 2 in Western and Southern Switzerland in adults aged 25-74 in 1992-93: a population-based study.

BACKGROUND: Genital herpes is one of the most prevalent sexually-transmitted diseases, and accounts for a substantial morbidity. Genital herpes puts newborns at risk for very severe disease and also increases the risk of horizontal HIV transmission. It thus stands as an important public health problem. The recent availability of type-specific gG-based assays detecting IgG against HSV-1 and HSV-2 allows to establish the prevalence of each subtype. Worldwide, few data have been published regarding the seroprevalence in general populations of HSV-2, the major causative agent for genital herpes, while no data exist regarding the Swiss population. METHODS: To evaluate the prevalence of IgG antibodies against HSV-1 and HSV-2 in Switzerland, we used a population-based serum repository from a health examination survey conducted in the Western and Southern area of Switzerland in 1992-93. A total of 3,120 sera were analysed by type-specific gG-based ELISA and seroprevalence was correlated with available volunteers characteristics by logistic regression. RESULTS: Overall, seroprevalence rates were 80.0 +/- 0.9% (SE, 95% CI: 78.1-81.8) for HSV-1 and 19.3 +/- 0.9% (SE, 95% CI: 17.6-21.1) for HSV-2 in adults 35-64 year old. HSV-1 and HSV-2 seroprevalence increased with age, with a peak HSV-2 seroprevalence in elderly gentlemen, possibly a seroarcheological evidence of sexually transmitted disease epidemics during World War II. Risk factors for HSV-2 infection included female sex, marital status other than married, and size of town of residence larger than 1500 inhabitants. Unexpectedly and conversely to HSV-1, HSV-2 seroprevalence increased with educational level. HSV-2 infection was less prevalent among HSV-1 infected individuals when compared to HSV-1 uninfected individuals. This effect was most apparent among women at high risk for HSV-2 infection. CONCLUSIONS: Our data demonstrate that by the early nineties, HSV-2 had spread quite largely in the Swiss population. However, the epidemiology of HSV-2 in Switzerland presents paradoxical characteristics, e.g. positive correlation with education level, that have not been observed elsewhere.

Changes in antihypertensive drug treatment in the general population: the Colaus Study

Background and aims: there is little information regar ding changes in antihypertensive drug treatment in Switzerland. We aimed at assessing those changes in a population-based, prospective study. Methods: 768 hypertensive subjects (372 women, 397 men) followed for 5 years. Subjects were defined as continuers (no change), switchers (one antihypertensive class replace by another), combiners (one antihypertensive class added) and discontinuers (stopped treatment). Results: Analysis of all patients (mono or combination therapy) showed that 54.6% were continuers, 27.2% combiners, 12.9% switchers and 5.3 % discontinuers. Similar findings were obtained for participants on monotherapy only: 42.2% continuers, 36.7% combiners, 13.4% switchers and 7.7% discontinuers. Combiners had higher systolic and diastolic blood pressure values at baseline than the other groups (p<0.001), while no difference were found for personal and family history and other clinical and biological variables. Compared to continuers, combiners and switchers improved their blood pressure status at follow-up: 26.7% of combiners and 26.3% of switchers improved, versus 17.7% of continuers and 7.3% of discontinuers (p<0.001). Among participants on monotherapy at baseline, continuation was greatest for angiotensin II type 1 receptor blocking agents (ARBs, 53.1%), angiotensin-converting enzyme inhibitors (44.4%) and β-blockers (41.8%). Only one quarter of participants treated with diuretic or calcium channel blockers at baseline remained so at follow-up. Conclusion: Antihypertensivedrug treatment is very stable in Switzerland. There are no big differences in persistence between antihypertensive classes, even if ARBs had the most favorable utilization pattern. Changes are only due to blood pressure level and improve blood pressure status.

Prevalence, awareness, treatment and control of high blood pressure in a Swiss city general population: the CoLaus study.

BACKGROUND: This study is aimed to assess the prevalence of awareness, treatment and control of high blood pressure (HBP) and associated factors in a Swiss city. DESIGN: Population-based cross-sectional study of 6182 participants (52.5% women) aged 35-75 years living in Lausanne, Switzerland. METHODS: HBP was defined as blood pressure >/=140/90 mmHg or current antihypertensive medication. RESULTS: The overall prevalence of HBP was 36% (95% confidence interval: 35-38%). Among participants with HBP, 63% were aware of it. Among participants aware of HBP, 78% were treated, and among those treated, 48% were controlled (BP <140/90 mmHg). In multivariate analysis, HBP prevalence was associated with older age, male sex, low educational level, high alcohol intake, awareness of diabetes or dyslipidaemia, obesity and parental history of myocardial infarction. HBP awareness was associated with older age, female sex, awareness of diabetes or dyslipidaemia, obesity and parental history of myocardial infarction. HBP control was associated with younger age, higher educational level and no alcohol intake. Alone or in combination, sartans were the most often prescribed antihypertensive medication category (41%), followed by diuretics, beta-blockers, angiotensin converting enzyme inhibitors and calcium channel blockers. Only 31% of participants treated for HBP were taking >/=2 antihypertensive medications. CONCLUSION: Although more than half of all participants with HBP were aware and more than three-quarters of them received a pharmacological treatment, less than half of those treated were adequately controlled.