Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection.

BACKGROUND: The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. OBJECTIVES: To determine whether single-nucleotide polymorphisms (SNPs) in TLR2-4 and TLR7-9 influenced the natural course of HIV-1 infection. METHODS: Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation-maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). RESULTS: Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7-9.2] for GA versus AA and OR, 4.7 (95% CI,1.9-12.0) for GG versus AA (P = 0.0008). CONCLUSION: Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.

Infective endocarditis.

Despite improvements in health care, the incidence of infective endocarditis has not decreased over the past decades. This apparent paradox is explained by a progressive evolution in risk factors; while classic predisposing conditions such as rheumatic heart disease have been all but eradicated, new risk factors for infective endocarditis have emerged. These include intravenous drug use, sclerotic valve disease in elderly patients, use of prosthetic valves, and nosocomial disease. Newly identified pathogens, which are difficult to cultivate--eg, Bartonella spp and Tropheryma whipplei--are present in selected individuals, and resistant organisms are challenging conventional antimicrobial therapy. Keeping up with these changes depends on a comprehensive approach, allying understanding of the pathogenesis of disease with the development of new drugs for infective endocarditis. Infection by staphylococci and streptococci is being dissected at the molecular level. New ideas for antimicrobial agents are being developed. These novel insights should help redefine preventive and therapeutic strategies against infective endocarditis.

Host- rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with decreased health-related quality of life (HRQOL). Although HCV has been suggested to directly impair neuropsychiatric functions, other factors may also play a role. PATIENTS AND METHODS: In this cross-sectional study, we assessed the impact of various host-, disease- and virus-related factors on HRQOL in a large, unselected population of anti-HCV-positive subjects. All individuals (n = 1736) enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were asked to complete the Short Form 36 (SF-36) and the Hospital Anxiety Depression Scale (HADS). RESULTS: 833 patients (48%) returned the questionnaires. Survey participants had significantly worse scores in both assessment instruments when compared to a general population. By multivariable analysis, reduced HRQOL (mental and physical summary scores of SF-36) was independently associated with income. In addition, a low physical summary score was associated with age and diabetes, whereas a low mental summary score was associated with intravenous drug use. HADS anxiety and depression scores were independently associated with income and intravenous drug use. In addition, HADS depression score was associated with diabetes. None of the SF-36 or HADS scores correlated with either the presence or the level of serum HCV RNA. In particular, SF-36 and HADS scores were comparable in 555 HCV RNA-positive and 262 HCV RNA-negative individuals. CONCLUSIONS: Anti-HCV-positive subjects have decreased HRQOL compared to controls. The magnitude of this decrease was clinically important for the SF-36 vitality score. Host and environmental, rather than viral factors, seem to impact on HRQOL level.

Profile, cost and pattern of prescriptions for polymedicated patients in Catalonia (Spain).

OBJECTIVES: Polypharmacy is one of the main management issues in public health policies because of its financial impact and the increasing number of people involved. The polymedicated population according to their demographic and therapeutic profile and the cost for the public healthcare system were characterised. DESIGN: Cross-sectional study. SETTING: Primary healthcare in Barcelona Health Region, Catalonia, Spain (5 105 551 inhabitants registered). PARTICIPANTS: All insured polymedicated patients. Polymedicated patients were those with a consumption of ≥16 drugs/month. MAIN OUTCOMES MEASURES: The study variables were related to age, gender and medication intake obtained from the 2008 census and records of prescriptions dispensed in pharmacies and charged to the public health system. RESULTS: There were 36 880 polymedicated patients (women: 64.2%; average age: 74.5±10.9 years). The total number of prescriptions billed in 2008 was 2 266 830 (2 272 920 total package units). The most polymedicated group (up to 40% of the total prescriptions) was patients between 75 and 84 years old. The average number of prescriptions billed monthly per patient was 32±2, with an average cost of 452.7±27.5. The total cost of those prescriptions corresponded to 2% of the drug expenditure in Catalonia. The groups N, C, A, R and M represented 71.4% of the total number of drug package units dispensed to polymedicated patients. Great variability was found between the medication profiles of men and women, and between age groups; greater discrepancies were found in paediatric patients (5-14 years) and the elderly (≥65 years). CONCLUSIONS: This study provides essential information to take steps towards rational drug use and a structured approach in the polymedicated population in primary healthcare.

Nonoccupational HIV post-exposure prophylaxis: a 10-year retrospective analysis.

BACKGROUND: We conducted a retrospective analysis of administration of nonoccupational HIV post-exposure prophylaxis (nPEP) in a single centre where tracing and testing of the source of exposure were carried out systematically over a 10-year period. METHODS: Files of all nPEP requests between 1998 and 2007 were reviewed. Characteristics of the exposed and source patients, the type of exposure, and clinical and serological outcomes were analysed. RESULTS: nPEP requests increased by 850% over 10 years. Among 910 events, 58% were heterosexual exposures, 15% homosexual exposures, 6% sexual assaults and 20% nonsexual exposures. In 208 events (23%), the source was reported to be HIV positive. In the remaining cases, active source tracing enabled 298 HIV tests to be performed (42%) and identified 11 HIV infections (3.7%). nPEP was able to be avoided or interrupted in 31% of 910 events when the source tested negative. Of 710 patients who started nPEP, 396 (56%) reported side effects, among whom 39 (5%) had to interrupt treatment. There were two HIV seroconversions, and neither was attributed to nPEP failure. CONCLUSIONS: nPEP requests increased over time. HIV testing of the source person avoided nPEP in 31% of events and was therefore paramount in the management of potential HIV exposures. Furthermore, it allowed active screening of populations potentially at risk for undiagnosed HIV infection, as shown by the increased HIV prevalence in these groups (3.7%) compared with a prevalence of 0.3% in Switzerland as a whole.

Longer term clinical and virological outcome of sub-Saharan African participants on antiretroviral treatment in the Swiss HIV Cohort Study.

OBJECTIVES: Persons from sub-Saharan Africa (SSA) are increasingly enrolled in the Swiss HIV Cohort Study (SHCS). Cohorts from other European countries showed higher rates of viral failure among their SSA participants. We analyzed long-term outcomes of SSA versus North Western European participants. DESIGN: We analyzed data of the SHCS, a nation-wide prospective cohort study of HIV-infected adults at 7 sites in Switzerland. METHODS: SSA and North Western European participants were included if their first treatment combination consisted of at least 3 antiretroviral drugs (cART), if they had at least 1 follow-up visit, did not report active injecting drug use, and did not start cART with CD4 counts >200 cells per microliter during pregnancy. Early viral response, CD4 cell recovery, viral failure, adherence, discontinuation from SHCS, new AIDS-defining events, and survival were analyzed using linear regression and Cox proportional hazard models. RESULTS: The proportion of participants from SSA within the SHCS increased from 2.6% (<1995) to 20.8% (2005-2009). Of 4656 included participants, 808 (17.4%) were from SSA. Early viral response (6 months) and rate of viral failure in an intent-to-stay-on-cART approach were similar. However, SSA participants had a higher risk of viral failure on cART (adjusted hazard ratio: 2.03, 95% confidence interval: 1.50 to 2.75). Self-reported adherence was inferior for SSA. There was no increase of AIDS-defining events or mortality in SSA participants. CONCLUSIONS: Increased attention must be given to factors negatively influencing adherence to cART in participants from SSA to guarantee equal longer-term results on cART.

Prevalence and predictors of suicide attempt in an incidence cohort of 661 young people with first-episode psychosis

OBJECTIVES: Studies investigating suicidal behaviour in psychosis rarely focus on incidence cohorts of first-episode patients. This is important, because patients who refuse study participation have higher rates of comorbid substance use disorders and longer duration of untreated psychosis as well as worse course illness, variables potentially linked to higher prevalence of suicidal behaviour. The aims of the present study were therefore to examine the prevalence and predictors of suicide and suicide attempt before and during the first 18-24 months of treatment. METHOD: A retrospective file audit of 661 patients was carried out. RESULTS: Six patients (0.9%) died by suicide, 93 (14.3%) attempted suicide prior to entry, and 57 (8.7%) did so during treatment. Predictors of suicide attempt were: previous attempt (odds ratio (OR)=45.54, 95% confidence interval (CI)=9.46-219.15), sexual abuse (OR=8.46, 95%CI=1.88-38.03), comorbid polysubstance (OR=13.63, 95%CI=2.58-71.99), greater insight (OR=0.17, 95%CI=0.06-0.49), lower baseline Global Assessment of Functioning Scale and Scale of Occupational and Functional Assessment score (OR=0.96, 95%CI=0.62-0.91; OR=0.98, 95%CI=0.95-0.99), and longer time in treatment (OR=1.05, 95%CI=1.03-1.08). CONCLUSIONS: The prevalence of suicidal behaviour was high, indicating that suicidal behaviour in incidence populations is higher than in non-epidemiological cohorts of first-episode patients. The rate of repetition of suicide attempt among the sample, however, was lower than expected, suggesting that specialist services can play a role in reducing suicide risk.

Soins intégrés: comment accompagner un changement de culture [Integrated care: how to support a culture change?].

The primary care center at Lausanne University Hospital trains residents to new models of integrated care. The future GPs discover new forms of collaboration with nurses, pharmacists or social workers. The collaboration model includes seeing patients together or delegating care to other providers, with the aim of improving the efficiency of a patient-centered care approach. The article includes examples of integrated care in consultation for travelers, victims of violence, pharmacist medication adherence counseling, medicosocial team work for alcohol use disorders and nurse practitioners' primary care for asylum seekers.

Violence-related injury and gender: The role of alcohol and alcohol combined with illicit drugs.

INTRODUCTION AND AIMS: The positive relationship between alcohol use, gender and violence-related injury is well established. However, less is known about injuries when alcohol is used in combination with other drugs. DESIGN AND METHODS: Self-report information was collected on alcohol and illicit drug use in the 6 h before a violence-related injury in probability samples of patients presenting to emergency departments (n = 9686). RESULTS: Patients with violence-related injuries reported the highest rates of alcohol use (49% of men; 23% of women) and alcohol use combined with illicit drugs (8% of men; 4% of women) whereas non-violent injury patients reported lower rates of alcohol use (17% of men; 8% of women) and alcohol use combined with drugs (2% for men; 1% for women). Marijuana/hashish was the most commonly reported drug. The odds of a violent injury were increased when alcohol was used [men: odds ratio (OR) = 5.4, 95% confidence interval (CI) 4.6-6.3; women: OR = 4.0, 95% CI 3.0-5.5] or when alcohol was combined with illicit drug use before the injury (men: OR = 6.6, 95% CI 4.7-9.3; women: OR = 5.7, 95% CI = 2.7-12.2) compared with non-users. No significant change in the odds of a violent injury was observed for men or women when alcohol users were compared with alcohol and drug users. DISCUSSION AND CONCLUSIONS: The positive association between alcohol and violent injury does not appear to be altered by the added use of drugs. Additional work is needed to understand the interpersonal, contextual and cultural factors related to substance use to identify best prevention practices and develop appropriate policies. [Korcha RA, Cherpitel CJ, Witbrodt J, Borges G, Hejazi-Bazargan S, Bond JC, Ye Y, Gmel G. Violence-related injury and gender: The role of alcohol and alcohol combined with illicit drugs. Drug Alcohol Rev 2014;33:43-50].

Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Gender inequalities in the response to combination antiretroviral therapy over time: the Swiss HIV Cohort Study.

OBJECTIVES: Gender-specific data on the outcome of combination antiretroviral therapy (cART) are a subject of controversy. We aimed to compare treatment responses between genders in a setting of equal access to cART over a 14-year period. METHODS: Analyses included treatment-naïve participants in the Swiss HIV Cohort Study starting cART between 1998 and 2011 and were restricted to patients infected by heterosexual contacts or injecting drug use, excluding men who have sex with men. RESULTS: A total of 3925 patients (1984 men and 1941 women) were included in the analysis. Women were younger and had higher CD4 cell counts and lower HIV RNA at baseline than men. Women were less likely to achieve virological suppression < 50 HIV-1 RNA copies/mL at 1 year (75.2% versus 78.1% of men; P = 0.029) and at 2 years (77.5% versus 81.1%, respectively; P = 0.008), whereas no difference between sexes was observed at 5 years (81.3% versus 80.5%, respectively; P = 0.635). The probability of virological suppression increased in both genders over time (test for trend, P < 0.001). The median increase in CD4 cell count at 1, 2 and 5 years was generally higher in women during the whole study period, but it gradually improved over time in both sexes (P < 0.001). Women also were more likely to switch or stop treatment during the first year of cART, and stops were only partly driven by pregnancy. In multivariate analysis, after adjustment for sociodemographic factors, HIV-related factors, cART and calendar period, female gender was no longer associated with lower odds of virological suppression. CONCLUSIONS: Gender inequalities in the response to cART are mainly explained by the different prevalence of socioeconomic characteristics in women compared with men.

Frequent users of the emergency department in a universal health coverage system : a randomized controlled trial of a case-management intervention

BACKGROUND: Frequent emergency department users represent a small number of patients but account for a large number of emergency department visits. They should be a focus because they are often vulnerable patients with many risk factors affecting their quality of life (QoL). Case management interventions have resulted in a significant decrease in emergency department visits, but association with QoL has not been assessed. One aim of our study was to examine to what extent an interdisciplinary case management intervention, compared to standard emergency care, improved frequent emergency department users' QoL. METHODS: Data are part of a randomized, controlled trial designed to improve frequent emergency department users' QoL and use of health-care resources at the Lausanne University Hospital, Switzerland. In total, 250 frequent emergency department users (≥5 attendances during the previous 12 months; ≥ 18 years of age) were interviewed between May 2012 and July 2013. Following an assessment focused on social characteristics; social, mental, and somatic determinants of health; risk behaviors; health care use; and QoL, participants were randomly assigned to the control or the intervention group (n=125 in each group). The final sample included 194 participants (20 deaths, 36 dropouts, n=96 in the intervention group, n=99 in the control group). Participants in the intervention group received a case management intervention by an interdisciplinary, mobile team in addition to standard emergency care. The case management intervention involved four nurses and a physician who provided counseling and assistance concerning social determinants of health, substance-use disorders, and access to the health-care system. The participants' QoL was evaluated by a study nurse using the WHOQOL-BREF five times during the study (at baseline, and at 2, 5.5, 9, and 12 months). Four of the six WHOQOL dimensions of QoL were retained here: physical health, psychological health, social relationship, and environment, with scores ranging from 0 (low QoL) to 100 (high QoL). A linear, mixed-effects model with participants as a random effect was run to analyze the change in QoL over time. The effects of time, participants' group, and the interaction between time and group were tested. These effects were controlled for sociodemographic characteristics and health-related variables (i.e., age, gender, education, citizenship, marital status, type of financial resources, proficiency in French, somatic and mental health problems, and behaviors at risk).

Impact of case management on frequent users quality of life : a randomized controlled trial

BACKGROUND: Frequent emergency department users represent a small number of patients but account for a large number of emergency department visits. They should be a focus because they are often vulnerable patients with many risk factors affecting their quality of life (QoL). Case management interventions have resulted in a significant decrease in emergency department visits, but association with QoL has not been assessed. One aim of our study was to examine to what extent an interdisciplinary case management intervention, compared to standard emergency care, improved frequent emergency department users' QoL. METHODS: Data are part of a randomized, controlled trial designed to improve frequent emergency department users' QoL and use of health-care resources at the Lausanne University Hospital, Switzerland. In total, 250 frequent emergency department users (≥5 attendances during the previous 12 months; ≥ 18 years of age) were interviewed between May 2012 and July 2013. Following an assessment focused on social characteristics; social, mental, and somatic determinants of health; risk behaviors; health care use; and QoL, participants were randomly assigned to the control or the intervention group (n=125 in each group). The final sample included 194 participants (20 deaths, 36 dropouts, n=96 in the intervention group, n=99 in the control group). Participants in the intervention group received a case management intervention by an interdisciplinary, mobile team in addition to standard emergency care. The case management intervention involved four nurses and a physician who provided counseling and assistance concerning social determinants of health, substance-use disorders, and access to the health-care system.

Direct to consumer advertising : the case for greater consumer control

A nyone traveling to the United States from countries other than New Zealand will be surprised by the prevalence of health-related advertisements on television, including ads for drugs. Typically, these TV ads follow a pattern: an ad for a burger at only 99 cents, followed by one for a proton-pump inhibitor, then an ad on healthy home-cooked food delivered directly to your home and an ad for a home-based abdominal workout DVD, followed by an ad for a lipid-lowering drug. There are, however, nuances. After 8 pm, the visitor might encounter an ad for the "little blue pill." This sequence sometimes includes an ad featuring antihistamines for allergic rhinitis in spring and one promoting antidepressants in the winter. Such direct-to-consumer advertising (DTCA) of prescription drugs is usual business in the United States and New Zealand but is prohibited in the rest of the world. Why? Because DTCA for prescribing drugs has pros and cons (discussed elsewhere,1-3 including in JGIM4) that are balanced differently in different countries. Constitutional factors-such as the First Amendment protections on speech, including commercial speech, in the United States5 -as well as patient and population safety considerations, which all differ across countries, modulate reactions to DTCA. Additionally, lack of robust data on the impact of DTCA on prescription drug use adds to the confusion. Evidence, though limited, suggests that DTCA increases drug sales. However, whether the increase in sales corrects existing underuse or encourages over/misuse is not clear.

Impact of case management on frequent users' quality of life : a randomized, controlled trial (FM 286)

Introduction: Frequent emergency department (ED) users are often vulnerable patients with many risk factors affecting their quality of life (QoL). The aim of this study was to examine to what extent a case management intervention improved frequent ED users' QoL. Methods: Data were part of a randomized, controlled trial designed to improve frequent ED users' QoL at the Lausanne University Hospital. A total of 194 frequent ED users (≥ 5 attendances during the previous 12 months; ≥ 18 years of age) were randomly assigned to the control or the intervention group. Participants in the intervention group received a case management intervention (i.e. counseling and assistance concerning social determinants of health, substance-use disorders, and access to the health-care system). QoL was evaluated using the WHOQOL-BREF at baseline and twelve months later. Four dimensions of QoL were retained: physical health, psychological health, social relationship, and environment, with scores ranging from 0 (low QoL) to 100 (high QoL).