Immunotherapeutic strategies for bladder cancer.

Bladder cancer is a common urologic malignancy with rising incidence in the elderly population. In most cases, bladder cancer is non-muscle-invasive at diagnosis and shows dramatically high recurrence rates, although current treatments often reduce the risk of disease progression. Immunotherapy using intravesical instillation of Bacillus Calmette-Guérin (BCG) remains the most effective therapy for patients with high risk tumors. However, BCG-therapy has important limitations including substantial adverse events and frequent treatment failure. Thus, it appears crucial to either improve or replace current therapy using new immunotherapeutic strategies. Here, we discuss the clinical trials that assessed therapeutic vaccination of bladder cancer patients using tumor associated antigens and we also argue for novel approaches arising from murine models. Vaccination routes to induce appropriate T-cell homing in the tumor site as well as the use of local immunostimulation to enhance recruitment of vaccine-induced T cells are discussed to highlight what we believe is a promising therapeutic vaccination strategy for patients with non-muscle-invasive bladder cancer.

Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence.

INTRODUCTION: Psychiatric disorders are among the leading causes of disability in Western societies. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs during pregnancy and the postpartum period. Over the last decade, conflicting findings regarding the safety of SSRI drugs during pregnancy and lactation have questioned whether such treatments should be used during this period. AREAS COVERED: We discuss the main criteria that should be considered in the risk/benefit assessment of SSRI treatment in pregnant and/or breastfeeding patients (i.e., risks associated with SSRI use and with untreated depression as well as therapeutic benefits of SSRI and some alternative treatment strategies). For each criterion, available evidence has been synthesized and stratified by methodological quality as well as discussed for clinical impact. EXPERT OPINION: Currently, it is impossible for most of the evaluated outcomes to distinguish between the effects related to the mother's underlying disease and those inherent to SSRI treatment. In women suffering from major depression and responding to a pharmacological treatment, introduction or continuation of an SSRI should be encouraged in order to prevent maternal complications and to preserve maternal-infant bonding. The choice of the right drug depends above all on individual patient characteristics such as prior treatment response, diagnoses and comorbid conditions.

Divergent fifteen-year trends in traditional and cardiometabolic risk factors of cardiovascular diseases in the Seychelles.

OBJECTIVE: Few studies have assessed secular changes in the levels of cardiovascular risk factors (CV-RF) in populations of low or middle income countries. The systematic collection of a broad set of both traditional and metabolic CV-RF in 1989 and 2004 in the population of the Seychelles islands provides a unique opportunity to examine trends at a fairly early stage of the "diabesity" era in a country in the African region. METHODS: Two examination surveys were conducted in independent random samples of the population aged 25-64 years in 1989 and 2004, attended by respectively 1081 and 1255 participants (participation rates >80%). All results are age-standardized to the WHO standard population. RESULTS: In 2004 vs. 1989, the levels of the main traditional CV-RF have either decreased, e.g. smoking (17% vs. 30%, p < 0.001), mean blood pressure (127.8/84.8 vs. 130.0/83.4 mmHg, p < 0.05), or only moderately increased, e.g. median LDL-cholesterol (3.58 vs. 3.36 mmol/l, p < 0. 01). In contrast, marked detrimental trends were found for obesity (37% vs. 21%, p < 0.001) and several cardiometabolic CVD-RF, e.g. mean HDL-cholesterol (1.36 vs. 1.40 mmol/l, p < 0.05), median triglycerides (0.80 vs. 0.78 mmol/l, p < 0.01), mean blood glucose (5.89 vs. 5.22 mmol/l, p < 0.001), median insulin (11.6 vs. 8.3 micromol/l, p < 0.001), median HOMA-IR (2.9 vs. 1.8, p < 0.001) and diabetes (9.4% vs. 6.2%, p < 0.001). At age 40-64, the prevalence of elevated total cardiovascular risk tended to decrease (e.g. WHO-ISH risk score > or =10; 11% vs. 13%, ns), whereas the prevalence of the metabolic syndrome (which integrates several cardiometabolic CVD-RF) nearly doubled (36% vs. 20%, p < 0.001). Data on physical activity and on intake of alcohol, fruit and vegetables are also provided. Awareness and treatment rates improved substantially for hypertension and diabetes, but control rates improved for the former only. Median levels of the cardiometabolic CVD-RF increased between 1989 and 2004 within all BMI strata, suggesting that the worsening levels of cardiometabolic CVD-RF in the population were not only related to increasing BMI levels in the interval. CONCLUSION: The levels of several traditional CVD-RF improved over time, while marked detrimental trends were observed for obesity, diabetes and several cardiometabolic factors. Thus, in this population, the rapid health transition was characterized by substantial changes in the patterns of CVD-RF. More generally, this analysis suggests the importance of surveillance systems to identify risk factor trends and the need for preventive strategies to promote healthy lifestyles and nutrition.

Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma.

OBJECTIVE: To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with hepatitis C and B viruses. DESIGN: A case-control study nested in the Swiss HIV Cohort Study. METHODS: Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrollment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression. RESULTS: All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count [Odds ratio (OR) per 100 cells/mul decrease = 1.33, 95% confidence interval (CI) 1.06-1.68] and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01-2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18-1.91). CONCLUSION: Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.

Piercing among adolescents: body art as risk marker.

PURPOSE: To ascertain the prevalence of piercing among a nationally representative sample of adolescents; to assess whether having a piercing is a marker for risk behaviors; and to determine whether having more than one piercing is a cumulative marker for risk behaviors. METHODS: Data were drawn from a cross-sectional survey of a nationally representative sample of adolescents aged 16 to 20 years (N=7548). Controlling for background variables, pierced and non-pierced youth were compared on risk behaviors related to drug use, sexual behavior, and suicide. In a second step, adolescents having one piercing were compared with those having more than one. In both cases, statistically significant variables in the bivariate analysis were included in a logistic regression. Analyses were conducted separately by gender. RESULTS: Overall, 20.2% of our sample had a piercing (excluding earlobes), and it was significantly more prevalent among females than among males (33.8% vs. 7.4%; P<.001). In the bivariate analysis, all risk behaviors were significantly associated with having a piercing, and most of them remained significant in the multivariate analysis. One third of pierced subjects had more than one piercing, with no gender difference in prevalence. In the multivariate analysis, females with more than one piercing were more likely to have had multiple partners and to use cannabis, while no differences were noted for males. CONCLUSIONS: Body piercing is becoming popular among Swiss adolescents, especially females. Having a body piercing seems to be a risk marker for risk behaviors. Moreover, having multiple piercings is a cumulative risk marker for females.

Using register data to assess the impact of response enhancement methods on the risk of nonresponse bias and survey costs

The pursuit of high response rates to minimise the threat of nonresponse bias continues to dominate decisions about resource allocation in survey research. Yet a growing body of research has begun to question this practice. In this study, we use previously unavailable data from a new sampling frame based on population registers to assess the value of different methods designed to increase response rates on the European Social Survey in Switzerland. Using sampling data provides information about both respondents and nonrespondents, making it possible to examine how changes in response rates resulting from the use of different fieldwork methods relate to changes in the composition and representativeness of the responding sample. We compute an R-indicator to assess representativity with respect to the sampling register variables, and find little improvement in the sample composition as response rates increase. We then examine the impact of response rate increases on the risk of nonresponse bias based on Maximal Absolute Bias (MAB), and coefficients of variation between subgroup response rates, alongside the associated costs of different types of fieldwork effort. The results show that increases in response rate help to reduce MAB, while only small but important improvements to sample representativity are gained by varying the type of effort. These findings lend further support to research that has called into question the value of extensive investment in procedures aimed at reaching response rate targets and the need for more tailored fieldwork strategies aimed both at reducing survey costs and minimising the risk of bias.

Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118), a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108), or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103). The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 +/- 70.5 (mean +/- SD) using the fixed-dose combination strategy, compared with -7.2 +/- 81.0 using the sequential monotherapy approach and -17.5 +/- 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril) and a diuretic (indapamide).

Serum resistin concentrations and risk of new onset heart failure in older persons: the health, aging, and body composition (Health ABC) study.

OBJECTIVE: Resistin is associated with inflammation and insulin resistance and exerts direct effects on myocardial cells including hypertrophy and altered contraction. We investigated the association of serum resistin concentrations with risk for incident heart failure (HF) in humans. METHODS AND RESULTS: We studied 2902 older persons without prevalent HF (age, 73.6+/-2.9 years; 48.1% men; 58.8% white) enrolled in the Health, Aging, and Body Composition (Health ABC) Study. Correlation between baseline serum resistin concentrations (20.3+/-10.0 ng/mL) and clinical variables, biochemistry panel, markers of inflammation and insulin resistance, adipocytokines, and measures of adiposity was weak (all rho <0.25). During a median follow-up of 9.4 years, 341 participants (11.8%) developed HF. Resistin was strongly associated with risk for incident HF in Cox proportional hazards models controlling for clinical variables, biomarkers, and measures of adiposity (HR, 1.15 per 10.0 ng/mL in adjusted model; 95% CI, 1.05 to 1.27; P=0.003). Results were comparable across sex, race, diabetes mellitus, and prevalent and incident coronary heart disease subgroups. In participants with available left ventricular ejection fraction at HF diagnosis (265 of 341; 77.7%), association of resistin with HF risk was comparable for cases with reduced versus preserved ejection fraction. CONCLUSIONS: Serum resistin concentrations are independently associated with risk for incident HF in older persons.

Strategies for preventing late-onset cytomegalovirus disease in organ transplant recipients.

Objective: The incidence of late-onset cytomegalovirus disease (i.e. disease appearing after discontinuation of antiviral prophylaxis) in solid-organ transplant recipients remains excessively high. This review will focus on describing the several strategies that could potentially reduce the incidence of late-onset cytomegalovirus disease. Methods: We reviewed the literature and presented our own clinical experience in the field. Results: The incidence of late-onset cytomegalovirus disease in recent trials can be as high as 36% in high-risk patients (donor positive/recipient negative for cytomegalovirus). The extension of antiviral prophylaxis to six months has recently proven in a prospective randomized controlled trial to be effective for reducing late-onset cytomegalovirus disease. The monitoring of cytomegalovirus viral load by PCR after the discontinuation of prophylaxis seems to be of moderate usefulness in low/intermediate-risk patients. The use of low-dose valganciclovir could reduce drug toxicity and costs while maintaining similar efficacy, but further studies are needed. A potentially interesting approach to predict the individual risk for development of cytomegalovirus disease appears to be the assessment of specific cell-mediated immune response. If cell-mediated immunity assays become widely available in transplant centers in the future, these assays may possibly be used to tailor the cytomegalovirus preventive strategy on an individual basis. Finally, recent prospective trials have evaluated novel cytomegalovirus vaccines that merit further evaluation in the transplant setting, although currently there is no cytomegalovirus vaccine that has been approved for routine clinical use. Conclusions: Several studies have recently evaluated novel strategies to reduce the incidence of late-onset cytomegalovirus disease. It is therefore expected that this improvement in preventive strategies will allow to further reduce the negative effects of cytomegalovirus disease after transplantation.

Rationale and first results of developing at-risk (prodromal) criteria for bipolar disorder.

Bipolar affective disorder (BD) is a severe, recurrent and disabling disorder with devastating consequences for individuals, families and society. Although these hazards and costs provide a compelling rationale for development of early detection and early intervention strategies in BD, the development of at-risk criteria for first episode mania is still in an early stage of development. In this paper we review the literature with respect to the clinical, neuroantomical and neuropsychological data, which support this goal. We also describe our recently developed bipolar at-risk criteria (BAR). This criteria comprises the peak age range of the first onset of bipolar disorder, genetic risk, presenting with sub-threshold mania, cyclothymic features or depressive symptoms. An initial pilot evaluation of the BAR criteria in 22 subjects indicated conversion rates to proxies of first-episode mania of 23% within 265 days on average, and high specificity and sensitivity of the criteria. If prospective studies confirm the validity of the BAR criteria, then the criteria would have the potential to open up new avenues of research for indicated prevention in BD and might therefore offer opportunities to ameliorate the severity of, or even prevent BD.

Patterns of Adherence to Raltegravir-Based Regimens and the Risk of Virological Failure Among HIV-Infected Patients: The RALTECAPS Cohort Study.

ABSTRACT:: Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients.

We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant recipients. Risk factors associated with CMV disease and graft failure-free survival were analyzed using Cox regression models. One thousand two hundred thirty-nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (D+/R- vs. R+, hazard ratio [HR] 5.36 [95% CI 3.14-9.14], pâeuro0/00<âeuro0/000.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 [95% CI 0.63-2.17], pâeuro0/00=âeuro0/000.63). CMV disease was not associated with a lower graft failure-free survival (HR 1.27 [95% CI 0.64-2.53], pâeuro0/00=âeuro0/000.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure-free survival after a median of 1.05 years of follow-up (HR 1.63 [95% CI 1.01-2.64], pâeuro0/00=âeuro0/000.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.

Comparison of two strategies to prevent varicella outbreaks in housing facilities for asylum seekers.

BACKGROUND: The proportion of adults with positive varicella serology is lower in populations from tropical countries. Therefore immigrants to countries with a temperate climate are at risk of acquiring varicella infection during adulthood. METHODS: We tested two different strategies to prevent varicella outbreaks in housing facilities for asylum seekers arriving in the Canton of Vaud, Switzerland. The first strategy consisted of a rapid response with isolation of the affected individuals and vaccination of the susceptible contacts. The second strategy consisted of a general vaccination upon arrival of all asylum seekers aged 15-39 years with no history of chickenpox. RESULTS: From May 2008 to January 2009 we applied the rapid response strategy. Eight hundred and fifty-eight asylum seekers arrived in the Canton and an attack rate of 2.8% (seven cases among 248 exposed asylum seekers) was observed. The mean cost was US$ 31.35 per asylum seeker. The general vaccination strategy was applied from February 2009 to May 2010, a period during which 966 asylum seekers were registered. This second strategy completely prevented any outbreak at a mean cost of US$ 83.85 per asylum seeker. CONCLUSIONS: Of the two analyzed interventions to prevent varicella outbreaks in housing facilities for asylum seekers, the general vaccination strategy was more effective, more sustainable, and ethically preferable, although more costly.

Combining clinical factors and quantitative ultrasound improves the detection of women both at low and high risk for hip fracture.

We hypothesized that combining clinical risk factors (CRF) with the heel stiffness index (SI) measured via quantitative ultrasound (QUS) would improve the detection of women both at low and high risk for hip fracture. Categorizing women by risk score improved the specificity of detection to 42.4%, versus 33.8% using CRF alone and 38.4% using the SI alone. This combined CRF-SI score could be used wherever and whenever DXA is not readily accessible. INTRODUCTION AND HYPOTHESIS: Several strategies have been proposed to identify women at high risk for osteoporosis-related fractures; we wanted to investigate whether combining clinical risk factors (CRF) and heel QUS parameters could provide a more accurate tool to identify women at both low and high risk for hip fracture than either CRF or QUS alone. METHODS: We pooled two Caucasian cohorts, EPIDOS and SEMOF, into a large database named "EPISEM", in which 12,064 women, 70 to 100 years old, were analyzed. Amongst all the CRF available in EPISEM, we used only the ones which were statistically significant in a Cox multivariate model. Then, we constructed a risk score, by combining the QUS-derived heel stiffness index (SI) and the following seven CRF: patient age, body mass index (BMI), fracture history, fall history, diabetes history, chair-test results, and past estrogen treatment. RESULTS: Using the composite SI-CRF score, 42% of the women who did not report a hip fracture were found to be at low risk at baseline, and 57% of those who subsequently sustained a fracture were at high risk. Using the SI alone, corresponding percentages were 38% and 52%; using CRF alone, 34% and 53%. The number of subjects in the intermediate group was reduced from 5,400 (including 112 hip fractures) and 5,032 (including 111 hip fractures) to 4,549 (including 100 including fractures) for the CRF and QUS alone versus the combination score. CONCLUSIONS: Combining clinical risk factors to heel bone ultrasound appears to correctly identify more women at low risk for hip fracture than either the stiffness index or the CRF alone; it improves the detection of women both at low and high risk.

Parents - child role reversal in trilogue play: case studies of trajectories from pregnancy to toddlerhood

Role reversal, whereby a child attempts to meet her parent's adult needs for parenting, intimacy, or companionship, has been identified as a risk factor for developmental disturbances. It has been defined from diverse perspectives as a child attachment strategy, a parent - toddler relational disturbance, and a boundary disturbance between parents and child. The recently discovered infant's triangular capacity, namely the sharing of her attention and affects with both parents, allows one to analyse the infant's contribution to early family dynamics. Role reversal was detected in 4 out of 45 father - mother - infant interactions observed in trilogue play from pregnancy to toddlerhood. The developmental trajectories towards role reversal are explored by means of case analyses. Results are compared with cases of problematic triangulation encountered in the same sample. In role reversal, family interactions are rigidly organized around a "two against one" coalition, whereby the normative hierarchy between parents and child is reversed. The child's triangular capacity is overactivated, controlling the tension between her parents by provocation - animation strategies