Efficacy, tolerability and risk factors for virological failure of darunavir-based therapy for treatment-experienced HIV-infected patients: the Swiss HIV Cohort Study.

OBJECTIVES: Darunavir was designed for activity against HIV resistant to other protease inhibitors (PIs). We assessed the efficacy, tolerability and risk factors for virological failure of darunavir for treatment-experienced patients seen in clinical practice. METHODS: We included all patients in the Swiss HIV Cohort Study starting darunavir after recording a viral load above 1000 HIV-1 RNA copies/mL given prior exposure to both PIs and nonnucleoside reverse transcriptase inhibitors. We followed these patients for up to 72 weeks, assessed virological failure using different loss of virological response algorithms and evaluated risk factors for virological failure using a Bayesian method to fit discrete Cox proportional hazard models. RESULTS: Among 130 treatment-experienced patients starting darunavir, the median age was 47 years, the median duration of HIV infection was 16 years, and 82% received mono or dual antiretroviral therapy before starting highly active antiretroviral therapy. During a median patient follow-up period of 45 weeks, 17% of patients stopped taking darunavir after a median exposure of 20 weeks. In patients followed beyond 48 weeks, the rate of virological failure at 48 weeks was at most 20%. Virological failure was more likely where patients had previously failed on both amprenavir and saquinavir and as the number of previously failed PI regimens increased. CONCLUSIONS: As a component of therapy for treatment-experienced patients, darunavir can achieve a similar efficacy and tolerability in clinical practice to that seen in clinical trials. Clinicians should consider whether a patient has failed on both amprenavir and saquinavir and the number of failed PI regimens before prescribing darunavir.

MHC class I expression dependent on bacterial infection and parental factors in whitefish embryos (Salmonidae).

Ecological conditions can influence not only the expression of a phenotype, but also the heritability of a trait. As such, heritable variation for a trait needs to be studied across environments. We have investigated how pathogen challenge affects the expression of MHC genes in embryos of the lake whitefish Coregonus palaea. In order to experimentally separate paternal (i.e. genetic) from maternal and environmental effects, and determine whether and how stress affects the heritable variation for MHC expression, embryos were produced in full-factorial in vitro fertilizations, reared singly, and exposed at 208 degree days (late-eyed stage) to either one of two strains of Pseudomonas fluorescens that differ in their virulence characteristics (one increased mortality, while both delayed hatching time). Gene expression was assessed 48 h postinoculation, and virulence effects of the bacterial infection were monitored until hatching. We found no evidence of MHC class II expression at this stage of development. MHC class I expression was markedly down-regulated in reaction to both pseudomonads. While MHC expression could not be linked to embryo survival, the less the gene was expressed, the earlier the embryos hatched within each treatment group, possibly due to trade-offs between immune function and developmental rate or further factors that affect both hatching timing and MHC expression. We found significant additive genetic variance for MHC class I expression in some treatments. That is, changes in pathogen pressures could induce rapid evolution in MHC class I expression. However, we found no additive genetic variance in reaction norms in our study population.

Incidence, complications and risk factors for severe falls in patients on maintenance haemodialysis.

BACKGROUND: Falls have been insufficiently studied in patients on maintenance haemodialysis (MHD). This study assessed the incidence and complications of severe falls and the ability of risk factors, including the Performance-Oriented Mobility Assessment (POMA) test, to predict them in this population. METHODS: All patients on MHD from our centre were asked to participate in this survey. POMA test and a record of risk factors for falls were obtained at baseline. Severe falls, as defined by an admission in an emergency ward, were documented prospectively. RESULTS: Eighty-four patients (median age 69.5 years, minimum 26 years, maximum 85 years) were enrolled. Predialytic POMA scores were low (median 20, minimum 5, maximum 26). After a mean follow-up of 20.6 months (142.2 patient-years), 31 severe falls were recorded in 24 patients (28.6%; incidence 0.22 per patient-year) and complicated by fractures in 54.8% of severe falls. In univariate analysis, age, a past history of falls, malnutrition, depression, but not POMA score, were associated with severe falls. A POMA score of >21 had a negative predictive value of 82%. CONCLUSIONS: Severe falls were common in MHD patients in this study and resulted in fractures in >50% of the cases. They were associated with ageing, a past history of falls, malnutrition and depression. Although there was a trend towards a lower POMA score in fallers as compared to non-fallers, the POMA score was not an independent predictor of severe falls in this study. These data may help to stratify the patient's risk of falling in order to target programmes to prevent falls in this population.

Relationship between empty seed and genetic factors in European beech (Fagus sylvatica L.)

Abstract

Cellular and viral factors implicated in persistent infection in canine distemper virus

Summary SLAM (signalling lymphocyte activation molecule, CD150) serves as a cellular receptor for different morbiliviruses, including measles virus and canine distemper virus. Laboratory cell lines that do not express dog SLAM are therefore quite refractory to infection by wildtype CDV. SLAM expression is not only required for CDV virion attachment, but also for the establishment of cytolytic infection characterized by syncytia formation. In order to determine if SLAM has a direct influence on CDV replication, we compared wild-type and mutated SLAM variants for their capacity to influence viral polymerase activity and syncytia formation. Deletion of immunoreceptor tyrosine-based signalling motif (ITSM) in the cytoplasmic tail of SLAM did not seem to influence viral replication, viral polymerase activity or cell-to cell fusion. Instead, it was the level of cell surface expression of SLAM, which was important. Additional experiments corroborated the importance of SLAM for efficient cell-to cell fusion: Both SLAM, as well as viral fusion (F) and attachment (H) glycoproteins, were found to be required for efficient cell-to-cell fusion, which, in turn, enhanced the activity of the viral polymerase and, viral replication. Wild-type A75/17 canine distemper virus (CDV) strain is known to induce a persistent infection in the central nervous system and in dog footpad keratinocytes in vivo. Recently, it has been shown that the A75/17 virus could also infect canine footpad keratinocytes (CFKs) in vitro. CFK infection with A75/17 was initially inefficient and produced very little virus progeny, however, after only three passages the adapted virus produced more progeny and induced limited syncytia formation. Sequence comparison between the A75/17 and the CFKadapted A75/17-K virus revealed three amino acid differences, one in the phosphoprotein (P), one in the matrix protein (M) and one in the H protein. In order to identify viral determinants of A75/17-K adaptation, recombinant viruses containing one, two or three nucleotides substitutions were analyzed. The amino acid substitution in the M protein was without effect on viral particle formation. In contrast, the amino acid substitution in the cytoplasmic tail of H protein was clearly important for syncytia formation. Concerning the mutation in the P protein, it led to an increase in viral replication. However, we cannot rule out that the observed effect is due to the amino acid substitutions in the overlapping accessory proteins C and V, also affected by the P mutation. The adaptation of wild-type CDV strains to cell culture almost always involves modifications of M protein. In order to understand the influence of these modifications, we tested recombinant A75/17 viruses bearing different M proteins. Preliminary results demonstrated that the M protein from the Vero-adapted strain reduced syncytia formation. Future studies will focus on the M mRNA and protein stability, its expression level, localisation and its effect on viral particles formation and on the phenotype of infection. Résumé La protéine SLAM (signalling lymphocyte activation molecule ou CD150) est utilisée comme récepteur cellulaire par les morbillivirus parmi lesquels on trouve le virus de la rougeole (VR) ainsi que le virus de la maladie de Carré (CDV). Les lignées cellulaires qui n'expriment pas la protéine SLAM du chien à leur surface sont réfractaires à l'infection par les souches sauvages de CDV. Le récepteur SLAM n'est pas seulement requis pour l'attachement du virion à la surface de la cellule, mais il participe également de façon active à l'établissement d'une infection cytolytique à travers la formation de syncytia. Afin de déterminer si la protéine SLAM exerce une influence directe sur la réplication virale du virus de la maladie de Carré, nous avons généré différentes protéines tronquées de SLAM et comparé leurs capacités à influencer l'activité de la polymérase ainsi que la formation de syncytia. Nos résultas ont montré que la réplication virale, l'activité de la polymérase ainsi que la fusion cellulaire ne semblent pas être influencées par les délétions dans les régions cytoplasmiques du récepteur SLAM. Cependant, ces délétions agissent sur l'expression de la protéine SLAM à la surface des cellules. Les expériences additionnelles ont permis de souligner l'importance de la protéine SLAM dans le phénomène de fusion entre cellules. En effet, la protéine SLAM ainsi que les deux glycoprotéines virales F et H sont requises pour la formation de syncytia, laquelle induit une augmentation de l'activité de la polymérase ainsi que de la réplication virale. La souche virulente A75/17 du virus, de la Maladie de Carré est connue pour induire une infection persistante au niveau du système nerveux central ainsi que dans les kératinocytes de pattes chez le chien. Des études récentes ont montré que des cultures primaires de kératinocytes de chien pouvaient aussi êtres infectées par la souche A75/17 de CDV. En effet, le virus induit une infection persistante en produisant très peu de progéniture. Cependant, trois passages du virus sauvage A75/17 dans ces cultures aboutissent à la sélection d'un virus produisant plus de progéniture et favorisant la formation limitée de syncytia. La comparaison des séquences génomique entre la souche A75/17 et la souche adaptée A75/17-K montre une différence de trois nucléotides. La première mutation, située dans le gène P, modifie la phosphoprotéine (P) ainsi que les protéines V et C. La deuxième se situe dans le gène de la protéine matricielle (M) et la dernière dans celui de la protéine d'attachement (H). Afin de déterminer les facteurs viraux impliqués lors de l'adaptation virale dans la culture primaire de kératinocytes, des virus recombinants contenant une, deux ou trois de ces mutations ont été analysés. La substitution d'un acide aminé dans la protéine M reste sans effet sur la production de particules virales. En revanche, la substitution d'un acide aminé dans la queue cytoplasmique de la protéine H s'avère clairement importante pour la formation de syncytia. Quant à la mutation dans le gène P, elle permet une augmentation de la réplication virale. Cependant, nous ne pouvons pas écarter l'hypothèse que l'augmentation de la réplication virale soit due aux substitutions d'un acide aminé dans les protéines accessoires V et C qui sont, elles aussi, affectées par la mutation dans le gène P. L'adaptation des souches sauvages de CDV aux cultures de cellules induit presque toujours des modifications de la protéine matricielle M. Afin de comprendre l'influence de ces modifications, nous avons testé 'des virus A75/17 recombinants contenant différentes protéines M. Les résultats préliminaires ont démontré que la protéine M de la souche adaptée aux cellules Vero réduisait la formation de syncytia. Les études futures seront axées sur la stabilité de l'ARN messager, celle de la protéine M, de son niveau d'expression, de sa localisation cellulaire et de son effet sur la formation de particules virale ainsi que sur le phénotype de l'infection.

An epidemiological study of dental agenesis in a primary health area in Spain: estimated prevalence and associated factors

Objectives: To evaluate the prevalence of dental agenesis and its possible association with other developmental dental anomalies and systemic entities. Setting and Sample Population: Descriptive transversal study, for which 1518 clinical records, of patients visited by the Odontological Service of the Primary Health Centre of Cassà de la Selva (Girona-Spain) between December 2002 and February 2006 were reviewed. The data were recorded in relation to the oral and dental anomalies and the associated systemic entities, between the ones referred as concomitant in literature. Results: Values of 9.48% (7.25% excluding the third molars) for dental agenesis and 0.39% for oligodontia were obtained. The presence of dental agenesis concomitant with some other forms of oral and dental anomalies was observed. Attention must be drawn to the fact that a greater number of concomitant systemic entities were observed in those patients that presented a severe phenotypical pattern of dental agenesis. Conclusions: The results of the present study do not differ from the ones reported in studies of similar characteristics among Occidental and Spanish populations. The relationship observed between certain systemic entities and developmental dental anomalies suggest a possible common genetic etiology

Self-reported adherence and associated factors regarding antihypertensive medication in Seychelles

Introduction. Adherence to medication for asymptomatic disease is often low. We assessed factors associated with good adherence to medication for high blood pressure (HBP) in a country of the African region. Methods. A population-based survey of adults aged 25-64 years (N=1240 and participation rate=73%). Information was available in knowledge attitude and practice, SES and other variables. One question assessed adherence. Good adherence to treatment was defined as answering "I forget very rarely" vs "I forget on 1-2 days in a week" or "I forget on 3 or more days in a week". Results. In a univariate model adherence was strongly associated with belief that hypertension is a long-term disease (OR 2.6, p<0.001) and was negatively associated with concomitant use of traditional medicine (OR 0.36, p<0.005). The following variables tended to be associated with good adherence for HBP treatment: age, SES, BMI, belief that HBP is not symptomatic, going to government's clinics, medium stress level, controlled hypertension, taking statins. The following variables were not associated with good adherence for HBP treatment: education, higher BP, knowing people who had a stroke/MI, suffering from another chronic condition. In a multivariate model, pseudo R2 was 0.14. Conclusion. We built a multidimensional model including a wide range of variable. This model only predicted 14% of adherence variability. Variables associated with good adherence were demographics or related to knowledge attitude and practice. The latter one is modifiable by different type of interventions.

Incidence and risk factors for chronic elevation of alanine aminotransferase levels in HIV-infected persons without hepatitis b or c virus co-infection.

BACKGROUND: Chronic liver disease in human immunodeficiency virus (HIV)-infected patients is mostly caused by hepatitis virus co-infection. Other reasons for chronic alanine aminotransferase (ALT) elevation are more difficult to diagnose. METHODS: We studied the incidence of and risk factors for chronic elevation of ALT levels (greater than the upper limit of normal at 2 consecutive semi-annual visits) in participants of the Swiss HIV Cohort Study without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection who were seen during the period 2002-2008. Poisson regression analysis was used. RESULTS: A total of 2365 participants were followed up for 9972 person-years (median age, 38 years; male sex, 66%; median CD4+ cell count, 426/microL; receipt of antiretroviral therapy [ART], 56%). A total of 385 participants (16%) developed chronic elevated ALT levels, with an incidence of 3.9 cases per 100 person-years (95% confidence interval [CI], 3.5-4.3 cases per 100 person-years). In multivariable analysis, chronic elevated ALT levels were associated with HIV RNA level >100,000 copies/mL (incidence rate ratio [IRR], 2.23; 95% CI, 1.45-3.43), increased body mass index (BMI, defined as weight in kilograms divided by the square of height in meters) (BMI of 25-29.9 was associated with an IRR of 1.56 [95% CI, 1.24-1.96]; a BMI 30 was associated with an IRR of 1.70 [95% CI, 1.16-2.51]), severe alcohol use (1.83 [1.19-2.80]), exposure to stavudine (IRR per year exposure, 1.12 [95% CI, 1.07-1.17]) and zidovudine (IRR per years of exposure, 1.04 [95% CI, 1.00-1.08]). Associations with cumulative exposure to combination ART, nucleoside reverse-transcriptase inhibitors, and unboosted protease inhibitors did not remain statistically significant after adjustment for exposure to stavudine. Black ethnicity was inversely correlated (IRR, 0.52 [95% CI, 0.33-0.82]). Treatment outcome and mortality did not differ between groups with and groups without elevated ALT levels. CONCLUSIONS: Among patients without hepatitis virus co-infection, the incidence of chronic elevated ALT levels was 3.9 cases per 100 person-years, which was associated with high HIV RNA levels, increased BMI, severe alcohol use, and prolonged stavudine and zidovudine exposure. Long-term follow-up is needed to assess whether chronic elevation of ALT levels will result in increased morbidity or mortality.

Primary breast lymphoma: patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study.

BACKGROUND: To asses the clinical profile, treatment outcome and prognostic factors in primary breast lymphoma (PBL). METHODS: Between 1970 and 2000, 84 consecutive patients with PBL were treated in 20 institutions of the Rare Cancer Network. Forty-six patients had Ann Arbor stage IE, 33 stage IIE, 1 stage IIIE, 2 stage IVE and 2 an unknown stage. Twenty-one underwent a mastectomy, 39 conservative surgery and 23 biopsy; 51 received radiotherapy (RT) with (n = 37) or without (n = 14) chemotherapy. Median RT dose was 40 Gy (range 12-55 Gy). RESULTS: Ten (12%) patients progressed locally and 43 (55%) had a systemic relapse. Central nervous system (CNS) was the site of relapse in 12 (14%) cases. The 5-yr overall survival, lymphoma-specific survival, disease-free survival and local control rates were 53%, 59%, 41% and 87% respectively. In the univariate analyses, favorable prognostic factors were early stage, conservative surgery, RT administration and combined modality treatment. Multivariate analysis showed that early stage and the use of RT were favorable prognostic factors. CONCLUSION: The outcome of PBL is fair. Local control is excellent with RT or combined modality treatment but systemic relapses, including that in the CNS, occurs frequently.

Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors.

Angio-oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE-I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE-I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE-I-related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE-I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE-I treatment-related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE-I AE.

RiskDiff: A web tool for the analysis of the difference due to risk and demographic factors for incidence or mortality data.

Background Analysing the observed differences for incidence or mortality of a particular disease between two different situations (such as time points, geographical areas, gender or other social characteristics) can be useful both for scientific or administrative purposes. From an epidemiological and public health point of view, it is of great interest to assess the effect of demographic factors in these observed differences in order to elucidate the effect of the risk of developing a disease or dying from it. The method proposed by Bashir and Estève, which splits the observed variation into three components: risk, population structure and population size is a common choice at practice. Results A web-based application, called RiskDiff has been implemented (available at http://rht.iconcologia.net/riskdiff.htm webcite), to perform this kind of statistical analyses, providing text and graphical summaries. Code from the implemented functions in R is also provided. An application to cancer mortality data from Catalonia is used for illustration. Conclusions Combining epidemiological with demographical factors is crucial for analysing incidence or mortality from a disease, especially if the population pyramids show substantial differences. The tool implemented may serve to promote and divulgate the use of this method to give advice for epidemiologic interpretation and decision making in public health.