Impact of Switching From Zidovudine to Tenofovir Disoproxil Fumarate on Bone Mineral Density and Markers of Bone Metabolism in Virologically Suppressed HIV-1 Infected Patients; A Substudy of the PREPARE Study

Context: In virologically suppressed, antiretroviral-treated patients, the effect of switching to tenofovir (TDF) on bone biomarkers compared to patients remaining on stable antiretroviral therapy is unknown. Methods: We examined bone biomarkers (osteocalcin [OC], procollagen type 1 amino-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen) and bone mineral density (BMD) over 48 weeks in virologically suppressed patients (HIV RNA < 50 copies/ml) randomized to switch to TDF/emtricitabine (FTC) or remain on first-line zidovudine (AZT)/lamivudine (3TC). PTH was also measured. Between-group differences in bone biomarkers and associations between change in bone biomarkers and BMD measures were assessed by Student's t tests, Pearson correlation, and multivariable linear regression, respectively. All data are expressed as mean (SD), unless otherwise specified. Results: Of 53 subjects (aged 46.0 y; 84.9% male; 75.5% Caucasian), 29 switched to TDF/FTC. There were reductions in total hip and lumbar spine BMD in those switching to TDF/FTC (total hip, TDF/FTC, −1.73 (2.76)% vs AZT/3TC, −0.39 (2.41)%; between-group P = .07; lumbar spine, TDF/FTC, −1.50 (3.49)% vs AZT/3TC, +0.25 (2.82)%; between-group P = .06), but they did not reach statistical significance. Greater declines in lumbar spine BMD correlated with greater increases in OC (r = −0.28; P = .05). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender, and ethnicity. There was no difference in change in PTH levels over 48 weeks between treatment groups (between-group P = .23). All biomarkers increased significantly from weeks 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (between-group, all biomarkers, P < .0001). Conclusion: A switch to TDF/FTC compared to remaining on a stable regimen is associated with increases in bone turnover that correlate with reductions in BMD, suggesting that TDF exposure directly affects bone metabolism in vivo.

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

A comparison of estimated glomerular filtration rates using Cockcroft−Gault and the Chronic Kidney Disease Epidemiology Collaboration estimating equations in HIV infection

OBJECTIVES: The aim of this study was to determine whether the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)- or Cockcroft-Gault (CG)-based estimated glomerular filtration rates (eGFRs) performs better in the cohort setting for predicting moderate/advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD). METHODS: A total of 9521 persons in the EuroSIDA study contributed 133 873 eGFRs. Poisson regression was used to model the incidence of moderate and advanced CKD (confirmed eGFR < 60 and < 30 mL/min/1.73 m(2) , respectively) or ESRD (fatal/nonfatal) using CG and CKD-EPI eGFRs. RESULTS: Of 133 873 eGFR values, the ratio of CG to CKD-EPI was ≥ 1.1 in 22 092 (16.5%) and the difference between them (CG minus CKD-EPI) was ≥ 10 mL/min/1.73 m(2) in 20 867 (15.6%). Differences between CKD-EPI and CG were much greater when CG was not standardized for body surface area (BSA). A total of 403 persons developed moderate CKD using CG [incidence 8.9/1000 person-years of follow-up (PYFU); 95% confidence interval (CI) 8.0-9.8] and 364 using CKD-EPI (incidence 7.3/1000 PYFU; 95% CI 6.5-8.0). CG-derived eGFRs were equal to CKD-EPI-derived eGFRs at predicting ESRD (n = 36) and death (n = 565), as measured by the Akaike information criterion. CG-based moderate and advanced CKDs were associated with ESRD [adjusted incidence rate ratio (aIRR) 7.17; 95% CI 2.65-19.36 and aIRR 23.46; 95% CI 8.54-64.48, respectively], as were CKD-EPI-based moderate and advanced CKDs (aIRR 12.41; 95% CI 4.74-32.51 and aIRR 12.44; 95% CI 4.83-32.03, respectively). CONCLUSIONS: Differences between eGFRs using CG adjusted for BSA or CKD-EPI were modest. In the absence of a gold standard, the two formulae predicted clinical outcomes with equal precision and can be used to estimate GFR in HIV-positive persons.

Magnitude and frequency: challenges for the assessment of vulnerability to geomorphic hazards

In natural hazard research, risk is defined as a function of (1) the probability of occurrence of a hazardous process, and (2) the assessment of the related extent of damage, defined by the value of elements at risk exposed and their physical vulnerability. Until now, various works have been undertaken to determine vulnerability values for objects exposed to geomorphic hazards such as mountain torrents. Yet, many studies only provide rough estimates for vulnerability values based on proxies for process intensities. However, the deduced vulnerability functions proposed in the literature show a wide range, in particular with respect to medium and high process magnitudes. In our study, we compare vulnerability functions for torrent processes derived from studies in test sites located in the Austrian Alps and in Taiwan. Based on this comparison we expose needs for future research in order to enhance mountain hazard risk management with a particular focus on the question of vulnerability on a catchment scale.

Landmark Detection for Fusion of Fundus and MRI Towards a Patient-Specific Multi-Modal Eye Model

Ophthalmologists typically acquire different image modalities to diagnose eye pathologies. They comprise e.g., Fundus photography, Optical Coherence Tomography (OCT), Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Yet, these images are often complementary and do express the same pathologies in a different way. Some pathologies are only visible in a particular modality. Thus, it is beneficial for the ophthalmologist to have these modalities fused into a single patient-specific model. The presented article’s goal is a fusion of Fundus photography with segmented MRI volumes. This adds information to MRI which was not visible before like vessels and the macula. This article’s contributions include automatic detection of the optic disc, the fovea, the optic axis and an automatic segmentation of the vitreous humor of the eye.

Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the d: a: d study.

BACKGROUND The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma). RESULTS A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)]. CONCLUSIONS Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.

Using Factorial Surveys and Stated Choice Experiments to Investigate Discriminatory Attitudes and Preferences

Empirical research on discriminatory attitudes and behaviour grapples with the social undesirability of its object. In many studies using regular survey methods, estimates are biased, and the social context of discrimination is not taken into account. Several methods have been developed, especially to deal with the first problem. In this regard, the estimation of the ‘true value’ of discriminatory attitudes is at the centre of interest. However, methodological contributions focusing on the social context of attitude communication and discriminatory behaviour, as well as the correlation between both, are rare. We present two experimental methods which address those issues: factorial surveys and stated choice experiments. In a first study, the usefulness of factorial surveys is demonstrated with data on German anti-Semitism (N=279). We show that the rate of approval with anti-Semitic statements increases if (a) respondents are told that the majority of fellows agree with such statements, (b) the term “Jews” is replaced by the term “Israelis”, and (c) reference to the Holocaust is made. Apart from the main effects of these experimental factors, significant interaction effects regarding the political attitudes and social status of respondents are observed. In a second study, a stated choice experiment on the purchase of olive oil and tomatoes was conducted in Germany (N=440). We find that respondents prefer Italian and Dutch products (control treatment) compared to Israeli and Palestinian ones (discrimination treatments). There are no significant differences between preferences for a so called ‘Peace product’ (which is produced jointly by Israelis and Palestinians) and products from Italy as well as the Netherlands. Yet, taking discriminatory attitudes (anti-Semitic and anti-Arabic attitudes) into account, a strong correlation between those attitudes and stated behaviour (purchase of Israeli, Palestinian and jointly produced products) can be found. This adds support to the hypothesis that discriminatory attitudes hold behavioural consequences.

Pre-therapy inflammation and coagulation activation and long-term CD4 count responses to the initiation of antiretroviral therapy

OBJECTIVES Pre-antiretroviral therapy (ART) inflammation and coagulation activation predict clinical outcomes in HIV-positive individuals. We assessed whether pre-ART inflammatory marker levels predicted the CD4 count response to ART. METHODS Analyses were based on data from the Strategic Management of Antiretroviral Therapy (SMART) trial, an international trial evaluating continuous vs. interrupted ART, and the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, evaluating three first-line ART regimens with at least two drug classes. For this analysis, participants had to be ART-naïve or off ART at randomization and (re)starting ART and have C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer measured pre-ART. Using random effects linear models, we assessed the association between each of the biomarker levels, categorized as quartiles, and change in CD4 count from ART initiation to 24 months post-ART. Analyses adjusted for CD4 count at ART initiation (baseline), study arm, follow-up time and other known confounders. RESULTS Overall, 1084 individuals [659 from SMART (26% ART naïve) and 425 from FIRST] met the eligibility criteria, providing 8264 CD4 count measurements. Seventy-five per cent of individuals were male with the mean age of 42 years. The median (interquartile range) baseline CD4 counts were 416 (350-530) and 100 (22-300) cells/μL in SMART and FIRST, respectively. All of the biomarkers were inversely associated with baseline CD4 count in FIRST but not in SMART. In adjusted models, there was no clear relationship between changing biomarker levels and mean change in CD4 count post-ART (P for trend: CRP, P = 0.97; IL-6, P = 0.25; and D-dimer, P = 0.29). CONCLUSIONS Pre-ART inflammation and coagulation activation do not predict CD4 count response to ART and appear to influence the risk of clinical outcomes through other mechanisms than blunting long-term CD4 count gain.

Estimating HIV Incidence, Time to Diagnosis, and the Undiagnosed HIV Epidemic Using Routine Surveillance Data.

BACKGROUND Estimates of the size of the undiagnosed HIV-infected population are important to understand the HIV epidemic and to plan interventions, including "test-and-treat" strategies. METHODS We developed a multi-state back-calculation model to estimate HIV incidence, time between infection and diagnosis, and the undiagnosed population by CD4 count strata, using surveillance data on new HIV and AIDS diagnoses. The HIV incidence curve was modelled using cubic splines. The model was tested on simulated data and applied to surveillance data on men who have sex with men in The Netherlands. RESULTS The number of HIV infections could be estimated accurately using simulated data, with most values within the 95% confidence intervals of model predictions. When applying the model to Dutch surveillance data, 15,400 (95% confidence interval [CI] = 15,000, 16,000) men who have sex with men were estimated to have been infected between 1980 and 2011. HIV incidence showed a bimodal distribution, with peaks around 1985 and 2005 and a decline in recent years. Mean time to diagnosis was 6.1 (95% CI = 5.8, 6.4) years between 1984 and 1995 and decreased to 2.6 (2.3, 3.0) years in 2011. By the end of 2011, 11,500 (11,000, 12,000) men who have sex with men in The Netherlands were estimated to be living with HIV, of whom 1,750 (1,450, 2,200) were still undiagnosed. Of the undiagnosed men who have sex with men, 29% (22, 37) were infected for less than 1 year, and 16% (13, 20) for more than 5 years. CONCLUSIONS This multi-state back-calculation model will be useful to estimate HIV incidence, time to diagnosis, and the undiagnosed HIV epidemic based on routine surveillance data.

Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes.

AIMS We aimed to assess the prevalence and management of clinical familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). METHODS AND RESULTS We studied 4778 patients with ACS from a multi-centre cohort study in Switzerland. Based on personal and familial history of premature cardiovascular disease and LDL-cholesterol levels, two validated algorithms for diagnosis of clinical FH were used: the Dutch Lipid Clinic Network algorithm to assess possible (score 3-5 points) or probable/definite FH (>5 points), and the Simon Broome Register algorithm to assess possible FH. At the time of hospitalization for ACS, 1.6% had probable/definite FH [95% confidence interval (CI) 1.3-2.0%, n = 78] and 17.8% possible FH (95% CI 16.8-18.9%, n = 852), respectively, according to the Dutch Lipid Clinic algorithm. The Simon Broome algorithm identified 5.4% (95% CI 4.8-6.1%, n = 259) patients with possible FH. Among 1451 young patients with premature ACS, the Dutch Lipid Clinic algorithm identified 70 (4.8%, 95% CI 3.8-6.1%) patients with probable/definite FH, and 684 (47.1%, 95% CI 44.6-49.7%) patients had possible FH. Excluding patients with secondary causes of dyslipidaemia such as alcohol consumption, acute renal failure, or hyperglycaemia did not change prevalence. One year after ACS, among 69 survivors with probable/definite FH and available follow-up information, 64.7% were using high-dose statins, 69.0% had decreased LDL-cholesterol from at least 50, and 4.6% had LDL-cholesterol ≤1.8 mmol/L. CONCLUSION A phenotypic diagnosis of possible FH is common in patients hospitalized with ACS, particularly among those with premature ACS. Optimizing long-term lipid treatment of patients with FH after ACS is required.

The use of electromyography interference pattern analysis to determine muscle force of the deep digital flexor muscle in healthy and laminitic horses

BACKGROUND: In equine laminitis, the deep digital flexor muscle (DDFM) appears to have increased muscle force, but evidence-based confirmation is lacking. OBJECTIVES: The purpose of this study was to test if the DDFM of laminitic equines has an increased muscle force detectable by needle electromyography interference pattern analysis (IPA). ANIMALS AND METHODS: The control group included six Royal Dutch Sport horses, three Shetland ponies and one Welsh pony [10 healthy, sound adults weighing 411 ± 217 kg (mean ± SD) and aged 10 ± 5 years]. The laminitic group included three Royal Dutch Sport horses, one Friesian, one Haflinger, one Icelandic horse, one Welsh pony, one miniature Appaloosa and six Shetland ponies (14 adults, weight 310 ± 178 kg, aged 13 ± 6 years) with acute/chronic laminitis. The electromyography IPA measurements included firing rate, turns/second (T), amplitude/turn (M) and M/T ratio. Statistical analysis used a general linear model with outcomes transformed to geometric means. RESULTS: The firing rate of the total laminitic group was higher than the total control group. This difference was smaller for the ponies compared to the horses; in the horses, the geometric mean difference of the laminitic group was 1.73 [geometric 95% confidence interval (CI) 1.29-2.32], and in the ponies this value was 1.09 (geometric 95% CI 0.82-1.45). CONCLUSION AND CLINICAL RELEVANCE: In human medicine, an increased firing rate is characteristic of increased muscle force. Thus, the increased firing rate of the DDFM in the context of laminitis suggests an elevated muscle force. However, this seems to be only a partial effect as in this study, the unchanged turns/second and amplitude/turn failed to prove the recruitment of larger motor units with larger amplitude motor unit potentials in laminitic equids.

Transregional Interactions between Jansenists, other Catholics, and Protestants in Seventeenth Century Northern Europe

This paper discusses the theological and cultural exchanges between Catholic clergy and theologians, and specifically between the neo-Augustinian-minded, the so-called “Jansenists”, and other Catholics, in Northern Europe during the seventeenth century. It also explores the Jansenists’ encounters and theological engagement with Protestantism. In this period, interaction and transfer between French Jansenist Catholics and other Catholics in other countries took place in various ways: 1. Via traveling and migration: French theologians and clergy returned home from their travels with reports about the situation of Catholicism and Protestantism in other countries; moreover, in the second half of the 17th century, French Jansenists fled to the northern Netherlands. 2. Via networking: it is little known that for a brief period on the North Sea island of Nordstrand, adherents to Port-Royal were buying land, and clergy of the Flemish Oratory provided pastoral care for the island’s Catholics. This project was not successful, but at the end it strengthened the network between French “Jansenists” and Catholics in the Dutch Republic. 3. Via publications by leading Jansenists and their counterparts. In this paper, the focus is on the view of Protestantism held by Jansenist writers.

The role of LMX1B and PITX2 in anterior segment development and adult ocular function

Several congenital syndromes associated with anterior segment (AS) anomalies can lead to impaired vision and glaucoma, such as nail-patella syndrome (NPS), caused by mutations in the LIM homeodomain transcription factor LMX1B and Axenfeld-Rieger's syndrome (ARS), caused by mutations in the bicoid-related homeodomain transcription factor PITX2. Targeted mutations in lmx1b and pitx2 and RNA in situ analysis reveal that both genes are required for AS development and are co-expressed within the periocular mesenchyme, suggesting they participate in a shared genetic pathway. Lmx1b homozygous mutants display iris and corneal stroma hypoplasia, and defects in ciliary body formation. In contrast, pitx2 homozygous mutants exhibit a more severe phenotype: the AS chamber, corneal endothelium, and extraocular muscles (EOM) fail to develop. The absence of EOM in pitx2 mutants suggests pitx2 acts upstream of lmx1b, or that other lmx1b family members, such as lmx1a, can compensate for lmx1b function. Lmxla/lmx1b double homozygous mutants have a reduced capacity to generate EOM, implying that lmx1 gene products have a redundant function in EOM development and that lmx1 family members may act downstream of pitx2. However, analysis of pitx2 expression in the AS tissues of lmx1b mutants and reciprocal studies of lmx1b expression in pitx2 mutants indicate that these genes do not function in a simple linear pathway. Instead, lmx1b and pitx2 may regulate a shared set of downstream targets or both genes may work in parallel transcribing unique targets required for a common biological process. Ultrastructural analysis of lmx1b and pitx2 mutant corneas indicates that collagen fibrillogenesis is perturbed, revealing a common role for both genes in the deposition of extracellular matrix. Furthermore, lmx1b/pitx2 double heterozygotes develop corneal opacities not observed in single heterozygotes demonstrating that lmx1b and pitx2 genetically interact. Data suggests that defects in the basement membrane of the corneal endothelium underlie the opacities observed in double heterozygotes. Additionally, double heterozygotes develop anterior synechias that occlude the trabecular meshwork, potentially blocking aqueous humor drainage. These data suggest that lmx1b and pitx2 are responsible for ECM deposition in multiple cell types and imply that such defects may contribute to the glaucomas observed in NPS and ARS patients. ^

The function of math5 and myocilin in mammalian eye development and disease

Complex molecular events underlie vertebrate eye development and disease. The eye is composed of two major tissue types: the anterior and posterior segments. During development, the retinal progenitor cells differentiate into six neuronal and one non-neuronal cell types. These cell types later organize into the distinct laminar structure of the mature retina which occupies the posterior segment. In the developed anterior segment, both the ciliary body and trabecular meshwork regulate intraocular pressure created by the aqueous humor. The disruption in intraocular pressure can lead to a blinding condition called glaucoma. To characterize molecular mechanisms governing retinal development and glaucoma, two separate mouse knockout lines carrying mutations in math5 and myocilin were subjected to a series of in vivo analyses. ^ Math5 is a murine homologue of Drosophila atonal , a bHLH proneural gene essential for the formation of photoreceptor cells. The expression of math5 coincides with the onset of retinal ganglion cell differentiation. The targeted deletion of mouse math5 revealed that a null mutation inhibits the formation of a majority of the retinal ganglion cells. The mutation also interferes with the normal development of other retinal cell types such as amacrine, bipolar and photoreceptor cells. These results suggest that math5 is a proneural gene responsible for differentiation of retinal ganglion cells and may also have a role in normal development of other neuronal cell types within the retina. ^ Myocilin has two unique protein coding regions bearing homology to non-muscle myosin of Dictyostelium discoideum and to olfactomedin, an extracellular matrix molecule first described in the olfactory epithelium of the bullfrog. Recently, autosomal dominant forms of myocilin mutations have been found in individuals with primary open-angle glaucoma. The genetic linkage to glaucoma suggests a role of myocilin in normal intraocular pressure and ocular function. However, the analysis of mice heterozygous and homozygous for a targeted null mutation in myocilin indicates that it is dispensable for normal intraocular pressure or ocular function. Additionally, the lack of a discernable phenotype in both heterozygous and null mice suggests that haploinsufficiency is not a critical mechanism for MYOC-associated glaucoma in humans. Instead, disease-causing mutations likely act by gain of function. ^ In summary, these studies provide novel insights into the embryonic development of the vertebrate retina, and also begin to uncover the molecular mechanisms responsible for the pathogenesis of glaucoma. ^