Cardiovascular and respiratory hospitalizations and mortality among users of tiotropium in Denmark

Tiotropium (Spiriva is an inhaled, once-daily anticholinergic medication for chronic obstructive pulmonary disease (COPD). We conducted a population-based cohort study to examine the risk of cardiovascular and respiratory hospitalizations and mortality with tiotropium. Using the Danish healthcare registries, we identified persons >/=40 years old in three counties who were hospitalized for COPD from 1/1/1977 to 12/31/2003. Respiratory and cardiovascular medications were assessed from dispensing records. Cox regression was used to compute incidence rate ratios (RR) and 95% confidence intervals (CI) for hospitalization and death between 1/1/2002 and 12/31/2003, associated with periods of tiotropium use compared to non-use, controlling for age, gender, time since COPD, concomitant respiratory and cardiovascular medications, prior hospitalizations and Charlson comorbidity index. Among persons with COPD (10,603), 75% were >/=60 years old. Follow-up was >/=18 months for 64%. Among those exposed to tiotropium compared to periods of non-use, the RR for total and cause-specific hospitalization endpoints were not elevated except for COPD hospitalization (RR = 1.52, 95% CI: 1.29, 1.79). Mortality endpoints included total mortality (RR = 0.77, 95% CI: 0.65, 0.91), respiratory mortality (RR = 0.79, 95% CI: 0.60, 1.04), sudden death (RR = 0.71, 95% CI: 0.21, 2.34), cardiac arrest (RR = 0.74, 95% CI: 0.42, 1.32), heart failure (RR = 0.84, 95% CI: 0.41, 1.75), and myocardial infarction (RR = 1.25, 95% CI: 0.49, 3.17). Compared to periods of non-use, tiotropium was associated with reduced respiratory and overall mortality and was not associated with increased cardiac mortality. An increase in COPD hospitalization is inconsistent with clinical trial data and suggests preferential prescribing due to disease severity.     

Electrical isolation of pulmonary veins in patients with atrial fibrillation: reduction of fluoroscopy exposure and procedure duration by the use of a non-fluoroscopic navigation system (NavX).

AIMS: The aim of the study was to investigate the feasibility of performing segmental pulmonary vein (PV) isolation guided by the NavX (Endocardial Solutions, St Jude Medical, Inc., St Paul, MN, USA) system without the three-dimensional (3D) geometric reconstruction option and whether the use of NavX system will reduce the radiation exposure and procedure duration. METHODS AND RESULTS: The study included 64 patients with symptomatic paroxysmal or permanent atrial fibrillation, in whom PV isolation was performed using fluoroscopic guidance (n=32) or the NavX system (n=32). Pulmonary vein mapping with a circular mapping catheter allowed the identification and localization of myocardial connections between the PV and the left atrium. PV isolation was performed by radiofrequency ablation of these connections at the atrial aspect of the PV ostium. Primary success rate for isolated PVs did not differ significantly in patients ablated under fluoroscopic guidance vs. those ablated under guidance of NavX system [100/107 PVs (93.5%) vs. 120/124 PV (96.8%; P=n.s.)]. Compared with fluoroscopy guided procedures, NavX-guided procedures showed a significant reduction in the fluoroscopy time (75.8+/-24.5 vs. 38.9+/-19.3 min, P<0.05), total X-ray exposure (93.2+/-51.6 vs. 56.6+/-37.9 Gy cm(2), P=0.03), and total procedural time (237.7+/-65.4 vs. 188.6+/-62.7 min, P=0.01). The mean follow-up was 9.5+/-3.0 months. One patient in each group was lost to follow-up. Seven-day Holter monitoring showed that 23 of 31 patients (74.2%) in the NavX-guided group and 21 of 31 patients (67.7%) in the fluoroscopy-guided group were in sinus rhythm (P=0.57). CONCLUSION: The 3D visualization of the catheters by NavX system allows a rapid and precise visualization of the mapping and ablation catheters at the PV ostia and markedly reduces fluoroscopy time, total X-ray exposure, and procedural duration during PV isolation compared with ablation performed under fluoroscopy guidance.     

Schizophrenia and Autism as Contrasting Minds: Neural Evidence for the Hypo-Hyper-Intentionality Hypothesis

Both schizophrenia (SCZ) and autism spectrum disorder (ASD) are characterized by mentalizing problems and associated neural dysfunction of the social brain. However, the deficits in mental state attribution are somehow opposed: Whereas patients with SCZ tend to over-attribute intentions to agents and physical events (“hyper-intentionality”), patients with autism treat people as devoid of intentions (“hypo-intentionality”). Here we aimed to investigate whether this hypo-hyper-intentionality hypothesis can be supported by neural evidence during a mentalizing task. Using functional magnetic resonance imaging (fMRI), we investigated the neural responses and functional connectivity during reading others intention. Scanning was performed in 23 individuals with ASD, 18 with paranoid SCZ and 23 gender and IQ matched control subjects. Both clinical groups showed reduced brain activation compared to controls for the contrast intentional vs physical information processing in left posterior superior temporal sulcus (pSTS) and ventral medial prefrontal cortex (vMPFC) for SCZ, and right pSTS in ASD. As predicted, these effects were caused in a group specific way: Relative increased activation for physical information processing in SCZ that was also correlated with positive PANNS score and relative decreased activation for intentional information processing in ASD. Additionally, we could demonstrate opposed connectivity patterns between the right pSTS and vMPFC in the clinical groups, ie, increased for SCZ, decreased for ASD. These findings represent opposed neural signatures in key regions of the social brain as predicted by the hyper-hypo-intentionality hypothesis.     

Experimental validation of the RATE tool for inferring HLA restrictions of T cell epitopes

Background

The RATE tool was recently developed to computationally infer the HLA restriction of given epitopes from immune response data of HLA typed subjects without additional cumbersome experimentation.

Results

Here, RATE was validated using experimentally defined restriction data from a set of 191 tuberculosis-derived epitopes and 63 healthy individuals with MTB infection from the Western Cape Region of South Africa. Using this experimental dataset, the parameters utilized by the RATE tool to infer restriction were optimized, which included relative frequency (RF) of the subjects responding to a given epitope and expressing a given allele as compared to the general test population and the associated p-value in a Fisher’s exact test. We also examined the potential for further optimization based on the predicted binding affinity of epitopes to potential restricting HLA alleles, and the absolute number of individuals expressing a given allele and responding to the specific epitope. Different statistical measures, including Matthew’s correlation coefficient, accuracy, sensitivity and specificity were used to evaluate performance of RATE as a function of these criteria. Based on our results we recommend selection of HLA restrictions with cutoffs of p-value?<?0.01 and RF?≥?1.3. The usefulness of the tool was demonstrated by inferring new HLA restrictions for epitope sets where restrictions could not be experimentally determined due to lack of necessary cell lines and for an additional data set related to recognition of pollen derived epitopes from allergic patients.

Conclusions

Experimental data sets were used to validate RATE tool and the parameters used by the RATE tool to infer restriction were optimized. New HLA restrictions were identified using the optimized RATE tool.

     

A high and increasing HPV prevalence in tonsillar cancers in Eastern Denmark, 2000–2010: The largest registry‐based study to date

The aim was to explore whether the incidence of tonsillar squamous cell carcinomas (TSCCs) increased in Eastern Denmark, 2000–2010, and whether human papillomavirus (HPV) could explain the increase, and to assess the association of HPV prevalence with gender, age, and origin (i.e., the certainty of tonsillar tumor origin). We applied HPV DNA PCR and p16 immunohistochemistry to all TSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and in the Danish Pathology Data Bank (n = 632). Pathologists reviewed and subdivided the tumors into two groups: specified and nonspecified TSCCs. Approximately 10% of HPV‐positive tumors was genotyped by amplicon next‐generation sequencing. The overall crude incidence of TSCCs increased significantly (2.7% per year) and was explained by an increasing incidence of HPV‐positive TSCCs (4.9% per year). The overall HPV prevalence was 58%, with HPV16 being the predominant HPV type. In multivariate analysis, the HPV prevalence was associated with age (<55 vs. >60 years) (OR, 1.72; 95% CI 1.13–2.63) and origin (nonspecified vs. specified TSCCs) (OR, 0.15; 95% CI 0.11–0.22). The association of HPV prevalence with origin increased over time in specified TSCCs (OR per year, 1.10; 95% CI 1.01–1.19), whereas no change over time was observed among nonspecified TSCCs (OR per year, 0.99; 95% CI 0.90–1.08). In conclusion, the observed increase in the number of HPV‐positive TSCCs can explain the increasing number of TSCCs in Eastern Denmark, 2000–2010. HPV prevalence was associated with younger age (<55 years) and a high certainty of tonsillar tumor origin.     

Heritable variation in telomere length predicts mortality in Soay sheep

Telomere length (TL) is considered an important biomarker of whole-organism health and aging. Across humans and other vertebrates, short telomeres are associated with increased subsequent mortality risk, but the processes responsible for this correlation remain uncertain. A key unanswered question is whether TL–mortality associations arise due to positive effects of genes or early-life environment on both an individual’s average lifetime TL and their longevity, or due to more immediate effects of environmental stressors on within-individual TL loss and increased mortality risk. Addressing this question requires longitudinal TL and life history data across the entire lifetimes of many individuals, which are difficult to obtain for long-lived species like humans. Using longitudinal data and samples collected over nearly two decades, as part of a long-term study of wild Soay sheep, we dissected an observed positive association between TL and subsequent survival using multivariate quantitative genetic models. We found no evidence that telomere attrition was associated with increased mortality risk, suggesting that TL is not an important marker of biological aging or exposure to environmental stress in our study system. Instead, we find that among-individual differences in average TL are associated with increased lifespan. Our analyses suggest that this correlation between an individual’s average TL and lifespan has a genetic basis. This demonstrates that TL has the potential to evolve under natural conditions, and suggests an important role of genetics underlying the widespread observation that short telomeres predict mortality.

Telomeres are repetitive sequences of noncoding DNA found at the terminal ends of linear chromosomes, and they play an important role in maintaining DNA stability and integrity (1–3). Telomeres shorten during cell replication and in response to oxidative stress (4, 5), and cellular senescence and apoptosis is triggered once telomeres reach a critically short threshold (2). The important role of telomeres in cellular senescence has led to telomere shortening being considered as one of nine “hallmarks of aging,” and average telomere length (TL) as an important biomarker of whole-organism health and biological aging (6). In humans, relatively short leukocyte telomeres have been linked to a range of age-related diseases such as diabetes, cancer, and cardiovascular disease (7–9) and increased subsequent mortality risk (10–12). A recent metaanalysis suggests this pattern may generalize beyond humans: Across studies from 20 nonmodel vertebrate species (predominantly birds), there was an overall positive association between TL and subsequent survival (13). Although evidence for a causal role for telomeres in whole-organism aging and longevity remains weak (14), these findings highlight the potential significance of TL as a biomarker of human and animal health (15, 16) and for our understanding of life history evolution (17, 18).Studies in humans and other vertebrates have found evidence for consistent differences in TL among individuals over multiple measurements (19, 20). Such repeatable among-individual differences in any trait may result from the trait being under genetic influence, from long-term effects of the early-life environment, and/or environmental conditions that persist across the lifetime. There is good evidence that variation in average TL in blood cells has a genetic basis in humans and other vertebrates, although estimates of the heritability (the proportion of variation attributed to additive genetic effects) of TL are variable (21, 22). Recent studies of wild vertebrates have also revealed considerable variation in adult TL among birth cohorts, suggesting persistent impacts of early-life environment (23, 24). At the same time, there is growing evidence that TL is highly dynamic across an individual’s lifetime, and metaanalyses of human and nonhuman animal studies show that experience of diverse forms of environmental stress are predictive of shorter TL (25–27). Indeed, some studies using longitudinal TL data have found that telomere shortening over successive measurements rather than TL per se is predictive of mortality (28–30). Thus, the emerging picture from studies in humans and other vertebrates is that shorter TL generally predicts increased risk of subsequent mortality, and that variation in TL is under the influence of both genetics and environmental stressors.The observation that shorter TL measurements predict increased mortality risk could be underpinned by two nonmutually exclusive processes operating across the lifetimes of individuals. Firstly, individuals may differ in their average TL across life, and individuals with shorter TL may be shorter lived. This pattern is referred to as the “selective disappearance” of individuals with shorter telomeres, and it implies that TL reflects constitutive differences among individuals (for example, due to genetics or differences in early-life environment) which shape their longevity (31, 32). Secondly, individuals may differ in their pattern of TL change over time, and individuals showing the greatest telomere loss across successive measurements are more likely to die subsequently. This pattern is consistent with the idea that within-individual telomere dynamics reflect recent and cumulative experiences of environmental stress and physiological deterioration that also predict mortality. Neither pattern necessarily implies a causal role for telomeres in driving the mortality risk of an organism, because associations between TL and survival could result from both traits being correlated with underlying, unmeasured variables which causally impact survival (14, 18). Nevertheless, unraveling the contribution of genetics, early-life environment, and more immediate telomere shortening to the observed association between TL and survival is essential for our understanding of TL as a biomarker of health and aging (19).To our knowledge, no study to date has assessed the relative importance of the different processes underlying the relationship between TL and mortality risk across the entire lifespan. To do so demands repeated measurements from across life to characterize among- and within-individual variation in TL, a population pedigree or genomic information to separate genetic and environmental sources of variation, and detailed information on individual health and fitness outcomes over the lifetime. Here, we use a multivariate mixed-effects modeling approach to analyze extensive, longitudinal data from a long-term study of wild Soay sheep living on St Kilda, Scotland, to distinguish between possible models of why shorter TL predicts increased mortality risk. We find that the observed positive association between TL and mortality in this system is underpinned by selective disappearance of individuals with shorter average TL. Importantly, our results suggest this is largely driven by genetically based differences in both TL and longevity.