Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration : a Patient-Level Pooled Analysis

Topic: This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham \ub1 verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance: Intravitreal anti\u2013vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods: Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists\u2019 Collaboration (APTC). Results: The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72\u20131.88) for ATE, 1.33 (0.59\u20132.97) for MI, 1.43 (0.54\u20133.77) for stroke excluding TIA, 1.25 (0.61\u20132.55) for stroke or TIA, 0.57 (0.18\u20131.78) for vascular death, and 1.12 (0.64\u20131.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions: The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit\u2013risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses

Adjunctive long-acting risperidone in patients with bipolar disorder who relapse frequently and have active mood symptoms

<p>Abstract</p> <p>Background</p> <p>The objective of this exploratory analysis was to characterize efficacy and onset of action of a 3-month treatment period with risperidone long-acting injection (RLAI), adjunctive to an individual's treatment regimen, in subjects with symptomatic bipolar disorder who relapsed frequently and had significant symptoms of mania and/or depression.</p> <p>Methods</p> <p>Subjects with bipolar disorder with ≥4 mood episodes in the past 12 months entered the open-label stabilization phase preceding a placebo-controlled, double-blind study. Subjects with significant depressive or manic/mixed symptoms at baseline were analyzed. Significant depressive symptoms were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) ≥16 and Young Mania Rating Scale (YMRS) < 16; manic/mixed symptoms were YMRS ≥16 with any MADRS score. Subjects received open-label RLAI (25-50 mg every 2 weeks) for 16 weeks, adjunctive to a subject's individualized treatment for bipolar disorder (mood stabilizers, antidepressants, and/or anxiolytics). Clinical status was evaluated with the Clinical Global Impressions of Bipolar Disorder-Severity (CGI-BP-S) scale and changes on the MADRS and YMRS scales. Within-group changes were evaluated using paired <it>t </it>tests; categorical differences were assessed using Fisher exact test. No adjustment was made for multiplicity.</p> <p>Results</p> <p>162 subjects who relapsed frequently met criteria for significant mood symptoms at open-label baseline; 59/162 (36.4%) had depressive symptoms, 103/162 (63.6%) had manic/mixed symptoms. Most subjects (89.5%) were receiving ≥1 medication for bipolar disorder before enrollment. Significant improvements were observed for the total population on the CGI-BP-S, MADRS, and YMRS scales (p < .001 vs. baseline, all variables). Eighty-two (53.3%) subjects achieved remission at the week 16 LOCF end point. The subpopulation with depressive symptoms at open-label baseline experienced significant improvement on the CGI-BP-S and MADRS scales (p < .001 vs. baseline, all variables). Subjects with manic/mixed symptoms at baseline had significant improvements on the CGI-BP-S and YMRS scales (p < .001 vs. baseline, all variables). No unexpected tolerability findings were observed.</p> <p>Conclusions</p> <p>Exploratory analysis of changes in overall clinical status and depression/mania symptoms in subjects with symptomatic bipolar disorder who relapse frequently showed improvements in each of these areas after treatment with RLAI, adjunctive to a subject's individualized treatment. Prospective controlled studies are needed to confirm these findings.</p

Mitochondrial phylogeography and demographic history of the Vicuña: implications for conservation

The vicuña (Vicugna vicugna; Miller, 1924) is a conservation success story, having recovered from near extinction in the 1960s to current population levels estimated at 275 000. However, lack of information about its demographic history and genetic diversity has limited both our understanding of its recovery and the development of science-based conservation measures. To examine the evolution and recent demographic history of the vicuña across its current range and to assess its genetic variation and population structure, we sequenced mitochondrial DNA from the control region (CR) for 261 individuals from 29 populations across Peru, Chile and Argentina. Our results suggest that populations currently designated as Vicugna vicugna vicugna and Vicugna vicugna mensalis comprise separate mitochondrial lineages. The current population distribution appears to be the result of a recent demographic expansion associated with the last major glacial event of the Pleistocene in the northern (18 to 22°S) dry Andes 14–12 000 years ago and the establishment of an extremely arid belt known as the 'Dry Diagonal' to 29°S. Within the Dry Diagonal, small populations of V. v. vicugna appear to have survived showing the genetic signature of demographic isolation, whereas to the north V. v. mensalis populations underwent a rapid demographic expansion before recent anthropogenic impacts

Effects of Global Warming on Ancient Mammalian Communities and Their Environments

Current global warming affects the composition and dynamics of mammalian communities and can increase extinction risk; however, long-term effects of warming on mammals are less understood. Dietary reconstructions inferred from stable isotopes of fossil herbivorous mammalian tooth enamel document environmental and climatic changes in ancient ecosystems, including C(3)/C(4) transitions and relative seasonality.Here, we use stable carbon and oxygen isotopes preserved in fossil teeth to document the magnitude of mammalian dietary shifts and ancient floral change during geologically documented glacial and interglacial periods during the Pliocene (approximately 1.9 million years ago) and Pleistocene (approximately 1.3 million years ago) in Florida. Stable isotope data demonstrate increased aridity, increased C(4) grass consumption, inter-faunal dietary partitioning, increased isotopic niche breadth of mixed feeders, niche partitioning of phylogenetically similar taxa, and differences in relative seasonality with warming.Our data show that global warming resulted in dramatic vegetation and dietary changes even at lower latitudes (approximately 28 degrees N). Our results also question the use of models that predict the long term decline and extinction of species based on the assumption that niches are conserved over time. These findings have immediate relevance to clarifying possible biotic responses to current global warming in modern ecosystems

Assessment of effectiveness measures in patients with schizophrenia initiated on risperidone long-acting therapy: the SOURCE study results

<p>Abstract</p> <p>Background</p> <p>To evaluate effectiveness outcomes in a real-world setting in patients with schizophrenia initiating risperidone long-acting therapy (RLAT).</p> <p>Methods</p> <p>This was a 24-month, multicenter, prospective, longitudinal, observational study in patients with schizophrenia who were initiated on RLAT. Physicians could change treatment during the study as clinically warranted. Data were collected at baseline and subsequently every 3 months up to 24 months. Effectiveness outcomes included changes in illness severity as measured by Clinical Global Impression-Severity (CGI-S) scale; functional scores as measured by Personal and Social Performance (PSP) scale, Global Assessment of Functioning (GAF), and Strauss-Carpenter Levels of Functioning (LOF); and health status (Medical Outcomes Survey Short Form-36 [SF-36]). Life-table methodology was used to estimate the cumulative probability of relapse over time. Adverse events were evaluated for safety.</p> <p>Results</p> <p>532 patients were enrolled in the study; 209 (39.3%) completed the 24-month study and 305 (57.3%) had at least 12 months of follow-up data. The mean (SD) age of patients was 42.3 (12.8) years. Most patients were male (66.4%) and either Caucasian (60.3%) or African American (23.7%). All changes in CGI-S from baseline at each subsequent 3-month follow-up visit were statistically significant (<it>p </it>< .0001), indicating improvement in disease severity. Improvements were also noted for the PSP, GAF, and total LOF, indicating improvement in daily functioning and health outcome.</p> <p>Conclusions</p> <p>Patients with schizophrenia who were initiated on RLAT demonstrated improvements in measures of effectiveness within 3 months, which persisted over 24 months.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00246194">NCT00246194</a></p

The multi-peak adaptive landscape of crocodylomorph body size evolution

Background: Little is known about the long-term patterns of body size evolution in Crocodylomorpha, the > 200-million-year-old group that includes living crocodylians and their extinct relatives. Extant crocodylians are mostly large-bodied (3–7 m) predators. However, extinct crocodylomorphs exhibit a wider range of phenotypes, and many of the earliest taxa were much smaller ( Results: Crocodylomorphs reached an early peak in body size disparity during the Late Jurassic, and underwent an essentially continual decline since then. A multi-peak Ornstein-Uhlenbeck model outperforms all other evolutionary models fitted to our data (including both uniform and non-uniform), indicating that the macroevolutionary dynamics of crocodylomorph body size are better described within the concept of an adaptive landscape, with most body size variation emerging after shifts to new macroevolutionary regimes (analogous to adaptive zones). We did not find support for a consistent evolutionary trend towards larger sizes among lineages (i.e., Cope’s rule), or strong correlations of body size with climate. Instead, the intermediate to large body sizes of some crocodylomorphs are better explained by group-specific adaptations. In particular, the evolution of a more aquatic lifestyle (especially marine) correlates with increases in average body size, though not without exceptions. Conclusions: Shifts between macroevolutionary regimes provide a better explanation of crocodylomorph body size evolution on large phylogenetic and temporal scales, suggesting a central role for lineage-specific adaptations rather than climatic forcing. Shifts leading to larger body sizes occurred in most aquatic and semi-aquatic groups. This, combined with extinctions of groups occupying smaller body size regimes (particularly during the Late Cretaceous and Cenozoic), gave rise to the upward-shifted body size distribution of extant crocodylomorphs compared to their smaller-bodied terrestrial ancestors.</p

Phylogenetic relationships of the New World titi monkeys (Callicebus): First appraisal of taxonomy based on molecular evidence

Background: Titi monkeys, Callicebus, comprise the most species-rich primate genus-34 species are currently recognised, five of them described since 2005. The lack of molecular data for titi monkeys has meant that little is known of their phylogenetic relationships and divergence times. To clarify their evolutionary history, we assembled a large molecular dataset by sequencing 20 nuclear and two mitochondrial loci for 15 species, including representatives from all recognised species groups. Phylogenetic relationships were inferred using concatenated maximum likelihood and Bayesian analyses, allowing us to evaluate the current taxonomic hypothesis for the genus. Results: Our results show four distinct Callicebus clades, for the most part concordant with the currently recognised morphological species-groups-the torquatus group, the personatus group, the donacophilus group, and the moloch group. The cupreus and moloch groups are not monophyletic, and all species of the formerly recognized cupreus group are reassigned to the moloch group. Two of the major divergence events are dated to the Miocene. The torquatus group, the oldest radiation, diverged c. 11 Ma; and the Atlantic forest personatus group split from the ancestor of all donacophilus and moloch species at 9-8 Ma. There is little molecular evidence for the separation of Callicebus caligatus and C. dubius, and we suggest that C. dubius should be considered a junior synonym of a polymorphic C. caligatus. Conclusions: Considering molecular, morphological and biogeographic evidence, we propose a new genus level taxonomy for titi monkeys: Cheracebus n. gen. in the Orinoco, Negro and upper Amazon basins (torquatus group), Callicebus Thomas, 1903, in the Atlantic Forest (personatus group), and Plecturocebus n. gen. in the Amazon basin and Chaco region (donacophilus and moloch groups). © 2016 Byrne et al

The history of banking in North Dakota / by W.C. Macfadden, 1934.

Copy of typescript history of the early banks in Dakota Territory, and including information on the Dakota Bankers Association and the North Dakota Bankers Association