Market Heterogeneity and Drug Innovation

The Induced Innovation Hypothesis (IIH) describes the causal effect of market size (i.e., product demand) on innovation output - larger value markets offer larger profit potential which leads to higher rates of new product entry. Empirical literature has supported the IIH but the estimated effects of market size on pharmaceutical innovation are curious in two respects: they are much higher than predicted and they vary across innovation measures (e.g., new molecules, new non-generic drugs, new patents). I propose and investigate an extended Induced Innovation Hypothesis (eIIH) which posits how non-size characteristics of markets or market heterogeneity (e.g., compositional structure, R&D riskiness) together with aggregate market size can influence the introduction rate of new drugs and associated outputs. My empirical approach exploits a panel dataset constructed from publicly available data from the U.S. Food and Drug Administration, Agency for Healthcare Research and Quality, and World Health Organization that links market size and heterogeneity measures with innovation counts associated with New Drug Application (NDA) approvals. Consistent with previously reported estimates, I find that a 1% increase in market size produces a 2%-6% increase in innovation entry under a traditional IIH setup. However, in closer alignment with theoretical predictions, controlling for market population characteristics such as disease severity, physiology types, and treatment preferences lowers the estimated effect of market size to the 1%-4% range. These results appear reasonably robust across different innovation count measures with significance levels sensitive to specification and variable construction choices. Thus, initial evidence suggests that an extended IIH can provide a more informative model of induced drug innovation than the traditional IIH. It also suggests how policy levers might be more effectively used to direct pharmaceutical innovation toward under-served as well as un-served markets

Forests and water: a state-of-the-art review for Colorado

Includes bibliographical references (pages 65-75).Forests occupy 22.6 million acres in Colorado, or 32 percent of the land area, and nearly three-quarters of the forest lands in Colorado are in public ownership. About 55 percent of the forested area is considered suitable for forest harvest. National forests comprise nearly half of the forested area and approximately 60 percent of the area is considered suitable for forest harvest. There are no significant, privately-owned, industrial forest lands in Colorado. Historic photographs, forest stand records, and other data indicate that forest density in Colorado is generally greater than in the mid to late 1800s. This increase in forest density, attributed to suppression of forest fires, reduced grazing, and lower rates of forest harvest for timber, fuel, and other products, are generally believed to have decreased annual water yields. Annual water yields from the 1.34 million acres of national forest lands in the North Platte River basin are estimated to have decreased by approximately 8 to 14 percent or 135,000 to 185,000 acre-feet per year, depending on the assumed stand history for the spruce-fir forests. Hydrologic models indicate that average annual water yields could be increased in the North Platte River basin by about 55,000 acre-feet per year if all 502,000 acres designated as suitable for timber harvest were regularly harvested on a sustained yield basis. Similar data are not available for other river basins in Colorado, although the overall trends are probably similar. This research looked at how reducing forest canopy affects the rate of spring snowmelt and water yield, how it affects evapotranspiration, what happens when the forest regrows, whether reducing forest density affects water yields if annual precipitation is a factor, the effects on water quality, and the necessity for water storage facilities to store the increased runoff. The report does not attempt to address the myriad of other issues that must be considered when evaluating various management alternatives for forested lands. Some of these issues include the numerous laws and regulations that affect land management, economic considerations, the downstream uses of water and water storage capacities, and the effects of forest management on recreation, local communities, aesthetics, and other plant and animal species.Sponsored by: Colorado River Water Conservation District, Colorado Water Resources Research Institute, Denver Water, Northern Colorado Water Conservancy District and financed in part by the U.S. Department of the Interior, Geological Survey, through the Colorado Water Resources Research Institute and Grant no. 01HQGR0077

Search for rare or forbidden decays of the D0 meson

We present a search for nine lepton-number-violating and three lepton-flavor-violating neutral charm decays of the type D0→h'−h−ℓ'+ℓ+ and D0→h'−h+ℓ'±ℓ∓, where h and h′ represent a K or π meson and ℓ and ℓ′ an electron or muon. The analysis is based on 468 fb−1 of e+e− annihilation data collected at or close to the Υ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signal is observed for any of the twelve modes, and we establish 90% confidence level upper limits on the branching fractions in the range (1.0–30.6)×10−7. The limits are between 1 and 3 orders of magnitude more stringent than previous measurements.publishedVersio

Measurements of the absolute branching fractions of B± →k±Xc c

A study of the two-body decays B±→Xc¯cK±, where Xc¯c refers to one charmonium state, is reported by the BABAR Collaboration using a data sample of 424 fb−1. The absolute determination of branching fractions for these decays are significantly improved compared to previous BABAR measurements. Evidence is found for the decay B+→X(3872)K+ at the 3σ level. The absolute branching fraction B[B+→X(3872)K+]=[2.1±0.6(stat)±0.3(syst)]×10−4 is measured for the first time. It follows that B[X(3872)→J/ψπ+π−]=(4.1±1.3)%, supporting the hypothesis of a molecular component for this resonance.publishedVersio

Light meson spectroscopy from Dalitz plot analyses of ηc decays to η0 K+K− , η0 π + π − , and ηπ + π − produced in two-photon interactions

We study the processes γγ→ηc→η′K+K−, η′π+π−, and ηπ+π− using a data sample of 519  fb−1 recorded with the BABAR detector operating at the SLAC PEP-II asymmetric-energy e+e− collider at center-of-mass energies at and near the Υ(nS) (n=2, 3, 4) resonances. This is the first observation of the decay ηc→η′K+K− and we measure the branching fraction Γ(ηc→η′K+K−)/(Γ(ηc→η′π+π−)=0.644±0.039stat±0.032sys. Significant interference is observed between γγ→ηc→ηπ+π− and the nonresonant two-photon process γγ→ηπ+π−. A Dalitz plot analysis is performed of ηc decays to η′K+K−, η′π+π−, and ηπ+π−. Combined with our previous analysis of ηc→K¯Kπ, we measure the K∗0(1430) parameters and the ratio between its η′K and πK couplings. The decay ηc→η′π+π− is dominated by the f0(2100) resonance, also observed in J/ψ radiative decays. A new a0(1700)→ηπ resonance is observed in the ηc→ηπ+π− channel. We also compare ηc decays to η and η′ final states in association with scalar mesons as they relate to the identification of the scalar glueball.publishedVersio

Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop

In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect '.... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest