The Measurement and Evolution of Health Inequality: Evidence from the U.S. Medicare Population

Has U.S. health care for the elderly become more equitable during the past several decades? When inequality is measured by Medicare expenditures, the answer is yes. During 1987-2001, low income households experienced an increase of 78 percent ($2624) in per capita expenditures, double the increase of 34 percent ($1214) in the highest income group. When inequality is measured by life expectancy, the answer is no. Survival for the lowest income decile grew by 0.2 years during the 1990s compared to 0.8 years in the highest income group. That the two measures deliver such discordant messages may reflect their intrinsic shortcomings; expenditures depend on preferences, health status, and prices, while outcomes are strongly affected by health behavior and past illness. We suggest a new approach to measuring inequality: the use of quality-based effective care measures. For these measures, efficacy is well proven and nearly all of the relevant population should be receiving it, regardless of health status or preferences. Using Medicare claims data matched to zip code income, we find greater use of mammography screening, diabetic eye exams, and the use of ââ blockers and reperfusion following heart attacks among higher income households, and these differences appear to be stable or growing slowly over time. In sum, the rapid relative growth in health care expenditures among low income elderly people has not translated into relative improvement either in survival or rates of effective care.

Early LQT2 Nonsense Mutation Generates N-Terminally Truncated hERG Channels with Altered Gating Properties by the Reinitiation of Translation

Mutations in the human ether-a-go-go-related gene (hERG) result in long QT syndrome type 2 (LQT2). The hERG gene encodes a K+ channel that contributes to the repolarization of the cardiac action potential. We have previously shown that hERG mRNA transcripts that contain premature termination codon mutations are rapidly degraded by nonsense-mediated mRNA decay (NMD). In this study, we identified a LQT2 nonsense mutation, Q81X, which escapes degradation by the reinitiation of translation and generates N-terminally truncated channels. RNA analysis of hERG minigenes revealed equivalent levels of wild-type and Q81X mRNA while the mRNA expressed from minigenes containing the LQT2 frameshift mutation, P141fs+2X, was significantly reduced by NMD. Western blot analysis revealed that Q81X minigenes expressed truncated channels. Q81X channels exhibited decreased tail current levels and increased deactivation kinetics compared to wild-type channels. These results are consistent with the disruption of the N-terminus, which is known to regulate hERG deactivation. Site-specificmutagenesis studies showed that translation of the Q81X transcript is reinitiated atMet124 following premature termination. Q81X co-assembled with hERG to form heteromeric channels that exhibited increased deactivation rates compared to wild-type channels. Mutant channels also generated less outward current and transferred less charge at late phases of repolarization during ventricular action potential clamp. These results provide new mechanistic insight into the prolongation of the QT interval in LQT2 patients. Our findings indicate that the reinitiation of translation may be an important pathogenic mechanism in patients with nonsense and frameshift LQT2 mutations near the 5′ end of the hERG gene

3.5Å cryoEM structure of hepatitis B virus core assembled from full-length core protein.

The capsid shell of infectious hepatitis B virus (HBV) is composed of 240 copies of a single protein called HBV core antigen (HBc). An atomic model of a core assembled from truncated HBc was determined previously by X-ray crystallography. In an attempt to obtain atomic structural information of HBV core in a near native, non-crystalline environment, we reconstructed a 3.5Å-resolution structure of a recombinant core assembled from full-length HBc by cryo electron microscopy (cryoEM) and derived an atomic model. The structure shows that the 240 molecules of full-length HBc form a core with two layers. The outer layer, composed of the N-terminal assembly domain, is similar to the crystal structure of the truncated HBc, but has three differences. First, unlike the crystal structure, our cryoEM structure shows no disulfide bond between the Cys61 residues of the two subunits within the dimer building block, indicating such bond is not required for core formation. Second, our cryoEM structure reveals up to four more residues in the linker region (amino acids 140-149). Third, the loops in the cryoEM structures containing this linker region in subunits B and C are oriented differently (~30° and ~90°) from their counterparts in the crystal structure. The inner layer, composed of the C-terminal arginine-rich domain (ARD) and the ARD-bound RNAs, is partially-ordered and connected with the outer layer through linkers positioned around the two-fold axes. Weak densities emanate from the rims of positively charged channels through the icosahedral three-fold and local three-fold axes. We attribute these densities to the exposed portions of some ARDs, thus explaining ARD's accessibility by proteases and antibodies. Our data supports a role of ARD in mediating communication between inside and outside of the core during HBV maturation and envelopment

Theorizing and Generalizing About Risk Assessment and Regulation Through Comparative Nested Analysis of Representative Cases

This article provides a framework and offers strategies for theorizing and generalizing about risk assessment and regulation developed in the context of an on-going comparative study of regulatory behavior. Construction of a universe of nearly 3,000 risks and study of a random sample of 100 of these risks allowed us to estimate relative U.S. and European regulatory precaution over a thirty-five-year period. Comparative nested analysis of cases selected from this universe of ecological, health, safety, and other risks or its eighteen categories or ninety-two subcategories of risk sources or causes will allow theory-testing and -building and many further descriptive and causal comparative generalizations

Cryo-EM structures of herpes simplex virus type 1 portal vertex and packaged genome.

Herpesviruses are enveloped viruses that are prevalent in the human population and are responsible for diverse pathologies, including cold sores, birth defects and cancers. They are characterized by a highly pressurized pseudo-icosahedral capsid-with triangulation number (T) equal to 16-encapsidating a tightly packed double-stranded DNA (dsDNA) genome1-3. A key process in the herpesvirus life cycle involves the recruitment of an ATP-driven terminase to a unique portal vertex to recognize, package and cleave concatemeric dsDNA, ultimately giving rise to a pressurized, genome-containing virion4,5. Although this process has been studied in dsDNA phages6-9-with which herpesviruses bear some similarities-a lack of high-resolution in situ structures of genome-packaging machinery has prevented the elucidation of how these multi-step reactions, which require close coordination among multiple actors, occur in an integrated environment. To better define the structural basis of genome packaging and organization in herpes simplex virus type 1 (HSV-1), we developed sequential localized classification and symmetry relaxation methods to process cryo-electron microscopy (cryo-EM) images of HSV-1 virions, which enabled us to decouple and reconstruct hetero-symmetric and asymmetric elements within the pseudo-icosahedral capsid. Here we present in situ structures of the unique portal vertex, genomic termini and ordered dsDNA coils in the capsid spooled around a disordered dsDNA core. We identify tentacle-like helices and a globular complex capping the portal vertex that is not observed in phages, indicative of herpesvirus-specific adaptations in the DNA-packaging process. Finally, our atomic models of portal vertex elements reveal how the fivefold-related capsid accommodates symmetry mismatch imparted by the dodecameric portal-a longstanding mystery in icosahedral viruses-and inform possible DNA-sequence recognition and headful-sensing pathways involved in genome packaging. This work showcases how to resolve symmetry-mismatched elements in a large eukaryotic virus and provides insights into the mechanisms of herpesvirus genome packaging

Video-rate 3D Particle Tracking with Extended Depth-of-field in Thick Biological Samples

We present a single-aperture 3D particle localisation and tracking technique with a vastly increased depth-of-field without compromising optical resolution and throughput. Flow measurements in a FEP capillary and a zebrafish blood vessel are demonstrated experimentally