Payment reform a primer for taking on risk.

To reduce unnecessary care and improve patient outcomes through bundled payments or population health management, healthcare organizations must define both the population for which they are assuming risk and the services that they will provide. Organizations also must be able to manage variations in cost and quality and demonstrate both the economic and clinical value they provide to the populations they serve. To effectively coordinate care across a patient population, providers--including physicians, hospitals, and postacute care facilities--must be willing to collaborate on efforts to reengineer care delivery.

The 2012 West Nile encephalitis epidemic in Dallas, Texas.

IMPORTANCE: After progressive declines over recent years, in 2012 West Nile virus epidemics resurged nationwide, with the greatest number of cases centered in Dallas County, Texas. OBJECTIVE: To analyze the epidemiologic, meteorologic, and geospatial features of the 2012 Dallas West Nile virus epidemic to guide future prevention efforts. DESIGN, SETTING, AND PATIENTS: Public health surveillance of Dallas County, an area of 2257 km2 and population of 2.4 million. Surveillance data included numbers of residents diagnosed with West Nile virus infection between May 30, 2012, and December 3, 2012; mosquito trap results; weather data; and syndromic surveillance from area emergency departments. MAIN OUTCOMES AND MEASURES: Incidence and age-adjusted incidence rates of West Nile neuroinvasive disease (WNND), daily prevalence of emergency department visits for asthma and skin rash, and Culex quinquefasciatus species-specific vector index (an estimate of the average number of West Nile virus-infected mosquitoes per trap-night). RESULTS: The investigation identified 173 cases of WNND, 225 of West Nile fever, 17 West Nile virus-positive blood donors, and 19 deaths in 2012. The incidence rate for WNND was 7.30 per 100,000 residents in 2012, compared with 2.91 per 100,000 in 2006, the largest previous Dallas County outbreak. An unusually rapid and early escalation of large numbers of human cases closely followed increasing infection trends in mosquitoes. The Cx quinquefasciatus species-specific vector index predicted the onset of symptoms among WNND cases 1 to 2 weeks later (count regression ß = 2.97 [95% CI, 2.34 to 3.60]; P < .001). Although initially widely distributed, WNND cases soon clustered in neighborhoods with high housing density in the north central area of the county, reflecting higher vector indices and following geospatial patterns of West Nile virus in prior years. During the 11 years since West Nile virus was first identified in Dallas, the log-transformed annual prevalence of WNND was inversely associated with the number of days with low temperatures below 28°F (-2.2°C) in December through February (ß = -0.29 [95% CI, -0.36 to -0.21]; P < .001). Aerial insecticide spraying was not associated with increases in emergency department visits for respiratory symptoms (ß = -4.03 [95% CI, -13.76 to 5.70]; P = .42) or skin rash (ß = -1.00 [95% CI, -6.92 to 4.92]; P = .74). CONCLUSIONS AND RELEVANCE: Large West Nile virus epidemics in Dallas County begin early after unusually warm winters, revisit similar geographical distributions, and are strongly predicted by the mosquito vector index. Consideration of weather patterns and historical geographical hot spots and acting on the vector index may help prevent West Nile virus-associated illness.

The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines.

Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.

Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells.

Telomeres are thought to be maintained by the preferential recruitment of telomerase to the shortest telomeres. The extension of the G-rich telomeric strand by telomerase is also believed to be coordinated with the complementary synthesis of the C strand by the conventional replication machinery. However, we show that under telomere length-maintenance conditions in cancer cells, human telomerase extends most chromosome ends during each S phase and is not preferentially recruited to the shortest telomeres. Telomerase rapidly extends the G-rich strand following telomere replication but fill-in of the C strand is delayed into late S phase. This late C-strand fill-in is not executed by conventional Okazaki fragment synthesis but by a mechanism using a series of small incremental steps. These findings highlight differences between telomerase actions during steady state versus nonequilibrium conditions and reveal steps in the human telomere maintenance pathway that may provide additional targets for the development of anti-telomerase therapeutics.

Wounding stimulates the accumulation of glycerolipids containing oxophytodienoic acid and dinor-oxophytodienoic acid in Arabidopsis leaves.

Although oxylipins can be synthesized from free fatty acids, recent evidence suggests that oxylipins are components of plastid-localized polar complex lipids in Arabidopsis (Arabidopsis thaliana). Using a combination of electrospray ionization (ESI) collisionally induced dissociation time-of-flight mass spectrometry (MS) to identify acyl chains, ESI triple-quadrupole (Q) MS in the precursor mode to identify the nominal masses of complex polar lipids containing each acyl chain, and ESI Q-time-of-flight MS to confirm the identifications of the complex polar lipid species, 17 species of oxylipin-containing phosphatidylglycerols, monogalactosyldiacylglycerols (MGDG), and digalactosyldiacylglycerols (DGDG) were identified. The oxylipins of these polar complex lipid species include oxophytodienoic acid (OPDA), dinor-OPDA (dnOPDA), 18-carbon ketol acids, and 16-carbon ketol acids. Using ESI triple-Q MS in the precursor mode, the accumulation of five OPDA- and/or dnOPDA-containing MGDG and two OPDA-containing DGDG species were monitored as a function of time in mechanically wounded leaves. In unwounded leaves, the levels of these oxylipin-containing complex lipid species were low, between 0.001 and 0.023 nmol/mg dry weight. However, within the first 15 min after wounding, the levels of OPDA-dnOPDA MGDG, OPDA-OPDA MGDG, and OPDA-OPDA DGDG, each containing two oxylipin chains, increased 200- to 1,000-fold. In contrast, levels of OPDA-hexadecatrienoic acid MGDG, linolenic acid (18:3)-dnOPDA MGDG, OPDA-18:3 MGDG, and OPDA-18:3 DGDG, each containing a single oxylipin chain, rose 2- to 9-fold. The rapid accumulation of high levels of galactolipid species containing OPDA-OPDA and OPDA-dnOPDA in wounded leaves is consistent with these lipids being the primary products of plastidic oxylipin biosynthesis.

Arabidopsis sfd mutants affect plastidic lipid composition and suppress dwarfing, cell death, and the enhanced disease resistance phenotypes resulting from the deficiency of a fatty acid desaturase.

A loss-of-function mutation in the Arabidopsis SSI2/FAB2 gene, which encodes a plastidic stearoyl-acyl-carrier protein desaturase, has pleiotropic effects. The ssi2 mutant plant is dwarf, spontaneously develops lesions containing dead cells, accumulates increased salicylic acid (SA) levels, and constitutively expresses SA-mediated, NPR1-dependent and -independent defense responses. In parallel, jasmonic acid-regulated signaling is compromised in the ssi2 mutant. In an effort to discern the involvement of lipids in the ssi2-conferred developmental and defense phenotypes, we identified suppressors of fatty acid (stearoyl) desaturase deficiency (sfd) mutants. The sfd1, sfd2, and sfd4 mutant alleles suppress the ssi2-conferred dwarfing and lesion development, the NPR1-independent expression of the PATHOGENESIS-RELATED1 (PR1) gene, and resistance to Pseudomonas syringae pv maculicola. The sfd1 and sfd4 mutant alleles also depress ssi2-conferred PR1 expression in NPR1-containing sfd1 ssi2 and sfd4 ssi2 plants. By contrast, the sfd2 ssi2 plant retains the ssi2-conferred high-level expression of PR1. In parallel with the loss of ssi2-conferred constitutive SA signaling, the ability of jasmonic acid to activate PDF1.2 expression is reinstated in the sfd1 ssi2 npr1 plant. sfd4 is a mutation in the FAD6 gene that encodes a plastidic omega6-desaturase that is involved in the synthesis of polyunsaturated fatty acid-containing lipids. Because the levels of plastid complex lipid species containing hexadecatrienoic acid are depressed in all of the sfd ssi2 npr1 plants, we propose that these lipids are involved in the manifestation of the ssi2-conferred phenotypes.