Accountability by Design: Moving Primary Care Reform Ahead in Alberta

Health-care reform is perennially popular in Alberta, but reality doesn’t match the rhetoric. Government has invested more than $700 million in Primary Care Networks — with little beyond anecdotal evidence of the value achieved with this investment. As the province redirects primary care to Family Care Clinics, the authors assert that simply tinkering with one part of the system is not the answer: health care must change on a system-wide basis. Drawing on the experiences of frontline staff and a rich body of literature, the authors present their vision for integrated team-based primary care, designed to be accountable to meet the needs of populations. This will require governance that makes primary care the hub of the system, and brings together government and health-services leadership to support the integration of primary and specialty care. There are shared accountabilities for achieving primary care that exhibits the attributes of high performing primary care systems, and these exist at multiple levels, from individuals seeking primary care, up to and including government. The authors make these accountabilities explicit, and outline strategies to secure their achievement that include system redesign, service delivery redesign and payment reform. All of this demands whole-system reform focused on primary care, and it won’t be easy. There are plenty of vested interests at stake, and a truly transformative vision requires buy-in at every level. However, Alberta’s rapidly growing and aging population makes it more urgent than ever to realize such a vision. This paper offers guidelines to spark the fresh thinking required

Antibiotic use during pregnancy increases offspring asthma severity in a dose‐dependent manner

Background: The use of antibiotics during pregnancy is associated with increased allergic asthma risk in the offspring, and given that approximately 25% of pregnant women are prescribed antibiotics, it is important to understand the mechanisms contributing to this phenomenon. Currently, there are no studies that directly test this association experimentally. Our objective was to develop a mouse model in which antibiotic treatment during pregnancy results in increased offspring asthma susceptibility. Methods: Pregnant mice were treated daily from gestation day 8-17 with an oral solution of the antibiotic vancomycin, and three concentrations were tested. At weaning, offspring were subjected to an adjuvant-free experimental asthma protocol using ovalbumin as an allergen. The composition of the gut microbiome was determined in mothers and offspring with samples collected from five different time points; shortchain fatty acids were also analyzed in allergic offspring. Results: We found that maternal antibiotic treatment during pregnancy was associated with increased offspring asthma severity in a dose-dependent manner. Furthermore, maternal vancomycin treatment during pregnancy caused marked changes in the gut microbiome composition in both mothers and pups at several different time points. The increased asthma severity and intestinal microbiome changes in pups were also associated with significantly decreased cecal short-chain fatty acid concentrations. Conclusion: Consistent with the "Developmental Origins Hypothesis," our results confirm that exposure to antibiotics during pregnancy shapes the neonatal intestinal environment and increases offspring allergic lung inflammation

Construction and functional analyses of a comprehensive σ54 site-directed mutant library using alanine–cysteine mutagenesis

The σ54 factor associates with core RNA polymerase (RNAP) to form a holoenzyme that is unable to initiate transcription unless acted on by an activator protein. σ54 is closely involved in many steps of activator-dependent transcription, such as core RNAP binding, promoter recognition, activator interaction and open complex formation. To systematically define σ54 residues that contribute to each of these functions and to generate a resource for site specific protein labeling, a complete mutant library of σ54 was constructed by alanine–cysteine scanning mutagenesis. Amino acid residues from 3 to 476 of Cys(-)σ54 were systematically mutated to alanine and cysteine in groups of two adjacent residues at a time. The influences of each substitution pair upon the functions of σ54 were analyzed in vivo and in vitro and the functions of many residues were revealed for the first time. Increased σ54 isomerization activity seldom corresponded with an increased transcription activity of the holoenzyme, suggesting the steps after σ54 isomerization, likely to be changes in core RNAP structure, are also strictly regulated or rate limiting to open complex formation. A linkage between core RNAP-binding activity and activator responsiveness indicates that the σ54-core RNAP interface changes upon activation

Marketing Actions and the Value of Customer Assets: A Framework for Customer Asset Management

This article develops a framework for assessing how marketing actions affect customers’lifetime value to the firm. The framework is organized around four critical actions that firms must take to effectively manage the asset value of the customer base: database creation, market segmentation, forecasting customer purchase behavior, and resource allocation. In this framework, customer lifetime value is treated as a dynamic construct, that is, it influences the eventual allocation of marketing resources but is also influenced by that allocation. By viewing customers as assets and systematically managing these assets, a firm can identify the most appropriate marketing actions to acquire, maintain, and enhance customer assets and thereby maximize financial returns. The article discusses in detail how to assess customer lifetime value and manage customers as assets. Then, it identifies key research challenges in studying customer asset management and the managerial challenges associated with implementing effective customer asset management practices.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Flexibility along the Neck of the Neogene Terror Bird Andalgalornis steulleti (Aves Phorusrhacidae)

BACKGROUND: Andalgalornis steulleti from the upper Miocene-lower Pliocene (≈6 million years ago) of Argentina is a medium-sized patagornithine phorusrhacid. It was a member of the predominantly South American radiation of 'terror birds' (Phorusrhacidae) that were apex predators throughout much of the Cenozoic. A previous biomechanical study suggests that the skull would be prepared to make sudden movements in the sagittal plane to subdue prey. METHODOLOGY/PRINCIPAL FINDINGS: We analyze the flexion patterns of the neck of Andalgalornis based on the neck vertebrae morphology and biometrics. The transitional cervical vertebrae 5th and 9th clearly separate regions 1-2 and 2-3 respectively. Bifurcate neural spines are developed in the cervical vertebrae 7th to 12th suggesting the presence of a very intricate ligamentary system and of a very well developed epaxial musculature. The presence of the lig. elasticum interespinale is inferred. High neural spines of R3 suggest that this region concentrates the major stresses during downstrokes. CONCLUSIONS/SIGNIFICANCE: The musculoskeletal system of Andalgalornis seems to be prepared (1) to support a particularly big head during normal stance, and (2) to help the neck (and the head) rising after the maximum ventroflexion during a strike. The study herein is the first interpretation of the potential performance of the neck of Andalgalornis in its entirety and we considered this an important starting point to understand and reconstruct the flexion pattern of other phorusrhacids from which the neck is unknown

Fluorescent Fusion Proteins of Soluble Guanylyl Cyclase Indicate Proximity of the Heme Nitric Oxide Domain and Catalytic Domain

BACKGROUND: To examine the structural organisation of heterodimeric soluble guanylyl cyclase (sGC) Förster resonance energy transfer (FRET) was measured between fluorescent proteins fused to the amino- and carboxy-terminal ends of the sGC beta1 and alpha subunits. METHODOLOGY/PRINCIPAL FINDINGS: Cyan fluorescent protein (CFP) was used as FRET donor and yellow fluorescent protein (YFP) as FRET acceptor. After generation of recombinant baculovirus, fluorescent-tagged sGC subunits were co-expressed in Sf9 cells. Fluorescent variants of sGC were analyzed in vitro in cytosolic fractions by sensitized emission FRET. Co-expression of the amino-terminally tagged alpha subunits with the carboxy-terminally tagged beta1 subunit resulted in an enzyme complex that showed a FRET efficiency of 10% similar to fluorescent proteins separated by a helix of only 48 amino acids. Because these findings indicated that the amino-terminus of the alpha subunits is close to the carboxy-terminus of the beta1 subunit we constructed fusion proteins where both subunits are connected by a fluorescent protein. The resulting constructs were not only fluorescent, they also showed preserved enzyme activity and regulation by NO. CONCLUSIONS/SIGNIFICANCE: Based on the ability of an amino-terminal fragment of the beta1 subunit to inhibit activity of an heterodimer consisting only of the catalytic domains (alphacatbetacat), Winger and Marletta (Biochemistry 2005, 44:4083-90) have proposed a direct interaction of the amino-terminal region of beta1 with the catalytic domains. In support of such a concept of "trans" regulation of sGC activity by the H-NOX domains our results indicate that the domains within sGC are organized in a way that allows for direct interaction of the amino-terminal regulatory domains with the carboxy-terminal catalytic region. In addition, we constructed "fluorescent-conjoined" sGC's by fusion of the alpha amino-terminus to the beta1 carboxy-terminus leading to a monomeric, fluorescent and functional enzyme complex. To our knowledge this represents the first example where a fluorescent protein links two different subunits of a higher ordered complex to yield a stoichometrically fixed functionally active monomer