Rushing the Value Cockpit.

The 2015 merger of health authorities in Nova Scotia was aggressive in pursuit of greater value. The goal was to create an integrated, accountable care network across the entire province. Years of pent-up frustration, death by a thousand cuts, declining service and growing expectations merged into a slow, insidious bleeding of support for change. The lessons learned from Nova Scotia are vital to achieving a value-based health system. The article describes some of the barriers to progress and the steps needed to achieve the goal of a value-based healthcare system for Canadians.

Quality and Innovation: Redesigning a Coordinated and Connected Health System.

Nova Scotia's consolidated health system was launched on April 1, 2015. This new approach to organizing health administration and services in the province arose out of necessity. When planning began, Nova Scotia was spending 41% of its annual budget on health services. In comparison to other provinces and territories, our per capita health-related spending was among the highest in the country, we had one of Canada's oldest populations and we had some of the worst health outcomes. Clearly, we could not continue to do the same things and expect different results. Both the life sciences and technology are changing at breakneck speed, while design of healthcare delivery has barely moved beyond a mid-twentieth century paternalistic provider-centric model. Nova Scotia's transformation journey was facilitated by a major policy effort 20 years earlier that had integrated emergency health services across the province. Our aim was to build on that foundation by integrating administration in order to build primary care networks with enhanced regional specialty services, with tertiary services located in Halifax. The goal of health system innovation in Nova Scotia was - and is - based firmly on the dimensions of quality: safe care that avoids harming patients; effective care that is based on levels of evidence to achieve scalability; access to care that is focused on individuals; efficient care that reduces waste, time, energy and supplies; and equitable care that ensures a system is in place that mitigates differences in geography and social economic status. The author offers a sketch of the principal initiatives, challenges, considerations, approaches and lessons involved in this multi-factorial, multi-stakeholder innovation process.

Optical-parametric-amplification imaging of complex objects.

We used ultrafast Fourier-plane optical-parametric-amplification (OPA) imaging to simultaneously image, wavelength-shift, and amplify complex two-dimensional objects with spatial features from 1.1 to 10.1 line pairs/millimeter (lp/mm) in the vertical dimension and from 2.0 to 16.0 lp/mm in the horizontal dimension, corresponding to a two-dimensional space-bandwidth product (SBP) of ~46,000. This represents an increase in image complexity over previous analogous OPA imaging systems by over three orders of magnitude. We observe both wavelength-shifting the image from 930 nm to a wavelength of 700 nm and image amplification by two orders of magnitude. Our wavelength-shifted image has a SBP of ~30,000.

Measuring extremely complex pulses with time-bandwidth products exceeding 65,000 using multiple-delay crossed-beam spectral interferometry.

We measure the complete electric field of extremely complex ultrafast waveforms using the simple linear-optical, interferometric pulse-measurement technique, MUD TADPOLE. The waveforms were measured with ~40 fs temporal resolution over a temporal range of ~3.5 ns and had time-bandwidth products exceeding 65,000. The approach is general and could allow the measurement of arbitrary optical waveforms.

Highly simplified device for measuring the intensity and phase of picosecond pulses.

We demonstrate an extremely simple frequency-resolved-optical-gating (GRENOUILLE) device for measuring the intensity and phase of relatively long--ps--pulses. In order to achieve the required high spectral resolution and large temporal range, it uses a few-cm-thick second-harmonic-generation crystal in the shape of a pentagon. This has the additional advantage of reducing the device's total number of components to as few as three simple easily aligned optics, making it the simplest device ever developed for complete pulse measurement. We report complete intensity-and-phase measurements of pulses up to 15ps long with a time-bandwidth product of 21.

The evolution of Rare Pride: using evaluation to drive adaptive management in a biodiversity conservation organization.

Rare Pride is a social marketing program that stimulates human behavior change in order to promote biodiversity conservation in critically threatened regions in developing countries. A series of formal evaluation studies, networking strategies, and evaluative inquiries have driven a 20-year process of adaptive management that has resulted in extensive programmatic changes within Pride. This paper describes the types of evaluation that Rare used to drive adaptive management and the changes it caused in Pride's theory-of-change and programmatic structure. We argue that (a) qualitative data gathered from partners and staff through structured interviews is most effective at identifying problems with current programs and procedures, (b) networking with other organizations is the most effective strategy for learning of new management strategies, and (c) quantitative data gathered through surveys is effective at measuring program impact and quality. Adaptive management has allowed Rare to increase its Pride program from implementing about two campaigns per year in 2001 to more than 40 per year in 2009 while improving program quality and maintaining program impact.

Diversity arrays technology (DArT) for high-throughput profiling of the hexaploid wheat genome.

Despite a substantial investment in the development of panels of single nucleotide polymorphism (SNP) markers, the simple sequence repeat (SSR) technology with a limited multiplexing capability remains a standard, even for applications requiring whole-genome information. Diversity arrays technology (DArT) types hundreds to thousands of genomic loci in parallel, as previously demonstrated in a number diploid plant species. Here we show that DArT performs similarly well for the hexaploid genome of bread wheat (Triticum aestivum L.). The methodology previously used to generate DArT fingerprints of barley also generated a large number of high-quality markers in wheat (99.8% allele-calling concordance and approximately 95% call rate). The genetic relationships among bread wheat cultivars revealed by DArT coincided with knowledge generated with other methods, and even closely related cultivars could be distinguished. To verify the Mendelian behaviour of DArT markers, we typed a set of 90 Cranbrook x Halberd doubled haploid lines for which a framework (FW) map comprising a total of 339 SSR, restriction fragment length polymorphism (RFLP) and amplified fragment length polymorphism (AFLP) markers was available. We added an equal number of DArT markers to this data set and also incorporated 71 sequence tagged microsatellite (STM) markers. A comparison of logarithm of the odds (LOD) scores, call rates and the degree of genome coverage indicated that the quality and information content of the DArT data set was comparable to that of the combined SSR/RFLP/AFLP data set of the FW map.

Chronic hypoxia in the human neuroblastoma SH-SY5Y causes reduced expression of the putative alpha-secretases, ADAM10 and TACE, without altering their mRNA levels.

Alzheimer's disease is more frequent following an ischemic or hypoxic episode, with levels of beta-amyloid peptides elevated in brains from patients. Similar increases are found after experimental ischemia in animals. It is possible that increased beta-amyloid deposition arises from alterations in amyloid precursor protein (APP) metabolism, indeed, we have shown that exposing cells of neuronal origin to chronic hypoxia decreased the secretion of soluble APP (sAPPalpha) derived by action of alpha-secretase on APP, coinciding with a decrease in protein levels of ADAM10, a disintegrin metalloprotease which is thought to be the major alpha-secretase. In the current study, we extended those observations to determine whether the expression of ADAM10 and another putative alpha-secretase, TACE, as well as the beta-secretase, BACE1 were regulated by chronic hypoxia at the level of protein and mRNA. Using Western blotting and RT-PCR, we demonstrate that after 48 h chronic hypoxia, such that sAPPalpha secretion is decreased by over 50%, protein levels of ADAM10 and TACE and by approximately 60% and 40% respectively with no significant decrease in BACE1 levels. In contrast, no change in the expression of the mRNA for these proteins could be detected. Thus, we conclude that under CH the level of the putative alpha-secretases, ADAM10 and TACE are regulated by post-translational mechanisms, most probably proteolysis, rather than at the level of transcription.

Altered processing of the amyloid precursor protein and decreased expression of ADAM 10 by chronic hypoxia in SH-SY5Y: no role for the stress-activated JNK and p38 signalling pathways.

Clinical studies suggest that the incidence of Alzheimer's disease (AD) is increased following an ischaemic or hypoxic episode, such as stroke. Furthermore, levels of the AD-associated amyloid beta-peptides (Abeta) and the amyloid precursor protein (APP) are enhanced in experimental ischaemia. In our previous study [Webster, N.J., Green, K.N., Peers, C., Vaughan, P.F., Altered processing of amyloid precursor protein in the human neuroblastoma SH-SY5Y by chronic hypoxia, J. Neurochem., 83 (2002) 1262-1271] we reported that exposing cells of neuronal origin to a period of chronic hypoxia (CH; 2.5% O(2), 24 h) led to a decrease in processing of the amyloid precursor protein (APP) by the alternative and neuroprotective alpha-secretase pathway. In SH-SY5Y cells, the most likely mechanism was that CH inhibits the protein level of ADAM 10, a disintegrin metalloprotease widely believed to be the alpha-secretase. One effect of CH is to alter the activity of the stress-activated protein kinases (SAPKs) c-Jun amino terminal kinase (JNK) and p38. Thus, the main aims of this study were to investigate the effect of CH on (1) the activity of these SAPKs in SH-SY5Y and (2) whether changes in the activity of these kinases may account for the CH-induced decreases in ADAM 10 expression and sAPPalpha secretion. We demonstrated that the phosphorylation (activity) of JNK was decreased approximately 50% following a period of CH. An inhibitor of JNK did not mimic the effects of CH on either ADAM 10 expression or sAPPalpha secretion under conditions in which the phosphorylation of c-Jun was inhibited by approximately 80%. Thus the loss of JNK activity does not appear to be linked to the decrease in expression of ADAM 10 and secretion of sAPPalpha. In contrast, phosphorylation (activity) of p38 was enhanced approximately 300% following a period of CH. However, inhibitors of p38 were unable to reverse the loss of sAPPalpha in CH cells, indicating that this increase in activity was not linked to the altered processing of APP.

Ethics in practice: managed care and the changing health care environment: medicine as a profession managed care ethics working group statement.

Cost pressures and changes in the health care environment pose ethical challenges and hard choices for patients, physicians, policymakers, and society. In 2000 and 2001, the American College of Physicians, with the Harvard Pilgrim Health Care Ethics Program, convened a working group of stakeholders--patients, physicians, and managed care representatives, along with medical ethicists--to develop a statement of ethics for managed care. The group explored the impact of a changing health care environment on patient-physician relationships and how to best apply the principles of professionalism in this environment. The statement that emerged offers guidance on preserving the patient-clinician relationship, patient rights and responsibilities, confidentiality and privacy, resource allocation and stewardship, the obligation of health plans to foster an ethical environment for the delivery of care, and the clinician's responsibility to individual patients, the community, and the public health, among other issues.

Altered processing of amyloid precursor protein in the human neuroblastoma SH-SY5Y by chronic hypoxia.

Alzheimer's disease (AD) is more prevalent following an ischemic or hypoxic episode, such as stroke. Indeed, brain levels of amyloid precursor protein (APP) and the cytotoxic amyloid beta peptide (Abeta) fragment are enhanced in these patients and in animal models following experimental ischaemia. We have investigated the effect of chronic hypoxia (CH; 2.5% O2, 24 h) on processing of APP in the human neuroblastoma, SH-SY5Y. We demonstrate that constitutive and muscarinic-receptor-enhanced secretion of the alpha-secretase cleaved fragment of APP, sAPPalpha, was reduced by approximately 60% in CH cells. The caspase inhibitor BOC-D(Ome)FMK did not reverse this effect of CH, and CH cells were as viable as controls, based on MTT assays. Thus, loss of sAPPalpha is not related to cell death or caspase processing of APP. Pre-incubation with antioxidants did not reverse the effect of CH, and the effect could not be mimicked by H2O2, discounting the involvement of reactive oxygen species in hypoxic loss of sAPPalpha. CH did not affect muscarinic activation of extracellular-signal regulated kinase. However, expression of ADAM 10 (widely believed to be alpha-secretase) was decreased approximately 50% following CH. Thus, CH selectively decreases processing of APP by the alpha-secretase pathway, most likely by decreasing levels of ADAM 10.

Chronic treatment with nicotine or potassium attenuates depolarisation-evoked noradrenaline release from the human neuroblastoma SH-SY5Y.

Chronic treatment, of SH-SY5Y cells, with KCl (20 mM) for 4 days decreased 100 mM KCl-evoked noradrenaline (NA) release by 50% and nicotine (100 microM)-evoked NA release by 55%. Pretreatment with the L-type calcium channel antagonist, nifedipine, prevented this inhibitory effect of chronic exposure to 20 mM KCl on NA release. In contrast pretreatment with 10 microM nicotine for 4 days had no effect on 100 mM KCl -evoked secretion and decreased nicotinic -evoked NA release by only 25%. Inclusion of nifedipine prevented the inhibition of NA release by chronic nicotine treatment. These data are discussed in relation to effects of chronic moderate, depolarisation by either K(+) or nicotine on influx of Ca(2+) via L-type voltage sensitive calcium channels.

Presenilin-1 mutations alter K+ currents in the human neuroblastoma cell line, SH-SY5Y.

Mutations in presenilin 1 (PS1) are the major cause of autosomal dominant Alzheimer's disease. We have measured the voltage-gated K+ current in the human neuroblastoma cell line SH-SY5Y using whole-cell patch-clamp. When cells were stably transfected to over-express PS1, no change in K+ current was observed. However, over-expression of a deletion mutation (deltaE9) in PS1 led to a decreased K+ current. These changes were channel specific since no change in the Na+ current could be observed in the same cells. Confocal microscopy revealed that the K(V)3.1 K+ channel subunit had a diminished plasma membrane distribution when the deltaE9 over-expressing cells were compared to control cells. Intracellular retention of Kv3.1 is consistent with the notion that PS1 can modulate the activity and trafficking of ion channels in central neurones and implicates a compromise in electrical signalling as an underlying factor in the pathogenesis of familial Alzheimer's disease.

Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5Y by a pathway dependent on protein kinase C(alpha), src-tyrosine kinase and extracellular signal-regulated kinase but not phospholipase C.

The signalling pathways by which muscarine and epidermal growth factor (EGF) regulate the secretion of the alpha-secretase cleavage product (sAPPalpha) of the amyloid precursor protein (APP) were examined in the human neuroblastoma SH-SY5Y. Using specific inhibitors it was found that over 80% of sAPPalpha secretion, enhanced by muscarine, occurred via the extracellular signal-regulated kinase (ERK1/2) member of the mitogen-activated protein kinase (MAPK) family and was dependent on protein kinase Calpha (PKCalpha) and a member of the Src family of non-receptor tyrosine kinases (Src-TK). In contrast the stimulation of sAPPalpha secretion by EGF was not affected by inhibitors of PKC nor Src-TK but was dependent on ERK1/2. In addition muscarine-enhanced sAPPalpha secretion and ERK1/2 activation were inhibited 60 and 80%, respectively, by micromolar concentrations of the phosphatidylinositol 3 kinase (PI-3K) inhibitor wortmannin. In comparison wortmannin decreased EGF stimulation of sAPPalpha secretion and ERK 1/2 activation by approximately 40%. Unexpectedly, U73122, an inhibitor of phosphoinositide-specific phospholipase C, did not inhibit muscarine enhancement of sAPPalpha secretion. These data are discussed in relation to a pathway for the enhancement of sAPPalpha secretion by muscarine which involves the activation of a Src-TK by G-protein beta/gamma-subunits leading to activation of PKCalpha, and ERK1/2 by a mechanism not involving phospholipase C.

Modeling above-canopy CO2 flux and evapotranspiration in wheat.

Simulations of above-canopy water vapor and CO2 fluxes were calculated by the USGF linked model of canopy gas exchange and subsurface processes for the 1996-1997 winter wheat season at the AmeriFlux Wheat Site, Oklahoma. Soil surface CO2 flux plus canopy gas exchange and transpiration plus soil evaporation modeled the CO2 and water vapor fluxes, respectively. Parameter values for net photosynthesis, respiration and transpiration were obtained from published sources, generated from Wheat Site data, or estimated by minimizing standard deviation between model and data. The mean measured downward flux of CO2 during rapid growth and maturity of the crop was -0.45 mg m(-2) s(-1) compared to simulated flux of -0.47. Simulated downward CO2 flux exceeded measured values during rapid growth of the crop but underestimated the flux during maturity. For the entire 285-day period, the mean measured upward CO2 flux at night was 0.06 and simulated flux was 0.05.