How One Health System is Demonstrating the Right Way to Build a Smart Growth Strategy.

SUMMARY: Across the United States, health system growth has been tied to significant investments in physical growth such as the build-out of large, traditional hospitals. Concurrent with this infrastructure investment, value frequently has been sought by cost cutting and large-scale closures of lower-margin facilities.At Froedtert Health, a philosophy of providing the right care at the right time in the right place is driving new growth. As the demand for unique tertiary services at its academic medical center has surged, Froedtert Health is leveraging and enhancing a new community hospital strategy while investing in new capability platforms to complement the health network's care model across Wisconsin.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.

Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.

Posttranslational modifications of tubulin and the polarized transport of kinesin-1 in neurons.

Polarized transport by microtubule-based motors is critical for neuronal development and function. Selective translocation of the Kinesin-1 motor domain is the earliest known marker of axonal identity, occurring before morphological differentiation. Thus, Kinesin-1-mediated transport may contribute to axonal specification. We tested whether posttranslational modifications of tubulin influence the ability of Kinesin-1 motors to distinguish microtubule tracks during neuronal development. We detected no difference in microtubule stability between axons and minor neurites in polarized stage 3 hippocampal neurons. In contrast, microtubule modifications were enriched in a subset of neurites in unpolarized stage 2 cells and the developing axon in polarized stage 3 cells. This enrichment correlated with the selective accumulation of constitutively active Kinesin-1 motors. Increasing tubulin acetylation, without altering the levels of other tubulin modifications, did not alter the selectivity of Kinesin-1 accumulation in polarized cells. However, globally enhancing tubulin acetylation, detyrosination, and polyglutamylation by Taxol treatment or inhibition of glycogen synthase kinase 3beta decreased the selectivity of Kinesin-1 translocation and led to the formation of multiple axons. Although microtubule acetylation enhances the motility of Kinesin-1, the preferential translocation of Kinesin-1 on axonal microtubules in polarized neuronal cells is not determined by acetylation alone but is probably specified by a combination of tubulin modifications.

Planning during turmoil: credit challenges and healthcare finance. Interview by Carole J. Bolster.

The crisis in the financial markets is having a major impact on hospitals' ability to access capital. Providers are seeking longer-term fixed-rate debt rather than shortterm debt. Hospital management teams and their boards need to understand the upside and downside of variable-rate debt and interest rate derivatives.

Catch the KIF5B train to the apical surface.

As epithelial cells become polarized, they develop new pathways to send proteins to the apical or basolateral domains of their plasma membrane. In this issue of Developmental Cell, Jaulin et al. (2007) show that as polarity develops, there is a shift in the kinesin motor protein used to transport an apical protein to the cell surface.

A change in the selective translocation of the Kinesin-1 motor domain marks the initial specification of the axon.

We used the accumulation of constitutively active kinesin motor domains as a measure of where kinesins translocate in developing neurons. Throughout development, truncated Kinesin-3 accumulates at the tips of all neurites. In contrast, Kinesin-1 selectively accumulates in only a subset of neurites. Before neurons become polarized, truncated Kinesin-1 accumulates transiently in a single neurite. Coincident with axon specification, truncated Kinesin-1 accumulates only in the emerging axon and no longer appears in any other neurite. The translocation of Kinesin-1 along a biochemically distinct track leading to the nascent axon could ensure the selective delivery of Kinesin-1 cargoes to the axon and hence contribute to its molecular specification. Imaging YFP-tagged truncated Kinesin-1 provides the most precise definition to date of when neuronal polarity first emerges and allows visualization of the molecular differentiation of the axon in real time.

Trichloroethylene-contaminated drinking water and congenital heart defects: a critical analysis of the literature.

The organic solvent trichloroethylene (TCE) is a metal degreasing agent and an intermediate in the production of fluorochemicals and polyvinyl chloride. TCE is also a common, persistent drinking water contaminant. Several epidemiological studies have alleged links between TCE exposure during pregnancy and offspring health problems including congenital heart defects (CHDs); however, the results of these studies are inconsistent, difficult to interpret, and involve several confounding factors. Similarly, the results of animal studies examining the potential of TCE to elicit cardiac anomalies have been inconsistent, and they have often been performed at doses far exceeding the highest levels ever reported in the drinking water. To determine what is known about the relationship between TCE and the incidence of CHDs, a comprehensive analysis of all available epidemiological data and animal studies was performed. Additionally, in vivo and in vitro studies examining possible mechanisms of action for TCE were evaluated. The specific types of heart defects alleged to have been caused by TCE in animal and human epidemiology studies were categorized by the morphogenetic process responsible for the defect in order to determine whether TCE might disrupt any specific developmental process. This analysis revealed that no single process was clearly affected by TCE, providing support that gestational TCE exposure does not increase the prevalence of CHDs. As a final evaluation, application of Hill's causality guidelines to the collective body of data revealed no indication of a causal link between gestational TCE exposure at environmentally relevant concentrations and CHDs.

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case-control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.g., gastroschisis/umbilical hernia, diaphragmatic hernia [DH]) when administered during sensitive windows of development. Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenases (COXs) 1 and 2. Hence, the developmental toxicity seen in rats after exposure to aspirin may be due to the irreversible inhibition of COX-1 and/or COX-2. If so, other NSAIDs, which act through a reversible inhibition of COX, may produce a weak developmental toxicity signal or no developmental toxicity signal when tested in preclinical models. To investigate this relationship, a comprehensive analysis of the NSAID developmental toxicity literature was undertaken to determine whether NSAIDs other than aspirin induce developmental anomalies similar to those elicited by aspirin. METHODS: Developmental toxicity studies were identified through literature searches of PubMed and TOXNET, and pregnancy outcome data were extracted and tabulated. By using a set of defined criteria, each study was evaluated for quality and assigned to one of five tiers. The relation between certain malformations and NSAID treatment was analyzed for the best studies (tiers 1-4) by using concurrent control data (Mantel-Haenszel and permutation tests) and by combining the concurrent control data with historical control data (chi2 test and permutation tests). RESULTS: A qualitative analysis of these data led to a focus on three types of malformations: DH, ventricular septal defects (VSDs), and midline defects (MDs). In rats, the incidences of VSD and MD were increased among fetuses treated with NSAIDs when compared with the concurrent controls. The extent of the increase was attenuated when the data from the aspirin studies were excluded from the analysis. There were no qualifying (i.e., tiers 1-4) aspirin studies conducted in rabbits, but the incidences of the three defects were increased over control incidences among non-aspirin NSAID-treated animals. Statistical analysis of these data was subsequently conducted. When tiers 1-4 were combined and compared with concurrent controls plus the most appropriate historical control database, the strongest associations were between NSAID treatment and VSD in rats, VSD in rabbits, and MD in rabbits. There also was some suggestion of an association between NSAID treatment and DH in rabbits. CONCLUSIONS: This analysis of the non-clinical NSAID literature demonstrated a possible association between exposure to NSAIDs and developmental anomalies. The anomalies were similar for aspirin and for other NSAIDs, but effects occurred at a much lower incidence with non-aspirin NSAIDs than previously reported with aspirin. Such a finding is consistent with the concept that reversible inhibition of COX-1 and/or COX-2 by other NSAIDs would produce weaker developmental toxicity signals than aspirin. However, there were limitations of the evaluated studies: (1) there were very few robust International Conference on Harmonization-compliant studies conducted with NSAIDs in the published literature; (2) many of the studies were conducted at doses well below the maximum tolerated dose (MTD), where effects are rarely seen; and (3) numerous studies were conducted above the MTD, where reduced numbers of fetuses hampered detection of low-incidence findings. Although weak associations were observed, these limitations prevented us from definitively determining the presence or absence of a developmental toxicity signal from the existing body of NSAID data. Further exploration of this hypothesis will require assessing the potential association in animal models by using dose levels centered around the MTD.