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On the day that Lincoln was inaugurated in 1861, twenty-seven-year-old William Dorsey Pender, en route to the provisional Confederate capital in Montgomery, Alabama, hurriedly scribbled a note to his wife, Fanny.

This report is an overview of two strategic issues currently facing the pharmaceutical industry: the high cost of client-server computing and ensuring that investments in information technology result in productivity gains. This report begins with a discussion of the high costs involved in supporting a client-server architecture (reported by KPMG Management Consulting and Nolan Norton & Co. to run as high as $20,000/year/PC). If a company is to maximize the returns from its current and future investment in information technology it is critical that it carefully limit the number of initiatives undertaken in this area. Companies must only undertake projects targeted at improving processes identified as critical to the success of the whole organization. Three observations drive this conclusion. One is the high cost of ownership associated with the client-server approach to computing. Two, computerization of organizations typically occurs along the vertical lines of the organizational chart and within functional departments. Three, findings indicate that the client-server architecture does not exhibit the same economies of scale associated with more traditional centralized architectures, which provide some forgiveness if trivial or peripheral applications are undertaken. These observations, coupled with the limited amount companies have to invest in information technology resources, make it critical that they carefully limit initiatives in this area.

Observations made during the New Horizons flyby provide a detailed snapshot of the current state of Pluto's atmosphere. While the lower atmosphere (at altitudes <200 km) is consistent with ground-based stellar occultations, the upper atmosphere is much colder and more compact than indicated by pre-encounter models. Molecular nitrogen (N\\(_2\\)) dominates the atmosphere (at altitudes <1800 km or so), while methane (CH\\(_4\\)), acetylene (C\\(_2\\)H\\(_2\\)), ethylene (C\\(_2\\)H\\(_4\\)), and ethane (C\\(_2\\)H\\(_6\\)) are abundant minor species, and likely feed the production of an extensive haze which encompasses Pluto. The cold upper atmosphere shuts off the anticipated enhanced-Jeans, hydrodynamic-like escape of Pluto's atmosphere to space. It is unclear whether the current state of Pluto's atmosphere is representative of its average state--over seasonal or geologic time scales.

Even now the question is asked \"Of what use is a stock exchange?\" To quote from a recognized authority, \"The foremost and perhaps most fundamental economic service performed by the commodity and stock exchanges is that they...

Biologists have developed a wide range of morphological, biochemical and physiological metrics to assess the health and, in particular, the energetic status of individual animals. These metrics originated to quantify aspects of human health, but have also proven useful to address questions in life history, ecology and resource management of game and commercial animals. We review the application of condition indices (CI) for conservation studies and focus on measures that quantify fat reserves, known to be critical for energetically challenging activities such as migration, reproduction and survival during periods of scarcity. Standard methods score fat content, or rely on a ratio of body mass rationalized by some measure of size, usually a linear dimension such as wing length or total body length. Higher numerical values of these indices are interpreted to mean an animal has greater energy reserves. Such CIs can provide predictive information about habitat quality and reproductive output, which in turn can help managers with conservation assessments and policies. We review the issues about the methods and metrics of measurement and describe the linkage of CIs to measures of body shape. Debates in the literature about the best statistical methods to use in computing and comparing CIs remain unresolved. Next, we comment on the diversity of methods used to measure body composition and the diversity of physiological models that compute body composition and CIs. The underlying physiological regulatory systems that govern the allocation of energy and nutrients among compartments and processes within the body are poorly understood, especially for field situations, and await basic data from additional laboratory studies and advanced measurement systems including telemetry. For now, standard physiological CIs can provide supporting evidence and mechanistic linkages for population studies that have traditionally been the focus of conservation biology. Physiologists can provide guidance for the field application of conditions indices with validation studies and development of new instruments.

Multicultural communities in Australia are recognised as a priority area for drowning prevention, but no evidence-based study has addressed their knowledge of beach safety. This study used an online survey tool to identify and examine risk factors relating to swimming ability, beach visitation characteristics and behaviour, and beach safety knowledge of the Australian Southern Asian community to assist in the development of future beach safety interventions. Data was obtained through 249 online and in-person surveys of people aged > 18 years. Most respondents reported poor swimming ability (80%), often swam in in the absence of lifeguards (77%), did not understand the rip current hazard (58%), but reported that they entered the water (76%) when visiting beaches. Close to one-quarter (28%) had not heard, or didn’t know the purpose, of the red and yellow beach flags, which identify lifeguard supervised areas on Australian beaches. Length of time living in Australia is an important beach safety consideration for this community, with minimal differences in terms of gender and age. Those who have lived < 10 years in Australia visit beaches more frequently and are less likely to have participated in swimming lessons, be able to swim, heard of the flags or swim between them, understand rip currents, or have participated in a beach safety program. Very few (3%) respondents received beach safety information from within their own community. The importance of beach safety education and swimming lessons within the Southern Asian community should be prioritised for new and recent migrants to Australia.

ObjectiveTo evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD).MethodPatients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as ‘Much Improved’ or ‘Very Much Improved’ on the Clinical Global Impression of Change.ResultsA total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was –4.9 (0.4) at Week 54 (n = 146), – 6.3 (0.7) at Week 80 (n = 66) and –5.1 (2.0) at Week 106 (n = 8).ConclusionsOverall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD.Trial registration number NCT02198794.

Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 ( Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.

Patients with Duchenne muscular dystrophy are living longer and are increasingly seen in Emergency Departments. Though the most common cause of death remains progressive respiratory failure, increased life expectancies have unmasked the significance of progressive myocardial dysfunction, now associated with nearly 40% of mortalities in the DMD population. Cardiac complications such as arrhythmias and cardiomyopathy are becoming ever more widely recognized. Emergency physicians may encounter DMD patients with untreated, undiagnosed or worsening of known heart disease. This review will initially familiarize the emergency physician with the pathophysiology and lifetime trajectory of care for these patients before describing specific emergency department evaluation and treatment.