Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia

The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3'-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair

Simplified Dosing of Gentamicin for Treatment of Sepsis in Bangladeshi Neonates

Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed <2,000 g (n=23), 10 mg every 24 hours if the infant weighed 2,000–2,249 g (n=12), or 13.5 mg every 24 hours if the infant weighed 2,500–3,000 g (n=24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean±standard deviation peak concentration of gentamicin was 12.3±3.7 µg/mL in infants weighing <2,000 g, 9.6±3.1 µg/mL in infants 2,000–2,249 g, and 10.0±3.4 µg/mL in infants 2,500–3,000 g. Initial peak concentration of gentamicin was >12 µg/mL in 28.8% and initial trough concentration was >2 µg/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis

Patterns of Drug Utilization in a Neonatal Intensive Care Unit

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97176/1/0091270005285456.pd

Ten lessons on the resilience of the EU common fisheries policy towards climate change and fuel efficiency - A call for adaptive, flexible and wellinformed fisheries management

To effectively future-proof the management of the European Union fishing fleets we have explored a suite of case studies encompassing the northeast and tropical Atlantic, the Mediterranean, Baltic and Black Seas. This study shows that European Union (EU) fisheries are likely resilient to climate-driven short-term stresses, but may be negatively impacted by long-term trends in climate change. However, fisheries’ long-term stock resilience can be improved (and therefore be more resilient to increasing changes in climate) by adopting robust and adaptive fisheries management, provided such measures are based on sound scientific advice which includes uncertainty. Such management requires regular updates of biological reference points. Such updates will delineate safe biological limits for exploitation, providing both high long-term yields with reduced risk of stock collapse when affected by short-term stresses, and enhanced compliance with advice to avoid higher than intended fishing mortality. However, high resilience of the exploited ecosystem does not necessarily lead to the resilience of the economy of EU fisheries from suffering shocks associated with reduced yields, neither to a reduced carbon footprint if fuel use increases from lower stock abundances. Fuel consumption is impacted by stock development, but also by changes in vessel and gear technologies, as well as fishing techniques. In this respect, energy-efficient fishing technologies already exist within the EU, though implementing them would require improving the uptake of innovations and demonstrating to stakeholders the potential for both reduced fuel costs and increased catch rates. A transition towards reducing fuel consumption and costs would need to be supported by the setup of EU regulatory instruments. Overall, to effectively manage EU fisheries within a changing climate, flexible, adaptive, well-informed and well-enforced management is needed, with incentives provided for innovations and ocean literacy to cope with the changing conditions, while also reducing the dependency of the capture fishing industry on fossil fuels. To support such management, we provide 10 lessons to characterize ‘win-win’ fishing strategies for the European Union, which develop leverages in which fishing effort deployed corresponds to Maximum Sustainable Yield targets and Common Fisheries Policy minimal effects objectives. In these strategies, higher catch is obtained in the long run, less fuel is spent to attain the catch, and the fisheries have a higher resistance and resilience to shock and long-term factors to face climate-induced stressesEn prens

Simplified Dosing of Gentamicin for Treatment of Sepsis in Bangladeshi Neonates

Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed &lt;2,000 g (n=23), 10 mg every 24 hours if the infant weighed 2,000-2,249 g (n=12), or 13.5 mg every 24 hours if the infant weighed 2,500-3,000 g (n=24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean\ub1standard deviation peak concentration of gentamicin was 12.3\ub13.7 \u3bcg/mL in infants weighing &lt;2,000 g, 9.6\ub13.1 \u3bcg/mL in infants 2,000-2,249 g, and 10.0\ub13.4 \u3bcg/mL in infants 2,500-3,000 g. Initial peak concentration of gentamicin was &gt;12 \u3bcg/mL in 28.8% and initial trough concentration was &gt;2 \u3bcg/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis

Ten lessons on the resilience of the EU common fisheries policy towards climate change and fuel efficiency - A call for adaptive, flexible and well-informed fisheries management

To effectively future-proof the management of the European Union fishing fleets we have explored a suite of case studies encompassing the northeast and tropical Atlantic, the Mediterranean, Baltic and Black Seas. This study shows that European Union (EU) fisheries are likely resilient to climate-driven short-term stresses, but may be negatively impacted by long-term trends in climate change. However, fisheries' long-term stock resilience can be improved (and therefore be more resilient to increasing changes in climate) by adopting robust and adaptive fisheries management, provided such measures are based on sound scientific advice which includes uncertainty. Such management requires regular updates of biological reference points. Such updates will delineate safe biological limits for exploitation, providing both high long-term yields with reduced risk of stock collapse when affected by short-term stresses, and enhanced compliance with advice to avoid higher than intended fishing mortality. However, high resilience of the exploited ecosystem does not necessarily lead to the resilience of the economy of EU fisheries from suffering shocks associated with reduced yields, neither to a reduced carbon footprint if fuel use increases from lower stock abundances. Fuel consumption is impacted by stock development, but also by changes in vessel and gear technologies, as well as fishing techniques. In this respect, energy-efficient fishing technologies already exist within the EU, though implementing them would require improving the uptake of innovations and demonstrating to stakeholders the potential for both reduced fuel costs and increased catch rates. A transition towards reducing fuel consumption and costs would need to be supported by the setup of EU regulatory instruments. Overall, to effectively manage EU fisheries within a changing climate, flexible, adaptive, well-informed and well-enforced management is needed, with incentives provided for innovations and ocean literacy to cope with the changing conditions, while also reducing the dependency of the capture fishing industry on fossil fuels. To support such management, we provide 10 lessons to characterize 'win-win' fishing strategies for the European Union, which develop leverages in which fishing effort deployed corresponds to Maximum Sustainable Yield targets and Common Fisheries Policy minimal effects objectives. In these strategies, higher catch is obtained in the long run, less fuel is spent to attain the catch, and the fisheries have a higher resistance and resilience to shock and long-term factors to face climate-induced stresses

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Older Adult Patients in the Emergency Department: Which Patients should be Selected for a Different Approach?

Background: While multidimensional and interdisciplinary assessment of older adult patients improves their short-term outcomes after evaluation in the emergency department (ED), this assessment is time-consuming and ill-suited for the busy environment. Thus, identifying patients who will benefit from this strategy is challenging. Therefore, this study aimed to identify older adult patients suitable for a different ED approach as well as independent variables associated with poor short-term clinical outcomes. Methods: We included all patients >= 65 years attending 52 EDs in Spain over 7 days. Sociodemographic, comorbidity, and baseline functional status data were collected. The outcomes were 30 -day mortality, re -presentation, hospital readmission, and the composite of all outcomes. Results: During the study among 96,014 patients evaluated in the ED, we included 23,338 patients >= 65 years-mean age, 78.4 +/- 8.1 years; 12,626 (54.1%) women. During follow-up, 5,776 patients (24.75%) had poor outcomes after evaluation in the ED: 1,140 (4.88%) died, 4,640 (20.51) returned to the ED, and 1,739 (7.69%) were readmitted 30 days after discharge following the index visit. A model including male sex, age >= 75 years, arrival by ambulance, Charlson Comorbidity Index >= 3, and functional impairment had a C -index of 0.81 (95% confidence interval, 0.80-0.82) for 30 -day mortality. Conclusion: Male sex, age >= 75 years, arrival by ambulance, functional impairment, or severe comorbidity are features of patients who could benefit from approaches in the ED different from the common triage to improve the poor short-term outcomes of this population