A Putative Multiple-Demand System in the Macaque Brain.

UNLABELLED: In humans, cognitively demanding tasks of many types recruit common frontoparietal brain areas. Pervasive activation of this "multiple-demand" (MD) network suggests a core function in supporting goal-oriented behavior. A similar network might therefore be predicted in nonhuman primates that readily perform similar tasks after training. However, an MD network in nonhuman primates has not been described. Single-cell recordings from macaque frontal and parietal cortex show some similar properties to human MD fMRI responses (e.g., adaptive coding of task-relevant information). Invasive recordings, however, come from limited prespecified locations, so they do not delineate a macaque homolog of the MD system and their positioning could benefit from knowledge of where MD foci lie. Challenges of scanning behaving animals mean that few macaque fMRI studies specifically contrast levels of cognitive demand, so we sought to identify a macaque counterpart to the human MD system using fMRI connectivity in 35 rhesus macaques. Putative macaque MD regions, mapped from frontoparietal MD regions defined in humans, were found to be functionally connected under anesthesia. To further refine these regions, an iterative process was used to maximize their connectivity cross-validated across animals. Finally, whole-brain connectivity analyses identified voxels that were robustly connected to MD regions, revealing seven clusters across frontoparietal and insular cortex comparable to human MD regions and one unexpected cluster in the lateral fissure. The proposed macaque MD regions can be used to guide future electrophysiological investigation of MD neural coding and in task-based fMRI to test predictions of similar functional properties to human MD cortex. SIGNIFICANCE STATEMENT: In humans, a frontoparietal "multiple-demand" (MD) brain network is recruited during a wide range of cognitively demanding tasks. Because this suggests a fundamental function, one might expect a similar network to exist in nonhuman primates, but this remains controversial. Here, we sought to identify a macaque counterpart to the human MD system using fMRI connectivity. Putative macaque MD regions were functionally connected under anesthesia and were further refined by iterative optimization. The result is a network including lateral frontal, dorsomedial frontal, and insular and inferior parietal regions closely similar to the human counterpart. The proposed macaque MD regions can be useful in guiding electrophysiological recordings or in task-based fMRI to test predictions of similar functional properties to human MD cortex

Phosphodiesterase-5 inhibitors in management of pulmonary hypertension: safety, tolerability, and efficacy

Pulmonary arterial hypertension (PAH) is a progressive disease that causes severe disability and has no cure. Over the past 20 years, a variety of treatment options have evolved for the management of PAH. With an expanded therapeutic armamentarium come more complex decisions regarding treatment options. Agent selection depends upon several factors including efficacy, side effect profile, and cost, as well as convenience of administration. We have undertaken a review of phosphodiesterase-5 (PDE-5) inhibitors in PAH with a focus on efficacy and safety. A literature search was conducted using the Medline and Cochrane Central Register of Controlled Trials databases (1966–February 2010) for relevant randomized clinical studies. Overall, 10 studies met our inclusion criteria. Sildenafil was the most commonly studied agent, followed by tadalafil and vardenafil. Most trials found that the PDE-5 inhibitors significantly improved exercise capacity and lowered pulmonary pressures. However, there were conflicting results regarding these agents’ impact on improving cardiac function and functional class. Overall, these medications were effective and well tolerated with a relatively benign side effect profile. The PDE-5 inhibitors are an important option in treating PAH. While most of the published clinical data involved sildenafil, the other PDE-5 inhibitors show promise as well. Further studies are needed to determine the optimal doses of this therapeutic drug class, as well as its effects as adjunctive therapy with other agents in PAH

Functional reorganisation and recovery following cortical lesions: A preliminary study in macaque monkeys.

Damage following traumatic brain injury or stroke can often extend beyond the boundaries of the initial insult and can lead to maladaptive cortical reorganisation. On the other hand, beneficial cortical reorganisation leading to recovery of function can also occur. We used resting state FMRI to investigate how cortical networks in the macaque brain change across time in response to lesions to the prefrontal cortex, and how this reorganisation correlated with changes in behavioural performance in cognitive tasks. After prelesion testing and scanning, two monkeys received a lesion to regions surrounding the left principal sulcus followed by periodic testing and scanning. Later, the animals received another lesion to the opposite hemisphere and additional testing and scanning. Following the first lesion, we observed both a behavioural impairment and decrease in functional connectivity, predominantly in frontal-frontal networks. Approximately 8 weeks later, performance and connectivity patterns both improved. Following the second lesion, we observed a further behavioural deficit and decrease in connectivity that showed little recovery. We discuss how different mechanisms including alternate behavioural strategies and reorganisation of specific prefrontal networks may have led to improvements in behaviour. Further work will be needed to confirm these mechanisms.This work was supported by the MRC intramural program MC-A060-5PQ10 (MA, DM, JD, AB), an MRC Career Development Award G0800329 (AM)

Implementation of a hospital-wide multidisciplinary blunt chest injury care bundle (ChIP): Fidelity of delivery evaluation

BackgroundIneffective intervention for patients with blunt chest wall injury results in high rates of morbidity and mortality. To address this, a blunt chest injury care bundle protocol (ChIP) was developed, and a multifaceted plan was implemented using the Behaviour Change Wheel.ObjectiveThe purpose of this study was to evaluate the reach, fidelity, and dose of the ChIP intervention to discern if it was activated and delivered to patients as intended at two regional Australian hospitals.MethodsThis is a pretest and post-test implementation evaluation study. The proportion of ChIP activations and adherence to ChIP components received by eligible patients were compared before and after intervention over a 4-year period. Sample medians were compared using the nonparametric median test, with 95% confidence intervals. Differences in proportions for categorical data were compared using the two-sample z-test.Results/findingsOver the 19-month postimplementation period, 97.1% (n = 440) of eligible patients received ChIP (reach). The median activation time was 134 min; there was no difference in time to activation between business hours and after-hours; time to activation was not associated with comorbidities and injury severity score. Compared with the preimplementation group, the postimplementation group were more likely to receive evidence-based treatments (dose), including high-flow nasal cannula use (odds ratio [OR] = 6.8 [95% confidence interval {CI} = 4.8-9.6]), incentive spirometry in the emergency department (OR = 7.5, [95% CI = 3.2-17.6]), regular analgesia (OR = 2.4 [95% CI = 1.5-3.8]), regional analgesia (OR = 2.8 [95% CI = 1.5-5.3]), patient-controlled analgesia (OR = 1.8 [95% CI = 1.3-2.4]), and multiple specialist team reviews, e.g., surgical review (OR = 9.9 [95% CI = 6.1-16.1]).ConclusionsHigh fidelity of delivery was achieved and sustained over 19 months for implementation of a complex intervention in the acute context through a robust implementation plan based on theoretical frameworks. There were significant and sustained improvements in care practices known to result in better patient outcomes. Findings from this evaluation can inform future implementation programs such as ChIP and other multidisciplinary interventions in an emergency or acute care context

Does environmental enrichment promote recovery from stress in rainbow trout?

The EC Directive on animal experimentation suggests that all protected animals should have enrichment to improve welfare yet relatively little research has been conducted on the impact of enrichment in fish. Studies employing enrichment in zebrafish have been contradictory and other fish species may require species-specific enrichments relevant to their ecology. Salmonids are important experimental models in studies within aquaculture, toxicology and natural ecosystems. This study therefore sought to establish whether an enriched environment in an experimental aquarium may promote improved welfare in rainbow trout (Oncorhynchus mykiss) by enhancing their recovery from invasive procedures. Trout were held individually in either barren (no tank ornamentation) or enriched (gravel, plants and an area of cover) conditions and recovery rates after a noxious stimulus and a standard stressor were investigated by monitoring behaviour, opercular beat rate and plasma cortisol concentrations. Fish were randomly assigned to one of four treatment groups: Control (undisturbed), Sham (handled but not manipulated), Stress (air emersion) and Pain (subcutaneous injection of acetic acid). The results suggest that for rainbow trout environmental enrichment may not be an important factor when the fish is responding to a painful stimulus. However, it does appear to promote recovery and ameliorate adverse effects following a stressor. Fish held in barren conditions were potentially more stressed as seen by increased activity following imposition of the stressor. These results have important implications for the husbandry and welfare of captive rainbow trout and suggest that enriched environments may be preferable to barren environments in experimental studies

A multi-centre, parallel group superiority trial of silk therapeutic clothing compared to standard care for the management of eczema in children (CLOTHES Trial): study protocol for a randomised controlled trial

Background - Eczema is a chronic, itchy skin condition that can have a large impact on the quality of life of patients and their families. People with eczema are often keen to try out non-pharmacological therapies like silk therapeutic garments that could reduce itching or the damage caused by scratching. However, the effectiveness and cost-effectiveness of these garments in the management of eczema has yet to be proven. The CLOTHES Trial will test the hypothesis that ‘silk therapeutic garments plus standard eczema care’ is superior to ‘standard care alone’ for children with moderate to severe eczema.Methods/Design - Parallel group, observer-blind, pragmatic, multi-centre randomised controlled trial of 6 months’ duration. Three hundred children aged 1 to 15 years with moderate to severe eczema will be randomised (1:1) to receive silk therapeutic garments plus standard eczema care, or standard eczema care alone. Primary outcome is eczema severity, as assessed by trained and blinded investigators at 2, 4 and 6 months (using the Eczema Area and Severity Index (EASI)). Secondary outcomes include: patient-reported eczema symptoms (collected weekly for 6 months to capture long-term control); global assessment of severity; quality of life of the child, family and main carer; use of standard eczema treatments (emollients, corticosteroids applied topically, calcineurin inhibitors applied topically and wet wraps); frequency of infections; and cost-effectiveness. The acceptability and durability of the clothing will also be assessed, as will adherence to wearing the garments. A nested qualitative study will assess the views of a subset of children wearing the garments and their parents, and those of healthcare providers and commissioners. Randomisation uses a computer-generated sequence of permuted blocks of randomly varying size, stratified by recruiting hospital and child’s age ( 5 years), and concealed using a secure web-based system. The sequence of treatment allocations will remain concealed until randomisation and data collection are complete.Recruitment is taking place from November 2013 to May 2015, and the trial will be completed in 2016. Full details of results will be published in the National Institute for Health Research Journal series.Trial registration - Current Controlled Trials ISRCTN77261365 (registered 11 November 2013)

On-orbit Operations and Offline Data Processing of CALET onboard the ISS

The CALorimetric Electron Telescope (CALET), launched for installation on the International Space Station (ISS) in August, 2015, has been accumulating scientific data since October, 2015. CALET is intended to perform long-duration observations of high-energy cosmic rays onboard the ISS. CALET directly measures the cosmic-ray electron spectrum in the energy range of 1 GeV to 20 TeV with a 2% energy resolution above 30 GeV. In addition, the instrument can measure the spectrum of gamma rays well into the TeV range, and the spectra of protons and nuclei up to a PeV. In order to operate the CALET onboard ISS, JAXA Ground Support Equipment (JAXA-GSE) and the Waseda CALET Operations Center (WCOC) have been established. Scientific operations using CALET are planned at WCOC, taking into account orbital variations of geomagnetic rigidity cutoff. Scheduled command sequences are used to control the CALET observation modes on orbit. Calibration data acquisition by, for example, recording pedestal and penetrating particle events, a low-energy electron trigger mode operating at high geomagnetic latitude, a low-energy gamma-ray trigger mode operating at low geomagnetic latitude, and an ultra heavy trigger mode, are scheduled around the ISS orbit while maintaining maximum exposure to high-energy electrons and other high-energy shower events by always having the high-energy trigger mode active. The WCOC also prepares and distributes CALET flight data to collaborators in Italy and the United States. As of August 31, 2017, the total observation time is 689 days with a live time fraction of the total time of approximately 84%. Nearly 450 million events are collected with a high-energy (E>10 GeV) trigger. By combining all operation modes with the excellent-quality on-orbit data collected thus far, it is expected that a five-year observation period will provide a wealth of new and interesting results.Comment: 11 pages, 7 figures, published online 27 February 201

Search for GeV Gamma-ray Counterparts of Gravitational Wave Events by CALET

We present results on searches for gamma-ray counterparts of the LIGO/Virgo gravitational-wave events using CALorimetric Electron Telescope ({\sl CALET}) observations. The main instrument of {\sl CALET}, CALorimeter (CAL), observes gamma-rays from $\sim1$ GeV up to 10 TeV with a field of view of nearly 2 sr. In addition, the {\sl CALET} gamma-ray burst monitor (CGBM) views $\sim$3 sr and $\sim2\pi$ sr of the sky in the 7 keV -- 1 MeV and the 40 keV -- 20 MeV bands, respectively, by using two different crystal scintillators. The {\sl CALET} observations on the International Space Station started in October 2015, and here we report analyses of events associated with the following gravitational wave events: GW151226, GW170104, GW170608, GW170814 and GW170817. Although only upper limits on gamma-ray emission are obtained, they correspond to a luminosity of $10^{49}\sim10^{53}$ erg s$^{-1}$ in the GeV energy band depending on the distance and the assumed time duration of each event, which is approximately the order of luminosity of typical short gamma-ray bursts. This implies there will be a favorable opportunity to detect high-energy gamma-ray emission in further observations if additional gravitational wave events with favorable geometry will occur within our field-of-view. We also show the sensitivity of {\sl CALET} for gamma-ray transient events which is the order of $10^{-7}$~erg\,cm$^{-2}$\,s$^{-1}$ for an observation of 100~s duration.Comment: 12 pages, 8 figures, 1 table. Accepted for publication in Astrophysical Journa

Balloon Measurements of Cosmic Ray Muon Spectra in the Atmosphere along with those of Primary Protons and Helium Nuclei over Mid-Latitude

We report here the measurements of the energy spectra of atmospheric muons and of the cosmic ray primary proton and helium nuclei in a single experiment. These were carried out using the MASS superconducting spectrometer in a balloon flight experiment in 1991. The relevance of these results to the atmospheric neutrino anomaly is emphasized. In particular, this approach allows uncertainties caused by the level of solar modulation, the geomagnetic cut-off of the primaries and possible experimental systematics to be decoupled in the comparison of calculated fluxes of muons to measured muon fluxes. The muon observations cover the momentum and depth ranges of 0.3-40 GeV/c and 5-886 g/cmsquared, respectively. The proton and helium primary measurements cover the rigidity range from 3 to 100 GV, in which both the solar modulation and the geomagnetic cut-off affect the energy spectra at low energies.Comment: 31 pages, including 17 figures, simplified apparatus figure, to appear in Phys. Rev.