miRNA-140-5p: new avenue for pulmonary arterial hypertension drug development?

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Pathologically, PAH is characterised by sustained vasoconstriction and progressive obliteration of small pulmonary arteries through a process of medial thickening, intimal fibrosis and the formation of angioproliferative lesions. Current treatments target the sustained vasoconstriction via either the prostacyclin, endothelin or nitric oxide pathway but do little to address the underlying progressive proliferative vascular disease. Dysregulated expression of microRNA (miR) has been identified in PAH and we have recently highlighted reduced miR-140-5p in patients with PAH. Replacement of miR-140-5p attenuated disease in animal models with the regulation of Smurf1, a E3 ubiquitin ligase targeting BMPR2 as one identified mechanism. These data highlight Smurf1 inhibition as a treatment for PAH

Far Infrared and Submillimeter Emission from Galactic and Extragalactic Photo-Dissociation Regions

Photodissociation Region (PDR) models are computed over a wide range of physical conditions, from those appropriate to giant molecular clouds illuminated by the interstellar radiation field to the conditions experienced by circumstellar disks very close to hot massive stars. These models use the most up-to-date values of atomic and molecular data, the most current chemical rate coefficients, and the newest grain photoelectric heating rates which include treatments of small grains and large molecules. In addition, we examine the effects of metallicity and cloud extinction on the predicted line intensities. Results are presented for PDR models with densities over the range n=10^1-10^7 cm^-3 and for incident far-ultraviolet radiation fields over the range G_0=10^-0.5-10^6.5, for metallicities Z=1 and 0.1 times the local Galactic value, and for a range of PDR cloud sizes. We present line strength and/or line ratio plots for a variety of useful PDR diagnostics: [C II] 158 micron, [O I] 63 and 145 micron, [C I] 370 and 609 micron, CO J=1-0, J=2-1, J=3-2, J=6-5 and J=15-14, as well as the strength of the far-infrared continuum. These plots will be useful for the interpretation of Galactic and extragalactic far infrared and submillimeter spectra observable with ISO, SOFIA, SWAS, FIRST and other orbital and suborbital platforms. As examples, we apply our results to ISO and ground based observations of M82, NGC 278, and the Large Magellenic Cloud.Comment: 54 pages, 20 figures, accepted for publication in The Astrophysical Journa

The Effect of Pre-Deployment Physiology as a Predictor of Post-Traumatic Stress Disorder Among a Sample of United States Army National Guard and Reserve Soldiers

Potential risk factors for development of Post-Traumatic Stress Disorder (PTSD) are still unclear. One potential risk factor for the development of PTSD is an individual’s cardiovascular reactivity and recovery in response to stressor tasks. The current study was conducted with 763 Army National Guard and Army Reserve soldiers. Participants completed a stressful induction along with self-report measures prior to deployment. Post-deployment, self-report measures were completed to assess PTSD symptomatology and experiences related to deployment and combat. Multiple regression was used to determine the ability of blood pressure response to stress to predict PTSD symptoms immediately and one-year after return from deployment. Results indicated that soldiers who had a less reactive systolic blood pressure response to and recovery from stressor tasks reported more PTSD symptomatology immediately after and one year after return from deployment. These results suggest that soldiers who develop PTSD after deployment have less pre-deployment emotion regulation ability

An Investigation of Neurological soft signs as a discriminating factor between Veterans with Post-traumatic Stress Disorder, mild Traumatic Brain Injury, and co-occurring Post-traumatic Stress Disorder and mild Traumatic Brain Injury

While multiple Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans suffer from mild Traumatic Brain Injury (mTBI), Post-traumatic Stress Disorder (PTSD), and co-morbid mTBI and PTSD, there remains difficulty disentangling the specific symptoms associated with each disorder using self-report and neurocognitive assessments. We propose that neurological soft signs (NSS), which are tasks associated with general neurologic compromise, may prove useful in this regard. Based on our review of the literature we hypothesized that individuals with PTSD would present with a greater number of NSS than controls or individuals with mTBI. Further, we hypothesized a synergistic effect, such that individuals with mTBI + PTSD would present with the greatest number of NSS. To test these hypotheses, we analyzed a subset of individuals (N=238) taken from a larger study of neurocognitive functioning in veterans. Participants completed a battery of neuropsychological measures, which included the Behavioral Dyscontrol Scale (BDS), the current study’s measure of NSS. A subset of other neuropsychological measures were also included to examine the utility of NSS over and above traditional neuropsychological measures. Individuals were removed from the study if they sustained a moderate/severe TBI or did not meet validity criteria on the Green’s Word Memory Test or the Negative Impression Management subscale of the Personality Assessment Inventory. Binomial logistic and multinomial logistic regression were used to examine the ability of NSS to discriminate between the study groups, first by themselves and then after the variance explained by the traditional neuropsychological measures was accounted for. Exploratory cluster analyses were performed on neuropsychological measures and NSS to identify profiles of cognitive performance in the data set. Results indicated that individuals in the mTBI and/or PTSD group had more NSS compared to controls. Of the individual NSS items only a go/no-go task of the BDS discriminated between groups, with worse performance among individuals in the mTBI, PTSD, and mTBI + PTSD group compared to controls. In contrast, the overall BDS score and individual NSS, in general, did not discriminate between the mTBI, PTSD, and mTBI + PTSD group. Overall, the current study suggests that, when eliminating participants who do not meet validity criteria, NSS do not aid in discriminating between individuals with mTBI, PTSD, and mTBI + PTSD

Revisionism Misplaced: Why This is Not the Time to Bury Autonomy

For the past twenty years, bioethics has exerted a profound influence on American medicine. Although its full impact cannot be precisely measured, one need only speak to European physicians and clinical investigators to grasp the full extent of the change. Americans may debate the sufficiency of the information that physicians share with their patients, but hear a European doctor exclaim angrily that it is criminal to ask a woman to decide whether to have a radical mstectomy or lumpectomy, and you know that bioethics has made a significant difference in the United States. So too, Americans, far more intensely than Europeans, will fiercly contest any proposed exception to informed consent in research protocols, and our Institutional Review Boards (IRBs) are unmatched for the protections they provide human subjects. Not only foreign comparisons but daily events point to the difference that bioethics has made: consider the newspaper space devoted to bioethical considerations, whether the case be multiple births, AIDS testing in Africa, cloning, or organ donation, to choose recent examples; or the readiness of lawyers to have clients sign an advanced directive and proxy assignment; or the intensity of public debate on physician-assisted suicide. Bioethics has clearly become the stuff of referendum campaigns and dinner-table discussions

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018

Coupling angle variability in healthy and patellofemoral pain runners

Background Patellofemoral pain is hypothesized to result in less joint coordination variability. The ability to relate coordination variability to patellofemoral pain pathology could have many clinical uses; however, evidence to support its clinical application is lacking. The aim was to determine if vector coding's coupling angle variability, as a measure of joint coordination variability, was less for runners with patellofemoral pain than healthy controls as is commonly postulated. Methods Nineteen female recreational runners with patellofemoral pain and eleven healthy controls performed a treadmill acclimation protocol then ran at a self-selected pace for 15 min. 3-D kinematics, force plate kinetics, knee pain and rating of perceived exertion were recorded each minute. Data were selected for the: pain group at the highest pain reached (pain � 3/10) in a non-exerted state (exertion < 14/20), and; non-exerted healthy group from the eleventh minute. Coupling angle variability was calculated over several portions of the stride for six knee-ankle combinations during five non-consecutive strides. Findings 46 of 48 coupling angle variability measures were greater for the pain group, with 7 significantly greater (P <.05). Interpretation These findings oppose the theory that less coupling angle variability is indicative of a pathological coordinate state during running. Greater coupling angle variability may be characteristic of patellofemoral pain in female treadmill running when a larger threshold of pain is reached than previously observed. A predictable and directional response of coupling angle variability measures in relation to knee pathology is not yet clear and requires further investigation prior to considerations for clinical utility. © 2013 Elsevier Ltd