Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are ...not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.
The European Society of Cardiology (ESC) 0/1-h high sensitivity troponin T (hs-cTnT) algorithm does not differentiate risk based on known coronary artery disease (CAD: prior myocardial infarction MI, ...coronary revascularization, or ≥ 70% coronary stenosis). We recently evaluated its performance among patients with known CAD at 30-days, but little is known about its longer-term risk prediction. The objective of this study is to determine and compare the performance of the algorithm at 90-days among patients with and without known CAD.
We performed a pre-planned subgroup analysis of the STOP-CP cohort, which prospectively enrolled ED patients ≥21 years old with symptoms suggestive of ACS without ST-elevation on initial ECG across 8 US sites (1/25/2017–9/6/2018). Participants with 0- and 1-h hs-cTnT measures (Roche, Basel, Switzerland) were stratified into rule-out, observe, and rule-in groups using the ESC 0/1-h algorithm. Algorithm performance was tested among patients with or without known CAD, as determined by the treating provider. The primary outcome was cardiac death or MI at 90-days. Fisher's exact tests were used to compare 90-day event and rule-out rates between patients with and without known CAD. Negative predictive values (NPVs) for 90-day cardiac death or MI with exact 95% confidence intervals were calculated and compared using Fisher's exact test.
The STOP-CP study accrued 1430 patients, of which 31.4% (449/1430) had known CAD. Cardiac death or MI at 90 days was more common in patients with known CAD than in those without 21.2% (95/449) vs. 10.0% (98/981); p < 0.001. Using the ESC 0/1-h algorithm, 39.6% (178/449) of patients with known CAD and 66.1% (648/981) of patients without known CAD were ruled-out (p < 0.001). Among rule-out patients, 90-day cardiac death or MI occurred in 3.4% (6/178) of patients with known CAD and 1.2% (8/648) without known CAD (p = 0.09). NPV for 90-day cardiac death or MI was 96.6% (95%CI 92.8–98.8) among patients with known CAD and 98.8% (95%CI 97.6–99.5) in patients without known CAD (p = 0.09).
Patients with known CAD who were ruled-out using the ESC 0/1-h hs-cTnT algorithm had a high rate of missed 90-day cardiac events, suggesting that the ESC 0/1-h hs-cTnT algorithm may not be safe for use among patients with known CAD.
High-Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification (STOP-CP; ClinicalTrials.gov: NCT02984436; https://clinicaltrials.gov/ct2/show/NCT02984436).
The diagnostic performance of the high‐sensitivity troponin T (hs‐cTnT) European Society of Cardiology (ESC) 0/1‐h algorithm in sex and race subgroups of US Emergency Department (ED) patients is ...unclear. A pre‐planned subgroup analysis of the STOP‐CP cohort study was conducted. Participants with 0‐ and 1‐h hs‐cTnT measures from eight US EDs (1/2017 to 9/2018) were stratified into rule‐out, observation, and rule‐in zones using the hs‐cTnT ESC 0/1 algorithm. The primary outcome was adjudicated 30‐day cardiac death or MI. The proportion with the primary outcome in each zone was compared between subgroups with Fisher's exact tests. The negative predictive value (NPV) of the ESC 0/1 rule‐out zone for 30‐day CDMI was calculated and compared between subgroups using Fisher's exact tests. Of the 1422 patients enrolled, 54.2% (770/1422) were male and 58.1% (826/1422) white with a mean age of 57.6 ± 12.8 years. At 30 days, cardiac death or myocardial infarction (MI) occurred in 12.9% (183/1422) of participants. Among patients stratified to the rule‐out zone, 30‐day cardiac death or MI occurred in 1.1% (5/436) of women versus 2.1% (8/436) of men (p = .40) and 1.2% (4/331) of non‐white patients versus 1.8% (9/490) of white patients (p = .58). The NPV for 30‐day cardiac death or MI was similar among women versus men (98.9% 95% confidence interval, CI: 97.3–99.6 vs. 97.9% 95% CI: 95.9–99.1; p = .40) and among white versus non‐white patients (98.8% 95% CI: 96.9–99.7 vs. 98.2% 95% CI: 96.5–99.2; p = .39). NPVs <99% in each subgroup suggest the hs‐cTnT ESC 0/1‐h algorithm may not be safe for use in US EDs. Trial Registration: High‐Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification (STOP‐CP; ClinicalTrials.gov: NCT02984436; https://clinicaltrials.gov/ct2/show/NCT02984436).
Primary outcome: Negative predictive value (NPV) for 30‐day cardiac death or myocardial infarction among sex and race subgroups of the STOP‐CP Study.
Women NPV: 97.9% (95% confidence interval CI: 95.9–99.1).
Men NPV: 98.9% (95% CI: 97.3‐99.6).
Non‐white patients NPV: 98.2% (95% CI: 96.5–99.2).
White patients NPV: 98.8% (95% CI: 96.9–99.7).
Conclusion: The ESC 0/1‐h hs‐cTnT rule failed to achieve the commonly accepted NPV safety threshold of 99% for all subgroups.
Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we ...demonstrate the application of high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis when compared to WT animals. Collectively, we provide conclusive evidence that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. In summary, our study provides a roadmap to leverage spatial metabolomics to understand foundational biology in pulmonary diseases.
In the 21st century, aquaculture is generally characterized as a foe to conservation efforts. Yet, much has changed in the two seemingly disparate practices over the last two decades, motivating an ...updated evaluation of the scientific evidence for how aquaculture currently impacts conservation, as well as prospects for further alignment and research. Here we present a new perspective on conservation aquaculture, which we redefine as “the use of human cultivation of an aquatic organism for the planned management and protection of a natural resource.” Looking across scales of conservation aquaculture that include single species to ecosystem level benefits (and limitations), we highlight ways aquaculture has historically, and is currently being integrated into conservation (e.g., habitat restoration of oyster beds) and areas that could be improved for the protection of critical species and habitats (e.g., aquarium trade of coral reef species). With a more strategic focus, there appears to be notable conservation aquaculture potential via the cultivation of species for harvest that could provide wild harvest alleviation through replacement or supplement – particularly for over-exploited species – and/or ecosystem services, such as improved water quality and reduction in greenhouse gas emissions. Given that aquaculture is the fastest growing food industry on the planet, aligning farming practices with conservation objectives is particularly pressing to ensure that growth happens in the service of conservation in the most effective and sustainable way possible. The sheer potential of conservation aquaculture suggests a tale of redemption for aquaculture and opportunity for conservationists to bring in a new age of collaborative practices to address global issues.
•We redefine conservation aquaculture (CA) to capture its current and potential role in conservation.•Aquaculture practices are already part of the conservation portfolio.•CA has great potential at the scale of species to ecosystems.•Conservation objectives for aquaculture could contribute to more sustainable development.
The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we ...identified dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has significant “off-target” effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether dorsomorphin’s antiangiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogues that target BMP but not VEGF signaling and vice versa. In a structure−activity relationship (SAR) study of dorsomorphin analogues based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the BMP inhibitors, DMH1, which exclusively targets the BMP but not the VEGF pathway, dorsalized the embryonic axis without disrupting the angiogenic process, demonstrating that BMP signaling was not involved in the angiogenic process. This is one of the first full-scale SAR studies performed in vertebrates and demonstrates the potential of zebrafish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.
...medical professionals have a stigma against the use of social media for medical purposes: in a survey by Bosslet et al., 68% of medical students, residents, and practicing physicians viewed ...interacting with patients on social media as “ethically unacceptable” for personal or patient-care related reasons 5. Unfortunately, the patient had eloped. Because we knew her name and a few other personal identifiers gathered during triage, we were able to find the patient on Facebook with reasonable certainty. Acknowledgment The manuscript was copyedited by Linda J. Kesselring, MS, ELS, the technical editor/writer in the Department of Emergency Medicine at the University of Maryland School of Medicine. 1 R.D. Madanick, Education becomes social: the intersection of social media and medical education, Gastroenterology, Vol. 149, Iss. 4, 2015, 844-847 2 K. Vance, W. Howe, R.P. Dellavalle, Social internet sites as a source of public health information, Dermatol Clin, Vol. 27, Iss. 2, 2009, 133-136 3 T. Simon, B. Adini, M. El-Hadid, L. Aharonson-Daniel, Competing to the rescue-leveraging social media for cross border collaboration in life-saving rescue operations, Am J Emerg Med, Vol. 31, Iss. 11, 2013, 1618-1619 4 M. Sharma, K. Yadav, N. Yadav, K.C. Ferdinand, Zika virus pandemic: analysis of Facebook as a social media health information platform, Am J Infect Control, Vol. 45, Iss. 3, 2017, 301-302 5 G.T. Bosslet, A.M. Torke, S.E. Hickman, C.L. Terry, P.R. Helft, The patient-doctor relationship and online social networks: results of a national survey, J Gen Intern Med, Vol. 26, Iss. 10, 2011, 1168-1174
ABSTRACT
Introduction: Osteogenesis imperfecta (OI) is characterized by skeletal fragility and muscle weakness. In this study we investigated the effects of soluble activin type IIB receptor ...(sActRIIB‐mFc) on muscle mass and function in 2 distinct mouse models of OI: osteogenesis imperfecta murine (oim) and +/G610C. Methods: Wild‐type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with Tris‐buffered saline (vehicle) or sActRIIB‐mFc and their hindlimb muscles evaluated for mass, morphology, and contractile function. Results: sActRIIB‐mFc‐treated WT, +/G610C, and oim/oim mice had increased hindlimb muscle weights and myofiber cross‐sectional area compared with vehicle‐treated counterparts. sActRIIB‐mFc‐treated oim/oim mice also exhibited increased contractile function relative to vehicle‐treated counterparts. Discussion: Blocking endogenous ActRIIB was effective at increasing muscle size in mouse models of OI, and increasing contractile function in oim/oim mice. ActRIIB inhibitors may provide a potential mutation‐specific therapeutic option for compromised muscle function in OI. Muscle Nerve 57: 294–304, 2018
Dopamine (DA) is critical for reward processing, but significantly less is known about its role in punishment avoidance. Using a combined approach-avoidance task, we measured phasic DA release in the ...nucleus accumbens (NAc) of rats during presentation of cues that predicted reward, punishment or neutral outcomes and investigated individual differences based on avoidance performance. Here we show that DA release within a single microenvironment is higher for reward and avoidance cues compared with neutral cues and positively correlated with poor avoidance behaviour. We found that DA release delineates trial-type during sessions with good avoidance but is non-selective during poor avoidance, with high release correlating with poor performance. These data demonstrate that phasic DA is released during cued approach and avoidance within the same microenvironment and abnormal processing of value signals is correlated with poor performance.
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