Geography of lumbar paravertebral muscle fatty infiltration

Study Design: Cross-sectional Objective: We quantified fatty infiltration (FI) geography of the lumbar spine to identify whether demographics, temporal low back pain (LBP), and disability influence FI patterns. Summary of Background Data: Lumbar paravertebral muscle FI has been associated with age, sex, LBP, and disability; yet, FI accumulation patterns are inadequately described to optimise interventions. Methods: This cross-sectional study employed lumbar axial T1-weighted MRI in 107 Southern-Chinese adults (54 females, 53 males). Single-slices at the vertebral inferior end-plate per lumbar level were measured for quartiled-FI, and analysed against demographics, LBP, and disability (ODI: Oswestry Disability Index). Results: Mean FI% was higher in females, on the right, increased per level caudally, and from medial to lateral in men (p 0.05). Conclusions: Lumbar paravertebral muscle FI predominates in the lower lumbar spine, notably for those aged 40-65, and depends more on sagittal than transverse distribution. Higher FI in females and differences of mean FI between sexes for BMI, LBP, and disabling ODI suggest sex-differential accumulation patterns. Our study contradicts pain models rationalising lumbar muscle FI and may reflect a normative sex-dependent feature of the natural history of lumbar paravertebral muscles

Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki = 1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1∶2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation

Geography of Lumbar Paravertebral Muscle Fatty Infiltration: The Influence of Demographics, Low Back Pain, and Disability

Study Design.Cross-sectional.Objective.We quantified fatty infiltration (FI) geography of the lumbar spine to identify whether demographics, temporal low back pain (LBP), and disability influence FI patterns.Summary of Background Data.Lumbar paravertebral muscle FI has been associated with age, sex, LBP, and disability; yet, FI accumulation patterns are inadequately described to optimize interventions.Methods.This cross-sectional study employed lumbar axial T1-weighted magnetic resonance imaging in 107 Southern-Chinese adults (54 females, 53 males). Single-slices at the vertebral inferior end-plate per lumbar level were measured for quartiled-FI, and analyzed against demographics, LBP, and disability (Oswestry Disability Index).Results.Mean FI% was higher in females, on the right, increased per level caudally, and from medial to lateral in men (P 0.05).Conclusion.Lumbar paravertebral muscle FI predominates in the lower lumbar spine, notably for those aged 40 to 65, and depends more on sagittal than transverse distribution. Higher FI in females and differences of mean FI between sexes for BMI, LBP, and disabling Oswestry Disability Index suggest sex-differential accumulation patterns. Our study contradicts pain models rationalizing lumbar muscle FI and may reflect a normative sex-dependent feature of the natural history of lumbar paravertebral muscles.Level of Evidence: 2

Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flows origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of Americas aspergillosis clinical practice guidelines, can guide decision-making in clinical settings

Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (Emax = 85%) and subnanomolar potency (EC50 = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC50 = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious

Application of remote real-time monitoring to offshore oil and gas operations

The U.S. outer continental shelf is a major source of energy for the United States, and over the past 25 years, deepwater oil and gas production in the Gulf of Mexico has increased significantly. With the move into greater water depths, industry is drilling deeper wells, where operations can experience higher pressures, higher temperatures, and greater uncertainty. Remote monitoring of drilling operations could help operators and regulators enhance the safety of these operations. This study advises the Bureau of Safety and Environmental Enforcement (BSEE) on the application and use of remote real-time monitoring (RRTM) to improve management of the safety and environmental risks of offshore oil and gas operations. As a central part of the charge (see Box 1 -1 in Chapter 1), BSEE asked the committee to conduct a workshop that addressed the critical operations and parameters to be monitored in real time, the role RRTM could play in automation and predictive software and condition-based maintenance (CBM), and how RRTM could be leveraged by BSEE and incorporated into its regulatory framework. Drillers have monitored drilling operations offshore in real time for decades; more recently, a few operators have also transmitted some of these data onshore to improve efficiency and risk management. During its information gathering, the committee was told that RRTM\u27s benefits include increased efficiency, decreased downtime and operational disruptions, reduced equipment damage, improved safety, and overall reduction in risk. Whereas RRTM can provide the rig with technical support and access to onshore expertise, during the committee\u27s workshop the U.S. industry expressed a belief that responsibility and authority for operational decision making should remain offshore. Situational awareness on the offshore facility is important, and RRTM data do not always provide the necessary context. The use of RRTM is variable across the offshore oil and gas industry, and diverse RRTM technologies are available. No RRTM industry standard or standard practice exists, and the industry exhibits varying levels of maturity in its use of RRTM. Thus, a standard approach is not likely to work or to be needed for every company or every well. The committee views RRTM as a best available and safest technology (BAST), when such technologies are consistent with the principles of ALARP (as low as reasonably practicable). The director of BSEE estab-lishes BAST through a documented process, but determining RRTM as BAST in some contexts would not mandate its use across the board. The decision to use RRTM occurs when such technologies are available and economically feasible. BSEE could use existing regulatory requirements, such as the Application for Permit to Drill (APD) and the Safety and Environmental Management System (SEMS) plan, to advance appropriate use of RRTM. By encouraging offshore operators to address RRTM in their APD or SEMS plans, BSEE could allow operators to determine the circumstances under which RRTM should be used and challenge them to do so when BSEE believes that RRTM is necessary for managing risk. RRTM information-whether in real time or archived-could also benefit BSEE in its inspection activities and support inspectors\u27 review of safety-related information before they visit offshore facilities. Preparation, prioritized by risk, could allow for more efficient scheduling and effective execution of BSEE inspections. The committee is not in a position to recommend or validate a definitive list of critical operations and parameters for RRTM. In the committee\u27s judgment, a single standard list for all operations is not practical in view of the variability in operating conditions, geology, and scope and scale of facilities; the evolution of technology; consideration of human factors; and the incorporation of RRTM in a risk-based approach to regulating offshore operations. However, companies using RRTM appear to monitor some of the same critical operations and parameters (see Chapter 2). As sensor technology advances and the ability to transmit that data improves, issues with regard to the management of massive volumes of real-time data will grow. Likewise, as more RRTM of offshore operations is introduced, cybersecurity risks associated with the increased use of technology will rise. Control systems for critical rig-based equipment, not originally designed for connectivity to Internet-facing systems, are likely be at risk. RRTM could contribute to achieving a longer-term goal of offshore systems CBM. Blowout preventers (BOPs) provide a promising case. However, before CBM can go forward, BOP operational data and maintenance history will need to be collected and stored continually over the lifetime of the equipment to allow development of predictive models. Retroactive analysis of BOP performance data may not be adequate due to the complexity and variability of offshore operations and incomplete BOP maintenance history. The committee\u27s consensus recommendations, which are listed below and elaborated in Chapter 4, provide guidance to BSEE and stakeholders in addressing the issues associated with the application of RRTM to offshore oil and gas operations. Recommendation 1. BSEE should pursue a more performance-based regulatory framework by focusing on a risk-based regime that allows industry to determine relevant uses of RRTM on the basis of assessed levels of risk and complexity. BSEE could assess decisions about the monitoring of well parameters or the application of RRTM through the review of a company\u27s APD or SEMS plans and challenge the company to apply RRTM to manage the risk of complex operations. Recommendation 2. The committee views RRTM as BAST when justified by the risk of particular wells. BSEE should monitor the spectrum of RRTM technologies and best practices by using either an internal BSEE group, such as the agency\u27s proposed Engineering Technology Assessment Center, or an external organization, such as the Ocean Energy Safety Institute. Recommendation 3. Consistent with recommendations of previous committees of the National Academies (NAE and NRC 2012; NAE and NRC 2013), BSEE should encourage involvement of all stakeholders in the development of risk-based goals and standards governing offshore oil and gas processes. Specifically, BSEE should work with the American Petroleum Institute (API), the International Association of Drilling Contractors, and other relevant stakeholders to form an API standing technical committee (as opposed to an ad hoc committee) that would establish minimum requirements for which critical operations (and parameters) are monitored and for which data are collected and monitored in real time. In addition, BSEE, along with this technical committee, should propose standards for communication protocols between onshore and offshore facilities when RRTM is used. Recommendation 4. BSEE should encourage API to work with original equipment manufacturers, drilling contractors, and industry trade associations to establish a BOP CBM pilot project, with the goal of an API publication

Validation française de l'échelle d'expérience temporelle du plaisir [Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment.]

INTRODUCTION: Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. OBJECTIVE: The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. METHODS: A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. RESULTS: Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. CONCLUSION: The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample