Miracle-dz/UniFAR-FTUs huggingface dataset:
A holistic approach to chronic pain management that involves all stakeholders: change is needed

Abstract Chronic pain affects a large proportion of the population, imposing significant individual distress and a considerable burden on society, yet treatment is not always instituted and/or adequate. Comprehensive multidisciplinary management based on the biopsychosocial model of pain has been shown to be clinically effective and cost-efficient, but is not widely available. A literature review of stakeholder groups revealed many reasons for this, including: i) many patients believe healthcare professionals lack relevant knowledge, and consultations are rushed, ii) general practitioners consider that pain management has a low priority and is under-resourced, iii) pain specialists cite non-adherence to evidence-based treatment, sub-optimal prescribing, and chronic pain not being regarded as a disease in its own right, iv) nurses’, pharmacists’ and physiotherapists’ skills are not fully utilized, and v) psychological therapy is employed infrequently and often too late. Many of the issues relating to physicians could be addressed by improving medical training, both at undergraduate and postgraduate levels – for example, by making pain medicine a compulsory core subject of the undergraduate medical curriculum. This would improve physician/patient communication, increase the use of standardized pain assessment tools, and allow more patients to participate in treatment decisions. Patient care would also benefit from improved training for other multidisciplinary team members; for example, nurses could provide counseling and follow-up support, psychologists offer coping skills training, and physiotherapists have a greater role in rehabilitation. Equally important measures include the widespread adoption of a patient-centered approach, chronic pain being recognized as a disease in its own right, and the development of universal guidelines for managing chronic non-cancer pain. Perhaps the greatest barrier to improvement is lack of political will at both national and international level. Some powerful initiatives and collaborations are currently lobbying policy-making bodies to raise standards and reduce unnecessary pain – it is vital they continue.
Polycyclic Aromatic Hydrocarbons (PAHs) Mediate Transcriptional Activation of the ATP Binding Cassette Transporter ABCB6 Gene via the Aryl Hydrocarbon Receptor (AhR)*

Background: ABCB6 is an ATP binding cassette transporter that regulates heme biosynthesis. Results: Polyaromatic hydrocarbons increase heme synthesis in liver by activating ABCB6 expression via the aryl hydrocarbon receptor. Conclusion: ABCB6 is required for PAH-mediated induction of heme biosynthesis. Significance: ABCB6 expression might be clinically relevant in polyaromatic hydrocarbon-induced porphyrias and carcinogenesis. Liver is endowed with a mechanism to induce hepatic cytochromes P450 (CYP450s) in response to therapeutic drugs and environmental contaminants, leading to increased detoxification and elimination of the xenobiotics. Each CYP450 is composed of an apoprotein moiety and a heme prosthetic group, which is required for CYP450 activity. Thus, under conditions of CYP450 induction, there is a coordinate increase in heme biosynthesis to compensate for the increased expression of CYP450s. ABCB6, a mitochondrial ATP binding cassette transporter, which regulates coproporphyrinogen transport from the cytoplasm into the mitochondria to complete heme biosynthesis, represents a previously unrecognized rate-limiting step in heme biosynthesis. However, it is not known if exposure to drugs and environmental contaminants induces ABCB6 expression, to assure an adequate and apparently coordinated supply of heme for the generation of functional cytochrome holoprotein. In the present study, we demonstrate that polycyclic aromatic hydrocarbons (PAHs), the widely distributed environmental toxicants shown to induce porphyrin accumulation causing hepatic porphyria, up-regulate ABCB6 expression in both mice and humans. Using siRNA technology and Abcb6 knock-out mice, we demonstrate that PAH-mediated increase in hepatic porphyrins is compromised in the absence of ABCB6. Moreover, in vivo studies in aryl hydrocarbon receptor (AhR) knock-out mice demonstrate that PAH induction of ABCB6 is mediated by AhR. Promoter activation studies combined with electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrate direct interactions between the AhR binding sites in the ABCB6 promoter and the AhR receptor, implicating drug activation mechanisms for ABCB6 similar to those found in inducible cytochrome P450s. These studies are the first to describe direct transcriptional activation of both mouse and human ABCB6 by xenobiotics.
Mechanography performance tests and their association with sarcopenia, falls and impairment in the activities of daily living – a pilot cross-sectional study in 293 older adults

Objectives: Muscle mass and muscle power considerably decline with aging. The aim of the present study was to determine the association between muscular function using mechanography and sarcopenia, falls and impairment in the activities of daily living (ADL) in a sample of 293 community-dwelling women and men aged 60-85 years in Berlin, Germany. Methods: Muscle function was determined by muscle power per body mass in vertical countermovement jumps (2LJPrel) and the chair rising test (CRTPrel) on a force plate. Sarcopenia status was assessed by estimating appendicular muscle mass with dual-X-ray absorptiometry. Self-reported ADL impairment and falls in the last 12 months were determined. Results: ADL impairment was significantly correlated with all performance tests but not with muscle mass. The 2LJPrel (OR 0.88, 95%-CI 0.79-0.98), the Esslinger Fitness Index (EFI) (OR 0.97, 95%-CI 0.94-1.00) and the maximal velocity of the CRT (OR 0.70, 95%-CI 0.53-0.93) remained significant correlates for sarcopenia independent of age in men but not in women. The EFI could differentiate female individuals who had past fall events (OR 0.96, 95%-CI 0.93-0.98). Conclusion: The results of the present study highlight the importance of assessing muscle power in older individuals as a relevant correlate for functional decline.
Demand, appropriateness and prescribing of 'lifestyle drugs': a consultation survey in general practice.

BACKGROUND The simultaneous launch of orlistat and sildenafil in 1998 provoked much media attention, particularly around the role of lifestyle drugs and their potential costs if controls were not established. Fears were also expressed that primary care would be overwhelmed by demand, and little information was available about the attitude of GPs to their new role as prescribers of lifestlye drugs. Partly in response to these concerns, tight prescribing guidelines and licensed indications, for sildenafil and orlistat, respectively, were issued. OBJECTIVE Our aim was to describe levels of demand for orlistat and sildenafil in general practice, whether this demand was translated into a prescription, adherence to prescribing guidelines/licensed indications and the GP perception of appropriateness of an NHS prescription for either of these drugs. METHOD We carried out an observational study in primary care conducted over a 6-week period during 1999. Twenty-seven GPs were recruited, each from a different practice. All GP consultations were recorded for the study period and the GP completed a structured questionnaire each time sildenafil or orlistat were discussed in a consultation. RESULTS Sildenafil was discussed in 0.5% (68/13 394) of consultations and orlistat in 0.3% (42/13 394). GPs thought that a corresponding NHS prescription would be highly appropriate in 57 and 74% of cases, respectively, although for both lifestyle drugs, nearly 20% of GPs thought such prescriptions were inappropriate. An NHS prescription was issued in 43% of consultations in which sildenafil had been discussed and 33% in which orlistat had been discussed. Five out of 29 NHS sildenafil prescriptions were issued to patients failing to fulfil the requirements of prescribing guidelines; similarly, one out of 14 orlistat prescriptions fell outside licensed indications. There were four examples of NHS prescriptions for sildenafil which were given even when the GP thought the drug to be inappropriate, whereas orlistat was never given when the GP thought it inappropriate. CONCLUSIONS Levels of demand for the two lifestyle drugs, sildenafil and orlistat, were modest when compared with earlier media predictions. Neither was there evidence that GP was pitted against patient in their negotiation concerning a lifestyle drug NHS prescription since most GPs agreed with their patients that such a prescription was appropriate. Prescribing guidelines and licensed indications were generally adhered to, but the modest level of demand raises questions about expanding the guidelines for sildenafil.
5G transport network blueprint and dimensioning for a dense urban scenario

In this paper, we provide a quantitative evaluation of the deployment aspects and dimensioning of the 5G transport architecture in a representative European city. In particular, we select an example dense urban city scenario based on the city of Barcelona, and illustrate how the transport network architecture defined by the 5G-XHaul project can be deployed in that environment. Building on the case of Barcelona, we discuss physical deployment aspects, such as the locations to deploy small cells, how many compute facilities should be scattered throughout the city, or where the control plane functions should be deployed. In addition, we provide a quantitative evaluation of the 5G-XHaul deployment in Barcelona, including the bandwidth required at the different segments of the architecture, i.e. the wireless segment, the WDM-PON access network, and the TSON metro network. We also evaluate control plane aspects, such as the number of 5G-XHaul SDN controllers required for a city like Barcelona.
Effect of Concurrent Training, Flexible Nonlinear Periodization, and Maximal-Effort Cycling on Strength and Power

Abstract McNamara, JM and Stearne, DJ. Effect of concurrent training, flexible nonlinear periodization, and maximal-effort cycling on strength and power. J Strength Cond Res 27(6): 1463–1470, 2013—Although there is considerable research on concurrent training, none has integrated flexible nonlinear periodization and maximal-effort cycling in the same design. The purpose of this investigation was to test outcome measures of strength and power using a pretest-posttest randomized groups design. A strength and endurance (SE) group was compared with a strength, endurance, and maximal-effort cycling (SEC) group. Both groups used a flexible nonlinear periodization design. Thirteen male and 7 female students (mean ± SD: age, 22.5 ± 4.1 years; height, 173.5 ± 12.4 cm; weight, 79.4 ± 20.2 kg; strength training experience, 2.4 ± 2.2 years) participated in this study. Groups were not matched for age, height, weight, strength training experience, or sex, but were randomly assigned to an SE (n = 10) or SEC (n = 10) group. All training was completed within 45 minutes, twice per week (Monday and Wednesday), over 12 consecutive weeks. Both groups were assigned 6.75 total hours of aerobic conditioning, and 13.5 hours of free weight and machine exercises totaling 3,188 repetitions ranging from 5 to 20 repetition maximums. The SEC group performed 2 cycling intervals per workout ranging from 10 to 45 seconds. Pretest and posttest measures included chest press and standing broad jump. Analysis of variance showed that there were no significant differences between the SE and SEC groups on measures of chest press or standing broad jump performance (p, not significant). Paired sample t-tests (p = 0.05) showed significant improvement in strength and power in all groups (pretest to posttest), except for SE jump performance (p, not significant). In conclusion, adding maximal-effort cycling does not provide additional strength or power benefits to a concurrent flexible nonlinear training program. However, an exercise professional can take confidence that a concurrent flexible nonlinear training program can increase strength and power in healthy individuals.
The mecA Homolog mecC Confers Resistance against β-Lactams in Staphylococcus aureus Irrespective of the Genetic Strain Background

ABSTRACT In staphylococci, methicillin resistance is mediated by mecA-encoded penicillin-binding protein 2a (PBP2a), which has a low affinity for beta-lactams. Recently, a novel PBP2a homolog was described as being encoded by mecC, which shares only 70% similarity to mecA. To prove that mecC is the genetic determinant that confers methicillin resistance in Staphylococcus aureus, a mecC knockout strain was generated. The S. aureus ΔmecC strain showed considerably reduced oxacillin and cefoxitin MICs (0.25 and 4 μg/ml, respectively) compared to those of the corresponding wild-type methicillin-resistant S. aureus (MRSA) strain (8 and 16 μg/ml, respectively). Complementing the mutant in trans with wild-type mecC restored the resistance to oxacillin and cefoxitin. By expressing mecC and mecA in different S. aureus clonal lineages, we found that mecC mediates resistance irrespective of the genetic strain background, yielding oxacillin and cefoxitin MIC values comparable to those with mecA. In addition, we showed that mecC expression is inducible by oxacillin, which supports the assumption that a functional beta-lactam-dependent regulatory system is active in MRSA strains possessing staphylococcal cassette chromosome mec (SCCmec) type XI. In summary, we showed that mecC is inducible by oxacillin and mediates beta-lactam resistance in SCCmec type XI-carrying strains as well as in different S. aureus genetic backgrounds. Furthermore, our results could explain the comparatively low MICs for clinical mecC-harboring S. aureus isolates.
Identification of yeast aspartyl aminopeptidase gene by purifying and characterizing its product from yeast cells

Aspartyl aminopeptidase (EC 3.4.11.21) cleaves only unblocked N‐terminal acidic amino‐acid residues. To date, it has been found only in mammals. We report here that aspartyl aminopeptidase activity is present in yeast. Yeast aminopeptidase is encoded by an uncharacterized gene in chromosome VIII (YHR113W, Saccharomyces Genome Database). Yeast aspartyl aminopeptidase preferentially cleaved the unblocked N‐terminal acidic amino‐acid residue of peptides; the optimum pH for this activity was within the neutral range. The metalloproteases inhibitors EDTA and 1.10‐phenanthroline both inhibited the activity of the enzyme, whereas bestatin, an inhibitor of most aminopeptidases, did not affect enzyme activity. Gel filtration chromatography revealed that the molecular mass of the native form of yeast aspartyl aminopeptidase is ≈ 680 000. SDS/PAGE of purified yeast aspartyl aminopeptidase produced a single 56‐kDa band, indicating that this enzyme comprises 12 identical subunits.
Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC50,u and Correlation of in Vitro, Preclinical, and Clinical Data

This study was conducted to assess the utility of unbound brain EC50 (EC50,u) as a measure of in vivo potency for centrally active drugs. Seven μ-opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as model central nervous system drugs because they elicit a readily measurable central effect (antinociception) and their clinical pharmacokinetics/pharmacodynamics are well understood. Mice received an equipotent subcutaneous dose of one of the model opioids. The time course of antinociception and the serum and brain concentrations were determined. A pharmacokinetic/pharmacodynamic model was used to estimate relevant parameters. In vitro measures of opioid binding affinity (Ki) and functional activity [EC50 for agonist stimulated guanosine 5′-O-(3-[35S]thio)triphosphate binding] and relevant clinical parameters were obtained to construct in vitro-to-preclinical and preclinical-to-clinical correlations. The strongest in vitro-to-in vivo correlation was observed between Ki and unbound brain EC50,u (r2 ∼ 0.8). A strong correlation between mouse serum and human plasma EC50 was observed (r2 = 0.949); the correlation was improved when corrected for protein binding (r2 = 0.995). Clinical equipotent i.v. dose was only moderately related to Ki. However, estimates of ED50 and EC50 (total serum, unbound serum, total brain, and unbound brain) were significant predictors of clinical equipotent i.v. dose; the best correlation was observed for brain EC50,u (r2 = 0.982). For each opioid, brain equilibration half-life in mice was almost identical to the plasma effect-site equilibration half-life measured clinically. These results indicate that the mouse is a good model for opioid human brain disposition and clinical pharmacology and that superior in vitro-to-preclinical and preclinicalto-clinical correlations can be achieved with relevant unbound concentrations.
Exposure Controls for Nanomaterials at Three Manufacturing Sites

Because nanomaterials are thought to be more biologically active than their larger parent compounds, careful control of exposures to nanomaterials is recommended. Field studies were conducted at three sites to develop information about the effectiveness of control measures including process changes, a downflow room, a ventilated enclosure, and an enclosed reactor. Aerosol mass and number concentrations were measured during specific operations with a photometer and an electrical mobility particle sizer to provide concentration measurements across a broad range of sizes (from 5.6 nm to 30 μm). At site A, the dust exposure and during product harvesting was eliminated by implementing a wait time of 30 -min following process completion. And, the dust exposure attributed to process tank cleaning was reduced from 0.7 to 0.2 mg/m3 by operating the available process ventilation during this task. At site B, a ventilated enclosure was used to control dust generated by the manual weigh-out and manipulation of powdered nanomaterials inside of a downflow room. Dust exposures were at room background (under 0.04 mg/m3 and 500 particles/cm3) during these tasks however, manipulations conducted outside of the enclosure were correlated with a transient increase in concentration measured at the source. At site C, a digitally controlled reactor was used to produce aligned carbon nanotubes. This reactor was a closed system and the ventilation functioned as a redundant control measure. Process emissions were well controlled by this system with the exception of increased concentrations measured during the unloading of the product. However, this emission source could be easily controlled through increasing cabinet ventilation. The identification and adoption of effective control technologies is an important first step in reducing the risk associated with worker exposure to engineered nanoparticles. Properly designing and evaluating the effectiveness of these controls is a key component in a comprehensive health and safety program.
Known players, new interplay in atherogenesis: Chronic shear stress and carbamylated-LDL induce and modulate expression of atherogenic LR11 in human coronary artery endothelium

Summary In this study we examined whether low-density lipoprotein (LDL) receptor family members represent a link between blood flow characteristics and modified low-density lipoproteins involved in endothelial injury, a pivotal factor in atherogenesis. We demonstrated the expression of pro-atherogenic LDL receptor relative (LR11) for the first time in human coronary artery endothelial cells (HCAEC) in vitro and in vivo. Next, LR11 expression and regulation were explored in HCAEC cultured conventionally or on the inner surface of hollow fiber capillaries under exposure to shear stress for 10 days in the presence or absence of LDL. There was no LR11 expression under static conditions. When exposed to chronic low shear stress (2.5 dynes/cm2) transmembrane and soluble endothelial-LR11 were detected in high levels irrespective of the type of LDL added (carbamylated or native). In contrast, chronic high shear stress (25 dynes/cm2) inhibited the LR11-inducing effect of LDL such that transmembrane and soluble LR11 expression became non-detectable with native LDL. Carbamylated LDL significantly counteracted this atheroprotective effect of high shear stress as shown by lower, yet sustained expression of soluble and transmembrane LR11. Oxidised LDL showed similar effects compared to carbamylated LDL but caused significantly lower LR11 expression under chronic high shear stress. Medium from HCAEC under LR11-inducing conditions enhanced vascular smooth muscle cell migration, which was abrogated by the anti-LR11 antibody. Expression of LR11 depended entirely on p38MAPK phosphorylation. We conclude that coronary endothelial LR11 expression modulated by LDL and chronic shear stress contributes to atherogenesis. LR11 and p38MAPK are potential targets for prevention of atherosclerosis.
Backbench Opinion in the House of Commons 1945–55 by Hugh Berrington (review)

But it certainly does not permit the drawing of some sort of balance sheet on conflict; nor would Marwick argue that it does. Maybe that is the weakness of his approach: his use of a model suggests that he can provide some answers which he cannot. The odd part of the work is that, having laid out his model, Marwick nearly pushes it aside in his second chapter, dealing with Germany and Russia in the First World War. He acknowledges that this section 'departs furthest from my conceptual framework,' but, considering the consequences of the conflict for these two countries, it is surprising that he did not labour more diligently in applying the history of these two nations to his model. Or, did he find in the fact of revolution as a consequence of war something that could not be managed; that is, when war rolled over into revolution was the attempt at neatness largely frustrated? Another problem of this work, possibly created by its compactness, isits almost antiseptic treatment of the impact of war on the societies involved (which, admittedly, is not necessarily the same as social change). A better, if broken, measure of this impact can be obtained by reading John Williams' The Home Fronts: Britain, France and Germany, •9•4-•9•8 on matters such as the growing food shortages in Germany. The breadth of the subject, as against he physical size of the book, also lead Marwick into the occasional error, as on page 63 when he mistakenly calls the eighteenth amendment to the United States constitution, the fifteenth. Finally, is it fair for Marwick to suggest hat institutions, aside from the military, are tested by war when, in most cases, they were not created for war, but for peace? All this said, the book is informative and the approach is such that it provides a further means of sorting out the very complex social consequences of war. The annotated bibliography is a sound guide to further reading and the note on the use of archive film material is a thoughtful addition.