Miracle-dz/UniFAR-FTUs huggingface dataset:
Placebo Effects in a Multiple Sclerosis Spasticity Enriched Clinical Trial with the Oromucosal Cannabinoid Spray (THC/CBD): Dimension and Possible Causes

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long‐term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash‐out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ9‐tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo‐allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27‐point improvement on the spasticity 0–10 Numerical Rating Scale (NRS; ~−20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid‐based medications are being investigated.
Minimally invasive surgery for achalasia: an 8-year experience with 168 patients.

BACKGROUND Seven years ago, the authors reported on the feasibility and short-term results of minimally invasive surgical methods to treat esophageal achalasia. In this report, they describe the evolution of the surgical technique and the clinical results in a large group of patients with long follow-up. PATIENTS AND METHODS Between January 1991 and October 1998, 168 patients (96 men, 72 women; mean age 45 years, median duration of symptoms 48 months), who fulfilled the clinical, radiographic, endoscopic, and manometric criteria for a diagnosis of achalasia, underwent esophagomyotomy by minimally invasive techniques. Forty-eight patients had marked esophageal dilatation (diameter >6.0 cm). Thirty-five patients had a left thoracoscopic myotomy, and 133 patients had a laparoscopic myotomy plus a partial fundoplication. Follow-up to October 1998 was complete in 145 patients (86%). RESULTS Median hospital stay was 72 hours for the thoracoscopic group and 48 hours for the laparoscopic group. Eight patients required a second operation for recurrent or persistent dysphagia, and two patients required an esophagectomy. There were no deaths. Good or excellent relief of dysphagia was obtained in 90% of patients (85% after thoracoscopic and 93% after laparoscopic myotomy). Gastroesophageal reflux developed in 60% of tested patients after thoracoscopic myotomy and in 17% after laparoscopic myotomy plus fundoplication. Laparoscopic myotomy plus fundoplication corrected reflux present before surgery in five of seven patients. Patients with a dilated esophagus had excellent relief of dysphagia after laparoscopic myotomy; none required an esophagectomy. CONCLUSIONS Minimally invasive techniques provided effective and long-lasting relief of dysphagia in patients with achalasia. The authors prefer the laparoscopic approach for three reasons: it more effectively relieved dysphagia, it was associated with a shorter hospital stay, and it was associated with less postoperative reflux. Laparoscopic Heller myotomy and partial fundoplication should be considered the primary treatment for esophageal achalasia.
Expert System for Power Quality Disturbance Classifier

Identification and classification of voltage and current disturbances in power systems are important tasks in the monitoring and protection of power system. Most power quality disturbances are non-stationary and transitory and the detection and classification have proved to be very demanding. The concept of discrete wavelet transform for feature extraction of power disturbance signal combined with artificial neural network and fuzzy logic incorporated as a powerful tool for detecting and classifying power quality problems. This paper employes a different type of univariate randomly optimized neural network combined with discrete wavelet transform and fuzzy logic to have a better power quality disturbance classification accuracy. The disturbances of interest include sag, swell, transient, fluctuation, and interruption. The system is modeled using VHSIC hardware description language (VHDL), a hardware description language, followed by extensive testing and simulation to verify the functionality of the system that allows efficient hardware implementation of the same. This proposed method classifies, and achieves 98.19% classification accuracy for the application of this system on software-generated signals and utility sampled disturbance events.
Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long‐term potentiation in the adult mouse CNS

The NMDA‐type glutamate receptor is a heteromeric complex composed of the NR1 and at least one of the NR2 subunits. Switching from the NR2B to the NR2A subunit is thought to underlie functional alteration of the NMDA receptor during synaptic maturation, and it is generally believed that it results in preferential localization of NR2A subunits on the synaptic site and that of NR2B subunits on the extracellular site in the mature brain. It has also been proposed that activation of the NR2A and NR2B subunits results in long‐term potentiation (LTP) and long‐term depression (LTD), respectively. Furthermore, recent reports suggest that synaptic and extrasynaptic receptors may have distinct roles in synaptic plasticity as well as in gene expression associated with neuronal death. Here, we have investigated whether NR2B subunit‐containing receptors are present and functional at mature synapses in the lateral nucleus of the amygdala (LA) and the CA1 region of the hippocampus, comparing their properties between the two brain regions. We have found, in contrast to the above hypotheses, that the NR2B subunit significantly contributes to synaptic transmission as well as LTP induction. Furthermore, its contribution is greater in the LA than in the CA1 region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit‐containing NMDA receptors accumulate on the synaptic site and are responsible for the unique properties of synaptic function and plasticity in the amygdala.
The Role of Stakeholders in the Context of Responsible Innovation: A Meta-Synthesis

This paper contributes to the sustainability debate by analyzing the inclusion dimension in the responsible research and innovation (RRI) process. RRI is claimed to be an important tool for addressing global challenges and achieving sustainable development goals. While stakeholder involvement is considered to be imperative for the RRI process, there is little empirical evidence on (1) who the stakeholders participating in the RRI process are; (2) when stakeholders participate; (3) how stakeholders’ inclusion contributes to the sustainable innovation process; and (4) who the agents are who orchestrate stakeholders’ inclusion. This paper addresses the issue of stakeholder involvement through the lens of innovation management literature by attempting to link the innovation process to the responsibility concept. We employed a meta-synthesis of empirical studies of RRI to develop a deep understanding of stakeholder inclusion. After screening 139 articles, we identified seven empirical papers highlighting RRI process, mainly from projects nested in academic contexts. The findings indicate that multiple stakeholders are included at a late stage of the innovation process—during the market launch. To some extent, this allows for the adaptation of the solution, but such adaptations are limited in nature. This study also identifies the agents who stimulate stakeholder inclusion as being mainly academic researchers and researchers linked to multi-institutional projects. Our findings indicate that innovation management thinking is rarely applied in the governance of research and innovation projects ‘born’ in academia. We suggest enhancing RRI theoretical development by incorporating elements of innovation management such as early inclusion of users in the innovation process. For practitioners, this means an extension of the design space to allow early stakeholder inclusion in the innovation process to ensure responsible outcomes. We also identified avenues for future research. There is a need to systematically investigate which tools and frameworks for deliberate stakeholder inclusion are relevant at the various stages of the innovation and development process.
Distribution of astroglia in glomeruli of the rat main olfactory bulb: Exclusion from the sensory subcompartment of neuropil

During an entire lifetime, sensory axons of regenerating olfactory receptor neurons can enter glomeruli in the olfactory bulb and establish synaptic junctions with central neurons. The role played by astrocytes in this unique permissiveness is still unclear. Glomerular astrocytes have been identified by immunocytochemistry for glial fibrillary acidic protein and S100 proteins at the light and electron microscopic levels. The latter labeling included submicroscopic lamellar and filopodial extensions of astroglial processes. Cell bodies and processes accumulate along the border between juxtaglomerular walls and glomerular neuropil. Within glomeruli, a network of astroglial processes encloses mesh‐like neuropil zones devoid of astroglia. Electron microscopy confirmed the division into subcompartments of glomerular neuropil: 1) The “sensory‐synaptic subcompartment” includes all sensory axon terminals and terminal dendritic branches receiving sensory input, whereas astroglia are excluded; 2) in the “central‐synaptic subcompartment,” astroglial processes are intermingled with other neuropil components: dendrites of relay cells and interneurons, dendrodendritic synapses, centrifugal (cholinergic and serotonergic) axons, their axodendritic synapses, and blood vessels. Unevenly distributed astroglial processes in this subcompartment are attached to vascular basal laminae, stem dendrites, and subpopulations of dendrodendritic synapses, especially those colocalized with centrifugal projections (“triadic synapses”). Astroglia‐free parts of the “central” subcompartment contain segments of dendrites and subpopulations of dendrodendritic synapses. Because of the subdivision of the glomerular neuropil into portions with and without glial components, glia do not completely demarcate the border between the “sensory” and the “central” subcompartments. Interdigitation between the subcompartments varies among glomeruli and even within a single glomerulus. The mesh width of astroglial networks covaries with numerical relations between sensory and dendrodendritic synapses. This distribution pattern of astrocytes suggests that these glial cells monitor brain‐derived effects on olfactory glomerular neuropil rather than olfactory input and that astroglial processes are (re‐)arranged accordingly. J. Comp. Neurol. 388:191–210, 1997. © 1997 Wiley‐Liss, Inc.
Age-related changes in cardiac and respiratory adaptation to acute ozone and carbon black exposures: Interstrain variation in mice

Context: Epidemiological studies show positive associations between increased ambient air pollutant levels and adverse cardiopulmonary effects. These studies suggest that the elderly and those with certain genetic polymorphisms are susceptible to adverse air pollution-associated health events. Hypothesis/objective: We hypothesize that physiological responses to air pollutants vary with age and are genetically influenced. Materials and methods: To test this hypothesis, we exposed mice from three inbred strains (C57BL/6J, B6; C3H/HeJ, HeJ; C3H/HeOuJ, OuJ) to ozone (O3) and carbon black (CB) at two ages, (5 months, 12 months), for 3 consecutive days, to either filtered air (FA), CB particles, or O3 and CB sequentially (O3CB) (CB, 550 µg/m3; O3, 600 ppb). Heart rate (HR), HR variability (HRV), breathing, and core temperature (Tco) responses were analyzed. Results: We observed time-dependent physiological changes in response to O3CB exposure in each strain, relative to FA exposure for both age groups. Each mouse strain showed distinct adaptation profiles to repeated acute exposures to O3. In younger mice, several time-dependent effects (decreased HR and increased HRV) were prominent in HeJ and OuJ mice but not B6 mice. We also observed variability in adaptation in older mice. However, responses in older mice were generally attenuated when compared to the younger mice. In addition, cardiac–respiratory interactions were affected with CB and O3CB exposures albeit with patterns differing by age or exposure. Discussion/conclusion: Our results suggest that age considerably attenuates physiological responses to O3 and O3CB exposures. Age-related physiological changes such as increased oxidative stress in mouse tissue may be involved in this attenuation.
Inequality, Bipolarization, and Tax Progressivity

The steady rise in income and wealth inequality in the last four decades, together with the evolution of a vanishing middle class, has raised concerns about potentially pernicious effects of these trends on social stability and economic growth. This paper evaluates the possibility of designing tax systems aimed at reducing income inequality and bipolarization. Using two fundamentally different metrics, we provide a unified foundation of tax progressivity whereby, roughly, taxes are progressive if and only if they are inequality reducing; and taxes are inequality reducing if and only if they are bipolarization reducing. (JEL D31, H22, H24)
Dissent, sabotage, and leader behaviour in contests: Evidence from European football

This paper provides an empirical investigation of misconducts in contests based on data from European football. We extend previous studies by differentiating between dissents with the referee and misconducts directly aimed at sabotaging the competitor. We find that sabotage is more likely committed by teams with lower ability. Dissent is more likely to be shown by teams lagging behind in score and by away teams. We further find that captains engage more in sabotage during important matches and challenge referees' decisions immediately after sanctions of teammates. Finally, we also observe a deterrence effect of sanctions on all types of misconduct.
Outcomes of Total Knee Arthroplasty in Relation to Preoperative Patient-Reported and Radiographic Measures

Introduction: Total knee arthroplasty (TKA) is the preferred surgical treatment for end-stage osteoarthritis. However, substantial numbers of patients still experience poor outcomes. Consequently, it is important to identify which patient characteristics are predictive of outcomes in order to guide clinical decisions. Our hypothesis is that preoperative patient-reported outcome measures and radiographic measures may help to predict TKA outcomes. Methods: Using cohort data from the Osteoarthritis Initiative, we studied 172 patients who underwent TKA. For each patient, we compiled pre- and postoperative Western Ontario and McMaster University Arthritis Index (WOMAC) scores. Radiographs were measured for knee joint angles, femorotibial angles, anatomical lateral distal femoral angles, and anatomical medial proximal tibial angles; Kellgren and Lawrence (KL) grades were assigned to each compartment of the knee. All studied measurements were compared to WOMAC outcomes. Results: Preoperative WOMAC disability, pain, and total scores were positively associated with postoperative WOMAC total scores (P = .010, P = .010, and P = .009, respectively) and were associated with improvement in WOMAC total scores (P < .001, P < .001, and P < .001, respectively). For radiographic measurements, preoperative joint angles were positively associated with improvements in postoperative WOMAC total scores (P = .044). Combined KL grades (medial and lateral compartments) were negatively correlated with postoperative WOMAC disability and pain scores (P = .045 and P = .044) and were positively correlated with improvements in WOMAC total scores (P = .001). Conclusions: All preoperative WOMAC scores demonstrated positive associations with postoperative WOMAC scores, while among the preoperative radiographic measurements only combined KL grades and joint angles showed any correlation with postoperative WOMAC scores. Higher preoperative KL grades and joint angles were associated with better (lower) postoperative WOMAC scores, demonstrating an inverse correlation.
Recovery of Sensorimotor Function after Experimental Stroke Correlates with Restoration of Resting-State Interhemispheric Functional Connectivity

Despite the success of functional imaging to map changes in brain activation patterns after stroke, spatiotemporal dynamics of cerebral reorganization in correlation with behavioral recovery remain incompletely characterized. Here, we applied resting-state functional magnetic resonance imaging (rs-fMRI) together with behavioral testing to longitudinally assess functional connectivity within neuronal networks, in relation to changes in associated function after unilateral stroke in rats. Our specific goals were (1) to identify temporal alterations in functional connectivity within the bilateral cortical sensorimotor system and (2) to elucidate the relationship between those alterations and changes in sensorimotor function. Our study revealed considerable loss of functional connectivity between ipsilesional and contralesional primary sensorimotor cortex regions, alongside significant sensorimotor function deficits in the first days after stroke. The interhemispheric functional connectivity restored in the following weeks, but remained significantly reduced up to 10 weeks after stroke in animals with lesions that comprised subcortical and cortical tissue, whereas transcallosal neuroanatomical connections were preserved. Intrahemispheric functional connectivity between primary somatosensory and motor cortex areas was preserved in the lesion border zone and moderately enhanced contralesionally. The temporal pattern of changes in functional connectivity between bilateral primary motor and somatosensory cortices correlated significantly with the evolution of sensorimotor function scores. Our study (1) demonstrates that poststroke loss and recovery of sensorimotor function is associated with acute deterioration and subsequent retrieval of interhemispheric functional connectivity within the sensorimotor system and (2) underscores the potential of rs-fMRI to assess spatiotemporal characteristics of functional brain reorganization that may underlie behavioral recovery after brain injury.
DSM-IV intermittent explosive disorder: a report of 27 cases.

BACKGROUND The authors' objective was to provide data regarding the demographic, phenomenological, course of illness, associated psychiatric and medical comorbidity, family history, and psychiatric treatment response characteristics of rigorously diagnosed subjects who met DSM-IV criteria for intermittent explosive disorder. METHOD Twenty-seven subjects meeting DSM-IV criteria for a current or past history of intermittent explosive disorder were given structured diagnostic interviews. The subjects' medical histories, family histories of psychiatric disorders, and responses to psychiatric treatments were also assessed. RESULTS Most subjects described their intermittent explosive disorder symptoms as very distressing and/or highly problematic. All 27 subjects described aggressive impulses prior to their aggressive acts. Of 24 subjects who were systematically queried, 21 (88%) experienced tension with the impulses; 18 (75%), relief with the aggressive acts; and 11 (48%), pleasure with the acts. Most subjects stated that their aggressive impulses and acts were also associated with affective symptoms, particularly changes in mood and energy level. Twenty-five (93%) subjects had lifetime DSM-IV diagnoses of mood disorders; 13 (48%), substance use disorders; 13 (48%), anxiety disorders; 6 (22%), eating disorders; and 12 (44%), an impulse-control disorder other than intermittent explosive disorder. Subjects also displayed high rates of comorbid migraine headaches. First-degree relatives displayed high rates of mood, substance use, and impulse-control disorders. Twelve (60%) of 20 subjects receiving monotherapy with an antidepressant or a mood stabilizer reported moderate or marked reduction of their aggressive impulses and/or episodes. CONCLUSION Intermittent explosive disorder appears to be a bona fide impulse-control disorder that may be related to mood disorder and may represent another form of affective spectrum disorder.
Immune Response Induced by an Immunodominant 60 kDa Glycoprotein of the Cell Wall of Sporothrix schenckii in Two Mice Strains with Experimental Sporotrichosis

Cell wall (CW) components of fungus Sporothrix schenckii are the major inductors antigens of immune responses. The immunodominant 60 kDa glycoprotein (gp60) has been shown to be associated with the virulence of this fungus but its role in experimental sporotrichosis is unknown. In this work, the immunological effects of CW-purified gp60 were investigated in a model of experimental subcutaneous sporotrichosis in normal and gp60-preimmunized C57BL/6 and BALB/c mice strains which were then infected with S. schenckii conidia. Results showed that both mice strains use different cytokine profiles in order to fight S. schenckii infection; C57BL/6 mice seem to use a Th17 response while BALB/c mice tend to depend on a Th1 profile. Preimmunization with gp60 showed a downregulatory effect on the immune response since cytokines levels were diminished in both strains. There were no significant differences in the magnitude of dorsoplantar inflammation between gp60-preimmunized and nonimmunized mice of both strains. However, skin lesions due to the infection in gp60-preimmunized mice were more severe in BALB/c than in C57BL/6 mice, suggesting that the antigen exerts a higher downregulatory effect on the Th1 response.
Catalytic efficiency of human alcohol dehydrogenases for retinol oxidation and retinal reduction.

Mammalian alcohol dehydrogenase (ADH) is thought to be involved in the reversible oxidation of vitamin A or retinol to retinal for retinoic acid synthesis. Retinoic acid is a potent transcriptional regulator and a morphogen. It was proposed that the competition of consumed ethanol with retinol oxidation by ADH might explain developmental disorders seen with fetal alcohol syndrome. We report herein the relative efficiency (V/Km) of eight human ADH isoenzymes for oxidation of all-trans-retinol and reduction of three retinal isomers (all-trans, 9-cis, and 13-cis-retinal). Class IV sigma sigma and class II pi pi isoenzymes are the most efficient forms, with V/Km values approximately 100 and 30 times greater, respectively, than class I beta 1 beta 1 or gamma 1 gamma 1, sigma sigma exhibits the highest V/Km (1-2 microns-1min-1), followed by pi pi, with V/Km of 0.5-0.6 microns-1min-1 for all-trans-retinol, all-trans-retinal, and 9-cis-retinal. pi pi also has the lowest Km (11-14 microns) for all-trans-retinol and three retinal isomers. alpha alpha shows an intermediate efficiency, with V/Km of 0.09-0.2 microns-1min-1 and a relatively low Km of 16-24 microns for all four substrates. alpha alpha has the highest efficiency of all tested isoenzymes for 13-cis-retinal. Class III chi chi is inactive with all the tested retinoids. (ABSTRACT TRUNCATED AT 250 WORDS)