Miracle-dz/UniFAR-FTUs huggingface dataset:
Inadequate Dissemination of Phase I Trials: A Retrospective Cohort Study

Background Drug development is ideally a logical sequence in which information from small early studies (Phase I) is subsequently used to inform and plan larger, more definitive studies (Phases II–IV). Phase I trials are unique because they generally provide the first evaluation of new drugs in humans. The conduct and dissemination of Phase I trials have not previously been empirically evaluated. Our objective was to describe the initiation, completion, and publication of Phase I trials in comparison with Phase II–IV trials. Methods and Findings We reviewed a cohort of all protocols approved by a sample of ethics committees in France from January 1, 1994 to December 31, 1994. The comparison of 140 Phase I trials with 304 Phase II–IV trials, showed that Phase I studies were more likely to be initiated (133/140 [95%] versus 269/304 [88%]), more likely to be completed (127/133 [95%] versus 218/269 [81%]), and more likely to produce confirmatory results (71/83 [86%] versus 125/175 [71%]) than Phase II–IV trials. Publication was less frequent for Phase I studies (21/127 [17%] versus 93/218 [43%]), even if only accounting for studies providing confirmatory results (18/71 [25%] versus 79/125 [63%]). Conclusions The initiation, completion, and publications of Phase I trials are different from those of other studies. Moreover, the results of these trials should be published in order to ensure the integrity of the overall body of scientific knowledge, and ultimately the safety of future trial participants and patients.
LTP and spatial learning—Where to next?

Hebb suggested, in 1949, that memories could be stored by forming associative connections between neurons if the criterion for increasing the connection strength between them be that they were active simultaneously. Much attention has been devoted towards trying to determine a) if there is a physiological substrate of such a rule, and b) if so, whether the phenomenon participates in real‐life memory formation. The discovery of the electrically induced increase in synaptic strength known as long‐term potentiation (LTP), in the early 1970s, demonstrated that a neural version of the Hebb rule could be observed under laboratory conditions in the hippocampus, a structure important for some types of learning. However, a quarter of a century later, the evidence linking LTP to learning and memory is still contradictory. The purpose of the present article is to review and assess the types of approach that have been taken in trying to determine whether hippocampal synaptic plasticity participates in memory formation. Hippocampus 7:95–110, 1997. © 1997 Wiley‐Liss, Inc.
Mechanism of K+ channel block by verapamil and related compounds in rat alveolar epithelial cells

The mechanism by which the phenylalkylamines, verapamil and D600, and related compounds, block inactivating delayed rectifier K+ currents in rat alveolar epithelial cells, was investigated using whole-cell tight- seal recording. Block by phenylalkylamines added to the bath resembles state-dependent block of squid K+ channels by internally applied quarternary ammonium ions (Armstrong, C.M. 1971. Journal of General Physiology. 58:413-437): open channels are blocked preferentially, increased [K+]o accelerates recovery from block, and recovery occurs mainly through the open state. Slow recovery from block is attributed to the existence of a blocked-inactivated state, because recovery was faster in three situations where recovery from inactivation is faster: (a) at high [K+]o, (b) at more negative potentials, and (c) in cells with type l K+ channels, which recover rapidly from inactivation. The block rate was used as a bioassay to reveal the effective concentration of drug at the block site. When external pH, pHo, was varied, block was much faster at pHo 10 than pHo 7.4, and very slow at pHo 4.5. The block rate was directly proportional to the concentration of neutral drug in the bath, suggesting that externally applied drug must enter the membrane in neutral form to reach the block site. High internal pH (pHi 10) reduced the apparent potency of externally applied phenylalkylamines, suggesting that the cationic form of these drugs blocks K+ channels at an internal site. The permanently charged analogue D890 blocked more potently when added to the pipette than to the bath. However, lowering pHi to 5.5 did not enhance block by external drug, and tertiary phenylalkylamines added to the pipette solution blocked weakly. This result can be explained if drug diffuses out of the cell faster than it is delivered from the pipette, the block site is reached preferentially via hydrophobic pathways, or both. Together, the data indicate the neutral membrane-bound drug blocks K+ channels more potently than intracellular cationic drug. Neutral drug has rapid access to the receptor, where block is stabilized by protonation of the drug from the internal solution. In summary, externally applied phenylalkylamines block open or inactivated K+ channels by partitioning into the cell membrane in neutral form and are stabilized at the block site by protonation.
Childhood onset schizophrenia: cortical brain abnormalities as young adults.

BACKGROUND Childhood onset schizophrenia (COS) is a rare but severe form of the adult onset disorder. While structural brain imaging studies show robust, widespread, and progressive gray matter loss in COS during adolescence, there have been no longitudinal studies of sufficient duration to examine comparability with the more common adult onset illness. METHODS Neuro-anatomic magnetic resonance scans were obtained prospectively from ages 7 through 26 in 70 children diagnosed with COS and age and sex matched healthy controls. Cortical thickness was measured at 40,962 points across the cerebral hemispheres using a novel, fully automated, validated method. Patterns of patient-control differences in cortical development were compared over a 19-year period. RESULTS Throughout the age range, the COS group had significantly smaller mean cortical thickness compared to controls. However, the COS brain developmental trajectory appeared to normalize in posterior (parietal) regions, and remained divergent in the anterior regions (frontal and temporal) regions, and the pattern of loss became more like that seen in adults. CONCLUSIONS Cortical thickness loss in COS appears to localize with age to prefrontal and temporal regions that are seen for both medication naïve and medicated adult onset patients.
Percutaneous tracheostomy by guidewire dilating forceps technique: is bronchoscopic guidance mandatory?

BACKGROUND AND OBJECTIVE Percutaneous tracheostomy is a blind technique where-in bronchoscopy is advocated but is rarely practiced. Our study is aimed at evaluating the potential safety of this procedure when performed without bronchoscopic guidance. METHODS This is a retrospective analysis of seventy-eight patients who underwent percutaneous tracheostomy using the Guide Wire Dilating Forceps method for prolonged periods of ventilation and/or for bronchial toileting for various underlying diseases. The procedure time and various complications were noted and compared with the historical controls from the literature. RESULTS The mean duration of the procedure was 3.09 +/- 0.49 minutes with a range of 1.5 to 14 minutes in comparison to 8.9 minutes with a range of 2 to 33 minutes as in literature where-in bronchoscopy was used. No major perioperative complications were encountered. Two patients (2.6%) had persistent peristomal oozing as an early complication when compared to that in the literature (12.5%) (p < 0.05). Twenty-seven patients were decannulated, with good tissue approximation (mean: 3.51 days). CONCLUSIONS In the absence of bronchoscopic guidance, percutaneous tracheostomy can be performed safely and speedily if simple precautions like ensuring free aspiration of air on needle insertion into trachea, bubbling of fluid placed over the hub of the cannula during ventilation and free mobility of guide wire at each step of the procedure were observed to secure the right positioning of the tracheostomy tube.
Deposition of inhaled particles in the mouth and throat of asthmatic subjects.

We previously studied the deposition of inhaled particles in the mouth and throat of asthmatic patients, and found large, reproducible differences among subjects. In the present study, we examined whether anatomical and/or functional differences in the pharynx and larynx could underlie this interindividual variation. Deposition in the mouth and throat, and in the lung was estimated in 16 asthmatic subjects after inhalation of 3.6 microns (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. The particles were inhaled at a flow rate of 0.5 l.s-1 with maximally deep breaths. Radioactivity was measured by external scanning over head and neck, lungs and stomach, immediately after the inhalation. Radioactivity in the lungs was also measured 24 h later. A measure of the total amount of particles deposited in the mouth and throat was obtained from the added activities in mouthwash, head and neck, and stomach, immediately after the inhalation of the test particles. Pharynx and larynx function was examined by fibreoptic laryngoscopy performed during a corresponding inhalation procedure. Deposition in the mouth and throat varied widely among the subjects, ranging 9-76% (median 12%). We found two subpopulations, 13 subjects in the range 9-34%, and 3 subjects with > 70% deposition. Deviations in pharyngeal configuration during inhalation were significantly related to high mouth and throat deposition, whereas functional differences in the larynx were not. Our study shows that mouth and throat deposition may be extremely high in some asthmatics, and that pharyngeal configuration affects deposition of particles in the mouth and throat.
Reactive Balance Control in Response to Perturbation in Unilateral Stance: Interaction Effects of Direction, Displacement and Velocity on Compensatory Neuromuscular and Kinematic Responses

Unexpected sudden perturbations challenge postural equilibrium and require reactive compensation. This study aimed to assess interaction effects of the direction, displacement and velocity of perturbations on electromyographic (EMG) activity, centre of pressure (COP) displacement and joint kinematics to detect neuromuscular characteristics (phasic and segmental) and kinematic strategies of compensatory reactions in an unilateral balance paradigm. In 20 subjects, COP displacement and velocity, ankle, knee and hip joint excursions and EMG during short (SLR), medium (MLR) and long latency response (LLR) of four shank and five thigh muscles were analysed during random surface translations varying in direction (anterior-posterior (sagittal plane), medial-lateral (frontal plane)), displacement (2 vs. 3cm) and velocity (0.11 vs. 0.18m/s) of perturbation when balancing on one leg on a movable platform. Phases: SLR and MLR were scaled to increased velocity (P<0.05); LLR was scaled to increased displacement (P<0.05). Segments: phasic interrelationships were accompanied by segmental distinctions: distal muscles were used for fast compensation in SLR (P<0.05) and proximal muscles to stabilise in LLR (P<0.05). Kinematics: ankle joints compensated for both increasing displacement and velocity in all directions (P<0.05), whereas knee joint deflections were particularly sensitive to increasing displacement in the sagittal (P<0.05) and hip joint deflections to increasing velocity in the frontal plane (P<0.05). COP measures increased with increasing perturbation velocity and displacement (P<0.05). Interaction effects indicate that compensatory responses are based on complex processes, including different postural strategies characterised by phasic and segmental specifications, precisely adjusted to the type of balance disturbance. To regain balance after surface translation, muscles of the distal segment govern the quick regain of equilibrium; the muscles of the proximal limb serve as delayed stabilisers after a balance disturbance. Further, a kinematic distinction regarding the compensation for balance disturbance indicated different plane- and segment-specific sensitivities with respect to the determinants displacement and velocity.
Angiographic Dilatation and Branch Extension of the Anterior Choroidal and Posterior Communicating Arteries Are Predictors of Hemorrhage in Adult Moyamoya Patients

Background and Purpose— The cause of intracranial bleeding in moyamoya disease patients is still unknown. To identify factors that contribute to bleeding, we assessed the angiographic findings of moyamoya disease patients. Methods— We examined angiograms obtained from 107 moyamoya patients; 70 manifested ischemic and 37 had hemorrhagic lesions. Patients with intracerebral aneurysms or both hemorrhagic and ischemic lesions in the same cerebral hemisphere were not included. Patients were divided into those <20 years of age (n=47) and those ≥20 years of age (n=60). The right and left hemispheres in each patient were individually classified as hemorrhagic, ischemic, or asymptomatic. Each hemisphere was assessed for dilatation and branch extension of the anterior choroidal artery (AChA) and posterior communicating artery (P-CoM) and for the degree of proliferation of basal moyamoya vessels. These data were then statistically analyzed for correlation with intracranial bleeding events. Results— The degree of proliferation of basal moyamoya vessels was not statistically correlated with hemorrhagic events. On the other hand, there was a correlation between hemorrhage and dilatation and abnormal branching of the AChA. In 27 of 37 hemorrhagic hemispheres (73.0%), this artery was dilated, and its abnormal branches served as collateral supply vessels to other regions. This phenomenon was observed in 4 of 5 hemorrhagic hemispheres from young patients; it was noted in fewer than one third of ischemic and asymptomatic hemispheres from this age group. Similarly, 71.9% of hemorrhagic hemispheres from adult patients manifested AChA dilatation and branching, and the difference between hemorrhagic hemispheres and those that were ischemic or asymptomatic was statistically significant (P <0.01). Although the incidence of dilatation and abnormal branching of the P-CoM was relatively low in hemorrhagic hemispheres from adult patients (18.8%), it was significantly higher than in the ischemic and asymptomatic hemispheres from this age group. Using dilatation and abnormal branching of the AChA and/or P-CoM as assessment criteria, we obtained high specificity (86.4%) and sensitivity (84.4%) for hemorrhagic events in adult moyamoya patients. Conclusions— In adult moyamoya patients, dilatation and abnormal branching of the AChA and/or P-CoM are strong predictors of hemorrhagic events.
Diversity in Robustness of Lactococcus lactis Strains during Heat Stress, Oxidative Stress, and Spray Drying Stress

ABSTRACT In this study we tested 39 Lactococcus lactis strains isolated from diverse habitats for their robustness under heat and oxidative stress, demonstrating high diversity in survival (up to 4 log units). Strains with an L. lactis subsp. lactis phenotype generally displayed more-robust phenotypes than strains with an L. lactis subsp. cremoris phenotype, whereas the habitat from which the strains had been isolated did not appear to influence stress survival. Comparison of the stress survival phenotypes with already available comparative genomic data sets revealed that the absence or presence of specific genes, including genes encoding a GntR family transcriptional regulator, a manganese ABC transporter permease, a cellobiose phosphotransferase system (PTS) component, the FtsY protein, and hypothetical proteins, was associated with heat or oxidative stress survival. Finally, 14 selected strains also displayed diversity in survival after spray drying, ranging from 20% survival for the most robust strains, which appears acceptable for industrial application, to 0.1% survival for the least-tolerant strains. The high and low levels of survival upon spray drying correlated clearly with the combined robustness under heat and oxidative stress. These results demonstrate the relevance of screening culture collections for robustness under heat and oxidative stress on top of the typical screening for acidifying and flavor-forming properties.
Proteomic analysis of effects by x-rays and heavy ion in HeLa cells

Abstract Background. Carbon ion therapy may be better against cancer than the effects of a photon beam. To investigate a biological advantage of carbon ion beam over X-rays, the radioresistant cell line HeLa cells were used. Radiationinduced changes in the biological processes were investigated post-irradiation at 1 h by a clinically relevant radiation dose (2 Gy X-ray and 2 Gy carbon beam). The differential expression proteins were collected for analysing biological effects. Materials and methods. The radioresistant cell line Hela cells were used. In our study, the stable isotope labelling with amino acids (SILAC) method coupled with 2D-LC-LTQ Orbitrap mass spectrometry was applied to identity and quantify the differentially expressed proteins after irradiation. The Western blotting experiment was used to validate the data. Results. A total of 123 and 155 significantly changed proteins were evaluated with treatment of 2 Gy carbon and X-rays after radiation 1 h, respectively. These deregulated proteins were found to be mainly involved in several kinds of metabolism processes through Gene Ontology (GO) enrichment analysis. The two groups perform different response to different types of irradiation. Conclusions. The radioresistance of the cancer cells treated with 2 Gy X-rays irradiation may be largely due to glycolysis enhancement, while the greater killing effect of 2 Gy carbon may be due to unchanged glycolysis and decreased amino acid metabolism.
RNase L Mediates the Antiviral Effect of Interferon through a Selective Reduction in Viral RNA during Encephalomyocarditis Virus Infection

ABSTRACT The 2′,5′-oligoadenylate (2-5A) system is an RNA degradation pathway which plays an important role in the antipicornavirus effects of interferon (IFN). RNase L, the terminal component of the 2-5A system, is thought to mediate this antiviral activity through the degradation of viral RNA; however, the capacity of RNase L to selectively target viral RNA has not been carefully examined in intact cells. Therefore, the mechanism of RNase L-mediated antiviral activity was investigated following encephalomyocarditis virus (EMCV) infection of cell lines in which expression of transfected RNase L was induced or endogenous RNase L activity was inhibited. RNase L induction markedly enhanced the anti-EMCV activity of IFN via a reduction in EMCV RNA. Inhibition of endogenous RNase L activity inhibited this reduction in viral RNA. RNase L had no effect on IFN-mediated protection from vesicular stomatitis virus. RNase L induction reduced the rate of EMCV RNA synthesis, suggesting that RNase L may target viral RNAs involved in replication early in the virus life cycle. The RNase L-mediated reduction in viral RNA occurred in the absence of detectable effects on specific cellular mRNAs and without any global alteration in the cellular RNA profile. Extensive rRNA cleavage, indicative of high levels of 2-5A, was not observed in RNase L-induced, EMCV-infected cells; however, transfection of 2-5A into cells resulted in widespread degradation of cellular RNAs. These findings provide the first demonstration of the selective capacity of RNase L in intact cells and link this selective activity to cellular levels of 2-5A.
Threshold voltage distribution in MLC NAND flash memory: Characterization, analysis, and modeling

With continued scaling of NAND flash memory process technology and multiple bits programmed per cell, NAND flash reliability and endurance are degrading. Understanding, characterizing, and modeling the distribution of the threshold voltages across different cells in a modern multi-level cell (MLC) flash memory can enable the design of more effective and efficient error correction mechanisms to combat this degradation. We show the first published experimental measurement-based characterization of the threshold voltage distribution of flash memory. To accomplish this, we develop a testing infrastructure that uses the read retry feature present in some 2Y-nm (i.e., 20–24nm) flash chips. We devise a model of the threshold voltage distributions taking into account program/erase (P/E) cycle effects, analyze the noise in the distributions, and evaluate the accuracy of our model. A key result is that the threshold voltage distribution can be modeled, with more than 95% accuracy, as a Gaussian distribution with additive white noise, which shifts to the right and widens as P/E cycles increase. The novel characterization and models provided in this paper can enable the design of more effective error tolerance mechanisms for future flash memories.
International Capital Flows and Aggregate Output

We show in a tractable, multi-country OLG model that cross-country differences in financial development explain three recent empirical patterns of international capital flows. International capital mobility affects output in each country directly through the size of domestic investment as well as indirectly through the composition of domestic investment and the level of domestic savings. In contrast to earlier literature, our model admits the possibility that the indirect effects dominate the direct effects and international capital mobility raises output in the poor country and globally, although net capital flows are in the direction of the rich country. Our model adds to the understanding of the benefits of international capital mobility in the presence of financial frictions.
Association of hypercapnia on admission with increased length of hospital stay and severity in patients admitted with community-acquired pneumonia: a prospective observational study from Pakistan

Objective To determine whether the presence of hypercapnia on admission in adult patients admitted to a university-based hospital in Karachi, Pakistan with community-acquired pneumonia (CAP) correlates with an increased length of hospital stay and severity compared with no hypercapnia on admission. Study design A prospective observational study. Settings Tertiary care hospital in Karachi, Pakistan. Methods Patients who met the inclusion criteria were enrolled in the study. The severity of pneumonia was assessed by CURB-65 and PSI scores. An arterial blood gas analysis was obtained within 24 hours of admission. Based on arterial PaCO2 levels, patients were divided into three groups: hypocapnic (PaCO2 <35 mm Hg), hypercapnic (PaCO2 >45 mm Hg) and normocapnic (PaCO2 <35–45 mm Hg). Outcomes The primary outcome was the association of hypercapnia on admission with mean length of hospital stay. Secondary outcomes were the need for mechanical ventilation, ICU admission and in-hospital mortality. Results A total of 295 patients of mean age 60.20±17.0 years (157 (53.22%) men) were enrolled over a 1-year period. Hypocapnia was found in 181 (61.35%) and hypercapnia in 57 (19.32%) patients. Hypercapnic patients had a longer hospital stay (mean 9.27±7.57 days), increased requirement for non-invasive mechanical ventilation (NIMV) on admission (n=45 (78.94%)) and longer mean time to clinical stability (4.39±2.0 days) compared with the other groups. Overall mortality was 41 (13.89%), but there was no statistically significant difference in mortality (p=0.35) and ICU admission (p=0.37) between the three groups. On multivariable analysis, increased length of hospital stay was associated with NIMV use, ICU admission, hypercapnia and normocapnia. Conclusion Hypercapnia on admission is associated with severity of CAP, longer time to clinical stability, increased length of hospital stay and need for NIMV. It should be considered as an important criterion to label the severity of the illness and also a determinant of patients who will require a higher level of hospital care. However, further validation is required.