Miracle-dz/UniFAR-FTUs huggingface dataset:
Population‐Based Assessments of Clinical Drug‐Drug Interactions: Qualitative Indices or Quantitative Measures?

Population‐based assessments of drug‐drug interactions have become more common since the introduction and acceptance of the population pharmacokinetic approach. Unlike traditional methods, population‐based studies provide clinically relevant results that can be applied directly to a target patient population. Furthermore, population‐based studies do not demand the traditional requirements of intensive pharmacokinetic sampling, rigorous inpatient stays, or stringent assessment schedules. As such, the population‐based approach can effectively be used to confirm known drug‐drug interactions and further characterize anticipated interactions. A prospectively designed analysis can also reveal drug‐drug interactions that might otherwise have gone undetected with traditional methods. Ultimately, these results could help to alleviate clinicians' concerns about using widely marketed drugs in combination therapies and also reduce patients' risk of experiencing unacceptable side effects. This article intends to provide a balanced overview of the population‐based approach and its merits, drawbacks, and potential utility in the assessment of drug‐drug interactions during clinical drug development.
Duplication of 9 base pairs in the critical cysteine‐rich domain of the RET proto‐oncogene causes multiple endocrine neoplasia type 2A

Activating germline mutations in the cysteine-rich domain of the RET proto-oncogene cause endocrine neoplasia type 2A, an autosomal dominant inherited cancer syndrome affecting cells derived from the neural crest, including medullary thyraid carcinoma (MTC) , pheochromocytoma (pheo), and parathyroid hyperplasia (primary hyperparathyroidism pHpt) (
Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan1

The incidence of cardiovascular diseases in premenopausal women is lower than in men or postmenopausal women. This study reports the discovery of a low grade of systemic inflammation, including monocyte adhesion to arterial endothelium, elicited by menopause or estrogen depletion. Chronic treatment with low dose of 17-β-estradiol or inhibition of the renin-angiotensin system reduced this inflammation. Using an in vitro flow chamber system with human arterial and venous endothelial cells, we found that leukocytes from healthy postmenopausal women were more adhesive to the arterial endothelium than those from premenopausal women regardless of the stimulus used on endothelial cells. Increased circulating levels of IL-8, MCP-1, RANTES, and MIP-1α and monocyte CD11b expression were also encountered in postmenopausal vs premenopausal subjects. This translational data led us to investigate the mechanisms in Sprague-Dawley rats. Using intravital microscopy, we imaged mesenteric arterioles and found significant increases in arteriolar leukocyte adhesion, cell adhesion molecule expression, and plasma levels of cytokine-induced neutrophil chemoattractant (CINC/KC), MCP-1, and MIP-1α in 1-mo ovariectomized rats. Chronic treatment of ovariectomized rats with low dose of 17-β-estradiol, losartan, both, or benazepril inhibited ovariectomy-induced arteriolar mononuclear leukocyte adhesion by 77%, 58%, 92%, and 65% respectively, partly by inhibition of cell adhesion molecule up-regulation and the increase in circulating chemokines. These results demonstrate that menopause and ovariectomy generate a low grade of systemic inflammation. Therefore, administration of low doses of estrogens or inhibition of the renin-angiotensin system, at early stages of estrogen deficiency, might prevent the systemic inflammation associated with menopause and decrease the risk of suffering further cardiovascular diseases.
Enhancement of Antibodies to the Human Immunodeficiency Virus Type 1 Envelope by Using the Molecular Adjuvant C3d

ABSTRACT DNA vaccines expressing the envelope (Env) protein of the human immunodeficiency virus have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, the murine and human homologues of the complement component, C3d, were used in a DNA vaccine to enhance the titers of antibody to Env. Initially, plasmids expressing a secreted form of Env (sgp120) fused to one, two, or three copies of the murine homologue of C3d (mC3d) were constructed. Mice were inoculated with four vaccinations of DNA or two DNA vaccinations, followed by two boosts of affinity-purified gp120 protein. Analyses of titers demonstrated that multiple copies of mC3d coupled to sgp120 induced long-lasting, high-titer anti-Env antibody. Priming mice with sgp120-mC3d-DNA, followed by inoculation of purified gp120 protein, elicited the strongest antibody titers; however, the avidity maturation of the antibody was accelerated in the mice inoculated with sgp120-mC3d3-DNA. In addition, DNAs expressing sgp120 fused to three copies of the human homologue of C3d (hC3d3) efficiently enhanced the anti-Env antibody in rabbits. Lastly, antisera from both mice and rabbits vaccinated with DNA expressing sgp120-C3d3 elicited higher titers of neutralizing antibody than did nonfused forms of Env. These results indicate that C3d, conjugated to sgp120, enhances the antibody responses to Env compared to non-C3d fused forms of Env, and this approach may be one way to overcome the poor ability of DNA vaccines to generate antibodies to Env.
In vivo mutation rates and the landscape of fitness costs of HIV-1

Abstract Mutation rates and fitness costs of deleterious mutations are difficult to measure in vivo but essential for a quantitative understanding of evolution. Using whole genome deep sequencing data from longitudinal samples during untreated HIV-1 infection, we estimated mutation rates and fitness costs in HIV-1 from the dynamics of genetic variation. At approximately neutral sites, mutations accumulate with a rate of 1.2 × 10−5 per site per day, in agreement with the rate measured in cell cultures. We estimated the rate from G to A to be the largest, followed by the other transitions C to T, T to C, and A to G, while transversions are less frequent. At other sites, mutations tend to reduce virus replication. We estimated the fitness cost of mutations at every site in the HIV-1 genome using a model of mutation selection balance. About half of all non-synonymous mutations have large fitness costs (>10 percent), while most synonymous mutations have costs <1 percent. The cost of synonymous mutations is especially low in most of pol where we could not detect measurable costs for the majority of synonymous mutations. In contrast, we find high costs for synonymous mutations in important RNA structures and regulatory regions. The intra-patient fitness cost estimates are consistent across multiple patients, indicating that the deleterious part of the fitness landscape is universal and explains a large fraction of global HIV-1 group M diversity.
Effect of Bifidobacterium animalis subsp lactis Supplementation in Preterm Infants: A Systematic Review of Randomized Controlled Trials

Objective: To systematically evaluate and update evidence on the efficacy and safety of Bifidobacterium animalis subsp lactis CNCM I-3446 supplementation in preterm infants. Materials and Methods: The Cochrane Library and MEDLINE databases and major pediatric conference proceedings were searched in December 2008 for randomized controlled trials (RCTs). The company that manufactures B lactis was contacted for unpublished data. The review was restricted to RCTs performed in preterm infants <37 weeks of gestation and/or with a birth weight <2500 g. Results: Four RCTs involving 324 infants met the inclusion criteria. Compared with controls, B lactis supplementation has the potential to increase fecal bifidobacteria counts and to reduce Enterobacteriaceae and Clostridium spp counts. It also can reduce stool pH and fecal calprotectin concentrations, increase fecal immunoglobulin A and short-chain fatty acid concentrations, and decrease intestinal permeability. Compared with controls, B lactis supplementation had no effect on the risk of necrotizing enterocolitis stage ≥2 (3 RCTs, n = 293, risk ratio [RR] 0.53, 95% CI 0.16–1.83), risk of sepsis (2 RCTs, 397 cultures, RR 0.6, 95% CI 0.07–5.2), and use of antibiotics (2 RCTs, n = 255, RR 0.67, 95% CI 0.28–1.62). The power of these studies, however, does not allow for a definitive statement regarding a reduced risk of necrotizing enterocolitis. B lactis supplementation did have some effects on anthropometric parameters. No adverse events associated with B lactis supplementation were reported. Conclusions: Evidence regarding the potential beneficial effects of B lactis supplementation in preterm infants is encouraging. Further studies to assess clinically relevant outcomes are needed.
High-Efficient Three-Way Doherty Amplifier with Improved Linearity

– In this paper the operation behavior of three-way Doherty amplifier is analyzed, including the efficiency and linearity. Amplifier is designed in the configuration with two quarter-wave impedance transformers in the output combining circuit with LDMOSFETs in carrier and peaking amplifies. The signals for linearization (the fundamental signals’ second harmonics-IM2 and fourth-order nonlinear signals-IM4 at frequencies that are close to the second harmonics) are extracted at the output of peaking cells biased at various points. The Doherty amplifier is designed with the frequency diplexer at the outputs of the Doherty cells that separates the fundamental signals and signals for linearization. The diplexer includes harmonic control circuit (HCC) which in combination with the output matching of the second harmonics provides optimal impedance for IM2 and IM4 signals enabling their adequate power level, and an open circuit for the third harmonics. The linearization technique results in the suppression of the thirdand fifth order intermodulation products of Doherty amplifier.
Two-scale image harmonious cloning

A novel two-scale decomposition-based harmonious cloning algorithm over images is presented in this paper. Different from previous methods, we first decompose the lightness channel of the image into two scales: the base layer and the detail layer. Then, we process each scale using different fashions. Finally, we use mean value interpolation to solve image cloning problem. Our cloned result matches well with the target image on the detail and is seamlessly. Our approach can obtain visually pleasing cloned result between different appearance images, which is problematic in previous image cloning methods. Experimental results demonstrate the effectiveness of our harmonious cloning algorithm.
Patients with acute myocardial infarction and severe target lesion calcifications undergoing percutaneous coronary intervention have poor long-term prognosis.

BACKGROUND To assess the influence of severe target lesion calcification (TLC) on the outcomes of patients undergoing percutaneous coronary interventions (PCI) due to acute myocardial infarction (AMI). AIM Contemporary data concerning coronary artery calcifications (CAC) are based on pooled analyses from randomised trials with short follow-up. We still lack the knowledge on how CAC in target lesions affect long-term prognosis of patients with AMI in everyday practice. METHODS We evaluated clinical and laboratory data of 206 consecutive patients who underwent coronary angiography and PCI due to AMI. Primary endpoints were all-cause death and recurrent hospitalisations due to acute coronary syndrome (ACS). RESULTS Severe TLC lesions were present in 17% of patients. These patients were older (71 vs. 65 years, p = 0.02) and more often diagnosed with non-ST segment elevation myocardial infarction (77% vs. 58%, p = 0.03). Patients with severe TLC had lower rates of PCI success (80% vs. 97%, p < 0.0001) and less often achieved full revascularisation during index procedure (14% vs. 41%, p = 0.003). During 30 months follow-up patients with severe TLC more often suffered from another ACS (37% vs. 13%, p = 0.0005) and had higher all-cause mortality (31% vs. 16%, p = 0.04). Multivariate Cox regression model showed severe TLC to be an independent predictor of another ACS (HR 2.8; 95% CI 1.4-5.6; p = 0.004). CONCLUSIONS Severe TLC are not uncommon in patients with ACS. The presence of severe TLC is a prognostic factor of another ACS in AMI patients undergoing PCI.
Plasticity of rat central inhibitory synapses through GABA metabolism

1 The production of the central inhibitory transmitter GABA (γ‐aminobutyric acid) varies in response to different patterns of activity. It therefore seems possible that GABA metabolism can determine inhibitory synaptic strength and that presynaptic GABA content is a regulated parameter for synaptic plasticity. 2 We altered presynaptic GABA metabolism in cultured rat hippocampal slices using pharmacological tools. Degradation of GABA by GABA‐transaminase (GABA‐T) was blocked by γ‐vinyl‐GABA (GVG) and synthesis of GABA through glutamate decarboxylase (GAD) was suppressed with 3‐mercaptopropionic acid (MPA). We measured miniature GABAergic postsynaptic currents (mIPSCs) in CA3 pyramidal cells using the whole‐cell patch clamp technique. 3 Elevated intra‐synaptic GABA levels after block of GABA‐T resulted in increased mIPSC amplitude and frequency. In addition, tonic GABAergic background noise was enhanced by GVG. Electron micrographs from inhibitory synapses identified by immunogold staining for GABA confirmed the enhanced GABA content but revealed no further morphological alterations. 4 The suppression of GABA synthesis by MPA had opposite functional consequences: mIPSC amplitude and frequency decreased and current noise was reduced compared with control. However, we were unable to demonstrate the decreased GABA content in biochemical analyses of whole slices or in electron micrographs. 5 We conclude that the transmitter content of GABAergic vesicles is variable and that postsynaptic receptors are usually not saturated, leaving room for up‐regulation of inhibitory synaptic strength. Our data reveal a new mechanism of plasticity at central inhibitory synapses and provide a rationale for the activity‐dependent regulation of GABA synthesis in mammals.
Statistical study of the effect of process variations on nano-scale CMOS circuits with scaling

In this paper, we study the effect of the variation of process parameters on the performance of a voltage controlled oscillator (VCO) and an inverter with technology scaling. The spread in performances is shown to be Gaussian in nature, considering the fact that the distributions of process parameters are also Gaussian in nature. The spreads in performances increase with technology scaling. These have been verified through HPSICE simulation results.
Secondary transporters of the 2HCT family contain two homologous domains with inverted membrane topology and trans re‐entrant loops

The 2‐hydroxycarboxylate transporter (2HCT) family of secondary transporters belongs to a much larger structural class of secondary transporters termed ST3 which contains about 2000 transporters in 32 families. The transporters of the 2HCT family are among the best studied in the class. Here we detect weak sequence similarity between the N‐ and C‐terminal halves of the proteins using a sensitive method which uses a database containing the N‐ and C‐terminal halves of all the sequences in ST3 and involves blast searches of each sequence in the database against the whole database. Unrelated families of secondary transporters of the same length and composition were used as controls. The sequence similarity involved major parts of the N‐ and C‐terminal halves and not just a small stretch. The membrane topology of the homologous N‐ and C‐terminal domains was deduced from the experimentally determined topology of the members of the 2HCT family. The domains consist of five transmembrane segments each and have opposite orientations in the membrane. The N terminus of the N‐terminal domain is extracellular, while the N terminus of the C‐terminal domain is cytoplasmic. The loops between the fourth and fifth transmembrane segment in each domain are well conserved throughout the class and contain a high fraction of residues with small side chains, Gly, Ala and Ser. Experimental work on the citrate transporter CitS in the 2HCT family indicates that the loops are re‐entrant or pore loops. The re‐entrant loops in the N‐ and C‐terminal domains enter the membrane from opposite sides (trans‐re‐entrant loops). The combination of inverted membrane topology and trans‐re‐entrant loops represents a new fold for secondary transporters and resembles the structure of aquaporins and models proposed for Na+/Ca2+ exchangers.
General intellectual impairment in chronic right hemisphere damaged patients with anosognosia: A group study

The study evaluates the possible relations between cognitive impairment, persisting anosognosia for hemiplegia and peripersonal neglect. Thirty eight chronic right hemisphere stroke patients were divided in three age- and education-matched groups: A (n = 13) patients with left hemiparesis, peripersonal neglect, and anosognosia for hemiplegia; B (n = 12) patients with left hemiparesis and peripersonal neglect, and C (n = 13) patients with left hemiparesis only. We used MMSE and WAIS Verbal IQ and verbal subtests to assess cognitive impairment in patients, in order to avoid a bias due to visuospatial deficit, which is common in patients with neglect. VIQ, Information, Digit Span and Vocabulary WAIS subtests as well as MMSE were found to be significantly lower in group A versus group B. No difference was found in any test between groups B and C, indicating a general worse cognition in patients compared to those without anosognosia for hemiplegia. Patients with anosognosia for hemiplegia also showed larger brain lesions and, more frequently, frontal, parietal, temporal and basal ganglia involvement, particularly if they had low verbal IQ, indicating a relationship between cognitive impairment, persisting anosognosia for hemiplegia and large right hemisphere lesions.
Quantum Dot Infrared Photodetector as an Element for Free-Space Optics Communication Systems

In this paper an estimation for the performance of QDIP as an element of FSO communication system is given and availiable solutions are compared against the requirements of FSO communication systems. A discussion of QDIP parameters has been presented through theoretical models and experimental data from literature. A relation is proposed for QDIP carrier capture limited modulation bandwith and some further investigation lines of QDIP dynamic propertis are suggested. Quantum Dot Infrared Photodetector as an Element For Free-Space Optics Communication Systems, Milan Maksimović
Practical implementation issues of out-of-sequence measurements

Summary form only given. Out-of-sequence measurements (OOSM) occur in multi-sensor systems in which there is latency between the reports of the sensors. Using these OOSM without damaging the overall tracking performance is critical to the performance of the overall tracking system. In particular, one would like to maintain the best track at any given time (i.e., process non-latent measurements) while providing an inexpensive method for updating the track state whenever the latent measurements appear. Approximation algorithms for updating both single filter (M. Malick et al., March 2001) (Y. Bar-Shalom et al., December 2002) and interacting multi-model (IMM) (Y. Bar-Shalom and H. Chen) have been suggested. All these algorithms make assumptions about the implementation that are not obvious. Among these assumptions, is the state of the system going into the update, which typically do not hold in a system with significant latencies, and assumptions about the system after the update which are unclear. Other issues, including gating, computational complexity, and missed detections have not been adequately addressed previously. We have implemented these algorithms in two of our production trackers and presents practical issues with their implementations. We discuss interpretation of the algorithms, gating, computational complexity and results from the implementation. We also presented a new approximation algorithm whose motivation is the gating problem.
Participants’ perception of a unique community of practice for substance abuse education in the Caribbean

Background: Substance abuse is a significant public health challenge in the Caribbean. It is important that health and allied professionals be adequately trained in this field. The Caribbean Institute on Alcoholism and other Drug Problems (CARIAD) was established to provide new knowledge and share successful best practices in substance abuse in the Caribbean. CARIAD brings together diverse participants from throughout the region in a structured community of practice and emphasizes local knowledge formation. This paper evaluates the acceptability and perceived impact of CARIAD to/on participants. Methods: The authors analyzed anonymous written evaluations of 458 CARIAD participants completed immediately after the program in 2003–2012. Questionnaires collected quantitative data on the acceptability of the program in meeting the learning needs of participants. Perception of program acceptability and impact on the participant were also obtained from descriptive content analysis of qualitative data obtained through open-ended questions. A 2013 online follow-up survey collected data about the utilization and dissemination of knowledge acquired at CARIAD from 141 graduates of the same period. Data analysis employed basic descriptive statistics and qualitative content analysis. Results: Participant evaluation immediately following CARIAD showed a high level of satisfaction with the organization, structure, content, and usefulness of the program. Participants valued the program's cultural relevance and the opportunity for networking and collaboration. They expressed a collective solidarity, and empowerment to address substance abuse problems. Participants reported that CARIAD had impacted positively on their professional practice and facilitated knowledge transfer to colleagues and communities. Conclusion: CARIAD is perceived as an effective community of practice, producing a network of graduates who use the acquired knowledge, skills, and motivation to lead in the field of substance abuse in the Caribbean. This process of learning can be recommended to countries where research is not prioritized and evidence-driven interventions are not always available.
Total population density during the first year of life as a major determinant of lifetime body‐length trajectory in marble trout

The conditions experienced early in life can strongly influence life-history trajectories in a variety of animal species. Here, we use data from four isolated populations of the endangered stream-dwelling salmonid marble trout (Salmo marmoratus Cuvier 1817) living in the Soca and Idrijca river basins (Slovenia) to explore the influence of the total density experienced during and after the first year of life by marble trout year- classes on body length of marble trout through the lifetime. Analyses were performed by pooling together the stream-specific datasets to cover a wider range of densities. Mean body length of marble trout year-classes through the lifetime (from age 1+ to 5+) was negatively related to total density of marble trout during the first year of life. The relationship between density during the first growth period and body length through the lifetime was well described by negative power curves. Total population density after the first year of life was not correlated with body length, thus suggesting that body growth trajectories are heavily determined early in life. Given size-dependent sexual maturity and egg production in marble trout, the relationship between density early in life and lifetime individual growth may have strong implications in terms of population dynamics and regulation of population size.