Miracle-dz/UniFAR-FTUs huggingface dataset:
A Comparison of Population-Averaged and Cluster-Specific Approaches in the Context of Unequal Probabilities of Selection

ABSTRACT Sampling designs of large-scale survey studies are typically complex, involving multiple design features such as clustering and unequal probabilities of selection. Single-level (i.e., population-averaged) methods that use adjusted variance estimators and multilevel (i.e., cluster-specific) methods provide two alternatives for modeling clustered data. Although the literature comparing these methods is vast, comparisons have been limited to the context in which all sampling units are selected with equal probabilities (thus circumventing the need for sampling weights). The goal of this study was to determine under what conditions single-level and multilevel estimators outperform one another in the context of a two-stage sampling design with unequal probabilities of selection. Monte Carlo simulation methods were used to evaluate the impact of several factors, including population model, informativeness of the design, distribution of the outcome variable, intraclass correlation coefficient, cluster size, and estimation method. Results indicated that the unweighted estimators performed similarly across conditions, whereas the weighted single-level estimators tended to outperform the weighted multilevel estimators, particularly under nonideal sample conditions. Multilevel weight approximation methods did not perform well when the design was informative. An empirical example is provided to demonstrate how researchers might investigate the implications of the simulation results in practice.
Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice

Drug-drug interactions (DDIs) occur when the action of one drug interferes with or alters the activity of another drug taken concomitantly. This can lead to decreased drug efficacy or increased toxicity. Because of DDIs, physicians in the clinical practice attempt to avoid potential interactions when multiple drugs are coadministrated; however, there is still a large knowledge gap in understanding how drugs taken in the past can contribute to DDIs in the future. The goal of this study was to investigate the consequence of neonatal drug exposure on efficacy of other drugs administered up through adult life. We selected a mouse model to test phenobarbital exposure at a neonatal age and its impact on efficacy of omeprazole in adult life. The results of our experiment show an observed decrease in omeprazole’s ability to raise gastric pH in adult mice that received single or multiple doses of phenobarbital at a neonatal age. This effect may be associated with the permanent induction of cytochrome P450 enzymes in adult liver after neonatal phenobarbital treatment. Our data indicates that DDIs may result from drugs administered in the past in an animal model and should prompt re-evaluation of how DDIs are viewed and how to avoid long-term DDIs in clinical practice.
NET23/STING Promotes Chromatin Compaction from the Nuclear Envelope

Changes in the peripheral distribution and amount of condensed chromatin are observed in a number of diseases linked to mutations in the lamin A protein of the nuclear envelope. We postulated that lamin A interactions with nuclear envelope transmembrane proteins (NETs) that affect chromatin structure might be altered in these diseases and so screened thirty-one NETs for those that promote chromatin compaction as determined by an increase in the number of chromatin clusters of high pixel intensity. One of these, NET23 (also called STING, MITA, MPYS, ERIS, Tmem173), strongly promoted chromatin compaction. A correlation between chromatin compaction and endogenous levels of NET23/STING was observed for a number of human cell lines, suggesting that NET23/STING may contribute generally to chromatin condensation. NET23/STING has separately been found to be involved in innate immune response signaling. Upon infection cells make a choice to either apoptose or to alter chromatin architecture to support focused expression of interferon genes and other response factors. We postulate that the chromatin compaction induced by NET23/STING may contribute to this choice because the cells expressing NET23/STING eventually apoptose, but the chromatin compaction effect is separate from this as the condensation was still observed when cells were treated with Z-VAD to block apoptosis. NET23/STING-induced compacted chromatin revealed changes in epigenetic marks including changes in histone methylation and acetylation. This indicates a previously uncharacterized nuclear role for NET23/STING potentially in both innate immune signaling and general chromatin architecture.
Biosynthesis of Diterpenoids in Tripterygium Adventitious Root Cultures1[OPEN]

Adventitious root cultures provide insights to elucidating the biosynthesis of pharmaceutically relevant diterpenoids in the model genus Tripterygium. Adventitious root cultures were developed from Tripterygium regelii, and growth conditions were optimized for the abundant production of diterpenoids, which can be collected directly from the medium. An analysis of publicly available transcriptome data sets collected with T. regelii roots and root cultures indicated the presence of a large gene family (with 20 members) for terpene synthases (TPSs). Nine candidate diterpene synthase genes were selected for follow-up functional evaluation, of which two belonged to the TPS-c, three to the TPS-e/f, and four to the TPS-b subfamilies. These genes were characterized by heterologous expression in a modular metabolic engineering system in Escherichia coli. Members of the TPS-c subfamily were characterized as copalyl diphosphate (diterpene) synthases, and those belonging to the TPS-e/f subfamily catalyzed the formation of precursors of kaurane diterpenoids. The TPS-b subfamily encompassed genes coding for enzymes involved in abietane diterpenoid biosynthesis and others with activities as monoterpene synthases. The structural characterization of diterpenoids accumulating in the medium of T. regelii adventitious root cultures, facilitated by searching the Spektraris online spectral database, enabled us to formulate a biosynthetic pathway for the biosynthesis of triptolide, a diterpenoid with pharmaceutical potential. Considering the significant enrichment of diterpenoids in the culture medium, fast-growing adventitious root cultures may hold promise as a sustainable resource for the large-scale production of triptolide.
Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2

Background: The sympathetic nervous system (SNS) regulates glucose metabolism in various organs including the kidneys. The sodium glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in renal proximal tubules and its inhibition has been shown to improve glucose control, cardiovascular and renal outcomes. We hypothesized that SNS-induced alterations of glucose metabolism may be mediated via regulation of SGLT2. Method: We used human renal proximal tubule cells to investigate the effects of noradrenaline on SGLT2 regulation. Mice fed a high-fat diet were oral gavaged with dapagliflozin and the expression of noradrenaline and tyrosine hydroxylase was measured in the kidney and heart. Results: Noradrenaline treatment resulted in a pronounced increase in SGLT2 and interleukin (IL)-6 expression in HK2 cells and promoted translocation of SGLT2 to the cell surface. In vivo, dapagliflozin treatment resulted in marked glucosuria in high-fat diet-fed mice. SGLT2 inhibition significantly reduced high-fat diet-induced elevations of tyrosine hydroxylase and noradrenaline in the kidney and heart. We also aimed to assess the levels of hypertension-related cytokines in the kidneys of our mice treated with and without dapagliflozin. Excitingly, we demonstrate that SGLT2 inhibition with dapagliflozin promoted a trend towards reduced tumour necrosis factor-alpha and elevated IL-1&bgr; protein levels in the kidney. Conclusion: Our in-vitro and in-vivo studies provide first evidence for an important cross-talk between the SNS and SGLT2 regulation that may not only account for SNS-induced alterations of glucose metabolism but potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors.
Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting.

OBJECTIVE Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02438072.
Immune Checkpoints as a Target for Colorectal Cancer Treatment

Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition.
Behavioral economic predictors of overweight children's weight loss.

OBJECTIVE Our goal was to determine whether behavioral economic constructs-including impulsivity (i.e., steep discounting of delayed food and monetary rewards), the relative reinforcing value of food (RRVfood), and environmental enrichment (i.e., the presence of alternatives to unhealthy foods in the home and neighborhood environments)-are significant pretreatment predictors of overweight children's weight loss within family-based treatment. METHOD Overweight children (N = 241; ages 7-12 years; 63% female; 65% non-Hispanic White) enrolled in a 16-week family-based obesity treatment with at least one parent. At baseline, children completed a task to assess RRVfood and delay discounting measures of snack foods and money to assess impulsivity. Parents completed questionnaires to assess environmental enrichment. RESULTS Children who found food highly reinforcing and steeply discounted future food rewards at baseline showed a blunted response to treatment compared with children without this combination of risk factors. High environmental enrichment was associated with treatment success only among children who did not find food highly reinforcing. Monetary discounting rate predicted weight loss, regardless of children's level of RRVfood. CONCLUSIONS Investigation is warranted into novel approaches to obesity treatment that target underlying impulsivity and RRVfood. Enriching the environment with alternatives to unhealthy eating may facilitate weight loss, especially for children with low RRVfood.
Threats or violence from patients was associated with turnover intention among foreign-born GPs – a comparison of four workplace factors associated with attitudes of wanting to quit one’s job as a GP

Abstract Objective: General practitioners (GPs) are crucial in medical healthcare, but there is currently a shortage of GPs in Sweden and elsewhere. Recruitment of GPs from abroad is essential, but foreign-born physicians face difficulties at work that may be related to turnover intention, i.e. wanting to quit one’s job. The study aims to explore the reasons to why foreign-born GPs may intend to quit their job. Design: Survey data were used to compare four work-related factors that can be associated with turnover intentions; patient-related stress, threats or violence from patients, control of work pace, and empowering leadership, among native-born and foreign-born GPs. These work-related factors were subsequently examined in relation to turnover intention among the foreign-born GPs by means of linear hierarchical regression analyses. The questionnaire consisted of items from the QPS Nordic and items constructed by the authors. Setting: A primary care setting in a central area of Sweden. Subjects: Native-born (n = 208) and foreign-born GPs (n = 73). Results: Turnover intention was more common among foreign-born GPs (19.2% compared with 14.9%), as was the experience of threats or violence from patients (22% compared with 3% of the native-born GPs). Threats or violence was also associated with increased turnover intention. Control of work pace and an empowering leadership was associated with reduced turnover intention. Practice implications: The organisations need to recognise that foreign-born GPs may face increased rates of threats and/or violence from patients, which may ultimately cause job turnover and be harmful to the exposed individual.
Effect of alcoholic treated MWCNT on tensile behavior of epoxy composite

In this work, the effect of alcoholic treatment of the multi-wall carbon nano-tube (MWCNT) on the mechanical properties of epoxy composites are investigated and compared. Nano-composites were developed by mixing 0.25%, 0.5% and 0.75wt% of MWCNT. Tensile strength, Young’s modulus, and Elongation are found to be effectively improved with the addition of alcoholic functionalized MWCNT in epoxy matrix. Increased tensile strength and elastic modulus of epoxy composites loaded with the alcoholic functionalized MWCNT are observed through experimental studies. The results were compared with neat epoxy composite. These findings confirm that the improved dispersion and interfacial interaction in the composites arising from covalent bonds between the MWCNT and the epoxy matrix. Keywords: MWCNT, tensile strength, alcoholic treatment, tensile modulus, epoxy
Multifocal electroretinographic evaluation of long-term hydroxychloroquine users.

OBJECTIVES To observe the long-term effects of hydroxychloroquine sulfate on retinal electrical activity by multifocal electroretinography (mfERG) and to evaluate the regional variation of retinal dysfunction in subjects with hydroxychloroquine retinopathy. METHODS Multifocal ERG with 103-hexagon stimulation was performed on 19 patients (36 eyes) treated with hydroxychloroquine for systemic lupus erythematosus, rheumatoid arthritis, or localized atypical scleroderma. Visual acuity testing, Amsler grid testing, and Ishihara color vision testing were also performed. In 2 of the patients, hydroxychloroquine was discontinued due to concerns about toxicity. Both of these patients had additional mfERG performed after discontinuation of medication. RESULTS Twelve patients (19 eyes) had a normal response density in one or both eyes, including 6 patients (12 eyes) with a low lifetime dose (< or =438 g) of hydroxychloroquine who had normal response densities in both eyes. Eleven patients (17 eyes) had abnormal response densities in one or both eyes, and 2 of these patients (4 eyes) had significant attenuation of response densities in almost the whole tested field; 4 patients had a normal mfERG result for one eye but had a slight decrease of response densities for the other eye. There were 4 patterns of abnormal mfERG amplitude change observed: (1) paracentral loss, (2) foveal loss, (3) peripheral loss, and (4) generalized loss. Implicit times were abnormal for pericentral responses in 3 patients. The results of color vision and Amsler grid testing were normal, except for one patient with a generalized loss pattern. In 2 subjects in whom hydroxychloroquine toxicity was suspected, response densities improved after termination of hydroxychloroquine. CONCLUSIONS Long-term hydroxychloroquine use may be associated with mfERG abnormalities. The mfERG appears to detect retinal physiological change earlier than visual acuity testing, color vision testing, or Amsler grid testing can. The greatest value of the mfERG is in differentiating a retinal cause and, hence, providing important evidence for hydroxychloroquine toxicity, for whatever visual field loss is apparent on perimetry.
Comparative Efficacy of Serological Tests for Detection of Brucella Antibodies in Sheep and Goats

Brucellosis is an important zoonosis and a significant cause of reproductive losses in animals. In view of the considerable problems related to direct diagnosis of brucellosis in animals, the present study envisaged the appraisal of seroepidemiology of brucellosis in sheep and goats by detection of brucella specific antibodies, comparison of two serological tests, viz., i-ELISA (Indirect Enzyme Linked Immunosorbent Assay) and RBPT expand for detection of Brucella-specific antibodies. Out of 1012 sheep and goat sera screened, 88 (8.70%) and 75 (7.41%) were detected positive by RBPT and i-ELISA, respectively. Species-wise seroprevalence was detected 12.26% and 10.97% in sheep and 5.67% and 4.39% in goats by RBPT and i-ELISA, respectively. During present investigation, RBPT detected more number of samples positive for brucella antibodies. However, compared to i-ELISA, overall sensitivity and specificity of RBPT were 80.00% and 97.01%, respectively. Species-wise sensitivity of RBPT found was 82.35% in sheep and 75.00% in goat, whereas specificity was 96.38% in sheep and 96.41% in goats.
Eggshell spot scoring methods cannot be used as a reliable proxy to determine pigment quantity

Eggshell maculation of most passerines is due to the deposition of the pigment protoporphyrin which is produced during biosynthesis of blood haem. Its functional significance has only received empirical attention in recent years. This interest has generated a number of hypotheses of which some remain untested partly because the quantification of protoporphyrin is analytically challenging and can be prohibitively expensive. Many studies have therefore used the extent of eggshell spotting as a proxy for total eggshell protoporphyrin concentration, although this has not been formally tested. Pigment scoring involves recording visible eggshell pigment attributes, such as spot intensity, distribution and size. Since even immaculate eggs can contain some protoporphyrin, there remains doubt over the degree to which visible pigment correlates with total pigment content of the shell. In this study, we test whether visible pigment scoring can be used as a proxy for protoporphyrin concentration of an eggshell. We use pigmented eggshells of two common British passerine species to compare eggshell spot intensity, distribution and spot size (as used by the visual pigment scoring method) with direct measures of eggshell protoporphyrin concentration. In addition, we compared an alternative method of pigment scoring, the pixel pigment scoring method, using a computer programme to quantify the number of pixels exceeding a specified colour threshold. We demonstrate that although results from both scoring methods were positively correlated with eggshell protoporphyrin concentrations, the correlations were not sufficiently strong to be used as surrogates in studies where actual pigment concentrations are required.
Natural Radioactivity in Tanzania Cements and their Raw Materials

This paper presents the study of natural radioactivity in Tanzania Portland cements and their raw materials. Samples collected as raw materials were pozzolan, sandstone, limestone, clay, gypsum and cement as finished products. The natural radioactivity due to the presence of radium 226 Ra, thorium 232 Th and potassium 40 K were measured by means of gamma spectrometer coupled with HPGe detector. The mean measured activity concentrations of 226 Ra, 232 Th and 40 K in the raw materials range from 2.6 to 93.2, 1.3 to 172.8 and 6.3 to 997 Bq/kg, respectively with higher activity concentrations in pozzolan and lower in gypsum. Activity concentrations of natural radionuclides in raw materials (excluding some materials from Songwe deposits in Mbeya region) are comparative with the worldwide average concentrations of these radionuclides in soil. The average activity concentration of 226 Ra, 232 Th and 40 K in the cements are 46, 28 and 228 Bq/kg, respectively. The calculated values of radiological indices are below 60% of the upper recommended values for building materials. The average annual effective dose to an occupant from use of these materials equals to 0.45 mSv. Average activity concentrations of the mentioned radionuclides in Tanzania cements are in the middle of the variability interval of the national averages.