Miracle-dz/UniFAR-FTUs huggingface dataset:
Accelerating Drug Development Using Biomarkers: A Case Study with Sitagliptin, A Novel DPP4 Inhibitor for Type 2 Diabetes

The leveraged use of biomarkers presents an opportunity in understanding target engagement and disease impact while accelerating drug development. For effective integration in drug development, it is essential for biomarkers to aid in the elucidation of mechanisms of action and disease progression. The recent years have witnessed significant progress in biomarker selection, validation, and qualification, while enabling surrogate and clinical endpoint qualification and application. Biomarkers play a central role in target validation for novel mechanisms. They also play a central role in the learning/confirming paradigm, particularly when utilized in concert with pharmacokinetic/pharmacodynamic modeling. Clearly, these attributes make biomarker integration attractive for scientific and regulatory applications to new drug development. In this review, applications of proximal, or target engagement, and distal, or disease-related, biomarkers are highlighted using the example of the recent development of sitagliptin for type 2 diabetes, wherein elucidation of target engagement and disease-related biomarkers significantly accelerated sitagliptin drug development. Importantly, use of biomarkers as tools facilitated design of clinical efficacy trials while streamlining dose focus and optimization, the net impact of which reduced overall cycle time to filing as compared to the industry average.
Optimal Pilot Spacing and Power in Rate-Adaptive MIMO Diversity Systems with Imperfect CSI

In this paper, performance of a rate-adaptive multiple-input multiple-output diversity system with imperfect channel state information is analyzed and optimized. Space-time block coding is utilized to exploit spatial diversity and to thereby combat some of the fading in wireless channel communications. The remaining fading is tacked by means of adaptive coded modulation. The pilot symbol period and the power allocated to pilot and data symbols are optimized in such a way that the average spectral efficiency is maximized. At the same time, the instantaneous (with respect to predicted channel-signal-to-noise ratio) bit error rate is maintained below a desired level. The average time duration that the channel stays within a certain interval, the average fade region duration, is also derived. A numerical example is given for uncorrelated flat Rayleigh fading subchannels with Jakes spectrum
Afghan Muslim male interpreters and translators: An examination of their identity changes and lived experiences during pre- and post-immigration to the United States during the Afghanistan War (2003-2012)

viii Chapter 1 – Introduction . 01 Rationale for Study . 15 Purpose and Goals . 17 Problem Statement . 18 Research Questions . 19 Reflexivity.20 Chapter 2 – Literature Review . 23 Global and Cultural Ideological Differences . 25 Afghanistan Individual Pre-Immigration Identity . 29 Afghan Tribal and Group Identities . 36 Religious Identity . 39 Afghan Individual Post-Immigration Identity. 41 Cultural Globalization . 43 Afghan Family Identity during Pre-Immigration . 47 Afghan Family Identity during Post-Immigration . 51 Pan-ethnic Identity . 54 ii Chapter 3 – Modern Afghanistan – Politics, Governance and History.57 Afghanistan’s Reform and Modernization Movement . 62 Period of Turmoil: 1978-1979. 65 Pashtun Ethnic Identity . 73 Hazara Ethnic Identity . 73 Tajik Ethnic Identity . 74 Chapter 4 – Afghanistan Modern Conflict And War . 78 Current Conflict . 78 Government Forces . 87 Insurgent Elements . 88 External Groups . 89 Chapter 5 – Theory . 92 Modern Afghanistan History and Timeline . 94 Post-Colonial Theory . 94 Diasporas . 100 International Relations / Islamic Theory . 107 Traditionalism . 110 Jihad. 112
Increasing the NaCl Concentration of the Preinjected Solution Enhances Monopolar Radiofrequency Lesion Size

Background The effect of altering the sodium chloride (NaCl) concentration of the preinjected solution on monopolar radiofrequency (RF) lesion characteristics has not been investigated with conventional pain medicine equipment. The purpose of this study was to examine the effects of increasing NaCl concentration on lesion dimensions. Methods Monopolar RF was performed with ex vivo chicken samples. Fifteen groups were used. Seven groups were used to investigate the preinjection of increasing NaCl concentrations. Two nonionic fluids (water and 5% dextrose in water) were also investigated. One group received no fluid preinjection. Five additional groups received increasing concentrations of NaCl combined with lidocaine. Horizontal diameter, vertical diameter, maximal effective radius, and distal radius of the lesion from the tip of the electrode were each measured in millimeters. The shape (horizontal diameter/vertical diameter) and overall surface area were calculated. Impedance and power values were measured. Results The addition of NaCl to the injected fluid alters mean lesion attributes beyond that observed with nonionic fluids. All NaCl concentrations 0.7% and above increased the mean surface area over that seen with water by 29% to 154%. Increasing the NaCl concentration from 0.7% NaCl to 23.4% NaCl resulted in a reduction in the impedance and an increase in power (mean watts of 1.4–3.25 W). The addition of lidocaine to NaCl solutions does not significantly alter the mean increases in lesion dimensions and modifications in electrical parameters. Conclusions Increasing NaCl concentrations significantly increases lesion size. NaCl may produce a larger lesion as a result of reduced impedance surrounding the RF cannula and increased power output.
Weight fluctuation, mortality and vascular disease in Pima Indians.

OBJECTIVE To examine the relationship of weight fluctuation to mortality rates and incidence of vascular disease. SUBJECTS A cohort of Pima Indians, 572 of whom had non-insulin-dependent diabetes mellitus and 766 without diabetes. DESIGN Individuals were invited biennially to research examinations. The root mean square error (RMSE) of the linear trend of weight with time for the first four examinations after age 20 years was used as an index of weight fluctuation. Subjects were followed from the fourth examination until death or until 31 December 1991. The mortality rate ratio (MRR) and its 95% confidence interval (CI) for those with a high weight fluctuation index relative to those with a lower value were determined. The median duration of follow up was 9.3 (range 0.1-22.6) years. MEASUREMENTS All cause mortality (n = 356); incidence of diabetic retinopathy (n = 145), diabetic nephropathy (n = 132) and electrocardiographic abnormalities (n = 82). RESULTS There was no significant relationship between weight fluctuation and mortality for diabetic subjects (MRR = 1.0, 95% CI 0.8-1.3, p = 0.91). Nondiabetic subjects with a high weight fluctuation index had a higher mortality rate than those with a lower index (MRR = 1.5, 95% CI 1.0-2.1, p = 0.03); the association was stronger among men than among women. The excess mortality in the high weight fluctuation group was not due to cardiovascular diseases, but to noncardiovascular causes and the risk for alcohol-related death was particularly increased. Weight fluctuation was not associated with the incidence of diabetic retinopathy, nephropathy or electrocardiographic abnormalities. CONCLUSIONS A high weight fluctuation index was associated with higher mortality rates in nondiabetic, but not in diabetic, Pima Indians. The excess mortality is largely due to noncardiovascular causes of death and may reflect lifestyle factors associated with weight fluctuation, rather than its metabolic effects.
Intermittent drivers anchoring to structural heterogeneities as a major pathophysiological mechanism of human persistent atrial fibrillation

The mechanisms responsible for perpetuation of human persistent atrial fibrillation (AF) are controversial and probably vary between individuals. A wide spectrum of mechanisms have been described in experimental studies, ranging from a single localized stable (focal/reentrant) source, to multiple sources, up to diffuse bi‐atrial wavelets. We characterized AF drivers in patients with persistent AF (lasting less than 1 year) using novel high resolution mapping, imaging and modelling approaches with the objective of evaluating their relationship to atrial structural heterogeneities. Using panoramic non‐invasive mapping in humans, focal or reentrant sources driving AF waves were identified, originating from multiple distinct regions and exhibiting short lifespans and periodic recurrences in the same locations. The reentrant driver regions harboured long, fractionated electrograms covering most of the fibrillatory cycle lengths with varying beat‐to‐beat sequences suggestive of unstable trajectories attached to slow conducting heterogeneous tissue. MRI atrial imaging demonstrated that such drivers preferentially clustered at the borders of fibrotic atrial regions. In patient‐specific computer simulations, sustained AF was shown to be driven by meandering transitory reentries attached to fibrosis borders expressing specific metrics in density and extent. Finally, random microstructural alterations devoid of cellular electrical changes were modelled, showing that a percolation mechanism could also explain atrial reentries and complex fractionated electrograms. These data from clinical, imaging and computational studies strongly suggest that intermittent and spatially unstable drivers anchoring to structural heterogeneities are a major pathophysiological mechanism in human persistent atrial fibrillation.
Higher risk of orofacial clefts in children born to mothers with angina pectoris: A population‐based case‐control study

Previously an unexpected association of maternal angina pectoris (MAP) during pregnancy with a higher risk of orofacial clefts in their children was found. There were three objectives of this study: (i) to evaluate the validity of MAP‐diagnoses in the previous study and the recent history of mothers with MAP in a follow‐up study; (ii) to estimate the prevalence of other congenital abnormalities in the offspring of mothers with MAP; and (iii) to analyze the possible effect of confounders for the risk of orofacial clefts. The large dataset of population‐based Hungarian Case‐Control Surveillance System of Congenital Abnormalities, 1980–1996 was evaluated including 22 843 cases with congenital abnormalities and 38 151 controls without any defect. Twenty‐two cases (0.10%) and 12 controls (0.03%) were born to mothers with medically recorded MAP (odds ratio [OR] with 95% confidence interval [CI]: 3.7, 1.8–7.3). Of 22 cases, six had isolated cleft lip ± palate (OR with 95% CI: 13.3, 4.9–35.9) and two were affected with isolated cleft palate (OR with 95% CI: 10.5, 2.3–47.6). The diagnosis of MAP was confirmed in seven women visited at home in 2009–2010, two had recent myocardial infarction and five were smokers. There was no higher risk for other congenital abnormalities. In conclusion the higher risk of orofacial clefts was confirmed in the children of mothers with MAP and smoking may trigger the genetic predisposition of both MAP and orofacial clefts. However, the number of cases was limited and therefore further studies are needed to confirm or reject this theoretically and practically important observation.
Predictive Factors for Percutaneous Endoscopic Gastrostomy in Patients with Spontaneous Intracranial Hemorrhage

Background: Dysphagia is frequent after hemorrhagic stroke, and some of the affected patients require prolonged enteral nutrition, most often via percutaneous endoscopic gastrostomy (PEG) tubes. The identification of patients at risk of prolonged dysphagia permits earlier tube placement and helps guide clinicians in the decision-making process. Methods: This retrospective study included all patients with spontaneous ICH admitted to a tertiary university hospital from 2007 until 2009 (n = 208). Fifty-one patients received PEG tubes. PEG tube placement was conducted in ventilated patients within 30 days and in spontaneously breathing patients if swallowing did not improve within 14 days. Results: Twenty-five percent of patients received PEG tubes. Those patients had larger lobar hemorrhages, intraventricular hemorrhage and occlusive hydrocephalus and higher ICH scores. Furthermore, patients with PEG scored worse on Glasgow Coma Scale (GCS), National Institute of Health Stroke Scale (NIHSS) and Acute Physiology And Chronic Health Evaluation (APACHE II), more frequently needed mechanical ventilation, and had more inflammatory and renal complications. A multivariate regression analysis identified GCS, occlusive hydrocephalus, mechanical ventilation, and systemic sepsis as independent risk factors for PEG tube placement. Conclusion: Disease severity and neurocritical care complications represent the major influencing parameters for PEG tube placement in spontaneous ICH patients.
Distribution of CYP2C polymorphisms in an Amerindian population of Brazil.

The human cytochrome P450 (CYP450) superfamily members CYP2C8, CYP2C9 and CYP2C19 are drugmetabolizing enzymes that provide the main pathway for the biotransformation of various therapeutic classes, including taxanes and antimalarials (CYP2C8) [1,2] anticoagulants, anticonvulsants, non-steroidal anti-inflammatory drugs (CYP2C9) [3–5], proton pump inhibitors and thienopyridine antiplatelet medicines (CYP2C19) [6,7]. The encoding CYP2C genes, located in a cluster on chromosome 10q23–24, are highly polymorphic (http://www.cypalleles.ki.se), and several functional variants have been shown to affect the clinical efficacy, toxicity and ⁄ or dose requirement of CYP2C substrates, notably clopidogrel and warfarin [8]. The frequency of distinct CYP2C polymorphisms varies significantly across and within continental populations [9,10] (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/ hapmap3r3_B36/) and also within different strata of admixed populations, such as Brazilians [11]. For example, the reduced activity of CYP2C8*2 allele [12] is absent in Japanese [13], rare (0–1%) in European populations [14], ranges in frequency from 11 to 17% in sub-Saharan Africans [15] and occurs in 2% and 12% of Brazilians, self-identified as White or Black, respectively [11]. A PubMed search on 31 August, 2011 retrieved no frequency data on CYP2C8 polymorphisms and a paucity of information on CYP2C9 and CYP2C19 genetic variation in native American (Amerindian) populations [16–21]. This prompted us to examine the distribution of twelve functional CYP2C polymorphisms in Guarani, an endogamous Amerindian group belonging to the TupiGuarani linguistic family living in the south, south–east and centre-west regions of Brazil and in neighbouring regions of Paraguay, Argentina and Bolivia [22]. Materials and Methods
Profitability of Technical Analysis Rules in Emerging and Developed Markets: Review

This study aims at reviewing the theoretical foundations and literature reviews for technical analysis approach, to examine the ability of this approach to predict the future stock value in both the emerging and developed financial markets. On reviewing several studies in emerging markets and as a result of financial inefficiency, the simplest technical trading rules are able to predict the future stock value. In contrast, the application of these same simple rules (models) for technical analysis results in inaccurate predictions in developed financial markets, however, with the use of some complex models, such as neural network, genetic algorithm, genetic programming, and chartist analysis system for trading (CAST), and technical analysis applied models, the result is so clear in the predictability of the future stock value using the technical analysis approach in developed financial markets. So it can be concluded that the technical analysis is profitable in both emerging and developed financial markets. The study recommended that research and study try to reach the best and most accurate technical analysis models that can be applied in both emerging and developed financial markets, which can then be generalized.
Maternal serum anti-Müllerian hormone at 11–13 weeks’ gestation in the prediction of preeclampsia

Abstract Objective: To investigate the potential value of maternal serum anti-Müllerian hormone (AMH) at 11–13 weeks’ gestation in the prediction of preeclampsia (PE). Methods: The serum concentration of AMH was measured at 11–13 weeks’ gestation in cases of PE (n = 50) and normotensive controls (n = 150). Backward stepwise multiple regression analysis was used to determine which of the factors amongst the maternal characteristics and gestation were significant predictors of the serum AMH in the control group and from the regression model the value in each case and control was expressed as a multiple of the expected median (MoM). Results: In normotensive pregnancies, the maternal serum concentration of AMH is higher in Afro-Caribbean than in Caucasian women and in smokers than in non-smokers. In the PE group, the median serum concentration of AMH was significantly higher than in the controls (2.140 ng/L, IQR 1.968–2.273 versus 2.062 ng/L, IQR 1.938–2.181; p = 0.025), but the median MoM value of AMH was not significantly different between the PE group and the controls (1.040, IQR 0.941–1.081 versus 0.995, IQR 0.939–1.065, p = 0.147). Conclusions: Maternal serum AMH is not an effective early predictor for PE.
Seasonal variation and characterization of Micrococcaceae present in ewes' raw milk

SUMMARY Samples (120) of ewes' raw milk collected over a 12-month period on arrival at the dairy and freshly drawn ewes’ milk samples (30) collected at the farm were analysed for total viable counts and staphylococci. Total viable counts reached on the average 54 × 106/ml in dairy samples and 6·0 × 105/ml in farm samples, whereas mean levels of staphylococci were 5·9 × 104/ml and 3·3 × 103/ml, respectively. A high proportion (62%) of coagulase-positive isolates from Baird-Parker agar plates was detected in spring months. Staphylococcus aureus (42%), Staph. haemolyticus (23%) and Staph. epidermidis (10%) were the predominant species in 210 characterized isolates of staphylococci from ewes' raw milk. Seven coagulase-positive, maltose-negative staphylococci could not be identified with any of the recognized Staphylococcus species. Eighteen Micrococcus strains were identified as M. varians, whereas 111 Micrococcus strains of uncertain taxonomic status were separated into three groups, according to their physiological characters.
Activator Gcn4p and Cyc8p/Tup1p Are Interdependent for Promoter Occupancy at ARG1 In Vivo

ABSTRACT The Cyc8p/Tup1p complex mediates repression of diverse genes in Saccharomyces cerevisiae and is recruited by DNA binding proteins specific for the different sets of repressed genes. By screening the yeast deletion library, we identified Cyc8p as a coactivator for Gcn4p, a transcriptional activator of amino acid biosynthetic genes. Deletion of CYC8 confers sensitivity to an inhibitor of isoleucine/valine biosynthesis and impairs activation of Gcn4p-dependent reporters and authentic amino acid biosynthetic target genes. Deletion of TUP1 produces similar but less severe activation defects in vivo. Although expression of Gcn4p is unaffected by deletion of CYC8, chromatin immunoprecipitation assays reveal a strong defect in binding of Gcn4p at the target genes ARG1 and ARG4 in cyc8Δ cells and to a lesser extent in tup1Δ cells. The defects in Gcn4p binding and transcriptional activation in cyc8Δ cells cannot be overcome by Gcn4p overexpression but are partially suppressed in tup1Δ cells. The impairment of Gcn4p binding in cyc8Δ and tup1Δ cells is severe enough to reduce recruitment of SAGA, Srb mediator, TATA binding protein, and RNA polymerase II to the ARG1 and ARG4 promoters, accounting for impaired transcriptional activation of these genes in both mutants. Cyc8p and Tup1p are recruited to the ARG1 and ARG4 promoters, consistent with a direct role for this complex in stimulating Gcn4p occupancy of the upstream activation sequence (UAS). Interestingly, Gcn4p also stimulates binding of Cyc8p/Tup1p at the 3′ ends of these genes, raising the possibility that Cyc8p/Tup1p influences transcription elongation. Our findings reveal a novel coactivator function for Cyc8p/Tup1p at the level of activator binding and suggest that Gcn4p may enhance its own binding to the UAS by recruiting Cyc8p/Tup1p.
The Antimicrobial Activity of Sub3 is Dependent on Membrane Binding and Cell‐Penetrating Ability

Because of their high activity against microorganisms and low cytotoxicity, cationic antimicrobial peptides (AMPs) have been explored as the next generation of antibiotics. Although they have common structural features, the modes of action of AMPs are extensively debated, and a single mechanism does not explain the activity of all AMPs reported so far. Here we investigated the mechanism of action of Sub3, an AMP previously designed and optimised from high‐throughput screening with bactenecin as the template. Sub3 has potent activity against Gram‐negative and Gram‐positive bacteria as well as against fungi, but its mechanism of action has remained elusive. By using AFM imaging, ζ potential, flow cytometry and fluorescence methodologies with model membranes and bacterial cells, we found that, although the mechanism of action involves membrane targeting, Sub3 internalises inside bacteria at lethal concentrations without permeabilising the membrane, thus suggesting that its antimicrobial activity might involve both the membrane and intracellular targets. In addition, we found that Sub3 can be internalised into human cells without being toxic. As some bacteria are able to survive intracellularly and consequently evade host defences and antibiotic treatment, our findings suggest that Sub3 could be useful as an intracellular antimicrobial agent for infections that are notoriously difficult to treat.
Providers' perspectives on male involvement in family planning in the context of a cluster-randomized controlled trial evaluating integrating family planning into HIV care in Nyanza Province, Kenya

Abstract Integration of family planning (FP) services into HIV care and increasing male partner involvement in FP are being explored as strategies to reduce unmet need for contraception. Providers' views can give valuable insight into current FP care. We evaluated the perspectives of HIV care providers working at HIV clinics in Nyanza Province, Kenya, on male partner involvement in FP. This qualitative study was part of a cluster-randomized controlled trial evaluating the impact of integrating FP into HIV services on contraceptive prevalence among HIV-positive patients in Nyanza Province, Kenya. Thirty individual interviews were conducted among health-care workers at 11 HIV care facilities in Nyanza Province, Kenya. Interviews were conducted from integrated and control sites one year after implementation of FP/HIV integration. Data were transcribed and analyzed using grounded theory methods and ATLAS-ti. Providers supported male partner inclusion when choosing FP and emphasized that decisions should be made collaboratively. Providers believed that men have traditionally played a prohibitive role in FP but identified several benefits to partner involvement in FP decision-making including: reducing relationship conflicts, improving FP knowledge and contraceptive continuation, and increasing partner cohesion. Providers suggested that integrated FP/HIV services facilitate male partner involvement in FP decision-making since HIV-positive men are already established patients in HIV clinics. Some providers stated that women had a right to choose and start FP alone if their partners did not agree with using FP. Integrated FP services may be a useful strategy to help increase male participation to reduce the unmet FP need in sub-Saharan Africa. It is important to determine effective ways to engage male partners in FP, without impinging upon women's autonomy and reproductive rights. Trial registration: ClinicalTrials.gov identifier: NCT01001507.