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Prognostic tools are an essential component of the clinical management of patients with renal cell carcinoma (RCC). Although tumour stage and grade can provide important information, they fail to consider patient- and tumour-specific biology. In this study, we set out to find a novel molecular marker of RCC by using hepatocyte nuclear factor 4A (HNF4A), a transcription factor implicated in RCC progression and malignancy, as a blueprint. Through transcriptomic analyses, we show that the nuclear factor I A (NFIA)-driven transcription network is active in primary RCC and that higher levels of NFIA confer a survival benefit. We validate our findings using immunohistochemical staining and analysis of a 363-patient tissue microarray (TMA), showing for the first time that NFIA can independently predict poor cancer-specific survival in clear cell RCC (ccRCC) patients (hazard ratio = 0.46, 95% CI = 0.24-0.85, p value = 0.014). Furthermore, we confirm the association of HNF4A with higher grades and stages in ccRCC in our TMA cohort. We present novel data that show HNF4A protein expression does not confer favourable prognosis in papillary RCC, confirming our survival analysis with publicly available HNF4A RNA expression data. Further work is required to elucidate the functional role of NFIA in RCC as well as the testing of these markers on patient material from diverse multi-centre cohorts, to establish their value for the prognostication of RCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Pronóstico , Análisis de Supervivencia , Núcleo Celular/patología , Factores de Transcripción NFI/genéticaRESUMEN
MOTIVATION: Advances in sequencing technologies have led to the sequencing of genomes of a multitude of organisms. However, draft genomes of many of these organisms contain a large number of gaps due to the repeats in genomes, low sequencing coverage and limitations in sequencing technologies. Although there exists several tools for filling gaps, many of these do not utilize all information relevant to gap filling. RESULTS: Here, we present a probabilistic method for filling gaps in draft genome assemblies using second-generation reads based on a generative model for sequencing that takes into account information on insert sizes and sequencing errors. Our method is based on the expectation-maximization algorithm unlike the graph-based methods adopted in the literature. Experiments on real biological datasets show that this novel approach can fill up large portions of gaps with small number of errors and misassemblies compared to other state-of-the-art gap-filling tools. AVAILABILITY AND IMPLEMENTATION: The method is implemented using C++ in a software named 'Filling Gaps by Iterative Read Distribution (Figbird)', which is available at https://github.com/SumitTarafder/Figbird. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Secuenciación de Nucleótidos de Alto Rendimiento , Programas Informáticos , Análisis de Secuencia de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Algoritmos , GenomaRESUMEN
Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.
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Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. We previously reported NEPHRIN and SD abnormalities in the podocytes of kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) with an NPHS1 missense mutation (E725D). However, the mechanisms underlying the disease may vary depending on the mutations involved, and thus generation of iPSCs from multiple patients is warranted. Here we established iPSCs from two additional patients with different NPHS1 mutations and examined the podocyte abnormalities in kidney organoids derived from these cells. One patient had truncating mutations, and NEPHRIN was undetectable in the resulting organoids. The other patient had a missense mutation (R460Q), and the mutant NEPHRIN in the organoids failed to accumulate on the podocyte surface to form SD precursors. However, the same mutant protein behaved normally when overexpressed in heterologous cells, suggesting that NEPHRIN localization is cell context-dependent. The localization of another SD-associated protein, PODOCIN, was impaired in both types of mutant organoids in a cell domain-specific manner. Thus, the new iPSC lines and resultant kidney organoids will be useful resources for dissecting the disease mechanisms, as well as for drug development for therapies.
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Células Madre Pluripotentes Inducidas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Mutantes/metabolismo , Síndrome Nefrótico/fisiopatología , Organoides/metabolismo , Secuencia de Aminoácidos , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón , Masculino , Proteínas de la Membrana/genética , Proteínas Mutantes/genética , Mutación MissenseRESUMEN
This study explored the physical and clinical phenotype of Bangladeshi children with autism spectrum disorder (ASD). A totally of 283 children who were referred for screening and administered Module 1 of the Autism Diagnostic Observation Schedule (ADOS) were included. Overall, 209 met the ADOS algorithmic cutoff for ASD. A trend for greater weight and head circumference was observed in children with ASD versus non-ASD. Head circumference was significantly (p < 0.03) larger in ASD males compared with non-ASD males. A trend was also observed for symptom severity, higher in females than males (p = 0.068), with further analyses demonstrating that social reciprocity (p < 0.014) and functional play (p < 0.03) were significantly more impaired in ASD females than males. The findings help understand sex differences in ASD.
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Trastorno del Espectro Autista/etnología , Trastorno del Espectro Autista/patología , Factores Sexuales , Adolescente , Bangladesh/etnología , Peso Corporal , Cefalometría , Niño , Preescolar , Femenino , Cabeza/patología , Humanos , Masculino , Fenotipo , Examen Físico , Índice de Severidad de la Enfermedad , Conducta SocialRESUMEN
Human skin is continuously subjected to environmental stresses, as well as extrinsic and intrinsic noxious agents. Although skin adopts various molecular mechanisms to maintain homeostasis, excessive and repeated stresses can overwhelm these systems, leading to serious cutaneous damage, including both melanoma and non-melanoma skin cancers. Phytochemicals present in the diet possess the desirable effects of protecting the skin from damaging free radicals as well as other benefits. Dietary phytochemicals appear to be effective in preventing skin cancer and are inexpensive, widely available, and well tolerated. Multiple in vitro and in vivo studies have demonstrated the significant anti-inflammatory, antioxidant, and anti-angiogenic characteristics of dietary phytochemicals against skin malignancy. Moreover, dietary phytochemicals affect multiple important cellular processes including cell cycle, angiogenesis, and metastasis to control skin cancer progression. Herein, we discuss the advantages of key dietary phytochemicals in whole fruits and vegetables, their bioavailability, and underlying molecular mechanisms for preventing skin cancer. Current challenges and future prospects for research are also reviewed. To date, most of the chemoprevention investigations have been conducted preclinically, and additional clinical trials are required to conform and validate the preclinical results in humans.
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BACKGROUND: Species tree estimation is frequently based on phylogenomic approaches that use multiple genes from throughout the genome. However, estimating a species tree from a collection of gene trees can be complicated due to the presence of gene tree incongruence resulting from incomplete lineage sorting (ILS), which is modelled by the multi-species coalescent process. Maximum likelihood and Bayesian MCMC methods can potentially result in accurate trees, but they do not scale well to large datasets. RESULTS: We present STELAR (Species Tree Estimation by maximizing tripLet AgReement), a new fast and highly accurate statistically consistent coalescent-based method for estimating species trees from a collection of gene trees. We formalized the constrained triplet consensus (CTC) problem and showed that the solution to the CTC problem is a statistically consistent estimate of the species tree under the multi-species coalescent (MSC) model. STELAR is an efficient dynamic programming based solution to the CTC problem which is highly accurate and scalable. We evaluated the accuracy of STELAR in comparison with SuperTriplets, which is an alternate fast and highly accurate triplet-based supertree method, and with MP-EST and ASTRAL - two of the most popular and accurate coalescent-based methods. Experimental results suggest that STELAR matches the accuracy of ASTRAL and improves on MP-EST and SuperTriplets. CONCLUSIONS: Theoretical and empirical results (on both simulated and real biological datasets) suggest that STELAR is a valuable technique for species tree estimation from gene tree distributions.
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Simulación por Computador/estadística & datos numéricos , Especiación Genética , Filogenia , Programas Informáticos , Algoritmos , Teorema de BayesRESUMEN
It is difficult to restore kidney function once it has become severely impaired. Although kidney transplantation is a curative therapy, donor numbers remain limited. Thus, the generation of kidney organoids (mainly comprising glomeruli and renal tubules) from multipotent stem cells represents an important advance in regenerative medicine of the kidney. Recently, a protocol that can generate the higher-order structure of the mouse embryonic kidney was reported. Kidney organoids are now being used for disease modelling, and may eventually be applicable for clinical transplantation. In this review, we summarize the recent advances in kidney organoid research, and discuss the issues to be resolved toward kidney reconstruction.
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Riñón/metabolismo , Organoides/metabolismo , Animales , Humanos , Modelos BiológicosRESUMEN
Dromedary camels have been shown to be the main reservoir for human Middle East respiratory syndrome (MERS) infections. This systematic review aims to compile and analyse all published data on MERS-coronavirus (CoV) in the global camel population to provide an overview of current knowledge on the distribution, spread and risk factors of infections in dromedary camels. We included original research articles containing laboratory evidence of MERS-CoV infections in dromedary camels in the field from 2013 to April 2018. In general, camels only show minor clinical signs of disease after being infected with MERS-CoV. Serological evidence of MERS-CoV in camels has been found in 20 countries, with molecular evidence for virus circulation in 13 countries. The seroprevalence of MERS-CoV antibodies increases with age in camels, while the prevalence of viral shedding as determined by MERS-CoV RNA detection in nasal swabs decreases. In several studies, camels that were sampled at animal markets or quarantine facilities were seropositive more often than camels at farms as well as imported camels vs. locally bred camels. Some studies show a relatively higher seroprevalence and viral detection during the cooler winter months. Knowledge of the animal reservoir of MERS-CoV is essential to develop intervention and control measures to prevent human infections.
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Camelus , Infecciones por Coronavirus , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Zoonosis , Animales , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Zoonosis/epidemiología , Zoonosis/transmisión , Zoonosis/virologíaRESUMEN
Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. However, methods for SD reconstitution have been unavailable, thereby limiting studies in the field. In the present study, we established human induced pluripotent stem cells (iPSCs) from a patient with an NPHS1 missense mutation, and reproduced the SD formation process using iPSC-derived kidney organoids. The mutant NEPHRIN failed to become localized on the cell surface for pre-SD domain formation in the induced podocytes. Upon transplantation, the mutant podocytes developed foot processes, but exhibited impaired SD formation. Genetic correction of the single amino acid mutation restored NEPHRIN localization and phosphorylation, colocalization of other SD-associated proteins, and SD formation. Thus, these kidney organoids from patient-derived iPSCs identified SD abnormalities in the podocytes at the initial phase of congenital nephrotic disease.
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Células Madre Pluripotentes Inducidas/patología , Proteínas de la Membrana/análisis , Síndrome Nefrótico/patología , Organoides/patología , Podocitos/patología , Animales , Células Cultivadas , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Riñón/metabolismo , Riñón/patología , Proteínas de la Membrana/genética , Ratones SCID , Mutación Missense , Síndrome Nefrótico/genética , Organoides/metabolismo , Podocitos/metabolismoRESUMEN
OBJECTIVE: To gain an understanding of what challenges pulse oximetry for paediatric pneumonia management poses, how it has changed service provision and what would improve this device for use across paediatric clinical settings in low-income countries. DESIGN: Focus group discussions (FGDs), with purposive sampling and thematic analysis using a framework approach. SETTING: Community, front-line outpatient, and hospital outpatient and inpatient settings in Malawi and Bangladesh, which provide paediatric pneumonia care. PARTICIPANTS: Healthcare providers (HCPs) from Malawi and Bangladesh who had received training in pulse oximetry and had been using oximeters in routine paediatric care, including community healthcare workers, non-physician clinicians or medical assistants, and hospital-based nurses and doctors. RESULTS: We conducted six FGDs, with 23 participants from Bangladesh and 26 from Malawi. We identified five emergent themes: trust, value, user-related experience, sustainability and design. HCPs discussed the confidence gained through the use of oximeters, resulting in improved trust from caregivers and valuing the device, although there were conflicts between the weight given to clinical judgement versus oximeter results. HCPs reported the ease of using oximeters, but identified movement and physically smaller children as measurement challenges. Challenges in sustainability related to battery durability and replacement parts, however many HCPs had used the same device longer than 4 years, demonstrating robustness within these settings. Desirable features included back-up power banks and integrated respiratory rate and thermometer capability. CONCLUSIONS: Pulse oximetry was generally deemed valuable by HCPs for use as a spot-check device in a range of paediatric low-income clinical settings. Areas highlighted as challenges by HCPs, and therefore opportunities for redesign, included battery charging and durability, probe fit and sensitivity in paediatric populations. TRIAL REGISTRATION NUMBER: NCT02941237.
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Personal de Salud/educación , Oximetría/instrumentación , Oxígeno/sangre , Neumonía/sangre , Bangladesh , Países en Desarrollo , Grupos Focales , Humanos , Malaui , Neumonía/fisiopatología , Frecuencia Respiratoria , TermómetrosRESUMEN
The present study investigates the effect of perceived social support (PSS) and perceived religious endorsement (PRE) on career commitment (CC) of Saudi nurses. The investigation also extends to the moderating role of different demographic and organizational factors in the extent of PSS, and career commitment these nurses report. Data required for meeting these study objectives were collected from male and female Saudi nurses through a structured questionnaire. Multiple regressions using Partial Least Squares based Structural Equation Model, Smart-PLS version 3.0, and independent sample t-test using SPSS version 22.0, were used to analyze data. The study findings reveal that both perceived social support and perceived religious endorsement are important antecedents of career commitment of Saudi nurses. However, private-sector nurses are found to exhibit a significantly higher level of career commitment compared to their public-sector counterparts. Nurses with greater educational attainment perceive higher level of social support and express greater career commitment than their less educated peers. These findings suggest that nursing as a profession should be more openly discussed in both secular and religious contexts, to ensure an adequate level of respect and compassion on behalf of the public. In particular, endorsement from the individual nurses' social networks is vital in maintaining their wellbeing and career commitment. Given the religious influence in all aspects of life in the Saudi society, the current practice of gender-based segregation in Saudi hospitals and clinics seems to be meaningful for sustaining the career commitment of the nurses.
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OBJECTIVE: To determine whether a powered ankle-foot orthosis (AFO) that provides dorsiflexor and plantar flexor assistance at the ankle can improve walking endurance of persons with multiple sclerosis (MS). DESIGN: Short-term intervention. SETTING: University research laboratory. PARTICIPANTS: Participants (N=16) with a neurologist-confirmed diagnosis of MS and daily use of a prescribed custom unilateral passive AFO. INTERVENTIONS: Three 6-minute walk tests (6MWTs), 1 per footwear condition: shoes (no AFO), prescribed passive AFO, and portable powered AFO (PPAFO). Assistive devices were worn on the impaired limb. MAIN OUTCOME MEASURES: Distance walked and metabolic cost of transport were recorded during each 6MWT and compared between footwear conditions. RESULTS: Each participant completed all three 6MWTs within the experimental design. PPAFO use resulted in a shorter 6MWT distance than did a passive AFO or shoe use. No differences were observed in metabolic cost of transport between footwear conditions. CONCLUSIONS: The current embodiment of this PPAFO did not improve endurance walking performance during the 6MWT in a sample of participants with gait impairment due to MS. Further research is required to determine whether expanded training or modified design of this powered orthosis can be effective in improving endurance walking performance in persons with gait impairment due to MS.
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Ortesis del Pié , Trastornos Neurológicos de la Marcha/terapia , Esclerosis Múltiple/terapia , Zapatos , Prueba de Paso , Tobillo/fisiopatología , Diseño de Equipo , Femenino , Marcha/fisiología , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/fisiopatologíaRESUMEN
This paper presents an algorithm, for use with a Portable Powered Ankle-Foot Orthosis (i.e., PPAFO) that can automatically detect changes in gait modes (level ground, ascent and descent of stairs or ramps), thus allowing for appropriate ankle actuation control during swing phase. An artificial neural network (ANN) algorithm used input signals from an inertial measurement unit and foot switches, that is, vertical velocity and segment angle of the foot. Output from the ANN was filtered and adjusted to generate a final data set used to classify different gait modes. Five healthy male subjects walked with the PPAFO on the right leg for two test scenarios (walking over level ground and up and down stairs or a ramp; three trials per scenario). Success rate was quantified by the number of correctly classified steps with respect to the total number of steps. The results indicated that the proposed algorithm's success rate was high (99.3%, 100%, and 98.3% for level, ascent, and descent modes in the stairs scenario, respectively; 98.9%, 97.8%, and 100% in the ramp scenario). The proposed algorithm continuously detected each step's gait mode with faster timing and higher accuracy compared to a previous algorithm that used a decision tree based on maximizing the reliability of the mode recognition.
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Although the Li diffusion in single crystalline γ-LiAlO2 was studied with temperature-dependent Li-7 NMR spectroscopy and conductivity measurements recently, the exact diffusion pathways are not yet clearly identified. Therefore, the present study aims at elucidating the diffusion pathways in γ-LiAlO2 theoretically from first principles. Competing pathways for Li diffusion are investigated using the climbing-image nudged-elastic-band approach with periodic quantum-chemical density functional theory (DFT) method. Li can migrate between two regular LiO4 tetrahedral sites via Li point defect (VLi) and via a Li Frenkel defect (VLi + Lii). On the basis of calculated activation energies for Li diffusion pathways, it is concluded that Li conductivity is strongly dependent on the distribution of Li vacancies and interstitial Li in the lattice. For Frenkel defects where Lii is far away from the migrating Li atom, the calculated activation energies for jumps to nearest-neighbor vacant sites agree with experimental values.
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We review recent theoretical studies on ion diffusion in (Li(2)O)(x)(B(2)O(3))(1-x) compounds and at the interfaces of Li(2)O :B(2)O(3) nanocomposite. The investigations were performed theoretically using DFT and HF/DFT hybrid methods with VASP and CRYSTAL codes. For the pure compound B(2)O(3), it was theoretically confirmed that the low-pressure phase B(2)O(3)-I has space group P3(1)21. For the first time, the structure, stability and electronic properties of various low-index surfaces of trigonal B(2)O(3)-I were investigated at the same theoretical level. The (101) surface is the most stable among the considered surfaces. Ionic conductivity was investigated systematically in Li(2)O, LiBO(2), and Li(2)B(4)O(7) solids and in Li(2)O:B(2)O(3) nanocomposites by calculating the activation energy (E(A)) for cation diffusion. The Li(+) ion migrates in an almost straight line in Li(2)O bulk whereas it moves in a zig-zag pathway along a direction parallel to the surface plane in Li(2)O surfaces. For LiBO(2), the migration along the c direction (E(A) = 0.55 eV) is slightly less preferable than that in the xy plane (E(A) = 0.43-0.54 eV). In Li(2)B(4)O(7), the Li(+) ion migrates through the large triangular faces of the two nearest oxygen five-vertex polyhedra facing each other where E(A) is in the range of 0.27-0.37 eV. A two-dimensional model system of the Li(2)O :B(2)O(3) interface region was created by the combination of supercells of the Li(2)O (111) surface and the B(2)O(3) (001) surface. It was found that the interface region of the Li(2)O:B(2)O(3) nanocomposite is more defective than Li(2)O bulk, which facilitates the conductivity in this region. In addition, the activation energy (E(A )) for local hopping processes is smaller in the Li(2)O :B(2)O(3) nanocomposite compared to the Li(2)O bulk. This confirms that the Li(2)O:B(2)O(3) nanocomposite shows enhanced conductivity along the phase boundary compared to that in the nanocrystalline Li(2)O.
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Magnetic, structural, and defect properties of lithium vanadium hexafluoride (α-Li3VF6) are investigated theoretically with periodic quantum chemical methods. It is found that the ferromagnetic phase is more stable than the antiferromagnetic phase. The crystal structure contains three inequivalent Li sites (Li(1), Li(2), and Li(3)), where Li(1) occupies the middle position of the triplet Li(2)-Li(1)-Li(3). The calculated Li vacancy formation energies show that vacancy formation is preferred for the Li(1) and Li(3) sites compared to the Li(2) position. The Li exchange processes between Li(1) â Li(3), Li(1) â Li(2), and Li(2) â Li(3) are studied by calculating the Li(+) migration between these sites using the climbing-image nudged elastic band approach. It is observed that Li exchange in α-Li3VF6 may take place in the following order: Li(1) â Li(3) > (Li(1) â Li(2) > Li(2) â Li(3). This is in agreement with recently published results obtained from 1D and 2D (6)Li exchange nuclear magnetic resonance spectroscopy.
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In Bangladesh, serological tests have been widely used for the primary screening of visceral leishmaniasis (VL). Several serologic tests are available for the diagnosis of VL. Selection of the best test is important to permit diagnostic differentiation between symptomatic and asymptomatic patients and to reduce cross-reactivity. We evaluated the effectiveness of a new serological test "Onsite Leishmania Ab Rapid Test" as a part of "quality assurance" activities for the kala azar elimination programme of the Government of Bangladesh. Plasma samples of 100 parasitologically confirmed cases of VL along with 101 healthy controls were tested, and "Onsite Leishmania Ab Rapid Test" strip tests were positive in 94 out of 100 confirmed VL cases, whereas four out of 51 healthy subjects from the VL endemic areas also tested positive. All the 50 healthy volunteers tested negative. Thus, the sensitivity and specificity of "Onsite Leishmania Ab Rapid Test" strip test were found to be 94% (95% CI: 87-98) and 96% (95% CI: 90-99), respectively. This study showed that the performance of the "Onsite Leishmania Ab Rapid Test" strip tests was up to the recommended level.
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The electronic properties of vanadium-doped rutile TiO(2) are investigated theoretically with a Hartree-Fock/DFT hybrid approach. The most common oxidation states (V(2+), V(3+), V(4+), and V(5+)) in different spin states are investigated and their relative stability is calculated. The most stable spin states are quartet, quintet, doublet, and singlet for V(2+), V(3+), V(4+), and V(5+) doping, respectively. By comparing the formation energy with respect to the parent oxides and gas-phase oxygen (ΔE), we conclude that V(4+) (ΔE=145.3 kJ mol(-1)) is the most likely oxidation state for vanadium doping with the possibility of V(5+) doping (ΔE=283.5 kJ mol(-1)). The energetic and electronic properties are converged with dopant concentrations in the range of 0.9 to 3.2%, which is within the experimentally accessible range. The investigation of electronic properties shows that V(4+) doping creates both occupied and unoccupied vanadium states in the band gap and V(5+) doping creates unoccupied states at the bottom of the conduction band. In both cases there is a significant reduction of the band gap by 0.65 to 0.75 eV compared to that of undoped rutile TiO(2).