Investigating the role of Gag in protease inhibitor susceptibility amongst West African HIV-1 subtypes

HIV-1 Gag contributes to susceptibility of protease inhibitors (PIs) in the absence of known resistance mutations in the protease gene. For the majority of HIV-infected patients worldwide, PIs are the second, and last-line of therapy. Clinically, only around 20% of individuals who fail PI regimen develop major resistance mutations in protease. We previously showed that full-length Gagprotease-derived phenotypic susceptibility to PIs differed between HIV-1 CRF02_AG and subtype G-infected patients who went on to successfully suppress viral replication versus those who experienced virological failure of boosted lopinavir monotherapy as first-line treatment in a clinical trial. We hypothesised therefore that baseline PI susceptibility by Gag-protease phenotyping could be used to predict treatment outcomes for patients on second line, boosted-PI treatment in the real-world clinical setting in Nigeria, where subtypes CRF02_AG/G dominate the epidemic. We used clinical and demographic data; HIV-1subtype, sex, age, viral load, duration of treatment and baseline CD4 count to match individuals who experienced second-line failure with ritonavir-boosted PI-based ART (‘baseline failures’) to those who achieved virological response (‘baseline successes’) with virological failure defined by viral load <400 copies of HIV-1 RNA/mL by week 48. Using a single replication-cycle assay, we carried out in vitro phenotypic susceptibility testing of patient-derived viruses from these two groups. We found no impact of baseline HIV-1 Gagprotease-derived phenotypic susceptibility on outcomes of PI-based second-line ART, treatment outcome could not be predicted using baseline susceptibility alone. Secondly, we sought to explore the role of mutation in Gag-protease genotypic and phenotypic changes within patients who failed PI-based regimens without known drug resistance-associated protease mutations in order to identify novel determinants of PI resistance. We used longitudinal samples collected at baseline, and at virological failure to explore the role of Gag mutations. Using target enrichment and next-generation sequencing (NGS), followed by haplotype reconstruction and phenotypic drug assays and phylogenetic analysis, we reported for the first time a four-amino acid mutation signature in HIV-1, CRF02_AG matrix (S126del, H127del, T122A and G123E) which confer reduced susceptibility to the PI, lopinavir and atazanavir. Our multi-pronged genotypic and phenotypic approach to document emergence and temporal dynamics of a novel protease inhibitor resistance signature in HIV- 1 matrix domain reveals the interplay between Gag associated resistance and fitness

Pubic bone injuries in primiparous women: magnetic resonance imaging in detection and differential diagnosis of structural injury

Objective To evaluate the utility of magnetic resonance imaging (MRI) in diagnosing structural injury in primiparous women at risk for pelvic floor injury. Methods This was an observational study of 77 women who underwent 3T MRI after delivery. Women were operationally defined as high risk ( n = 45) for levator ani muscle tears (risk factors: second‐stage labor > 150 min or 35 years and birth weight > 4000 g) or low risk ( n = 32): vaginally delivered without these risk factors ( n = 12); delivered by Cesarean section after second‐stage labor > 150 min ( n = 14) or delivered by Cesarean section without labor ( n = 6). All women were imaged using fluid‐sensitive MRI sequences. Two musculoskeletal radiologists reviewed images for bone marrow edema, fracture, pubic symphysis measurements and levator ani tear. Results MRI showed pubic bone fractures in 38% of women at high risk for pelvic floor injury and in 13% of women at low risk for pelvic floor injury (χ 2 (3) = 9.27, P = 0.03). Levator ani muscle tears were present in 44% of the high‐risk women and in 9% of the low‐risk women (χ 2 (3) = 11.57, P = 0.010). Bone marrow edema in the pubic bones was present in 61% of women studied across delivery categories. Complex patterns of injury included combinations of bone marrow edema, fractures, levator ani tears and pubic symphysis injuries. No MRI‐documented injuries were present in 18% of women at high risk and 44% at low risk for pelvic floor injury (χ 2 (1) = 6.2, P = 0.013). Conclusions Criteria identifying primiparous women at risk for pelvic floor injury can predict increased risk of bone and soft tissue changes at the pubic symphysis. Fluid‐sensitive MRI has utility for differential diagnosis of structural injury in postpartum women. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90593/1/9082_ftp.pd

OTMM based Proposal Classification and Clustering

In the current environment, important task in any agencies (government, private) are to be selection proper search proposal. The proposal groups into the respective discipline when the large number of proposals are received .There is need to classify research proposals into proper categories automatically this will speed up the research proposal classification work. The technique used for proposals classification is OTTM Based on this respective discipline proposal assign to their expert for verification and review purpose

Personal, Socio-economic, Communicational and Psychological Characteristics of Orange Growers

Maharashtra is the one of the largest producer of orange in the country. There is growing interest and awareness among the orange growers for adoption of latest technologies for commercial cultivation of citrus hence the research objective was formulated to study the personal, socio-economic, communicational and psychological characteristics of orange growers in Amravati and Nagpur district in Vidarbha region of Maharashtra state. An ex-post facto research design of social research was used for present investigation. The study was conducted in Amravati and Nagpur district in month of December, January and February, 2021, with 300 orange growers. The findings revealed that, more than one third of the respondents (34.00%) had education up to higher secondary school. More than two fifth of the respondents (44.00%) had medium family size. More than one third (38.67%) of the respondents were engaged in agriculture+ horticulture+ allied occupation as their main occupation in earning. Nearly half (46.33%) of the respondents had semi medium land holding (2.01 to 4.00 ha). More than half (60.67%) of the respondents were having small size of orchard. More than one third (37.33%) of the respondents had medium experience in orange cultivation (15.36 to 26.66 years). more than half (57.33%) of the respondents were belonged to medium level of social participation. Nearly half (45.67%) of the respondents were having annual income up to Rs. 7,96,000/-. Majority of the social media user respondents (88.00%) had high availability of social media. More than half (55.67%) of the respondents were having medium sources of information. More than half (59.67%) of the respondents were having medium innovativeness. More than half (56.67%) of the respondents were having medium risk orientation. Majority (63.33%) of the respondents were having medium market orientation. Overall 70.00 Percent of the social media user orange growers were having high utilization pattern index. It is suggested that, efforts should made by authorities to involve and retain the interest of innovative orange growers in adopting modern agricultural practices

Radio-histopathological Presentation and Multidisciplinary Treatment of Adolescent Paratesticular Rhabdomyosarcoma: A Case Report

Paratesticular rhabdomyosarcoma (PRMS) is a rare condition predominantly affecting the pediatric and adolescent population. In this case report, we discuss a 17-year-old male with a slow-growing, painless scrotal mass, ultimately diagnosed as embryonal PRMS — the most common and favorable rhabdomyosarcoma subtype. The report underscores the typical clinico-radiological presentation of PRMS and the pivotal part of histopathological evaluation in establishing a definitive diagnosis. Multidisciplinary intervention including surgery and chemoradiotherapy resulted in total remission. Therefore, this report underlines the significance of prompt diagnosis and comprehensive management in ensuring a favorable prognosis of PRMS

Transgenic Approaches for Nutritional Enhancement of Potato

Potatoes provide an excellent source of carbohydrates, minerals, vitamins, carotenoids, anthocyanins, and several other metabolites which play an important role in human nutrition. These bioactive compounds are effective in preventing diseases like cancer, diabetes, and heart-related issues. In addition to their industrial uses, potatoes are a major focus of genetic engineering programs for the modification of nutritional properties. Several important candidate genes operating in phenylpropanoid mechanism, ascorbic acid biosynthesis pathway, carbohydrate metabolism, steroidal glycoalkaloid biosynthesis pathway, and other-related metabolic steps have been cloned and characterized at the biochemical and molecular levels. Overexpression and down regulation of genes operating in these pathways has revealed important insights into improved nutritional quality. Expression of a transgene has successfully resulted in increasing carotenoids, anthocyanins, and vitamin content in transgenic tubers. Reduction in glycoalkaloid content, enzymatic browning, flesh color, and chipping quality has been achieved via modification of the genes involved in the respective biochemical pathway in potatoes. Transgenic approaches not only resulted in improved quality but also helped in understanding the biochemical and molecular mechanisms associated with the regulation of genes in these pathways. Although the commercialization of transgenic potatoes is still hindered by consumers approval and ethical restrictions, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system holds promise as a non-transgenic alternative for developing nutritionally enhanced potatoes

Expectations and Problems of Rural Youth to become Agri-entrepreneur

The present study was conducted in Chandrapur and Gadchiroli districts of Eastern Vidarbha Zone of Maharashtra. An exploratory research design of social research was used for investigation. A sample of 120 rural youth were selected by covering 20 villages from two districts on the basis of higher population of rural youth. The two objectives were studied, to study the expectations of rural youth towards agri-entrepreneurship and problems of rural youth to become agri-entrepreneur. Majority of the respondents had expectation to earn more money (95.00%), provide technical knowledge and skill oriented training program about agri-enterprises (84.16%), to gain social status through agri entrepreneurship (77.50%), provide market place to sell agri product (70.83%), government should provide credit/ loan facilities to start agri-enterprises (65.83%) and receive the higher prices to their agri products (70.83%), respectively.  The overall 45.00 per cent of respondents had high level of expectations about agri-entrepreneurship. Majority of the respondents were reported problems, lack of proper training and guidance (93.33%), lack of experience in agri-enterprises (90.00%), lack of support from government and other organizational policies, rules and regulations (85.00%), fear about starting of new enterprises (82.50%) and financial/ capital problem (78.33%), respectively

HIV-1 viral load is elevated in individuals with reverse transcriptase mutation M184V/I during virological failure of first line antiretroviral therapy and is associated with compensatory mutation L74I

Background: M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance, and increased tenofovir (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against HIV-1 with these mutations possibly as a result of reduced replication capacity. Here we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside RT inhibitor (NNRTI)-containing regimen. Methods: We compared VL in absence and presence M184V/I across studies using random effects meta-analysis. The effect of mutations on virus RT activity and infectiousness was analysed in vitro. Results: M184I/V was present in 817 (56.5%) of 1445 individuals with VF. VL was similar in individuals with or without M184I/V (difference in log10VL 0.18, 95% CI 0.05-0.31). CD4 count was lower both at initiation of ART and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (p<0.0001). In vitro, L74I compensated for defective replication of M184V mutated virus. Conclusion: Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. We therefore do not find evidence for a benefit of XTC in the context of first line failure on this combination

A Review on Topical Gels as Drug Delivery System

The clinical evidence indicates that topical gel is a safe and most effective treatment option for use in the management of skin related disease and used for local action to reduce the side effects associated with other conventional dosage form. Topical drug delivery systems include a large variety of pharmaceutical dosage form like semisolids, liquid preparation, sprays and solid powders. Most widely used semisolid preparation for topical drug delivery includes gels, creams and ointments. A gel is a cross-linked polymer network swollen in a liquid medium. Its properties depend strongly on the interaction between solid state polymer and the liquid component. Gels exhibit no steady-state flow. The interaction between polymer and the liquid dispersion medium form an interlacing three dimensional network of particles of dispersed phase. The increased viscosity caused by interlacing and consequential internal friction is responsible for the semisolid state. Topical gel formulation provides a suitable delivery system for drugs because they are less greasy and can be easily removed from the skin. Gel formulation provides better application property and stability in comparison to cream and ointments. Keywords: Topical, drug delivery, gels, review, skin. Percutaneous penetration, drug delivery, organogels, Hydrogel

HIV-1 viral load is elevated in individuals with reverse transcriptase mutation M184V/I during virological failure of first line antiretroviral therapy and is associated with compensatory mutation L74I

Background: M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance, and increased tenofovir (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against HIV-1 with these mutations possibly as a result of reduced replication capacity. Here we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside RT inhibitor (NNRTI)-containing regimen. / Methods: We compared VL in absence and presence M184V/I across studies using random effects meta-analysis. The effect of mutations on virus RT activity and infectiousness was analysed in vitro. / Results: M184I/V was present in 817 (56.5%) of 1445 individuals with VF. VL was similar in individuals with or without M184I/V (difference in log10VL 0.18, 95% CI 0.05-0.31). CD4 count was lower both at initiation of ART and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (p<0.0001). In vitro, L74I compensated for defective replication of M184V mutated virus. / Conclusion: Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. We therefore do not find evidence for a benefit of XTC in the context of first line failure on this combination