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AIDS (London, England) Jul 2020To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral...
OBJECTIVE
To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.
DESIGN
Prospective cohort study of CHEU enrolled from 2007 to 2017.
METHODS
We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.
RESULTS
Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4--7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94--2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09--3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11--4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07--4.87 and aRR = 2.02, 95% CI 1.01--4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75--7.84), which was observed consistently across several sensitivity analyses.
CONCLUSION
Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring.
Topics: Abnormalities, Drug-Induced; Adult; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Treatment Outcome
PubMed: 32310900
DOI: 10.1097/QAD.0000000000002550 -
MSystems Apr 2020As of today (7 April 2020), more than 81,000 people around the world have died from the coronavirus disease 19 (COVID-19) pandemic. There is no approved drug or vaccine...
As of today (7 April 2020), more than 81,000 people around the world have died from the coronavirus disease 19 (COVID-19) pandemic. There is no approved drug or vaccine for COVID-19, although more than 10 clinical trials have been launched to test potential drugs. In an urgent response to this pandemic, I developed a bioinformatics pipeline to identify compounds and drug candidates to potentially treat COVID-19. This pipeline is based on publicly available single-cell RNA sequencing (scRNA-seq) data and the drug perturbation database "Library of Integrated Network-Based Cellular Signatures" (LINCS). I developed a ranking score system that prioritizes these drugs or small molecules. The four drugs with the highest total score are didanosine, benzyl-quinazolin-4-yl-amine, camptothecin, and RO-90-7501. In conclusion, I have demonstrated the utility of bioinformatics for identifying drugs than can be repurposed for potentially treating COVID-19 patients.
PubMed: 32291351
DOI: 10.1128/mSystems.00297-20 -
Viruses Apr 2020Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the...
Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of -correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with . Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.
Topics: Angiotensin-Converting Enzyme 2; Anti-Inflammatory Agents; Antiviral Agents; Betacoronavirus; COVID-19; Computational Biology; Computer Simulation; Coronavirus Infections; Databases, Genetic; Drug Discovery; Gene Expression Profiling; Gene Regulatory Networks; Humans; Lung; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Interaction Mapping; Receptors, Coronavirus; Receptors, Virus; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32268515
DOI: 10.3390/v12040404 -
Saudi Pharmaceutical Journal : SPJ :... Mar 2020The aim of these studies was to determine the miscibility of different API with lipid excipients to predict drug loading and encapsulation properties for the production...
The use of quantitative analysis and Hansen solubility parameter predictions for the selection of excipients for lipid nanocarriers to be loaded with water soluble and insoluble compounds.
The aim of these studies was to determine the miscibility of different API with lipid excipients to predict drug loading and encapsulation properties for the production of solid lipid nanoparticles and nanostructured lipid carriers. Five API exhibiting different physicochemical characteristics, ., clarithromycin, efavirenz, minocycline hydrochloride, mometasone furoate, and didanosine were used and six solid lipids in addition to four liquid lipids were investigated. Determination of solid and liquid lipids with the best solubilization potential for each API were performed using a traditional shake-flask method and/or a modification thereof. Hansen solubility parameters of the API and different solid and liquid lipids were estimated from their chemical structure using Hiroshi Yamamoto's molecular breaking method of Hansen Solubility Parameters in Practice software. Experimental results were in close agreement with solubility parameter predictions for systems with ΔδT < 4.0 MPa. A combination of Hansen solubility parameters with experimental drug-lipid miscibility tests can be successfully applied to predict lipids with the best solubilizing potential for different API prior to manufacture of solid lipid nanoparticles and nanostructured lipid carriers.
PubMed: 32194332
DOI: 10.1016/j.jsps.2020.01.010 -
European Review For Medical and... Feb 2020The current study was designed to investigate the effects of some nucleoside reverse transcriptase inhibitors (NRTIs) on HSV-1 infection.
OBJECTIVE
The current study was designed to investigate the effects of some nucleoside reverse transcriptase inhibitors (NRTIs) on HSV-1 infection.
MATERIALS AND METHODS
Initially, the SwissTargetPrediction server was used to predict the interactions between HSV-1 thymidine kinase and acyclovir, stavudine, zidovudine, didanosine, and entecavir. The effect of each component on Vero cell viability was assessed by the MTT assay. After treatment, the cell supernatants were collected, and HSV-1 replication was analyzed by quantitative real-time PCR.
RESULTS
The qPCR results revealed that viral titers were reduced 41, 40, 19, 44, and 31-fold in the presence of acyclovir, zidovudine, stavudine, didanosine, and entecavir, respectively.
CONCLUSIONS
Our findings indicate that NRTIs significantly reduce HSV-1 replication in cell culture.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Dose-Response Relationship, Drug; Herpesvirus 1, Human; Reverse Transcriptase Inhibitors; Vero Cells; Virus Replication
PubMed: 32096195
DOI: 10.26355/eurrev_202002_20204 -
International Journal of Retina and... 2019To describe the peripheral retinal findings associated with systemic medication toxicity and to outline the importance of ultra-widefield imaging in the detection,... (Review)
Review
BACKGROUND
To describe the peripheral retinal findings associated with systemic medication toxicity and to outline the importance of ultra-widefield imaging in the detection, analysis and monitoring of these abnormalities.
MAIN TEXT
This review highlights the retinal manifestations associated with the more common drug toxicities, with emphasis on the peripheral features and the indications for wide field imaging. The presenting findings, underlying pathophysiology, and retinal alterations in hydroxychloroquine, thioridazine, didanosine, tamoxifen, MEK-inhibitor, and immune checkpoint inhibitor associated drug toxicity will be described and the importance of wide field imaging in the evaluation of these abnormalities will be emphasized.
CONCLUSIONS
Wide field retinal imaging can improve the detection of peripheral retinal abnormalities associated with drug toxicity and may be an important tool in the diagnosis and management of these disorders.
PubMed: 31890286
DOI: 10.1186/s40942-019-0172-0 -
AIDS Research and Human Retroviruses Mar 2020Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS... (Observational Study)
Observational Study
Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine whether haplogroup is associated with frailty and its components among older PWH. A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, gender, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (standard deviation 7.5) years and median nadir CD4 count was 212 (interquartile range 72, 324) cells/μL; 6% were frail, 7% had slow gait, and 21% weak grip. H haplogroup participants were more likely to be frail/prefrail ( = .064), have slow gait ( = .09), or weak grip ( = .017) compared with non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail versus nonfrail [odds ratio (OR) 4.0 (95% confidence interval 1.0-15.4)] and having weak grip [OR 2.1 (1.1, 4.1)], but not slow gait [OR 1.6 (0.5, 5.0)] compared with non-H haplogroup. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Among antiretroviral therapy (ART)-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.
Topics: Adult; Aging; CD4 Lymphocyte Count; Cohort Studies; Cross-Sectional Studies; DNA, Mitochondrial; Female; Frailty; HIV Infections; Haplotypes; Hispanic or Latino; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Factors; Walking Speed
PubMed: 31822125
DOI: 10.1089/AID.2019.0233 -
Medicine Nov 2019To assess the utility of spleen stiffness as a diagnostic tool in individuals with human immunodeficiency virus (HIV) and non-cirrhotic portal hypertension (NCPH).The...
To assess the utility of spleen stiffness as a diagnostic tool in individuals with human immunodeficiency virus (HIV) and non-cirrhotic portal hypertension (NCPH).The Philips EPIQ7, a new point shearwave elastography (pSWE) technique, was used to assess liver and spleen stiffness in 3 patient groups. Group 1: HIV and NCPH (n = 11); Group 2: HIV with past didanosine (ddI) exposure without known liver disease or NCPH (n = 5); Group 3: HIV without known liver disease or ddI exposure (n = 9).Groups were matched for age, HIV chronicity, and antiretroviral treatment (including cumulative ddI exposure in Groups 1 and 2). Differences in liver and spleen stiffness (in kPa) between groups were analyzed using the Mann-Whiney U test.Liver and spleen stiffness were both significantly higher in NCPH versus ddI-exposed (P = .019 and P = .006) and ddI-unexposed controls (P = .038 and P < .001). Spleen stiffness was more effective than liver stiffness at predicting NCPH, area under receiver operating characteristic (AUROC) 0.812 versus 0.948. Combining the 2 variables improved the diagnostic performance, AUROC 0.961. The optimal cut-off for predicting NCPH using splenic stiffness was 25.4 kPa, with sensitivity 91%, specificity 93%, positive predictive value (PPV) 91%, negative predictive value (NPV) 93%, positive likelihood ratio 12.73, negative likelihood ratio 0.10. Spleen and liver stiffness scores were strongly correlated (P = .0004, 95% confidence interval [CI] 18, 59).Elevated spleen stiffness is observed in HIV with NCPH and can be quantified easily using pSWE with high diagnostic accuracy. Novel strategies such as pSWE for longitudinal monitoring of patients with HIV and NCPH should be considered.
Topics: Cross-Sectional Studies; Elasticity Imaging Techniques; Female; HIV Infections; Humans; Hypertension, Portal; Male; Middle Aged; Prospective Studies; Spleen
PubMed: 31764798
DOI: 10.1097/MD.0000000000017961 -
Scientific Reports Oct 2019We investigated the effects of treating differentiated retinal pigment epithelial (RPE) cells with didanosine (ddI), which is associated with retinopathy in individuals...
We investigated the effects of treating differentiated retinal pigment epithelial (RPE) cells with didanosine (ddI), which is associated with retinopathy in individuals with HIV/AIDS. We hypothesized that such treatment would cause depletion of mitochondrial DNA and provide insight into the consequences of degradation of RPE mitochondrial function in aging and disease. Treatment of differentiated ARPE-19 or human primary RPE cells with 200 µM ddI for 6-24 days was not cytotoxic but caused up to 60% depletion of mitochondrial DNA, and a similar reduction in mitochondrial membrane potential and NDUFA9 protein abundance. Mitochondrial DNA-depleted RPE cells demonstrated enhanced aerobic glycolysis by extracellular flux analysis, increased AMP kinase activation, reduced mTOR activity, and increased resistance to cell death in response to treatment with the oxidant, sodium iodate. We conclude that ddI-mediated mitochondrial DNA depletion promotes a glycolytic shift in differentiated RPE cells and enhances resistance to oxidative damage. Our use of ddI treatment to induce progressive depletion of mitochondrial DNA in differentiated human RPE cells should be widely applicable for other studies aimed at understanding RPE mitochondrial dysfunction in aging and disease.
Topics: Adenylate Kinase; Cell Differentiation; Cell Line; DNA, Mitochondrial; Didanosine; Epithelial Cells; Glycolysis; Humans; Mechanistic Target of Rapamycin Complex 1; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Retinal Pigment Epithelium
PubMed: 31653972
DOI: 10.1038/s41598-019-51761-1 -
Southern African Journal of HIV Medicine 2019The extent of disclosure of HIV status to children and adolescents and the context facilitating their disclosure process have received little attention.
BACKGROUND
The extent of disclosure of HIV status to children and adolescents and the context facilitating their disclosure process have received little attention.
OBJECTIVES
To assess disclosure and provide a comprehensive analysis of characteristics associated with disclosure to children (3-14 years) receiving antiretroviral treatment in a South African semi-urban clinic.
METHODS
This cross-sectional study used structured interview administered questionnaires which were supplemented with medical record data. Predictors included child, caregiver, clinical and socio-economic characteristics, viral suppression, immune response, adherence, health-related quality of life and family functioning.
RESULTS
We included 190 children of whom 45 (23.7%) received disclosure about their HIV status, of whom 28 (14.7%) were partially disclosed and 17 (8.9%) were fully disclosed. Older age of the child and higher education of the caregiver were strongly associated with disclosure. Female caregivers, detectable viral load, syrup formulation, protease inhibitor (PI) regimens with stavudine and didanosine, and self-reported non-adherence were strongly associated with non-disclosure.
CONCLUSION
When children do well on treatment, caregivers feel less stringent need to disclose. Well-functioning families, higher educated caregivers and better socio-economic status enabled and promoted disclosure. Non-disclosure can indicate a sub-optimal social structure which could negatively affect adherence and viral suppression. There is an urgent need to address disclosure thoughtfully and proactively in the long-term disease management. For the disclosure process to be beneficial, an enabling supportive context is important, which will provide a great opportunity for future interventions.
PubMed: 31534786
DOI: 10.4102/sajhivmed.v20i1.884