Although combination antiretroviral therapy (ART) with three or more drugs is highly effective in suppressing viral load for people with HIV (human immunodeficiency virus), many ART agents may ...exacerbate mental health‐related adverse effects including depression. Therefore, understanding the effects of combination ART on mental health can help clinicians personalize medicine with less adverse effects to avoid undesirable health outcomes. The emergence of electronic health records offers researchers' unprecedented access to HIV data including individuals' mental health records, drug prescriptions, and clinical information over time. However, modeling such data is challenging due to high dimensionality of the drug combination space, the individual heterogeneity, and sparseness of the observed drug combinations. To address these challenges, we develop a Bayesian nonparametric approach to learn drug combination effect on mental health in people with HIV adjusting for sociodemographic, behavioral, and clinical factors. The proposed method is built upon the subset‐tree kernel that represents drug combinations in a way that synthesizes known regimen structure into a single mathematical representation. It also utilizes a distance‐dependent Chinese restaurant process to cluster heterogeneous populations while considering individuals' treatment histories. We evaluate the proposed approach through simulation studies, and apply the method to a dataset from the Women's Interagency HIV Study, showing the clinical utility of our model in guiding clinicians to prescribe informed and effective personalized treatment based on individuals' treatment histories and clinical characteristics.
Background Data on the prevalence and correlates of restless legs syndrome (RLS) in people with HIV are limited. This study sought to determine the prevalence of RLS, associated clinical correlates, ...and characterize sleep-related differences in men with and without HIV. Methods Sleep-related data were collected in men who have sex with men participating in the Multicenter AIDS Cohort Study (MACS). Demographic, health behaviors, HIV status, comorbidities, and serological data were obtained from the MACS visit coinciding with sleep assessments. Participants completed questionnaires, home polysomnography, and wrist actigraphy. RLS status was determined with the Cambridge-Hopkins RLS questionnaire. RLS prevalence was compared in men with and without HIV. Multinomial logistic regression was used to examine correlates of RLS among all participants and men with HIV alone. Sleep-related differences were examined in men with and without HIV by RLS status. Results The sample consisted of 942 men (56% HIV+; mean age 57 years; 69% white). The prevalence of definite RLS was comparable in men with and without HIV (9.1% vs 8.7%). In multinomial regression, HIV status was not associated with RLS prevalence. However, white race, anemia, depression, and antidepressant use were each independently associated with RLS. HIV disease duration was also associated with RLS. Men with HIV and RLS reported poorer sleep quality, greater sleepiness, and had worse objective sleep efficiency/fragmentation than men without HIV/RLS. Conclusions The prevalence of RLS in men with and without HIV was similar. Screening for RLS may be considered among people with HIV with insomnia and with long-standing disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Combination antiretroviral therapy (ART) with at least three different drugs has become the standard of care for people with HIV (PWH) due to its exceptional effectiveness in viral suppression. ...However, many ART drugs have been reported to associate with neuropsychiatric adverse effects including depression, especially when certain genetic polymorphisms exist. Pharmacogenetics is an important consideration for administering combination ART as it may influence drug efficacy and increase risk for neuropsychiatric conditions. Large-scale longitudinal HIV databases provide researchers opportunities to investigate the pharmacogenetics of combination ART in a data-driven manner. However, with more than 30 FDA-approved ART drugs, the interplay between the large number of possible ART drug combinations and genetic polymorphisms imposes statistical modeling challenges. We develop a Bayesian approach to examine the longitudinal effects of combination ART and their interactions with genetic polymorphisms on depressive symptoms in PWH. The proposed method utilizes a Gaussian process with a composite kernel function to capture the longitudinal combination ART effects by directly incorporating individuals' treatment histories, and a Bayesian classification and regression tree to account for individual heterogeneity. Through both simulation studies and an application to a dataset from the Women's Interagency HIV Study, we demonstrate the clinical utility of the proposed approach in investigating the pharmacogenetics of combination ART and assisting physicians to make effective individualized treatment decisions that can improve health outcomes for PWH.
Realistic in vitro models are critical in the drug development process. In this study, a novel in vitro platform is employed to assess drug penetration and metabolism. This platform, which utilizes a ...3D printed fluidic device, allows for dynamic dosing of three dimensional cell cultures, also known as spheroids. The penetration of the chemotherapeutic irinotecan into HCT 116 colon cancer spheroids was examined with MALDI imaging mass spectrometry (IMS). The active metabolite of irinotecan, SN‐38, was also detected. After twenty‐four hours of treatment, SN‐38 was concentrated to the outside of the spheroid, a region of actively dividing cells. The irinotecan prodrug localization contrasted with SN‐38 and was concentrated to the necrotic core of the spheroids, a region containing mostly dead and dying cells. These results demonstrate that this unique in vitro platform is an effective means to assess drug penetration and metabolism in 3D cell cultures. This innovative system can have a transformative impact on the preclinical evaluation of drug candidates due to its cost effectiveness and high throughput.
Objective
To examine the etiologies, risk factors, and microbiology of bloodstream infections (BSIs) among intestinal and multivisceral transplant recipients in the 2‐year post‐operative period.
...Methods
A retrospective medical record review of adult intestinal or multivisceral transplant recipients between 2003 and 2015. Descriptive statistics were used to describe cohort data. Logistic regression was used to assess factors related to BSIs using a backward selection process.
Results
One‐hundred and six intestinal or multivisceral transplants were performed in 103 individuals. Fifty‐eight percent (n = 62) developed a BSI in the 2‐year post‐operative period with a median time to first BSI of 53 days (interquartile range IQR 15, 169). The majority of BSIs were catheter related 38% (n = 58) when the source was known. Common microbiological isolates included enterococcus 20% (n = 36/174), coagulase‐negative staphylococcus 14% (n = 23), and 12% Klebsiella spp (n = 21). Forty‐seven percent (n = 17) of the enterococci were resistant to vancomycin, and 14% (n = 10/70) of the gram negatives were extended spectrum beta‐lactamase (ESBL) producers. In adjusted analyses, (OR: 0.200 95% CI: 0.2, 0.514, P = .009) men were less likely to have a BSI. Transplant recipient age, allograft type, comorbidities, rejection, and length of stay were not noted to be risk factors for development of BSIs in our cohort. Mortality at 2‐years post‐transplant was similar for those who did not develop a BSI and those that developed infection, P = .5028.
Conclusions
BSIs are a common complication of intestinal transplantation, and central venous catheters were a common source. Interventions such as early catheter removal should be implemented to prevent infections in this population. Female sex association with BSI requires further investigation.
Since 2000, there have been rising rates of syphilis infections nationally with higher incidence among minorities and persons living with human immunodeficiency virus (HIV) (PLWH). The purpose of ...this study was to determine syphilis treatment adequacy and factors associated with treatment delay.
This was a retrospective academic-public health collaboration with the District of Columbia Department of Public Health reviewing surveillance data of all primary, secondary, and early latent syphilis cases diagnosed between January 1, 2015, and December 31, 2019. Data were analyzed using multivariable logistic regression to identify factors associated with delayed treatment >14 days from diagnosis.
Among 1852 individuals diagnosed with early syphilis, 93% (1730/1852) were male; 48% (893/1852) were coinfected with HIV; 43% (n = 796/1852) were African American/Black, 27% (n = 492/1852) were White, and race/ethnicity was unknown for 17% (n = 318/1852) of cases. Among 679 PLWH for whom viral load (VL) was known, 41% (278/679) had a VL < 20 copies/mL, and 18% (123/679) had VL >10,000 copies/mL. Treatment adequacy overall was 96.5%. Median time to syphilis treatment was 6 days (interquartile range = 4-7). Factors associated with delay of treatment included refused/unknown race (adjusted odds ratio aOR, 1.95; 95% confidence interval CI, 1.00-3.79), and HIV VL > 10,000 copies/mL (aOR, 1.97; 95% CI, 1.08-3.58).
The factors we identified associated with delayed treatment may reflect systemic factors contributing to the increased rates of infection among key populations. This highlights the importance of targeted public health efforts with the goal of reducing transmission of both HIV and syphilis.
Access and adherence to antiretroviral therapy (ART) has transformed the face of HIV infection from a fatal to a chronic disease. However, ART is also known for its side effects. Studies have ...reported that ART is associated with depressive symptomatology. Large-scale HIV clinical databases with individuals' longitudinal depression records, ART medications, and clinical characteristics offer researchers unprecedented opportunities to study the effects of ART drugs on depression over time. We develop BAGEL, a Bayesian graphical model to investigate longitudinal effects of ART drugs on a range of depressive symptoms while adjusting for participants' demographic, behavior, and clinical characteristics, and taking into account the heterogeneous population through a Bayesian nonparametric prior. We evaluate BAGEL through simulation studies. Application to a dataset from the Women's Interagency HIV Study yields interpretable and clinically useful results. BAGEL not only can improve our understanding of ART drugs effects on disparate depression symptoms, but also has clinical utility in guiding informed and effective treatment selection to facilitate precision medicine in HIV.
While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and ...depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms.
Analysis of longitudinal data from the Women's Interagency HIV Study.
Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment.
The analysis included 1538 WWH who participated in 12 924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with nonsomatic symptoms in any group.
Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression.
Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus ...and age modify the GCR function-cognition association among women.
Eighty women with HIV ( n = 40, <40 years of age younger; n = 40, >50 years of age older) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates.
Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation.
Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.
This study compared the mutation profile and tumor mutational burden (TMB) in women with HIV (WWH) diagnosed with lung adenocarcinoma (n = 8) or breast ductal neoplasm (n = 13) who were enrolled into ...the Women's Interagency HIV Study (WIHS).
Previous studies tended to focus on single institutions based on sample availability. This study is based on a representative, multicenter cohort that represents the racial and ethnic composition of women with HIV in the United States.
The study sequenced the complete human exome of n = 26 cancer samples from HIV-positive women, using Ion torrent next-generation sequencing. The study cohort was compared with a HIV-negative cohort obtained from the Genomic Data Commons Data Portal of the NCI.
There were no differences in known cancer mutations between breast cancer and lung cancer that developed in WWH and those that developed in HIV-negative (HIV-) women; however, WWH presented a significantly higher TMB in comparison to HIV- patients. Seventy-five percent of lung cancers and 61% of breast cancers were defined as TMB-high (more than 10 mutation/mb of DNA).
This study affirms the recommendation that WWH be included in clinical trials of novel treatments for these cancers. Although these data are preliminary, the high TMB in WLHV suggests, paradoxically, that this immune challenged population may benefit greatly from immune checkpoint inhibitor therapies.
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