Comorbidities and Medication Adherence among Older Individuals Living with HIV in the United States

The number of people living with HIV (PLWH) ≥65 years old is increasing in the United States (US) as PLWH live longer. In 2015, there were nearly 1 million people living with diagnosed HIV in the US and under 10% were age ≥65. By 2035, the proportion of PLWH in this age group is projected to be 27%. Like the general population of elderly individuals, as they age, PLWH face age-related comorbidities, many of which require routine medical care and daily medications, in addition to daily antiretroviral therapy (ART) for treatment of HIV. Previous research has found that PLWH develop these conditions at higher rates and earlier ages than HIV-negative individuals. Therefore, elderly PLWH are particularly vulnerable to the challenges associated with multimorbidity and polypharmacy, including remaining adherent to their medications. However, in the context of PLWH, “older” has typically been defined as \u3e50 years old, with few studies analyzing PLWH age ≥65, a relevant population given Medicare insurance eligibility in the US. Additionally, there is a dearth of literature focusing on older HIV-positive women and comorbidities. Gaining a better understanding of the non-HIV-related comorbid disease and non-ART comedication burden among PLWH age ≥65 is important because these comorbidities often require care coordination among multiple providers and because comorbidities may negatively impact adherence to ART. With a focus on PLWH aged ≥65 living in the US, the objectives of this dissertation were: (1) to compare the non-HIV disease and non-ART medication burden among PLWH and HIV-negative individuals; (2) to describe patterns of non-HIV condition co-occurrence among PLWH and HIV-negative individuals; and (3) to examine the impact of comorbid disease and comedication burden on ART adherence among PLWH. Using data from 2010 to 2015 in the IBM Watson Health MarketScan® Medicare Supplemental insurance database, I selected PLWH and HIV-negative individuals ≥65 years old based on diagnoses on medical claims and pharmacy claims for ART. Outcomes included common diagnoses and medication classes, prevalence and number of non-HIV conditions, daily non-ART medications, and ART medication adherence (using proportion of days covered (PDC) over a 1-year period, all based on medical and pharmacy claims. To address the first dissertation objective, I examined age-standardized prevalence rates for non-HIV conditions and prevalence ratios (PRs) and fit sex-stratified multivariable generalized linear models for the number of non-HIV conditions and number of daily non-ART medications. For the second dissertation objective, I used latent class analysis to identify classes of individuals based on the presence of non-HIV comorbid conditions. Separate latent class models were fit to cohorts of PLWH, HIV-negative individuals, and HIV-negative individuals matched to the PLWH cohort on demographic characteristics. For the third dissertation objective, I modeled the odds of being adherent to ART (defined as PDC ≥80%) using separate adjusted logistic regression models for PLWH treated with ART with the number of comorbid conditions, the number of comedications, and comorbidity classes as the exposures of interest. Dissertation Objective 1: I assessed non-HIV conditions and daily non-ART medications among 2,359 elderly PLWH and 2,010,513 elderly HIV-negative individuals. PLWH were younger (mean age 71 vs. 76 years) and a larger proportion were men (81% vs. 45%). The most common diagnoses among both HIV-positive and HIV-negative cohorts were hypertension and dyslipidemia. Most non-HIV conditions were more prevalent among PLWH. The largest absolute difference was in anemia (29.6 cases per 100 people vs.11.7) and the largest relative difference was in hepatitis C (PR=22.0). The unadjusted mean number of non-HIV conditions and daily non-ART medications were higher for PLWH (4.61 conditions and 3.79 medications) than HIV-negative individuals (3.94 conditions and 3.41 medications), respectively. In generalized linear models with log link and negative binomial distribution where the outcome was the number of non-HIV conditions, PLWH had significantly more non-HIV conditions than HIV-negative individuals (ratios: men=1.272, [95% CI 1.233-1.312]; women=1.326 [1.245-1.413]). Among those with \u3e0 daily non-ART medications, men with HIV had significantly more non-ART medications than HIV-negative men (ratio=1.178 [1.133-1.226]) in a generalized linear model with log link and gamma distribution where the outcome was number of non-ART medications. Dissertation Objective 2: When conditions with prevalence ≥15% among PLWH were included in latent class models, a 3-class solution was identified for cohorts of PLWH, all HIV-negative individuals, and matched HIV-negative individuals: a sickest class with high probabilities of multiple non-HIV conditions, a class characterized by hypertension and dyslipidemia, and a healthiest class with low probabilities of non-HIV conditions. Nearly 20% of the PLWH were assigned to the sickest class compared to 10.5% of the matched HIV-negative cohort, with PLWH having higher probabilities of specific non-HIV diagnoses, including kidney disease and anemia. Dissertation Objective 3: Lastly, when analyzing the odds of being adherent to ART among 1,644 elderly PLWH with logistic regression models, I found that odds of non-adherence were significantly higher among PLWH with 5-6 comorbidities compared to PLWH with 0-2 comorbidities (adjusted odds ratio [AOR]=1.420 [95% CI 1.035-1.947]). After controlling for the number of comedications, PLWH with 5-6 comorbid conditions (AOR=1.589 [95% CI 1.131-2.232]) and PLWH with ≥7 conditions (AOR=1.528 [95% CI 1.049-2.225]) were 50%-60% more likely to be non-adherent than PLWH with 0-2 conditions. Additionally, PLWH belonging to the hypertension/dyslipidemia/diabetes comorbidity class were more likely to be non-adherent than PLWH in the healthiest class (AOR=1.319 [95% CI 1.047-1.661]). In conclusion, I found that the disease burden associated with aging is substantially higher among PLWH age ≥65 than similarly aged HIV-negative individuals, and that there was a trend of decreasing ART adherence with increasing comorbid disease burden among PLWH. Due to the greater comorbid disease burden, elderly PLWH in the US require additional services and care coordination to effectively manage both HIV and comorbid conditions, particularly those who have a large number of comorbid conditions. Because multimorbidity may have a negative impact of ART adherence, there is a need for interventions focused on primary and secondary prevention of comorbidities and ART adherence among elderly PLWH. Future analyses may include additional analyses with larger samples of older HIV-positive women, assessments of comorbidities and ART medication adherence using other data sources where HIV-specific variables like duration of infection, CD4 and viral load are available, an evaluation of PLWH’s adherence to comedications, such as antidiabetes medications and antihypertensives, and an estimation of the cost impact of comorbid conditions among older PLWH in the US

Racial and Ethnic Differences in What Smokers Report Paying for Their Cigarettes

Smoking rates and tobacco-related health problems vary by race and ethnicity. We explore whether cigarette prices, a determinant of tobacco use, differ across racial and ethnic groups, and whether consumer behaviors influence these differences

Increased R2* in the Caudate Nucleus of Asymptomatic Welders

Welding has been associated with neurobehavioral disorders. Welding fumes contain several metals including copper (Cu), manganese (Mn), and iron (Fe) that may interact to influence welding-related neurotoxicity. Although welding-related airborne Fe levels are about 10-fold higher than Mn, previous studies have focused on Mn and its accumulation in the basal ganglia. This study examined differences in the apparent transverse relaxation rates [R2* (1/T2*), estimate of Fe accumulation] in the basal ganglia (caudate nucleus, putamen, and globus pallidus) between welders and controls, and the dose–response relationship between estimated Fe exposure and R2* values. Occupational questionnaires estimated recent and lifetime Fe exposure, and blood Fe levels and brain magnetic resonance imaging (MRI) were obtained. Complete exposure and MRI R2* and R1 (1/T1: measure to estimate Mn accumulation) data from 42 subjects with welding exposure and 29 controls were analyzed. Welders had significantly greater exposure metrics and higher whole-blood Fe levels compared with controls. R2* in the caudate nucleus was significantly higher in welders after controlling for age, body mass index, respirator use, caudate R1, and blood metals of Cu and Mn, whereas there was no difference in R1 values in the basal ganglia between groups. The R2* in the caudate nucleus was positively correlated with whole-blood Fe concentration. This study provides the first evidence of higher R2* in the caudate nucleus of welders, which is suggestive of increased Fe accumulation in this area. Further studies are needed to replicate the findings and determine the neurobehavioral relevance

Rate-Induced Transitions in Networked Complex Adaptive Systems: Exploring Dynamics and Management Implications Across Ecological, Social, and Socioecological Systems

Complex adaptive systems (CASs), from ecosystems to economies, are open systems and inherently dependent on external conditions. While a system can transition from one state to another based on the magnitude of change in external conditions, the rate of change -- irrespective of magnitude -- may also lead to system state changes due to a phenomenon known as a rate-induced transition (RIT). This study presents a novel framework that captures RITs in CASs through a local model and a network extension where each node contributes to the structural adaptability of others. Our findings reveal how RITs occur at a critical environmental change rate, with lower-degree nodes tipping first due to fewer connections and reduced adaptive capacity. High-degree nodes tip later as their adaptability sources (lower-degree nodes) collapse. This pattern persists across various network structures. Our study calls for an extended perspective when managing CASs, emphasizing the need to focus not only on thresholds of external conditions but also the rate at which those conditions change, particularly in the context of the collapse of surrounding systems that contribute to the focal system's resilience. Our analytical method opens a path to designing management policies that mitigate RIT impacts and enhance resilience in ecological, social, and socioecological systems. These policies could include controlling environmental change rates, fostering system adaptability, implementing adaptive management strategies, and building capacity and knowledge exchange. Our study contributes to the understanding of RIT dynamics and informs effective management strategies for complex adaptive systems in the face of rapid environmental change.Comment: 25 pages, 4 figures, 1 box, supplementary informatio

Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD

Characterization of the apoptotic response of human leukemia cells to organosulfur compounds

Background: Novel therapeutic agents that selectively induce tumor cell death are urgently needed in the clinical management of cancers. Such agents would constitute effective adjuvant approaches to traditional chemotherapy regimens. Organosulfur compounds (OSCs), such as diallyl disulfide, have demonstrated anti-proliferative effects on cancer cells. We have previously shown that synthesized relatives of dysoxysulfone, a natural OSC derived from the Fijian medicinal plant, Dysoxylum richi, possess tumor-specific antiproliferative effects and are thus promising lead candidates. Methods: Because our structure-activity analyses showed that regions flanking the disulfide bond mediated specificity, we synthesized 18 novel OSCs by structural modification of the most promising dysoxysulfone derivatives. These compounds were tested for anti-proliferative and apoptotic activity in both normal and leukemic cells. Results: Six OSCs exhibited tumor-specific killing, having no effect on normal bone marrow, and are thus candidates for future toxicity studies. We then employed mRNA expression profiling to characterize the mechanisms by which different OSCs induce apoptosis. Using Gene Ontology analysis we show that each OSC altered a unique set of pathways, and that these differences could be partially rationalized from a transcription factor binding site analysis. For example, five compounds altered genes with a large enrichment of p53 binding sites in their promoter regions (p < 0.0001). Conclusions: Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of compounds for development as anti-cancer agents

Human Skin Microbiota: High Diversity of DNA Viruses Identified on the Human Skin by High Throughput Sequencing

The human skin is a complex ecosystem that hosts a heterogeneous flora. Until recently, the diversity of the cutaneous microbiota was mainly investigated for bacteria through culture based assays subsequently confirmed by molecular techniques. There are now many evidences that viruses represent a significant part of the cutaneous flora as demonstrated by the asymptomatic carriage of beta and gamma-human papillomaviruses on the healthy skin. Furthermore, it has been recently suggested that some representatives of the Polyomavirus genus might share a similar feature. In the present study, the cutaneous virome of the surface of the normal-appearing skin from five healthy individuals and one patient with Merkel cell carcinoma was investigated through a high throughput metagenomic sequencing approach in an attempt to provide a thorough description of the cutaneous flora, with a particular focus on its viral component. The results emphasize the high diversity of the viral cutaneous flora with multiple polyomaviruses, papillomaviruses and circoviruses being detected on normal-appearing skin. Moreover, this approach resulted in the identification of new Papillomavirus and Circovirus genomes and confirmed a very low level of genetic diversity within human polyomavirus species. Although viruses are generally considered as pathogen agents, our findings support the existence of a complex viral flora present at the surface of healthy-appearing human skin in various individuals. The dynamics and anatomical variations of this skin virome and its variations according to pathological conditions remain to be further studied. The potential involvement of these viruses, alone or in combination, in skin proliferative disorders and oncogenesis is another crucial issue to be elucidated

The Genome of Deep-Sea Vent Chemolithoautotroph Thiomicrospira crunogena XCL-2

Presented here is the complete genome sequence of Thiomicrospira crunogena XCL-2, representative of ubiquitous chemolithoautotrophic sulfur-oxidizing bacteria isolated from deep-sea hydrothermal vents. This gammaproteobacterium has a single chromosome (2,427,734 base pairs), and its genome illustrates many of the adaptations that have enabled it to thrive at vents globally. It has 14 methyl-accepting chemotaxis protein genes, including four that may assist in positioning it in the redoxcline. A relative abundance of coding sequences (CDSs) encoding regulatory proteins likely control the expression of genes encoding carboxysomes, multiple dissolved inorganic nitrogen and phosphate transporters, as well as a phosphonate operon, which provide this species with a variety of options for acquiring these substrates from the environment. Thiom. crunogena XCL-2 is unusual among obligate sulfur-oxidizing bacteria in relying on the Sox system for the oxidation of reduced sulfur compounds. The genome has characteristics consistent with an obligately chemolithoautotrophic lifestyle, including few transporters predicted to have organic allocrits, and Calvin-Benson-Bassham cycle CDSs scattered throughout the genome

Analysis of SNPs and Haplotypes in Vitamin D Pathway Genes and Renal Cancer Risk

In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR), most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. RCC cases (N = 777) and controls (N = 1,035) were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P) tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP) sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02) and retinoid-X-receptor-alpha (RXRA) (p-value = 0.10) were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991) across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09–1.57) haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3′ of the coding sequence (rs748964, rs3118523), increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings