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There is debate as to whether the neurocognitive changes associated with HIV infection represent an acceleration of the typical aging process or more simply reflect a greater accentuated risk for age-related declines. We aimed to determine whether accelerated neurocognitive aging is observable in a sample of older HIV-infected individuals compared to age-matched seronegatives and older old (i.e., aged ≥65) seronegative adults. Participants in a cross-sectional design included 48 HIV-seronegative (O-) and 40 HIV-positive (O+) participants between the ages of 50-65 (mean ages = 55 and 56, respectively) and 40 HIV-seronegative participants aged ≥65 (OO-; mean age = 74) who were comparable for other demographics. All participants were administered a brief neurocognitive battery of attention, episodic memory, speeded executive functions, and confrontation naming (i.e., Boston Naming Test). The O+ group performed more poorly than the O- group (i.e., accentuated aging), but not differently from the OO- on digit span and initial recall of a supraspan word list, consistent with an accelerating aging profile. However, the O+ group's performance was comparable to the O- group on all other neurocognitive tests (ps > 0.05). These data partially support a model of accelerated neurocognitive aging in HIV infection, which was observed in the domain of auditory verbal attention, but not in the areas of memory, language, or speeded executive functions. Future studies should examine whether HIV-infected adults over 65 evidence accelerated aging in downstream neurocognitive domains and subsequent everyday functioning outcomes.

ObjectiveHIV is associated with frontostriatal dysregulation and executive dysfunction. This study evaluated whether HIV-infected individuals evidence deficits in random number generation (RNG), which is a strategic task requiring paced, rule-guided production of digits.MethodIn total, 74 HIV+ adults and 54 seronegative comparison participants completed a comprehensive research neuropsychological battery. Participants produced a random digit sequence by avoiding any order and using numbers 1 through 10 for 100 s at a pace of 1 digit/s. Outcomes included intrusions, repetitions, seriation (1-2-3-4), and cycling (median length of gaps between repeating digits).ResultsHIV disease was associated with higher levels of seriation and cycling (ps < .05) but not intrusions or repetitions (ps > .10). Among HIV+ individuals, higher seriation was associated with neuropsychological performance including poorer auditory attention, verbal learning, and delayed memory, whereas higher cycling scores were associated with poorer delayed memory and verbal fluency (ps < .05). Higher seriation also was independently associated with self-reported declines in activities of daily living (ADLs) in the HIV+ group.ConclusionsIndividuals living with HIV disease evidence moderate difficulties in inhibiting statistically unlikely non-random sequences, which showed medium associations with higher order verbal abilities and may contribute to greater declines in everyday functioning outcomes. Future studies might examine RNG's role in health behaviors such as medical decision-making or medication adherence.

Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50 years) and 82 younger (

We examined the performance of healthy young (n=57) and older adults (n=43) genotyped as apolipoprotein E-ε4 (APOE-ε4) carriers or APOE-ε4 non-carriers on a delayed match-to-sample task involving varying degrees of spatial interference hypothesized to assess spatial pattern separation. Older adult ε4 carriers were further divided into "impaired" and "unimpaired" groups based on their performance on a standardized test of verbal memory. We found that performance on the spatial pattern separation test increased as a function of decreased spatial interference across all groups. The older ε4 carriers in the impaired group performed significantly worse (p

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.

With the rising number of individuals in their 50s and 60s who are infected with HIV, concerns have emerged about possible increases in the rates of non-HIV-associated dementias. The current study examined the prevalence of mild cognitive impairment (MCI) in older HIV-infected adults, since MCI is an intermediate state between typical cognitive aging and dementia that emerges in this age range. Participants included 75 adults with HIV disease aged 50 years and older who were on combination antiretroviral therapy (cART) and had undetectable plasma viral loads and 80 demographically similar HIV-seronegative comparison subjects. Participants completed a research neuropsychological evaluation that was used to classify MCI according to the comprehensive diagnostic scheme described by Bondi et al. (J Alzheimers Dis 42:275-289, 2014). HIV-infected persons were over seven times more likely to have an MCI designation (16 %) than their seronegative counterparts (2.5 %). Within the HIV+ cohort, MCI had minimal overlap with diagnoses of asymptomatic neurocognitive impairment and was significantly associated with older age, lower Karnofsky Scale of Performance Scores, and mild difficulties performing instrumental activities of daily living (iADLs). HIV infection in older adults is associated with a notably elevated concurrent risk of MCI, which may increase the likelihood of developing non-HIV-associated dementias as this population ages further.

ObjectiveThis study aimed to determine the combined effects of age and HIV infection on the risk of incident neurocognitive disorders.MethodA total of 146 neurocognitively normal participants were enrolled at baseline into one of four groups based on age (≤ 40 years and ≥ 50 years) and HIV serostatus resulting in 24 younger HIV-, 27 younger HIV+, 39 older HIV-, and 56 older HIV+ individuals. All participants were administered a standardized clinical neuropsychological battery at baseline and 14.3 ± .2 months later.ResultsA logistic regression predicting incident neurocognitive disorders from HIV, age group, and their interaction was significant (χ(2)[4] = 13.56, p = .009), with a significant main effect of HIV serostatus (χ(2)[1] = 5.01, p = .025), but no main effect of age or age by HIV interaction (ps > .10). Specifically, 15.7% of the HIV+ individuals had an incident neurocognitive disorder as compared to 3.2% of the HIV- group (odds ratio = 4.8 [1.2, 32.6]). Among older HIV+ adults, lower baseline cognitive reserve, prospective memory, and verbal fluency each predicted incident neurocognitive disorders at follow-up.ConclusionsIndependent of age, HIV infection confers a nearly fivefold risk for developing a neurocognitive disorder over approximately one year. Individuals with lower cognitive reserve and mild weaknesses in higher-order neurocognitive functions may be targeted for closer clinical monitoring and preventative measures.

Over the past decade, the improvement in cancer diagnostics and therapeutics has extended the overall survival of patients diagnosed with cancer including brain cancer. However, despite these unprecedented medical successes, patients continue to experience numerous neurologic complications after treatment that interfere with their independence, functionality, and overall quality of life. These include, among others, cognitive impairment, endocrinopathies, peripheral and cranial neuropathies, and vasculopathy. This article describes the long-term neurologic complications cancer survivors commonly experience to increase awareness of these complications and discuss treatments when available. Further research is necessary to understanding of mechanisms of neurologic injury and advance diagnosis and treatment. Effective patient education, monitoring, and managing neurologic issues after cancer treatment may improve independence, functionality, and quality of life during survivorship. [ABSTRACT FROM AUTHOR]

Some residues in the cystic fibrosis transmembrane conductance regulator (CFTR) channel are the site of more than one CFTR variant that cause cystic fibrosis. Here, we investigated the function of S1159F and S1159P, two variants associated with different clinical phenotypes, which affect the same pore‐lining residue in transmembrane segment 12 that are both strongly potentiated by ivacaftor when expressed in CFBE41o− bronchial epithelial cells. To study the single‐channel behaviour of CFTR, we applied the patch‐clamp technique to Chinese hamster ovary cells heterologously expressing CFTR variants incubated at 27°C to enhance channel residence at the plasma membrane. S1159F‐ and S1159P‐CFTR formed Cl− channels activated by cAMP‐dependent phosphorylation and gated by ATP that exhibited thermostability at 37°C. Both variants modestly reduced the single‐channel conductance of CFTR. By severely attenuating channel gating, S1159F‐ and S1159P‐CFTR reduced the open probability (Po) of wild‐type CFTR by ≥75% at ATP (1 mM); S1159F‐CFTR caused the greater decrease in Po consistent with its more severe clinical phenotype. Ivacaftor (10–100 nM) doubled the Po of both CFTR variants without restoring Po values to wild‐type levels, but concomitantly, ivacaftor decreased current flow through open channels. For S1159F‐CFTR, the reduction of current flow was marked at high (supersaturated) ivacaftor concentrations (0.5–1 μM) and voltage‐independent, identifying an additional detrimental action of elevated ivacaftor concentrations. In conclusion, S1159F and S1159P are gating variants, which also affect CFTR processing and conduction, but not stability, necessitating the use of combinations of CFTR modulators to optimally restore their channel activity. Key points: Dysfunction of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes the genetic disease cystic fibrosis (CF).This study investigated two rare pathogenic CFTR variants, S1159F and S1159P, which affect the same amino acid in CFTR, to understand the molecular basis of disease and response to the CFTR‐targeted therapy ivacaftor.Both rare variants diminished CFTR function by modestly reducing current flow through the channel and severely inhibiting ATP‐dependent channel gating with S1159F exerting the stronger adverse effect, which correlates with its association with more severe disease.Ivacaftor potentiated channel gating by both rare variants without restoring their activity to wild‐type levels, but concurrently reduced current flow through open channels, particularly those of S1159F‐CFTR.Our data demonstrate that S1159F and S1159P cause CFTR dysfunction by multiple mechanisms that require combinations of CFTR‐targeted therapies to fully restore channel function. [ABSTRACT FROM AUTHOR]

This document provides an overview of experimental pharmacology in precision medicine, focusing on recent advancements and challenges in the field. It discusses the application of precision medicine in areas such as drug metabolism, drug-drug interactions, therapeutic drug dose monitoring, and interventions for cystic fibrosis. The article also mentions the 19th World Congress of Basic & Clinical Pharmacology (WCP2023), which explored precision medicine approaches for improving human health. The importance of molecular information and quantitative proteomics in enhancing drug safety and efficacy, as well as predicting individual variations in drug absorption, distribution, metabolism, and elimination, is emphasized. The document highlights the success and challenges of precision medicine in specific cases, including drug-drug interactions, targeted cancer therapies, and cystic fibrosis. It also underscores the significance of collaboration between patient advocacy groups, academia, industry, and regulatory authorities in advancing precision medicine. [Extracted from the article]

Alcohol use is associated with memory problems in young adults with HIV, but the cognitive mechanisms of that association are not known. Sixty adults (aged 19–24 years) living with HIV were administered the Alcohol, Smoking, and Substance Involvement Screening Test to assess alcohol use, Behavior Rating Inventory of Executive Function for self-reported executive functions, and the Prospective and Retrospective Memory Questionnaire (PRMQ) for dailiy memory functioning. Controlling for mood, self-reported executive functions fully mediated the relationship between alcohol use and memory (indirect effect b=.568, 95%CI [.209,.888]). Findings suggest that self-reported executive dysregulation of memory processes (e.g., Strategic encoding and retrieval) may drive the effects of alcohol use on daily memory symptoms. [ABSTRACT FROM AUTHOR]

Subjective cognitive decline (SCD) is a risk factor for dementia that may occur at higher rates in people with HIV (PWH). Prospective memory (PM) is an aspect of cognition that may help us better understand how SCD impacts daily life. Paricipants were 62 PWH aged ≥ 50 years and 33 seronegative individuals. SCD was operationalized as normatively elevated cognitive symptoms on standardized questionnaires, but with normatively unimpaired performance-based cognition and no current affective disorders. PM was measured with the Comprehensive Assessment of Prospective Memory (CAPM), the Cambridge Test of Prospective Memory (CAMPROMPT), and an experimental computerized time-based PM task. A logistic regression revealed that older PWH had a three-fold increased likelihood for SCD. Among the PWH, SCD was associated with more frequent PM symptoms and poorer accuracy on the time-based scale of the CAMPROMPT. These findings suggest that SCD disrupts PM in older PWH. [ABSTRACT FROM AUTHOR]

Objective:Prospective memory (PM) or "remembering to remember" has been shown to be reduced in Veterans with histories of mild traumatic brain injury (mTBI), particularly on tasks with high strategic demands such as recalling time-based information in the absence of external cues. This study examined whether time monitoring during a PM task was reduced in Veterans with a history of mTBI and was associated with time-based PM performance. Method:Veterans with a history of mTBI (n = 49) and Veterans without a history of TBI (n = 16) completed the Memory for Intentions Screening Test (MIST) as a measure of PM during which their time monitoring (i.e. number of clock checks) was recorded. Results:Adjusting for age, education, depression, and PTSD symptoms, negative binomial regression revealed that the mTBI group checked the clock less frequently compared to the control group (Cohen's d = 0.84, p = 0.005). Within the mTBI group, less frequent time monitoring across the entire MIST task was associated with poorer time-based MIST performance (rs =.57, p < 0.001), but not with event-based MIST (rs =.04, p = 0.768). Conclusions:Veterans with a history of mTBI evidenced significantly reduced time monitoring during a PM task compared to Veterans without a history mTBI, which was associated with strategically-demanding PM. Current findings provide that mTBI-associated difficulties with strategic aspects of PM may be due to reduced time monitoring. Future studies are needed to determine if reduced time monitoring also contributes to mTBI-associated PM difficulties in the real-world (e.g. medication non-adherence). [ABSTRACT FROM AUTHOR]

ObjectiveThe Internet serves an increasingly critical role in health behaviors for older adults with chronic medical conditions. Guided by theories of health behaviors and literacy, this study examined whether the relationship between educational attainment and online pharmacy skills in older persons with HIV disease (PWH) is mediated by health literacy. Design: Participants included 98 PWH age 50 and older who completed the Test of Online Pharmacy Skills (TOPS), which required them to navigate an experimenter-controlled online pharmacy to perform several naturalistic tasks (e.g., refill an existing prescription). Participants also completed the Medication-Management Test-Revised (MMT-R). Results: Mediation analyses revealed a significant indirect effect of education on both online pharmacy accuracy and MMT-R, which was fully mediated by health literacy. In contrast, there was no direct or indirect effect of education on online pharmacy speed when health literacy was included as a mediator. Conclusion: Health literacy plays an important role in the relationship between years of education attained and the ability of older PWH to successfully navigate online pharmacy tasks and manage their medications. Future studies might examine whether interventions to improve electronic health literacy among older PWH who have lower educational attainment have beneficial effects on online health behaviors. [ABSTRACT FROM AUTHOR]