Does Social Support Play a Role in the Expression and Everyday Functioning Impact of Apathy in HIV Disease?

Clinically notable apathy occurs in approximately one-third of persons living with HIV (PLWH). Drawing from psychological theory, this cross-sectional study examined the interplay between apathy and social support in persons with (n = 143) and without (n = 61) HIV disease. Analyses were conducted using multiple regression and mediation procedures with 95th percentile bootstrap confidence intervals. Positive HIV serostatus and lower social support were associated with more frequent apathy, independent of other mood symptoms. Social support did not moderate apathy's associations with everyday functioning among PLWH, but post hoc analyses revealed that apathy mediated the relationship between social support and everyday functioning among PLWH. Stronger social support may provide a buffer against the frequency of apathy symptoms in persons with and without HIV disease. The relationship between lower social support and poorer everyday functioning in HIV might be partly explained by apathy. Longitudinal research is needed to examine the mechanisms of these relationships.

RESUMEN: La apatía clínicamente notable se produce en aproximadamente un tercio de las personas que viven con el VIH (PVVS). A partir de la teoría psicológica, este estudio transversal examinó la interacción entre la apatía y el apoyo social en personas con (n = 143) y sin (n = 61) enfermedad de VIH. Los análisis se llevaron utilizando procedimientos de regresión múltiple y mediación con intervalos de confianza bootstrap del 95º percentil. El estado serológico positivo respecto al VIH y un menor apoyo social se asociaron con una apatía más frecuente, independientemente de otros síntomas del estado de ánimo. El apoyo social no moderó las asociaciones de la apatía con el funcionamiento cotidiano entre las PVVS, pero los análisis post hoc revelaron que la apatía mediaba la relación entre el apoyo social y el funcionamiento cotidiano entre las PVVS. Un apoyo social más fuerte puede atenuar la frecuencia de los síntomas de apatía en personas con y sin VIH. La relación entre un menor apoyo social y un peor funcionamiento cotidiano en personas con VIH podría explicarse en parte por la apatía. Se necesitan investigaciones longitudinales para examinar los mecanismos de estas relaciones.

Self-perceived cognitive fluctuations and their relationship to everyday functioning in older adults with and without HIV disease.

Objective: HIV is associated with elevated performance-based cognitive intra-individual variability (IIV) in the laboratory that can reflect difficulty regulating cognitive resources over time (i.e., cognitive fluctuations) and disrupt everyday functioning. Whether persons living with HIV (PLWH) experience appreciable cognitive fluctuations in their daily lives is unclear. This study examined the presence of cognitive fluctuations and their relationship to everyday functioning in PLWH. Methods: Participants were 145 PLWH and 61 seronegative individuals age ≥ 50 years who completed a self-report version of the Mayo Fluctuations Scale (MFS), structured psychiatric interview, medical evaluation, and well-validated measures of mood, cognitive symptoms, and activities of daily living (ADLs). A confirmatory factor analysis of the MFS yielded three factors, including a 7-item cognitive fluctuations scale. Results: Univariable analyses showed that HIV was associated with moderately higher MFS Cognitive Fluctuation subscale scores (d = 0.46), but this effect was no longer significant a multiple regression model that included medical comorbidities and affective disorders, which emerged as unique predictors. Of clinical relevance, higher MFS Cognitive Fluctuation subscale scores were independently associated with more frequent cognitive symptoms and dependence in ADLs in the full sample. Conclusions: Higher frequency of self-perceived cognitive fluctuations disrupts management of ADLs among middle-aged and older adults independent of HIV status and general cognitive symptoms. Future studies are needed to understand the full clinical significance of self-perceived cognitive fluctuations among PLWH and their impact on daily life.

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations.

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.

An evaluation of the moderating effects of routine and busyness on the relationship between prospective memory and everyday functioning in older persons with HIV disease.

INTRODUCTION: People living with HIV (PLWH) often experience difficulties in everyday functioning, which can arise in part from deficits in the strategic/executive aspects of prospective memory (PM). Using Suchy's Contextually Valid Executive Assessment (ConVExA) framework, this study sought to determine whether the contextual factors of busyness and routine moderate the relationship between the strategic/executive aspects of PM and everyday functioning in older PLWH. METHODS: Participants in this cross-sectional analysis were 145 PLWH aged 50 years and older who had completed the Martin and Park Environmental Demands (MPED) questionnaire of routine and busyness, the performance-based Cambridge Test of Prospective Memory, and self-report measures of activities of daily living (ADLs) and cognitive symptoms in daily life. RESULTS: Multiple regression analyses covarying for relevant comorbidities showed that higher levels of busyness - but not routine - were associated with more frequent cognitive symptoms in daily life. Neither busyness nor routine interacted with PM in association with cognitive symptoms. However, routine and a strategic/executive measure of PM interacted in predicting ADLs; specifically, the association between time-based PM and ADLs was stronger in persons with higher levels of routine in their daily lives. Parallel analyses with less executively-demanding event-based PM were null and small. CONCLUSIONS: Overall, findings provided mixed - and unexpected - evidence for the associations between contextual factors (i.e. routine and busyness), everyday functioning, and PM in this sample of older adults with HIV disease. Results and clinical implications are interpreted and discussed in the framework of the ConVExA model.

Development of the Telephone-based Daily Instrumental Activities of Living (T-DIAL) to assess financial management remotely in older adults.

The current study evaluated the reliability and validity of a novel, performance-based banking task in 60 younger (18-34 years) and 60 older (50-85 years) adults. All participants completed the Telephone-based Daily Instrumental Activities of Living (T-DIAL) using interactive voice response technology to complete a series of mock actions with a financial institution via telephone. The T-DIAL showed strong inter-rater reliability and internal consistency. T-DIAL accuracy was significantly and independently related to better self-reported instrumental activities of daily living and executive functions at a large effect size. Findings from this study provided preliminary supportive evidence for the reliability and validity of the T-DIAL, which had robust associations with manifest everyday functioning and higher-order cognitive ability. Future work is needed on the psychometrics (e.g. test-retest reliability, normative standards), and construct validity (e.g. diagnostic accuracy) of the T-DIAL in neurocognitive disorders and under-served communities for whom remote evaluations might be particularly relevant.

Prospective memory is associated with aspects of disability and quality of life in people with epilepsy.

INTRODUCTION: Episodic memory disruptions in epilepsy stem from shared neurocircuitry. While prior research has focused on retrospective memory (RM), prospective memory (PM; i.e. remembering to remember) also deserves consideration given its critical role in the management of daily activities. The current investigation assessed whether PM is associated with disability and quality of life in people with epilepsy. METHODS: This cross-sectional, correlational study included a consecutive series of 50 people with epilepsy presenting for neuropsychological evaluation who completed the Royal Prince Alfred Prospective Memory Test (RPA) and Prospective and Retrospective Memory Questionnaire (PRMQ) and 63 demographically comparable healthy adults. The participants with epilepsy also completed clinical measures of neuropsychological ability and questionnaires assessing disability and quality of life. RESULTS: People with epilepsy had significantly more frequent memory symptoms as compared to healthy adults at a very large effect size. Worse mood was associated with lower PM ability at a medium effect size and more frequent PM symptoms at a large effect size. A hierarchical linear regression indicated that PM explained 52% of the variance in disability and 43% of the variance in quality of life after accounting for RM ability. CONCLUSIONS: PM is associated with poorer everyday functioning among people with epilepsy and shows evidence of incremental value beyond RM ability in that regard. Future studies are needed to understand the complex pathways from PM to functional limitations to inform clinical intervention.

A survey of the perceptions and practices of faculty in clinical neuropsychology doctoral training programs: is heterogeneity the norm?

Objective: Doctoral education is a cornerstone in the training of clinical neuropsychologists. However, we know little about perceptions, practices, and needs of the faculty who oversee doctoral training in clinical neuropsychology (CN). Method: Seventy-one faculty from 45 doctoral programs providing CN training completed at least part of a survey assessing characteristics of their programs, current training practices and views, and challenges to CN doctoral training. Results: Over half of CN faculty reported having zero or only one CN colleague. CN faculty reported that the goals of CN doctoral training are research training, clinical training, and acquisition of knowledge and skills reflected in the Houston Conference Guidelines (HCG). CN faculty reported that doctoral trainees obtain more clinical hours than faculty would like and endorsed alternative clinical metrics, including competency-based ratings. CN faculty are divided about the benefits of a required two-year postdoctoral CN fellowship. Conclusions: The HCG states that specialization in CN begins at the doctoral level. CN faculty in doctoral programs are fully immersed in the early development and education of future CN researchers and practitioners. Tensions between clinical and research training in CN at the doctoral level-and student overemphasis on accruing clinical hours-might place CN at risk for failing to make research innovations necessary for our field to evolve and thrive. More CN doctoral faculty are needed to serve as mentors to students, especially for students from backgrounds that have been historically excluded and marginalized. A greater voice from CN doctoral faculty in CN governance is needed.

Implications of vascular depression for successful cognitive aging in HIV Disease.

Although older adults with HIV are at high risk for mild neurocognitive disorders, a subset experience successful cognitive aging (SCA). HIV is associated with an increased risk of vascular depression (VasDep), which can affect cognitive and daily functioning. The current study examined whether VasDep impedes SCA among older adults with HIV. 136 persons with HIV aged 50 years and older were classified as either SCA+ (n = 37) or SCA- (n = 99) based on a battery of demographically adjusted neurocognitive tests and self-reported cognitive symptoms. Participants were also stratified on the presence of vascular disease (e.g., hypertension) and current depression as determined by the Composite International Diagnostic Interview and the Depression/Dejection scale of the Profile of Mood States. A Cochran-Armitage test revealed a significant additive effect of vascular disease and depression on SCA in this sample of older adults with HIV (z = 4.13, p <.0001). Individuals with VasDep had the lowest frequency of SCA+ (0%), which differed significantly from the group with only vascular disease (30%, OR = 0.04, CI = 0.002,0.68)) and the group with neither vascular disease nor depression (47% OR = 0.02, CI = 0.33,0.001). Findings were not confounded by demographics, HIV disease severity, or other psychiatric and medical factors (ps > 0.05). These data suggest that presence of VasDep may be a barrier to SCA in older adults with HIV disease. Prospective, longitudinal studies with neuroimaging-based operationalizations of VasDep are needed to further clarify this risk factor's role in the maintenance of cognitive and brain health in persons with HIV disease.

Development and Validity of Norms for Cognitive Dispersion on the Uniform Data Set 3.0 Neuropsychological Battery.

OBJECTIVE: Cognitive dispersion indexes intraindividual variability in performance across a battery of neuropsychological tests. Measures of dispersion show promise as markers of cognitive dyscontrol and everyday functioning difficulties; however, they have limited practical applicability due to a lack of normative data. This study aimed to develop and evaluate normed scores for cognitive dispersion among older adults. METHOD: We analyzed data from 4,283 cognitively normal participants aged ≥50 years from the Uniform Data Set (UDS) 3.0. We describe methods for calculating intraindividual standard deviation (ISD) and coefficient of variation (CoV), as well as associated unadjusted scaled scores and demographically adjusted z-scores. We also examined the ability of ISD and CoV scores to differentiate between cognitively normal individuals (n = 4,283) and those with cognitive impairment due to Lewy body disease (n = 282). RESULTS: We generated normative tables to map raw ISD and CoV scores onto a normal distribution of scaled scores. Cognitive dispersion indices were associated with age, education, and race/ethnicity but not sex. Regression equations were used to develop a freely accessible Excel calculator for deriving demographically adjusted normed scores for ISD and CoV. All measures of dispersion demonstrated excellent diagnostic utility when evaluated by the area under the curve produced from receiver operating characteristic curves. CONCLUSIONS: Results of this study provide evidence for the clinical utility of sample-based and demographically adjusted normative standards for cognitive dispersion on the UDS 3.0. These standards can be used to guide interpretation of intraindividual variability among older adults in clinical and research settings.

Health literacy mediates the association between cognition and healthcare provider interactions among gay and bisexual men with HIV disease.

Introduction: Gay and bisexual men (GBM) account for the highest rates of incident infection with HIV in the U.S., and experience social, systemic barriers to accessing and engaging in healthcare services. Interacting with healthcare providers can be a complex process for some GBM with HIV disease. The current study examined the contributions of cognition and health literacy to perceived interactions with healthcare providers among GBM with HIV disease. Methods: The sample included 100 adults with HIV disease (ages 24-75) who identified as GBM. All participants completed the Dealing with Health Professionals subscale of the Beliefs Related to Medication Adherence survey, as well as the Cogstate neuropsychological battery, self-report measures of cognitive symptoms, and well-validated measures of health literacy. Results: Worse performance-based cognition and subjective cognitive symptoms were both associated with perceived difficulties dealing with healthcare providers, but these associations were fully mediated by lower health literacy. Conclusion: Health literacy may play a role in the association between poorer cognitive functioning and difficulties navigating healthcare interactions among GBM with HIV disease. Further studies are needed to determine whether cognitive approaches to enhancing the access, understanding, and use of health information in GBM with HIV disease improves healthcare interactions and outcomes.

Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis.

Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.

Graphene oxide activates canonical TGFß signalling in a human chondrocyte cell line via increased plasma membrane tension.

Graphene Oxide (GO) has been shown to increase the expression of key cartilage genes and matrix components within 3D scaffolds. Understanding the mechanisms behind the chondroinductive ability of GO is critical for developing articular cartilage regeneration therapies but remains poorly understood. The objectives of this work were to elucidate the effects of GO on the key chondrogenic signalling pathway - TGFß and identify the mechanism through which signal activation is achieved in human chondrocytes. Activation of canonical signalling was validated through GO-induced SMAD-2 phosphorylation and upregulation of known TGFß response genes, while the use of a TGFß signalling reporter assay allowed us to identify the onset of GO-induced signal activation which has not been previously reported. Importantly, we investigate the cell-material interactions and molecular mechanisms behind these effects, establishing a novel link between GO, the plasma membrane and intracellular signalling. By leveraging fluorescent lifetime imaging (FLIM) and a membrane tension probe, we reveal GO-mediated increases in plasma membrane tension, in real-time for the first time. Furthermore, we report the activation of mechanosensory pathways which are known to be regulated by changes in plasma membrane tension and reveal the activation of endogenous latent TGFß in the presence of GO, providing a mechanism for signal activation. The data presented here are critical to understanding the chondroinductive properties of GO and are important for the implementation of GO in regenerative medicine.

Apathy in persons living with HIV disease: A systematic narrative review.

BACKGROUND: Apathy was identified as a feature of HIV early in the epidemic; however, there are no systematic reviews of the diverse literature on the sociodemographic and clinical correlates of apathy in HIV disease. METHODS: The current study adopted a hybrid systematic-narrative review methodology in which we used PRISMA guidelines to identify, summarize, and critique peer-reviewed, empirical studies of apathy in HIV disease in the era of combination antiretroviral therapy. RESULTS: A total of 34 studies of apathy in persons living with HIV (PLWH) were identified. Findings across these studies showed that apathy was reliably related to the structure of grey and white matter pathways commonly implicated in apathy, poorer everyday functioning, education, and other neuropsychiatric symptoms (e.g., depression). Apathy was not reliably associated with age, sex, race/ethnicity, cognition, and clinical markers of HIV disease. LIMITATIONS: The current review does not provide rigorous quantitative estimates of clinical correlates of apathy, and the exclusion criteria of non-English and non-peer reviewed publications introduces risk of bias and Type I error. CONCLUSIONS: Apathy occurs at higher rates in PLWH and is linked to neuroanatomical differences, as well as negative outcomes for everyday functions, aspects of neurocognition, and neuropsychiatric symptoms. As such, apathy is an important component to consider in the clinical assessment, diagnosis, and management of neurocognitive disorders in PLWH. Future work is needed to replicate existing findings with larger sample sizes and longitudinal designs, examine apathy as a multi-dimensional construct, and develop evidence-based treatments for apathy in PLWH.

Ecological validity of cognitive fluctuations in dementia with Lewy bodies.

OBJECTIVES: Cognitive fluctuations are a core clinical feature of dementia with Lewy bodies (DLB), but their contribution to the everyday functioning difficulties evident DLB are not well understood. The current study evaluated whether intraindividual variability across a battery of neurocognitive tests (intraindividual variability-dispersion) and daily cognitive fluctuations as measured by informant report are associated with worse daily functioning in DLB. METHODS: The study sample included 97 participants with consensus-defined DLB from the National Alzheimer's Coordinating Center (NACC). Intraindividual variability-dispersion was measured using the coefficient of variation, which divides the standard deviation of an individual's performance scores across 12 normed neurocognitive indices from the NACC neuropsychological battery by that individual's performance mean. Informants reported on daily cognitive fluctuations using the Mayo Fluctuations Scale (MFS) and on daily functioning using the functional activities questionnaire (FAQ). RESULTS: Logistic regression identified a large univariate association of intraindividual variability-dispersion and presence of daily cognitive fluctuations on the MFS (Odds Ratio = 73.27, 95% Confidence Interval = 1.38, 3,895.05). Multiple linear regression demonstrated that higher intraindividual variability-dispersion and presence of daily cognitive fluctuations as assessed by the MFS were significantly and independently related to worse daily functioning (FAQ scores). CONCLUSIONS: Among those with DLB, informant-rated daily cognitive fluctuations and cognitive fluctuations measured in the clinic (as indexed by intraindividual variability-dispersion across a battery of tests) were independently associated with poorer everyday functioning. These data demonstrate ecological validity in measures of cognitive fluctuations in DLB.

Successful Aging is Associated with Better Health Literacy in Older Adults with HIV Disease.

People with HIV (PWH) are susceptible to neurocognitive, physical, and mental health problems that may decrease their likelihood of experiencing successful aging. This cross-sectional, retrospective study estimated the extent to which health literacy is associated with successful aging among 116 older PWH and 60 persons without HIV. Successful aging was defined using indicators of biological health, cognitive efficiency, mental health, and productivity. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine, Newest Vital Sign, Brief Health Literacy Screening, and Beliefs Related to Medication Adherence. A series of logistic regressions covarying for education showed that better health literacy was associated with a higher frequency of successful aging among older PWH. Older PWH were approximately three times less likely to experience successful aging as compared to older adults without HIV. Future studies may examine whether improving health literacy among younger PWH increases the likelihood of successful aging.

Cognitive Intra-individual Variability in the Laboratory Is Associated With Greater Executive Dysfunction in the Daily Lives of Older Adults With HIV.

BACKGROUND: Executive dysfunction, which is common among persons with HIV (PWH), can have an adverse impact on health behaviors and quality of life. Intra-individual variability (IIV) is a measure of within-person variability across cognitive tests that is higher in PWH and is thought to reflect cognitive dyscontrol. OBJECTIVE: To assess whether cognitive IIV in the laboratory is associated with self-reported executive dysfunction in daily life among older PWH. METHOD: Participants included 71 PWH aged ≥50 years who completed six subtests from the Cogstate battery and two subscales from the Frontal Systems Behavior Scale (FrSBe; self-report version). Cognitive IIV was calculated from the Cogstate as the coefficient of variation derived from age-adjusted normative T scores. RESULTS: Cognitive IIV as measured by the Cogstate showed a significant, positive, medium-sized association with current FrSBe ratings of executive dysfunction but not disinhibition. CONCLUSION: Higher cognitive IIV in the laboratory as measured by the Cogstate may be related to the expression of HIV-associated symptoms of executive dysfunction in daily life for older PWH.

The Relationship Between Apathy and Cognitive Impairment Among Hispanic/Latin Americans: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses Systematic Review.

OBJECTIVES: The primary aim was to evaluate apathy assessment measures in relation to cognitive impairment among Hispanic/Latin Americans. METHODS: A systematic review on the relationship between apathy and cognitive impairment among Hispanic/Latin Americans across normal aging and neurocognitive disorders was conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and using APA PsycInfo, Embase, and PubMed databases. Inclusion criteria required (1) a sample of English or Spanish-speaking adults ages 18 years and older, (2) with measures of apathy, (3) assessment of cognitive functioning or diagnosis of neurocognitive disorder, (4) with at least 18.5% Hispanic/Latin American represented in the sample. RESULTS: Only 14 papers met criteria to be included in this review. Of the 12 cross-sectional studies, 9 demonstrated significant associations between increased apathy and cognitive impairment, 1 demonstrated a descriptive difference between apathy and cognitive status (ie, no hypothesis test conducted), while 2 demonstrated null effects. These cross-sectional studies consisted of community and clinic samples of participants across North and South America. Two longitudinal studies conducted in North America demonstrated non-significant associations of apathy with cognitive status. CONCLUSIONS: The Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) apathy subscales were the most used measures for apathy in this review (85.7% of included studies). However, validity evidence from a review of apathy measures has warranted caution against the use of the NPI outside the context of screening for apathy. This potential measurement bias with Hispanic/Latin Americans apathy research limits conclusions drawn from the present review.

Changes in the immune landscape of TNBC after neoadjuvant chemotherapy: correlation with relapse.

Introduction: Patients with high-risk, triple negative breast cancer (TNBC) often receive neoadjuvant chemotherapy (NAC) alone or with immunotherapy. Various single-cell and spatially resolved techniques have demonstrated heterogeneity in the phenotype and distribution of macrophages and T cells in this form of breast cancer. Furthermore, recent studies in mice have implicated immune cells in perivascular (PV) areas of tumors in the regulation of metastasis and anti-tumor immunity. However, little is known of how the latter change during NAC in human TNBC or their impact on subsequent relapse, or the likely efficacy of immunotherapy given with or after NAC. Methods: We have used multiplex immunofluorescence and AI-based image analysis to compare the immune landscape in untreated and NAC-treated human TNBCs. We quantified changes in the phenotype, distribution and intercellular contacts of subsets of tumor-associated macrophages (TAMs), CD4+ and CD8+ T cells, and regulatory T cells (Tregs) in PV and non-PV various areas of the stroma and tumor cell islands. These were compared in tumors from patients who had either developed metastases or were disease-free (DF) after a three-year follow up period. Results: In tumors from patients who remained DF after NAC, there was a marked increase in stromal CD163+ TAMs, especially those expressing the negative checkpoint regulator, T-cell immunoglobulin and mucin domain 3 (TIM-3). Whereas CD4+ T cells preferentially located to PV areas in the stroma of both untreated and NAC-treated tumors, specific subsets of TAMs and Tregs only did so only after NAC. Distinct subsets of CD4+ and CD8+ T cells formed PV clusters with CD163+ TAMs and Tregs. These were retained after NAC. Discussion: Quantification of stromal TIM-3+CD163+ TAMs in tumor residues after NAC may represent a new way of identifying patients at high risk of relapse. PV clustering of immune cells is highly likely to regulate the activation and function of T cells, and thus the efficacy of T cell-based immunotherapies administered with or after NAC.

A Process Analysis of Rey-Osterrieth Complex Figure Test Performance Using the Boston Qualitative Scoring System in HIV-Associated Neurocognitive Disorders.

Deficits in episodic verbal memory are commonly observed in persons with HIV (PWH) disease, in whom they are characterized by dysregulation of the executive aspects of encoding and retrieval and adversely impact everyday functioning. Deficits in episodic visual memory are also apparent in PWH, but we know less about their cognitive architecture. This study used the Boston Qualitative Scoring System (BQSS) for the Rey-Osterrieth Complex Figure (ROCF) to examine visual learning and recall in 43 individuals without HIV and 141 PWH who completed a full research neuropsychological, psychiatric, and medical assessment. A mixed model covarying for education and estimated verbal IQ showed that participants with HIV-associated neurocognitive disorders (HAND) performed worse than PWH without neurocognitive disorders and HIV- participants at comparable medium-to-large effect sizes across the Copy, Immediate, and Delayed trials of the BQSS-ROCF, suggesting a primary encoding deficit. A component process analysis of the BQSS-ROCF Copy Trial revealed that participants with HAND had specific difficulties with configural accuracy, cluster accuracy, and cluster placement. Within the PWH sample, measures of motor coordination and executive functions emerged as independent predictors of BQSS-ROCF Copy Trial performance. Findings extend prior research by showing that HAND may be associated with a primary encoding deficit for complex visuomotor learning and memory tasks that is driven by a combination of visuospatial, motor, and executive difficulties.