Davide De Francesco

Increased brain-predicted aging in treated HIV disease

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters. Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45–82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machine-learning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 18–90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age − chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out. Results: HIV-positive individuals had greater brain-PAD score (mean ± SD 2.15 ± 7.79 years) compared to HIV-negative individuals (−0.87 ± 8.40 years; b = 3.48, p < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures. Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging.

From ‘reckless’ to ‘mindful’ in the use of outcome data to inform service-level performance management: perspectives from child mental health

In the recent report on patient safety in the National Health Service (NHS) in England, Don Berwick calls on the NHS to align the necessity for increased ‘accountability’ with the necessity to ‘abandon blame as a tool’ in order to develop a ‘transparent learning culture’.1 Sir Bruce Keogh, Medical Director NHS, and colleagues’ recent analysis of outlier hospitals based on mortality data marks a key step on this journey, but has led to high-profile debate about the risk of possible ‘reckless’ (Sir Bruce Keoghs term) use of data if appropriate parameters are not established.2 ,3 If these and other equivalent proxies for outcomes are to be used safely and effectively to support performance management and quality improvement in the ways envisioned by both Keogh and Berwick, it is crucial to establish clearly agreed operational procedures. Drawing on our experience of collecting and interpreting outcome data in the challenging context of child mental health across the UK, we suggest adoption of a MINDFUL framework involving consideration of m ultiple perspectives, i nterpreting differences in the light of current evidence base, focus on n egative differences when triangulated with other data, d irected discussions based on ‘what if this were a true difference’ (employing the 75–25% rule), use of f unnel plots as a starting point to consider outliers, appreciation of u ncertainty as a key contextual reality and the use of l earning collaborations to support appropriate implementation and action strategies. Any attempt to measure ‘impact’ of a service using a given ‘outcome’ is complex. The Keogh report acknowledges: “two different measures of mortality, HSMR [Hospital Standardised Mortality Ratio] and SHMI [Summary Hospital Level Mortality Indicator] generated two completely different lists of outlier trusts.” This was ‘solved’ by using both lists, but with a suggestion to move to …

Gray and White Matter Abnormalities in Treated Human Immunodeficiency Virus Disease and Their Relationship to Cognitive Function

Background Long-term comorbidities such as cognitive impairment remain prevalent in otherwise effectively treated people living with human immunodeficiency virus (HIV). We investigate the relationship between cognitive impairment and brain structure in successfully treated patients using multimodal neuroimaging from the Comorbidity in Relation to AIDS (COBRA) cohort. Methods Cognitive function, brain tissue volumes, and white matter microstructure were assessed in 134 HIV-infected patients and 79 controls. All patients had suppressed plasma HIV RNA at cohort entry. In addition to comprehensive voxelwise analyses of volumetric and diffusion tensor imaging, we used an unsupervised machine learning approach to combine cognitive, diffusion, and volumetric data, taking advantage of the complementary information they provide. Results Compared to the highly comparable control group, cognitive function was impaired in 4 of the 6 cognitive domains tested (median global T-scores: 50.8 vs 54.2; P < .001). Patients had lower gray but not white matter volumes, observed principally in regions where structure generally did not correlate with cognitive function. Widespread abnormalities in white matter microstructure were also seen, including reduced fractional anisotropy with increased mean and radial diffusivity. In contrast to the gray matter, these diffusion abnormalities correlated with cognitive function. Multivariate neuroimaging analysis identified a neuroimaging phenotype associated with poorer cognitive function, HIV infection, and systemic immune activation. Conclusions Cognitive impairment, lower gray matter volume, and white matter microstructural abnormalities were evident in HIV-infected individuals despite fully suppressive antiretroviral therapy. White matter abnormalities appear to be a particularly important determinant of cognitive dysfunction seen in well-treated HIV-infected individuals.

No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project

Background Despite successful antiretroviral therapy, people living with human immunodeficiency virus (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function, and cognitive impairment. This has raised concerns that PLWH may experience accelerated aging-related brain pathology. Methods We performed a multicenter longitudinal study of 134 virologically suppressed PLWH (median age, 56.0 years) and 79 demographically similar human immunodeficiency virus (HIV)-negative controls (median age, 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multimodality neuroimaging (T1-weighted, T2-weighted, diffusion magnetic resonance imaging [MRI], resting-state functional MRI, spectroscopy, arterial spin labeling) at baseline and at 2 years. Group differences in rates of change were assessed using linear mixed effects models. Results One hundred twenty-three PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval, 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking or alcohol use. At baseline, PLWH had poorer global cognitive performance (P < .01), lower gray matter volume (P = .04), higher white matter hyperintensity load (P = .02), abnormal white matter microstructure (P < .005), and greater brain-predicted age difference (P = .01). Longitudinally, there were no significant differences in rates of change in any neuroimaging measure between PLWH and HIV-negative controls (P > .1). Cognitive performance was longitudinally stable in both groups. Conclusions We found no evidence that middle-aged PLWH, when receiving successful treatment, are at increased risk of accelerated aging-related brain changes or cognitive decline over 2 years.

Development of a framework for prospective payment for child mental health services

Objectives There is a need to develop a payment system for services for children with mental health problems that allows more targeted commissioning based on fairness and need. This is currently constrained by lack of clinical consensus on the best way forward, wide variation in practice, and lack of data about activity and outcomes. In the context of a national initiative in England our aim was to develop a basis for an improved payment system. Methods Three inter-related studies: a qualitative consultation with child and adolescent mental health services (CAMHS) stakeholders on what the key principles for establishing a payment system should be, via online survey (n = 180) and two participatory workshops (n = 91); review of relevant national clinical guidelines (n = 15); and a quantitative study of the relationship between disorders and resource use (n = 1774 children from 23 teams). Results CAMHS stakeholders stressed the need for a broader definition of need than only diagnosis, including the measurement of indirect service activities and appropriate outcome measurement. National clinical guidance suggested key aspects of best practice for care packages but did not include consideration of contextual factors such as complexity. Modelling data on cases found that problem type and degree of impairment independently predicted resource use, alongside evidence for substantial service variation in the allocation of resources for similar problems. Conclusions A framework for an episode-based payment system for CAMHS should include consideration of: complexity and indirect service activities; evidence-based care packages; different needs in terms of impairment and symptoms; and outcome measurement as a core component.

Terminal differentiation of T cells is strongly associated with CMV infection and increased in HIV-positive individuals on ART and lifestyle matched controls

HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank. Despite long-term ART (median of 12.2 years), HIV-infected adults had lower CD4+ T-cell counts and higher CD8+ T-cell counts compared to well-matched HIV-negative COBRA participants. The proportion of CD38+HLA-DR+ and PD-1+ CD4+ T-cells was higher in HIV-positive cohort compared to the two HIV-negative cohorts. The proportion CD57+ and CD27−CD28− cells of both CD4+ and CD8+ T-cells in HIV-positives was higher compared to unselected adults (blood bank) as reported before but this difference was not apparent in comparison with well-matched HIV-negative COBRA participants. Multiple regression analysis showed that the presence of an increased proportion of terminally differentiated T cells was strongly associated with CMV infection. Compared to appropriately selected HIV-negative controls, HIV-positive individuals on ART with long-term suppressed viraemia exhibited incomplete immune recovery and increased immune activation/exhaustion. CMV infection rather than treated HIV infection appears to have more consistent effects on measures of terminal differentiation of T cells.

Associations between evidence-based practice and mental health outcomes in child and adolescent mental health services:

The effectiveness of evidence-based practice in the treatment of children with conduct disorder (n = 186) or emotional disorders (n = 490) in routine care was examined using naturalistic, previously collected data from 30 child and adolescent mental health services. Repeated measures analysis of covariance was used to compare the outcomes of children who received parent training for conduct disorder and cognitive behavioural therapy for emotional disorders (evidence-based practice) with children who did not receive these treatments (non-evidence-based practice). There was a relatively low occurrence of evidence-based practice, particularly for children with conduct disorder. Both the evidence-based practice and non-evidence-based practice groups improve over time, with moderate effect sizes, and there were greater improvements associated with evidence-based practice for children with emotional disorders, based on child self-reported symptoms but not on parent report. In the present sample, significant differences were not found for conduct disorder. Findings provide tentative support for evidence-based practice for the treatment of emotional disorders in routine care settings.

Medicalising normality? Using a simulated dataset to assess the performance of different diagnostic criteria of HIV-associated cognitive impairment

Objective The reported prevalence of cognitive impairment remains similar to that reported in the pre-antiretroviral therapy era. This may be partially artefactual due to the methods used to diagnose impairment. In this study, we evaluated the diagnostic performance of the HIV-associated neurocognitive disorder (Frascati criteria) and global deficit score (GDS) methods in comparison to a new, multivariate method of diagnosis. Methods Using a simulated ‘normative’ dataset informed by real-world cognitive data from the observational Pharmacokinetic and Clinical Observations in PeoPle Over fiftY (POPPY) cohort study, we evaluated the apparent prevalence of cognitive impairment using the Frascati and GDS definitions, as well as a novel multivariate method based on the Mahalanobis distance. We then quantified the diagnostic properties (including positive and negative predictive values and accuracy) of each method, using bootstrapping with 10,000 replicates, with a separate ‘test’ dataset to which a pre-defined proportion of ‘impaired’ individuals had been added. Results The simulated normative dataset demonstrated that up to ~26% of a normative control population would be diagnosed with cognitive impairment with the Frascati criteria and ~20% with the GDS. In contrast, the multivariate Mahalanobis distance method identified impairment in ~5%. Using the test dataset, diagnostic accuracy [95% confidence intervals] and positive predictive value (PPV) was best for the multivariate method vs. Frascati and GDS (accuracy: 92.8% [90.3–95.2%] vs. 76.1% [72.1–80.0%] and 80.6% [76.6–84.5%] respectively; PPV: 61.2% [48.3–72.2%] vs. 29.4% [22.2–36.8%] and 33.9% [25.6–42.3%] respectively). Increasing the a priori false positive rate for the multivariate Mahalanobis distance method from 5% to 15% resulted in an increase in sensitivity from 77.4% (64.5–89.4%) to 92.2% (83.3–100%) at a cost of specificity from 94.5% (92.8–95.2%) to 85.0% (81.2–88.5%). Conclusion Our simulations suggest that the commonly used diagnostic criteria of HIV-associated cognitive impairment label a significant proportion of a normative reference population as cognitively impaired, which will likely lead to a substantial over-estimate of the true proportion in a study population, due to their lower than expected specificity. These findings have important implications for clinical research regarding cognitive health in people living with HIV. More accurate methods of diagnosis should be implemented, with multivariate techniques offering a promising solution.

Patterns of co-occurring comorbidities in people living with HIV

Abstract Background The aims of this study were to identify common patterns of comorbidities observed in people living with HIV (PLWH), using a data-driven approach, and evaluate associations between patterns identified. Methods A wide range of comorbidities were assessed in PLWH participating in 2 independent cohorts (POPPY: UK/Ireland; AGEhIV: Netherlands). The presence/absence of each comorbidity was determined using a mix of self-reported medical history, concomitant medications, health care resource use, and laboratory parameters. Principal component analysis (PCA) based on Somers’ D statistic was applied to identify patterns of comorbidities. Results PCA identified 6 patterns among the 1073 POPPY PLWH (85.2% male; median age [interquartile range {IQR}], 52 [47–59] years): cardiovascular diseases (CVDs), sexually transmitted diseases (STDs), mental health problems, cancers, metabolic disorders, chest/other infections. The CVDs pattern was positively associated with cancer (r = .32), metabolic disorder (r = .38), mental health (r = .16), and chest/other infection (r = .17) patterns (all P < .001). The mental health pattern was correlated with all the other patterns (in particular cancers: r = .20; chest/other infections: r = .27; both P < .001). In the 598 AGEhIV PLWH (87.6% male; median age [IQR], 53 [48–59] years), 6 patterns were identified: CVDs, chest/liver, HIV/AIDS events, mental health/neurological problems, STDs, and general health. The general health pattern was correlated with all the other patterns (in particular CVDs: r = .14; chest/liver: r = .15; HIV/AIDS events: r = .31; all P < .001), except STDs (r = –.02; P = .64). Conclusions Comorbidities in PLWH tend to occur in nonrandom patterns, reflecting known pathological mechanisms and shared risk factors, but also suggesting potential previously unknown mechanisms. Their identification may assist in adequately addressing the pathophysiology of increasingly prevalent multimorbidity in PLWH.

Cohort profile: The Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study

http://sro.sussex.ac.uk Bagkeris, Emmanouil, Burgess, Laura, Mallon, Patrick W, Post, Frank A, Boffito, Marta, Sachikonye, Memory, Anderson, Jane, Asboe, David, Garvey, Lucy, Vera, Jaime, Williams, Ian, Johnson, Margaret, Babalis, Daphne, De Francesco, Davide, Winston, Alan et al. (2018) Cohort profile: the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study. International Journal of Epidemiology, dyy072. pp. 1-7. ISSN 0300-5771