Assessing Psychological Well-Being: Self-Report Instruments for the NIH Toolbox

Objective— Psychological well-being (PWB) has a significant relationship with physical and mental health. As part of the NIH Toolbox for the Assessment of Neurological and Behavioral Function, we developed self-report item banks and short forms to assess PWB. Study Design and Setting— Expert feedback and literature review informed the selection of PWB concepts and the development of item pools for Positive Affect, Life Satisfaction, and Meaning and Purpose. Items were tested with a community-dwelling U.S. internet panel sample of adults aged 18 and above (N=552). Classical and item response theory (IRT) approaches were used to evaluate unidimensionality, fit of items to the overall measure, and calibrations of those items, including differential item function (DIF). Results— IRT-calibrated item banks were produced for Positive Affect (34 items), Life Satisfaction (16 items), and Meaning and Purpose (18 items). Their psychometric properties were supported based on results of factor analysis, fit statistics, and DIF evaluation. All banks measured the concepts precisely (reliability ≥0.90) for more than 98% of participants. Conclusion— These adult scales and item banks for PWB provide the flexibility, efficiency, and precision necessary to promote future epidemiological, observational, and intervention research on the relationship of PWB with physical and mental health

Molecular imaging to support cancer immunotherapy

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic

Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia

Cranial radiation therapy in childhood acute lymphoblastic leukaemia has been associated with adverse neuropsychological effects, such as low intelligence. However, records show that these associations usually occur when the dose of radiation used is 2400 cGy. We investigated whether a lower dose of 1800 cGy had the same adverse effects on long-term survivors and whether high doses of methotrexate but no radiation therapy would have a more beneficial effect. We evaluated 203 children for six years in a multi-centre European study. The patients were divided into two groups: 129 children treated with 1800 cGy of cranial radiation therapy and 74 children who received high-dose methotrexate but no radiation therapy. We used full scale intelligence quotient, verbal, and performance IQ tests to assess the patient's intelligence. We found a significant decline in full scale intelligence quotient in the irradiated group that increased with the length of time from diagnosis. Younger age at diagnosis was associated with lower full scale intelligence quotient in the radiated group. Our results indicate that a radiation dose of 1800 cGy can have negative effects on neurocognitive function and we continue to question the benefit of low-dose cranial radiation therapy

Molecular imaging biomarkers for immune checkpoint inhibitor therapy

Immune checkpoint inhibitors (ICIs) have substantially changed the field of oncology over the past few years. ICIs offer an alternative treatment strategy by exploiting the patients’ immune system, resulting in a T cell mediated anti-tumor response. These therapies are effective in multiple different tumor types. Unfortunately, a substantial group of patients do not respond to ICIs. Molecular imaging, using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide non-invasive whole-body visualization of tumor and immune cell characteristics and might support patient selection or response evaluations for ICI therapies. In this review, recent studies with 18F-fluorodeoxyglucose-PET imaging, imaging of immune checkpoints and imaging of immune cells will be discussed. These studies are until now mainly exploratory, but the first results suggest that molecular imaging biomarkers could have a role in the evaluation of ICI therapy

Heart failure and inflammation-related biomarkers as predictors of new-onset diabetes in the general population

Background: There is a strong reciprocal relationship between heart failure (HF) and diabetes mellitus (DM). Shared pathophysiological mechanisms might be a possible explanation. Therefore, we hypothesised that biomarkers linked to HF would also predict new-onset type 2 DM in the general population. Methods and results: We utilized the Prevention of Vascular and Renal End-stage Disease (PREVEND) cohort (mean age 48.9 years, 51% female) to study the relationship between HF and DM in 7953 participants free of baseline HF and DM. Multiple HF-related, inflammation-related and renal function-related biomarkers were evaluated regarding their predictive utility in new-onset DM. Incidence of DM in participants who developed HF was 11.8%, versus 5.4% in those who had not developed HF (p <0.001). Incidence of HF in participants who developed DM was 8.5%, versus 3.8% in those who had not developed DM (p <0.001). Classical HF biomarkers, NT-proBNP and hs-TnT were not associated with an increased risk for new-onset DM. However, inflammatory biomarkers hs-CRP [hazard ratio (HR) 1.16, (95% CI 1.05 to 1.29), p = 0.005], procalcitonin [HR 1.34, (95% CI 1.07 to 1.69), p = 0.012] and PAI-1 [HR 1.55, (95% CI 1.37 to 1.75), p <0.001] remained significantly associated with new-onset DM, even after multivariable adjustment for established predictors of DM. Conclusions: Although HF and DM have a strong correlation with each other, systemic biomarkers that predict HF do not have a predictive value in new-onset DM. This suggests that other, indirect, pathophysiological mechanisms related to inflammation may explain their strong relation. (C) 2017 Elsevier B.V. All rights reserved

Sertraline Pharmacokinetics in HIV-Infected and Uninfected Children, Adolescents, and Young Adults

Objective: Due to potential disease and drug interactions, the appropriate sertraline starting dose and titration range may require adjustment in pediatric patients living with HIV. This is the first report of sertraline pharmacokinetics in HIV-infected youth.Methods: IMPAACT P1080 was a multicenter pilot study describing psychiatric medication pharmacokinetics in HIV-infected and uninfected youth. Participants were stable on sertraline, &gt;6 to &lt;25 years old, and (1) HIV-uninfected (HIV(–)), (2) HIV-infected taking efavirenz (EFV), or (3) HIV-infected taking boosting ritonavir/protease inhibitor (PI/r). Sampling occurred at pre-dose, 2, 4, 6, 12, and 24-h post-dose. Analyses were performed for sertraline and N-desmethylsertraline, and CYP2D6 phenotyping was completed with dextromethorphan.Results: Thirty-one participants (16 HIV(-), 12 PI/r, and 3 EFV) had median (range) weight, age, and dose of 69.5 (31.5–118.2) kg, 21.8 (9.1–24.7) years, and 75.0 (12.5–150.0) mg once daily. Sertraline exposure was highest for HIV(–) and lowest for EFV cohorts; median dose-normalized AUC0−24 was 1176 (HIV(–)), 791 (PI/r) and 473 (EFV) ng*hr/mL, and C24 was 32.7 (HIV(–)), 20.1 (PI/r), and 12.8 (EFV) ng/mL. The urinary dextromethorphan/dextrorphan (DXM/DXO) ratio was higher in HIV(–) vs. PI/r cohorts (p = 0.01). Four HIV(–) participants were CYP2D6 poor metabolizers (ln(DXM/DXO) of &gt;-0.5).Conclusions: HIV(–) cohort had the highest sertraline exposure. Sertraline exposure was ~40% lower in the PI/r cohort than in HIV(–); the need to alter sertraline dose ranges for PI/r participants is not clear. The impact of efavirenz on sertraline needs further investigation due to limited numbers of EFV participants

A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec