NK cells in self-limited HCV infection exhibit a more extensively differentiated, but not memory-like, repertoire

Natural killer (NK) cells have long been thought of as a purely innate immune cell population, but increasing reports have described developmental and functional qualities of NK cells that are commonly associated with cells of the adaptive immune system. Of these features, the ability of NK cells to acquire functional qualities associated with immunological memory and continuous differentiation resulting in the formation of specific NK cell repertoires has recently been highlighted in viral infection settings. By making use of a unique cohort of monitored, at-risk intravenous drug users in this study, we were able to dissect the phenotypic and functional parameters associated with NK cell differentiation and NK cell memory in patients 3 years after acute HCV infection and either the subsequent self-clearance or progression to chronicity. We observed increased expression of cytolytic mediators and markers CD56bright and NKp46+ of NK cells in patients with chronic, but not self-limited HCV infection. Patients with a self-limited infection expressed higher levels of differentiation-associated markers CD57 and KIRs, and lower levels of NKG2A. A more extensively differentiated NK cell phenotype is associated with self-clearance in HCV patients, while the NK cells of chronic patients exhibited more naïve and effector NK cell phenotypic and functional characteristics. The identification of these distinct NK cell repertoires may shed light on the role NK cells play in determining the outcome of acute HCV infections, and the underlying immunological defects that lead to chronicity

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure–response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism o

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets in the ENIGMA consortium, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macro-structural asymmetry may reflect differences at the molecular, cytoarchitectonic or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain

Do people living with HIV experience greater age advancement than their HIV-negative counterparts?

Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement. Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79 lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-mor- Bidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors. Methods: Biological age was estimated using a validated algorithm based on 10 biomarkers. Associations between ‘age advancement’ (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression. Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6–14.9) years] and HIV-negative [5.5 (3.8–7.2) years] COBRA participants compared with blood donors [7.0 (4.1 to 9.9) years, both P’s<0.001)], but also in HIV-positive compared with HIV-negative participants (P<0.001). Chronic HBV, higher anti-CMV IgG titer and CD8þ T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1–6.8) years among those with nadir CD4þ T-cell count less than 200 cells/ml and by 0.1 (0.06–0.2) years for each additional month of exposure to saquinavir

Tactual Profile, Reliability and Validity of the Instrument

Contains fulltext : 55312.pdf (publisher's version ) (Closed access)Tactual Profile is an observation instrument for charting the tactual functioning of children (age 0–16) with a severe visual impairment. In the period 2002–2004, a study was executed to determine basic psychometric qualities of Tactual Profile: difficulty level, test–retest reliability, inter-rater reliability and construct validity. The results of the study showed that most items had an acceptable difficulty level. There was a strong correlation between two administrations of the instrument. The inter-rater reliability was moderate and the correlation between Tactual Profile and haptic intelligence tests was higher than the correlation between Tactual Profile and verbal intelligence tests. The study showed that Tactual Profile is a reliable and valid instrument

Tactual profile, an assessment procedure for tactual functioning in children and adolescents

Contains fulltext : 55313.pdf (publisher's version ) (Closed access)Tactual Profile is an instrument that provides a procedure to assess tactual functioning in children who are blind or who have a severe visual impairment, from birth up to 15 years of age. The instrument concentrates on the tactual requirements that the everyday environment places on perception. Tactual Profile is based on practical experience checked against literature and developments in the scientific field of touch. The instrument has been outlined as a ‘structured observation’. Recently there has been a research on the reliability and validity of the instrument. The study has proved that Tactual Profile is a valid and reliable instrument that differentiates from intelligence tests

Therapeutic drug monitoring of small molecule kinase inhibitors in oncology in a real-world cohort study : does age matter?

Aim: Pharmacokinetics of small molecule kinase inhibitors (KIs) used in cancer treatment may alter with increasing age, but results are conflicting. This study aims to compare exposure to KIs between older and younger patients (≥70 and <70 years) in clinical practice. Methods: KI plasma concentrations of routinely treated patients were measured using validated assays. Calculated trough concentrations were compared in both age groups. For KIs with a clinically meaningful target concentration (erlotinib, imatinib, pazopanib, sunitinib and vemurafenib), influence of older age on target attainment was assessed. Results: We analysed 616 samples from 454 patients (median age: 61; range 20–93 years), treated with dabrafenib (n = 105), erlotinib (n = 49), imatinib (n = 165), pazopanib (n = 63), sunitinib (n = 87), trametinib (n = 95) and vemurafenib (n = 52). Older age did not significantly influence exposure to erlotinib, imatinib, pazopanib, sunitinib, trametinib and vemurafenib. Elderly patients had significantly higher dabrafenib trough concentrations than younger patients (P = 0.02; 62 ng ml−1 (coefficient of variation [CV] 41%), vs. 53 ng ml−1 (CV 46%), respectively). For KIs with a predefined target concentration, 68% of older and 61% of younger patients reached target. Conclusions: In this real-world study, exposure to most included KIs was comparable in older and younger patients, except for dabrafenib, which showed higher exposure in older patients. In the absence of an absolute target for this KI, clinical relevance remains unclear. For all other included KIs, our data suggest no clinically relevant influence of older age on KI exposure

Therapeutic drug monitoring of small molecule kinase inhibitors in oncology in a real-world cohort study : does age matter?

AIM: Pharmacokinetics of small molecule kinase inhibitors (KIs) used in cancer treatment may alter with increasing age, but results are conflicting. This study aims to compare exposure to KIs between older and younger patients (≥70 and <70 years) in clinical practice. METHODS: KI plasma concentrations of routinely treated patients were measured using validated assays. Calculated trough concentrations were compared in both age groups. For KIs with a clinically meaningful target concentration (erlotinib, imatinib, pazopanib, sunitinib and vemurafenib), influence of older age on target attainment was assessed. RESULTS: We analysed 616 samples from 454 patients (median age: 61; range 20-93 years), treated with dabrafenib (n = 105), erlotinib (n = 49), imatinib (n = 165), pazopanib (n = 63), sunitinib (n = 87), trametinib (n = 95) and vemurafenib (n = 52). Older age did not significantly influence exposure to erlotinib, imatinib, pazopanib, sunitinib, trametinib and vemurafenib. Elderly patients had significantly higher dabrafenib trough concentrations than younger patients (P = 0.02; 62 ng ml-1 (coefficient of variation [CV] 41%), vs. 53 ng ml-1 (CV 46%), respectively). For KIs with a predefined target concentration, 68% of older and 61% of younger patients reached target. CONCLUSIONS: In this real-world study, exposure to most included KIs was comparable in older and younger patients, except for dabrafenib, which showed higher exposure in older patients. In the absence of an absolute target for this KI, clinical relevance remains unclear. For all other included KIs, our data suggest no clinically relevant influence of older age on KI exposure