To what extent does IQ 'explain' socio-economic variations in function?

Background  

The aims of this study were to examine the extent to which higher intellectual abilities protect higher socio-economic groups from functional decline and to examine whether the contribution of intellectual abilities is independent of childhood deprivation and low birth weight and other socio-economic and developmental factors in early life.     

Survival of Single Positive Thymocytes Depends upon Developmental Control of RIPK1 Kinase Signaling by the IKK Complex Independent of NF-κB

1. Download high-res image (162KB)
2. Download full-size image

     

Systematic review of accelerometer-based methods for 24-h physical behavior assessment in young children (0–5 years old)

Background

Accurate accelerometer-based methods are required for assessment of 24-h physical behavior in young children. We aimed to summarize evidence on measurement properties of accelerometer-based methods for assessing 24-h physical behavior in young children.

Methods

We searched PubMed (MEDLINE) up to June 2021 for studies evaluating reliability or validity of accelerometer-based methods for assessing physical activity (PA), sedentary behavior (SB), or sleep in 0–5-year-olds. Studies using a subjective comparison measure or an accelerometer-based device that did not directly output time series data were excluded. We developed a Checklist for Assessing the Methodological Quality of studies using Accelerometer-based Methods (CAMQAM) inspired by COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN).

Results

Sixty-two studies were included, examining conventional cut-point-based methods or multi-parameter methods. For infants (0—12 months), several multi-parameter methods proved valid for classifying SB and PA. From three months of age, methods were valid for identifying sleep. In toddlers (1—3 years), cut-points appeared valid for distinguishing SB and light PA (LPA) from moderate-to-vigorous PA (MVPA). One multi-parameter method distinguished toddler specific SB. For sleep, no studies were found in toddlers. In preschoolers (3—5 years), valid hip and wrist cut-points for assessing SB, LPA, MVPA, and wrist cut-points for sleep were identified. Several multi-parameter methods proved valid for identifying SB, LPA, and MVPA, and sleep.

Despite promising results of multi-parameter methods, few models were open-source. While most studies used a single device or axis to measure physical behavior, more promising results were found when combining data derived from different sensor placements or multiple axes.

Conclusions

Up to age three, valid cut-points to assess 24-h physical behavior were lacking, while multi-parameter methods proved valid for distinguishing some waking behaviors. For preschoolers, valid cut-points and algorithms were identified for all physical behaviors. Overall, we recommend more high-quality studies evaluating 24-h accelerometer data from multiple sensor placements and axes for physical behavior assessment. Standardized protocols focusing on including well-defined physical behaviors in different settings representative for children’s developmental stage are required. Using our CAMQAM checklist may further improve methodological study quality.

PROSPERO Registration number

CRD42020184751.

     

11C]flumazenil metabolite measurement in plasma is not necessary for accurate brain benzodiazepine receptor quantification

In this work, a mathematical correction for metabolites has been validated which estimates the relative amount of [11C]flumazenil ([11C]FMZ) in the total plasma curve from the tissue kinetic data without the need for direct metabolite measurement in blood plasma samples. Kinetic data were obtained using a 90-min three-injection protocol on five normal volunteers. First, the relative amount of [11C]FMZ in plasma was modelled by a two-parameter exponential function. The parameters were estimated either directly by fitting this model to the blood plasma metabolite measurements, or indirectly from the simultaneous fitting of tissue time activity curves from several brain regions with a non-linear FMZ kinetic model. Second, the direct and indirect metabolite corrections were fixed and the FMZ compartmental parameters were determined on a regional basis in the brain. The validation was performed by comparing the regional values of benzodiazepine receptor density Bmax and equilibrium dissociation constant Kd obtained with the direct metabolite correction with those values obtained with the indirect correction. For Bmax, the correlation coefficient r2 was above 0.97 for all subjects and the slope values of the linear regression were within the interval [0.97, 1.2]. For Kd, r2 was above 0.96, and the slope values of the linear regression were within the interval [0.99, 1.1]. Simulation studies were performed in order to evaluate whether this metabolite correction method could be used in a clinical protocol where only a single [11C]FMZ injection and a linear compartmental model are used. The resulting [11C]FMZ distribution volume estimates were found to be linearly correlated with the true values, with r2=1.0 and a slope value of 1.1. The mathematical metabolite correction proved to be a feasible and reliable method to estimate the relative amount of [11C]FMZ in plasma and the compartmental model parameters for three-injection protocols. Although validation with real data is necessary, simulation results suggest that our analysis method may also be applied to single-injection protocols.     

Maternal death reviews at a rural hospital in Malawi

ObjectiveTo analyze maternal deaths at Nkhoma Church of Central Africa Presbyterian (CCAP) Hospital and identify factors causing delays in care.MethodsMaternal death audits are performed after every maternal death at Nkhoma CCAP Hospital. Information regarding the care provided at the health facility, the referral process, and any delays in the community was collected by an audit team using a structured approach. Data from August 2007 to September 2011 were analyzed retrospectively.ResultsIn total, 61 maternal deaths occurred during the study period, of which 58 were analyzed. Most deaths were categorized as indirect (n = 34 [58.6%]). Non-pregnancy-related infections were the leading cause of indirect death (n = 22), with meningitis the most common (n = 13). Most patients experienced a delay in seeking care (n = 37 [63.8%]), a transport delay (n = 43 [74.1%]), or a delay in receiving adequate care (n = 34 [58.6%]).ConclusionMost maternal deaths had indirect causes and were associated with delays in all phases. An audit makes clear which part of the referral chain needs to be strengthened. Nkhoma CCAP Hospital has taken steps to address all phases of delay.     

Phage Display-directed Discovery of LEDGF/p75 Binding Cyclic Peptide Inhibitors of HIV Replication

The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75–IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics.     

Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra

Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (¹H‐MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well‐established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX₃CL1/CX₃CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX₃CR1^+/? C57BL/6 mice and wild type CX₃CR1^+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX₃CR1^?/? C57BL/6 mice. Second, we show that ¹H‐MRS metabolite spectra are different when comparing cuprizone‐treated CX₃CR1^?/? mice showing mild demyelination with cuprizone‐treated CX₃CR1^+/+ mice showing severe demyelination and demyelination‐associated inflammation. Following cuprizone treatment, CX₃CR1^+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX₃CR1^?/? mice only showed a decrease in tCho and tNAA concentrations. Therefore, ¹H‐MRS might possibly allow us to discriminate demyelination from demyelination‐associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone‐induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd.