Confirmatory factor analysis of the BRIEF2 in a sample of youth with Down syndrome.

BACKGROUND: The factor structure of the Behavior Rating Inventory of Executive Function, second edition (BRIEF2) has been widely examined in both typically developing children and specific clinical samples. Despite the frequent use of the BRIEF2 for measuring executive functioning in individuals with Down syndrome, no study has investigated the factorial validity or dimensionality of the BRIEF2 in this population. This study aimed to address this notable gap in the literature. METHODS: Parents of 407 children and youth with Down syndrome aged 6-18 years completed the BRIEF2 as part of different studies led by six sites. Three competing models proposed by previous studies were analysed using Confirmatory Factor Analysis: the theoretical structure of the BRIEF2 where the scales were constrained to load on three factors labelled as Cognitive, Behavioral, and Emotional Regulation, a two-factor correlated model with the merged Behavioral and Emotional regulation, and a single-factor model. RESULTS: The three-factor model provided a better fit than the one- and two-factor models, yet a large correlation was observed between Behavioural and Emotional regulation factors. The results provide meaningful explanatory value for the theoretical structure of the BRIEF2. However, the Behavioral and Emotional regulation factors might be less differentiated and the two-factor structure of the BRIEF2 may also make theoretical and empirical sense. CONCLUSIONS: Although more studies are needed to further examine the factor structure of the BRIEF2 in youth with Down syndrome, this investigation provides preliminary support for the interpretation of the three executive function index scores provided by the BRIEF2: Cognitive, Behavioral, and Emotional Regulation.

Investigation of the Clinical Utility of the BRIEF2 in Youth With and Without Intellectual Disability.

OBJECTIVE: Executive function (EF) difficulties are commonly found in youth with intellectual disability (ID). Given mixed results from studies using performance-based EF measures, the EF profile has not been well characterized for this population. No published work has examined the clinical utility of the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2) in distinguishing EF in ID. We hypothesized that the BRIEF2 would show greater elevations in youth with ID compared to the Average IQ comparison group. METHODS: Participants included a large sample of 504 youth (157 in ID group; aged 8-18 years) referred for (neuro)psychological evaluation (2015-2019) and identified as meeting criteria for either ID or Average IQ comparison group. RESULTS: Significant elevations were found across BRIEF2 indices and scales. Only mild elevations were noted in selective cognitive regulation scales within the Average IQ group. Groups differed significantly across all EF dimensions, with greater differences observed in behavioral regulation (Self-Monitoring, Inhibition), Shift, and Working Memory. An elevated but less variable pattern of index scores was noted in ID, while the overall pattern of scaled scores appeared similar between groups. CONCLUSIONS: The less variable and consistently elevated profile may suggest fewer EF dimensions in individuals with ID than the model proposed in the test manual. Similar profiles between groups may reflect differences in severity, rather than differences in constructs measured by the EF factors, per se. Additional examination is needed to confirm potential structural differences in EF for youth with ID as measured by BRIEF2, with a clinical implication for greater efficiency of EF assessment in this population.

If Opportunity Knocks: Understanding Contextual Factors' Influence on Cognitive Systems.

Central to the Research Domain Criteria (RDoC) framework is the idea that RDoC constructs, which vary dimensionally by individual, are heavily influenced by contextual factors. Perhaps chief among these contextual factors is structural opportunity - the quality of resources available to a child as they grow. The aim of this study is to understand the impact of access to opportunity during childhood on three central RDoC cognitive systems constructs: language, visual perception, and attention. These constructs were measured using clinical data from psychological evaluations of youth ages 4-18 years (N = 16,523; Mage = 10.57, 62.3% male, 55.3% White). Structural opportunity was measured using the geocoded Child Opportunity Index 2.0 (COI), a composite score reflecting 29 weighted indicators of access to the types of neighborhood conditions that help children thrive. Findings indicate that, controlling for demographic and socioeconomic factors, greater access to opportunity is associated with significantly stronger cognitive skills across all three constructs. However, opportunity uniquely explains the largest proportion of the variance in language skills (8.4%), compared to 5.8% of the variance in visual processing skills and less than 2% of the variance in attention. Further, a moderating effect of age was found on the relation between COI and language skills, suggesting that the longer children remain exposed to lower levels of opportunity, the lower their language skills tend to be. Understanding how opportunity impacts cognitive development allows clinicians to offer better tailored recommendations to support children with cognitive systems deficits, and will support policy recommendations around access to opportunity.

Pre-appointment online assessment of patient complexity: Towards a personalized model of neuropsychological assessment.

Recent events such as the global pandemic of COVID-19 have challenged neuropsychologists to scale up their capacity to conduct portions of their assessment remotely. While more complex patients will likely continue to require on-site, office-based interaction and assessment, the current emergency-based expansion of online and telehealth evaluation practices may ultimately lay the groundwork for more routine, online assessment of patients with less complex presentations in the future. To this end, the current study evaluated a pre-appointment, online methodology for differentiating referred pediatric patients based upon the scope and severity of their caregiver-reported adaptive, academic, attentional, behavioral, and emotional impairment. Prior to on-site assessment, parents/caregivers of 2197 children (Mean age = 10.0y, range = 4-19y, 62% male) completed an online developmental history form screening for symptoms of adaptive, attentional, learning, affective, and behavioral impairment; 71% of those children eventually underwent assessment. Using latent class analysis, the data supported a reproducible 4-class model consisting of groups of children at increased risk for: 1) severe multi-domain dysfunction; the "High Complexity" group, 30%, 2) behavioral-affective (but not academic) dysregulation; the "Behavioral Focus" group, 13%, 3) academic (but not behavioral-affective) problems; the "Academic and Inattention" group, 37%, and 4) patients with minimal clinical complexity; the "Low Complexity" group, 20%. Comparison of pre-visit classification with day-of-assessment standardized test scores supported the validity of patient subtypes. Moving forward, pre-appointment clarification of patient complexity may support efficient patient triage with regard to assessment modality (e.g., on-site or online) and length of appointment (e.g., comprehensive or targeted).

Caregiver Perspectives on Informed Consent for a Pediatric Learning Healthcare System Model of Care.

BACKGROUND: Data is needed to provide insight into the issue of preference around consent for use of pediatric clinical data for research. This study evaluated caregivers' preferences concerning use of their child's clinical information. METHODS: Caregivers of children (n = 101; response rate 81.5% of n = 124) presenting for psychological evaluation at an urban medical center viewed a video regarding how the information contained in their child's medical record could be used for research. RESULTS: An anonymous survey following the video indicated that: 1) >90% of caregivers felt comfortable with their child's information being used; 2) >90% of caregivers felt their child's privacy would be adequately protected; 3) 98% of caregivers reported themselves to be as or more likely to return to the institution after viewing the video; 4) 60% of caregivers felt no additional consent procedures beyond viewing the video were needed, while 20% preferred an opt-out and 20% preferred a traditional consent procedure. Caregiver demographic variables were largely unrelated to consent preferences. DISCUSSION: Overall, caregivers reported strong support for use of their child's clinical data for research purposes.

Structural and thermodynamic strategies for site-specific DNA binding proteins.

BACKGROUND: Site-specific protein-DNA complexes vary greatly in structural properties and in the thermodynamic strategy for achieving an appropriate binding free energy. A better understanding of the structural and energetic engineering principles might lead to rational methods for modification or design of such proteins. RESULTS: A novel analysis of ten site-specific protein-DNA complexes reveals a striking correspondence between the degree of imposed DNA distortion and the thermodynamic parameters of each system. For complexes with relatively undistorted DNA, favorable enthalpy change drives unfavorable entropy change, whereas for complexes with highly distorted DNA, unfavorable DeltaH degrees is driven by favorable DeltaS degrees. We show for the first time that protein-DNA associations have isothermal enthalpy-entropy compensation, distinct from temperature-dependent compensation, so DeltaH degrees and DeltaS degrees do not vary independently. All complexes have favorable DeltaH degrees from direct protein-DNA recognition interactions and favorable DeltaS degrees from water release. Systems that strongly distort the DNA nevertheless have net unfavorable DeltaH degrees as the result of molecular strain, primarily associated with the base pair destacking. These systems have little coupled protein folding and the strained interface suffers less immobilization, so DeltaS degrees is net favorable. By contrast, systems with little DNA distortion have net favorable DeltaH degrees, which must be counterbalanced by net unfavorable DeltaS degrees, derived from loss of vibrational entropy (a result of isothermal enthalpy-entropy compensation) and from coupling between DNA binding and protein folding. CONCLUSIONS: Isothermal enthalpy-entropy compensation implies that a structurally optimal, unstrained fit is achieved only at the cost of entropically unfavorable immobilization, whereas an enthalpically weaker, strained interface entails smaller entropic penalties.

Identification of a putative structural gene for cathepsin D in Caenorhabditis elegans.

Mutants of Caenorhabditis elegans having about 10% of wild-type activity of the aspartyl protease cathepsin D have been isolated by screening. Mutant homozygotes have normal growth rates and no obvious morphological or developmental abnormalities. The mutant gene (cad-1) has been mapped to the right extremity of linkage group II. Heterozygous animals (cad-1/+) show intermediate enzyme levels and animals heterozygous for chromosomal deficiencies of the right extremity of linkage group II have 50% of wild-type activity. Cathepsin D purified from a mutant strain has a lower activity per unit mass of pure enzyme. These data suggest that cad-1 is a structural gene for cathepsin D.

The autofluorescent "lipofuscin granules" in the intestinal cells of Caenorhabditis elegans are secondary lysosomes.

The nematode Caenorhabditis elegans contains autofluorescent lipofuscin granules, located exclusively in the 32-34 intestinal cells. Using epifluorescence microscopy on live adult animals, we have shown that fluorescent-labeled exogenous probes are taken up by endocytosis and accumulate within the granules. Macromolecular solutes such as proteins and dextran appear to be taken up by fluid-phase pinocytosis. There is no phagocytosis of latex particles with diameter greater than or equal to 0.25 micron. The granules concentrate the lysosomotropic weak base acridine orange, indicating that they have an acidic internal milieu. These observations imply that the lipofuscin granules in the intestinal cells are secondary lysosomes which remain active recipients of endocytosed materials.

Quantitative measures of aging in the nematode Caenorhabditis elegans. I. Population and longitudinal studies of two behavioral parameters.

As a first step in the quantitative characterization of senescence in the nematode Caenorhabditis elegans, we have studied movement wave frequency, defecation frequency, and whole-body water efflux as a function of age. Populations of C. elegans, strain N2, were cultured monoxenically on E. coli lawns at 20 degrees C. The median lifespan in such populations was approximately 12 days. Population mean movement wave frequency declined linearly with age (slope = -4.66 waves/minute per day). The decline in population mean defecation frequency (defecations per minute) was multiphasic, consisting of (1) a rapid decline (slope = -0.233 defecations/minute per day) from day 3 to day 6, (2) no apparent trend from day 6 to day 9, and (3) a gradual decline (slope = -0.089 defecations/minute per day) from 9 to day 14. Animals alive on or after day 15 were not observed to defecate. In longitudinal studies, individual animals exhibited linear declines in movement wave frequency and multiphasic declines in defecation frequency. For future population studies, the age-dependent declines in movement and defecation frequency appear sufficiently large and reproducible to a multiparametric description of senescence in C. elegans. One physiological parameter, 3H2O efflux, was found to be age-independent and to consist of two first-order rates. The half-times of the slow and fast efflux rates were approximately 15 and approximately 2.1 minutes, respectively. The two half-times and the fractions of 3H2O exhibiting the two half-times were invariant with age.

Quantitative measures of aging in the nematode Caenorhabditis elegans: II. Lysosomal hydrolases as markers of senescence.

In an attempt to provide additional quantitative markers of senescence in the nematode Caenorhabditis elegans, we have identified age-dependent increases in four lysosomal enzymes: acid phosphatase, beta-N-acetyl-D-glucosaminidase, beta-D-glucosidase, and alpha-D-mannosidase. These enzymes were judged to be lysosomal on the basis of their resemblance to analogous mammalian lysosomal enzymes with regard to subcellular fractionation, lectin binding, Km, molecular weights, inhibitor sensitivities, and pH optima. In nematode populations which had a median lifespan of 8.9 +/- 0.7 days and a maximum lifespan of 14-16 days, we observed the following increases in acid hydrolase activities per animal from day 3 (early adulthood) to day 10: (1) up to 2.5-fold for acid phosphatase; (2) 8-fold for beta-N-acetyl-D-glucosaminidase; (3) 9-fold for beta-D-glucosidase; and (4) 4-fold for alpha-D-mannosidase. Three forms of acid phosphatase and two forms of beta-D-glucosidase were separated by ion-exchange chromatography, but in each case only one form of the enzyme was primarily responsible for the age-dependent increase in total activity: acid phosphatase I increased 18-fold, while beta-D-glucosidase I increased 100-fold. By contrast, there were only slight age-dependent changes in choline acetyltransferase, acetylcholinesterase, or alpha-D-glucosidase activities after early adulthood. The age-dependent increases in acid phosphatase, beta-N-acetyl-D-glucosaminidase, beta-D-glucosidase, and alpha-D-mannosidase activities are sufficiently large and reproducible to be useful quantitative markers of senescence in C. elegans.

Decline in protease activities with age in the nematode Caenorhabditis elegans.

The activities of 3 lysosomal proteases in the nematode Caenorhabditis elegans are markedly lower in older animals. The aspartyl protease cathepsin D declines about 10-fold from day 3 (early adulthood) to day 11 (near the mean lifespan); this reflects a net decline in the amount of cathepsin D antigen. The specific activity of the thiol protease cathepsin Ce1 declines about 2.5-fold over the same period, and the specific activity of the thiol protease cathepsin Ce2 declines about 8-fold. The activity of a new non-lysosomal protease, designated cathepsin CeX, is invariant with age. The data are consistent with the hypothesis that reduced protease activity in older animals may cause a decline in the rate of protein turnover with age, but do not prove this hypothesis.

Control of stable ribonucleic acid chain initiation in Escherichia coli during diauxie lag.

During glucose-lactose diauxie lag, Escherichia coli synthesizes ribonucleic acid (RNA) at about 7% of the rate in exponentially growing cells. RNA synthesis could be restored to the log-phase rate within 3 min after the addition of glucose to the culture (shift-up). This stimulation occurred equally well in the presence of chloramphenicol and therefore did not require the synthesis of new proteins. RNA synthesis could also be stimulated by the addition of glycerol, but only after a delay of 15 to 20 min. Glycerol stimulation occurred more rapidly in cells preadapted by prior growth on glycerol and occurred immediately in a mutant (glpR) constitutive for the enzymes of glycerol catabolism. Measurement of a parameter related to the rate of initiation of stable (ribosomal and transfer) RNA chains showed that the initiation of transcription of these stable RNA species was completely inhibited during the diauxie lag, but could be restored to the rate characteristic of log-phase cells by shift-up with glucose. Sucrose gradient analysis of RNA purified from cells after a glucose shift-up indicated an increased rate of accumulation of the ribosomal and transfer RNA species. It is proposed that a specific mechanism to inhibit the initiation of transcription of ribosomal and transfer RNA operates during diauxie lag. This inhibitory mechanism is governed by the level of cellular energy resources insofar as the inhibition is readily reversed by metabolizable energy sources.

A concise method for reducing photographic spectrograph calibrations.

An accurate and concise method of fitting and presenting photographic spectrographic calibration data has been developed that overcomes the shortcomings imposed by polynomial fitting techniques. This approach utilizes hitherto ignored correlatible data from neighboring wavelengths to increase the accuracy and smoothness of data at each particular wavelength. The results empirically confirm the assumption that an over-all system H-D curve at one wavelength can be accurately mapped into the H-D curve at a near wavelength using only a scaling constant Agamma and a translation constant Bgamma. This method also allows extrapolation beyond some of the raw data calibration ranges.

Regulation of ribonucleic acid synthesis in Escherichia coli during diauxie lag: accumulation of heterogeneous ribonucleic acid.

The synthesis of ribonucleic acid (RNA) and of protein in Escherichia coli during glucose-lactose diauxie lag have been examined. The rate of RNA synthesis is about 7%, of the corresponding rate during exponential growth and the rate of protein synthesis 10 to 15%. Inhibition of RNA synthesis occurs to the same extent in both rel and rel(+) strains. The RNA which accumulates during 20 min in diauxie lag is composed of about 50% ribosomal and transfer RNA species and about 50% of a fraction which resembles messenger RNA (mRNA) in its heterogeneous sedimentation properties. Decay of the heterogeneous fraction occurs in the presence of glucose and actinomycin D with a half-life of 3 min, the same as that of pulse-labeled mRNA; however, during the diauxie lag, the half-life of this RNA is about 25 min. Accumulation of the heterogeneous RNA is further increased when protein synthesis is blocked by chloramphenicol. The data suggest that the disproportionate accumulation of mRNA during diauxie lag and energy source shift-down may be attributed at least in part to increased stability of mRNA, but do not rule out a preferential synthesis of mRNA.

Control of protein synthesis in Escherichia coli: strain differences in control of translational initiation after energy source shift-down.

We have studied the parameters of protein synthesis in a number of Escherichia coli strains after a shift-down from glucose-minimal to succinate-minimal medium. One group of strains, including K-12(lambda) (ATCC 10798) and NF162, showed a postshift translational yield of 50 to 65% and a 2- to 2.5-fold increase in the functional lifetime of general messenger ribonucleic acid. There was no change in the lag time for beta-galactosidase induction in these strains after the shift-down. A second group, including W1 and W2, showed no reduction in translational yield, no change in the functional lifetime of messenger ribonucleic acid, and a 50% increase in the lag time for beta-galactosidase induction. Evidence is presented which indicates that this increased lag time is not the result of a decreased rate of polypeptide chain propagation. A third group of strains, including NF161, CP78, and NF859, showed an intermediate pattern: translational yield was reduced to about 75% of normal, and the messenger ribonucleic acid functional lifetime was increased by about 50%. Calculation of the relative postshift rates of translational initiation gave about 0.2, 1.0, and 0.5, respectively, for the three groups. There was no apparent correlation between the ability to control translation and the genotypes of these strains at the relA, relX, or spoT loci. Measurements of the induction lag for beta-galactosidase during short-term glucose starvation or after a down-shift induced by alpha-methylglucoside indicated that these regimens elicit responses that are physiologically distinct from those elicited by a glucose-to-succinate shift-down.

The size and heterogeneity of the messenger RNA associated with 70 S monosomes from down-shifted Escherichia coli.

After an energy source shift-down, Escherichia coli accumulates 70 S ribosome-mRNA complexes ("70 S monosomes"). The monosome mRNA strands are predominantly primary transcription products with purine nucleoside 5'-triphosphate and 5'-diphosphate termini present at a 1:2 ratio. The number-average chain length is 564 +/- 30 nucleotides, indicating that the population represents primarily monocistronic mRNAs. Digestions with endonucleases and exonucleases indicate that the ribosomes lie near the 5' ends of the mRNA strands and that the majority of the mRNA strands contain 5'-proximal "leader" sequences (average 10 nucleotides) outside the protective boundary of the ribosome. These data are consistent with the hypothesis that the increased functional stability of mRNA in down-shifted cells may result from protection by bound ribosomes of endonuclease-susceptible site(s) near the 5' ends of the mRNA strands.

Self-quenched fluorogenic protein substrates for the detection of cathepsin D and other protease activities.

Self-quenched fluorogenic substrates for proteolytic enzymes have been prepared by alkylation of thiol groups in reduced bovine serum albumin with iodoacetamidofluorescein or iodoacetamidoeosin. Substrates immobilized by adsorption onto nitrocellulose membranes or by incorporation into agarose gel slabs are suitable for fluorescence zymography after electrophoretic separation of catalytically active proteases, including cathepsin D.

Association of messenger ribonucleic acid with 70S monosomes from down-shifted Escherichia coli.

The complexed 70S ribosomes (monosomes) that accumulate in Escherichia coli after an energy source shift-down were examined in an electron microscope. In all cases, the ribosomes lie at or near one end of a ribonucleic acid (RNA) strand. This messenger RNA (mRNA) has a mean length of 168 nm and a length-average length of 200 nm, sufficient to code for polypeptides of a weight-average molecular weight of 20,000. The length distribution indicates that these strands are a reasonable representation of the population of monocistronic mRNA's of E. coli. The mRNA strands disappear entirely upon digestion with pancreatic ribonuclease, phosphodiesterase I, or polynucleotide phosphorylase. The susceptibility to digestion by 3'-exonucleases indicate that the ribosomes lie at the 5' end of the mRNA strands. These results are consistent with the hypothesis that down-shifted cells have a translational defect at a point subsequent to the binding of ribosomes to mRNA but prior to the formation of the first peptide bond, such that ribosomes remain bound at or near their points of initial attachment to mRNA.