High Within-group Variability Research Articles

Modeling Parkinson's disease-related symptoms in alpha-synuclein overexpressing mice.

BackgroundIntracellular deposition of alpha‐synuclein (α‐syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other α‐synucleinopathies. Transgenic mouse models overexpressing human α‐syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop α‐syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of α‐syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions.PurposeOne of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within‐group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD‐related symptoms in such studies.MethodsWe have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) α‐syn in the context of their validity and utility for different types of behavioral studies.ConclusionsBy applying appropriate behavioral tests, α‐syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other α‐synucleinopathies.

Dynamic Inconsistency in Great Apes

This paper studies the nature of temporal preferences in humans by studying their basic structure in our closest living primate relatives. We investigate whether intertemporal choices in three great ape species are dynamically consistent. We present orangutans (Pongo abelii ), bonobos (Pan paniscus) and gorillas (Gorilla gorilla) with several series of choices among different quantities of food available after different delays. When apes can select either a reward that is available immediately or one reward three times bigger available three minutes later, they tend to act impatiently choosing the sooner, smaller reward. They also show high within-group variability. However, when a six-minute delay is added to both alternatives, apes tend to act patiently and show a more homogeneous behavior. Additional tests with constant size or delay suggest that participants trade-off the size and delay of the rewards in a temporal horizon extended up to several minutes. These results represent the first time that dynamic inconsistency is documented in our closest living primate relatives. As such, they are consistent with the hypothesis that time-inconsistent preferences are part of our evolutionary heritage.

User-centered design of a longitudinal care plan for children with medical complexity

To determine the content priorities and design preferences for a longitudinal care plan (LCP) among caregivers and healthcare providers who care for children with medical complexity (CMC) in acute care settings. We conducted iterative one-on-one design sessions with CMC caregivers (ie, parents/legal guardians) and providers from 5 groups: complex care, primary care, subspecialists, emergency care, and care coordinators. Audio-recorded sessions included content categorization activities, drawing exercises, and scenario-based testing of an electronic LCP prototype. We applied inductive content analysis of session materials to elicit content priorities and design preferences between sessions. Analysis informed iterative prototype revisions. We conducted 30 design sessions (10 with caregivers, 20 with providers). Caregivers expressed high within-group variability in their content priorities compared to provider groups. Emergency providers had the most unique content priorities among clinicians. We identified 6 key design preferences: a familiar yet customizable layout, a problem-based organization schema, linked content between sections, a table layout for most sections, a balance between unstructured and structured data fields, and use of family-centered terminology. Findings from this study will inform enhancements of electronic health record-embedded LCPs and the development of new LCP tools and applications. The design preferences we identified provide a framework for optimizing integration of family and provider content priorities while maintaining a user-tailored experience. Health information platforms that incorporate these design preferences into electronic LCPs will help meet the information needs of caregivers and providers caring for CMC in acute care settings.

The Relationship Between Speech Characteristics and Motor Subtypes of Parkinson's Disease

Purpose The aim of this study was to examine whether acoustic dysarthria characteristics align with overall motor profile in individuals with Parkinson's disease (PD). Potential speech differences between tremor-dominant and non-tremor-dominant subtypes are theoretically motivated but empirically inconclusive. Method Twenty-seven individuals with dysarthria from PD provided a contextual speech sample. Participants were grouped into non-tremor-dominant (n = 12) and tremor-dominant (n = 15) motor subtypes according to the Unified Parkinson Disease Rating Scale. Dependent speech variables included fundamental frequency range, average pause duration, cepstral peak prominence, stuttering dysfluencies, and maze dysfluencies. Results There were no significant differences between the speech of the tremor-dominant and non-tremor-dominant groups. High within-group variability existed across parameters and motor subtypes. Conclusion Speech characteristics across the areas of phonation, prosody, and fluency did not differ appreciably between PD motor subtypes.

Abstract MP052: Neither Insulin Secretion nor Genotype Pattern Modify 12-Month Weight Loss Effects of Healthy Low-Fat vs. Healthy Low-Carbohydrate Diets Among Adults with Obesity

Background: Dietary modification remains an essential component of successful weight loss strategies. No one dietary strategy has been determined to be superior to others for the general population. Studies that contrast reducing dietary fat vs. carbohydrate report consistently high within-group variability in dietary adherence and weight loss. Previous research by our group and others suggest that insulin-glucose dynamics or genotype patterns may modify diet effects. Objective: To determine if within-group weight loss variability on a Healthy Low-Fat (HLF) vs. a Healthy Low Carbohydrate (HLC) diet can be attributed to underlying factors such as insulin-glucose dynamics (i.e., insulin resistance and secretion) or genotype pattern. We hypothesized the above factors would be effect modifiers of HLF and HLC diets on 12-month weight loss. Methods: Generally healthy, non-diabetic adults, 18-50 years, BMI 28-40 kg/m 2 , were randomized to HLF or HLC with no specific prescribed energy restriction for 12 months (n=609). Health educators delivered the intervention in 22 1-hr group classes. Data were collected at 0, 3, 6, & 12 months. Dietary intake was assessed by three 24-hour recalls/time point. Clinical data includes: 75-g glucose oral glucose tolerance tests (insulin concentration at 30 minutes [Ins-30], a measure of insulin secretion), genotyping (3-SNP multilocus genotype: Low-Fat Genotype vs. Low-Carb Genotype, UK Biobank Axiom® array), body composition (DXA), resting energy expenditure (indirect calorimetry), epigenetics, proteomics, subcutaneous adipose tissue, microbiota, and standard CVD risk indicators. Results: At 12 months participants collectively lost 6,559 lbs. Retention was 79%, with equal dropout between arms. Range of weight change in both diet arms was ~80 lbs (-60 to +20 lbs). Macronutrient distribution at 12 months was 48% vs. 30% carbohydrate, 29% vs. 45% fat, and 21% vs. 23% protein for HLF and HLC, respectively. Both groups reported achieving and maintaining an average ~500 kcal deficit relative to baseline. Weight loss was similar for HLF vs. HLC: -12.1 ± 1.1 lbs vs. -13.8 ± 1.0 lbs, mean ± SEM. Neither Ins-30 (p for interaction = 0.84) nor genotype pattern (p for interaction = 0.20) modified the effect of diet on 12-month weight loss. Conclusions: Despite substantial weight loss, high within-group variability, and strong dietary differentiation between groups, neither baseline Ins-30 nor genotype pattern modified the effect of diet on 12-month weight loss. Focus on a healthy diet in both diet arms is novel in the context of many previous Low-Fat vs. Low-Carb studies and may have diminished expected effect modification. The extensive data set collected will be used to explore this and other potential explanatory factors.

Muscle coordination during breaststroke swimming: Comparison between elite swimmers and beginners

ABSTRACTThe present study aimed to compare muscle coordination strategies of the upper and lower limb muscles between beginners and elite breaststroke swimmers. Surface electromyography (EMG) of eight muscles was recorded in 16 swimmers (8 elite, 8 beginners) during a 25 m swimming breaststroke at 100% of maximal effort. A decomposition algorithm was used to identify the muscle synergies that represent the temporal and spatial organisation of muscle coordination. Between-groups indices of similarity and lag times were calculated. Individual muscle patterns were moderately to highly similar between groups (between-group indices range: 0.61 to 0.84). Significant differences were found in terms of lag time for pectoralis major (P < 0.05), biceps brachii, rectus femoris and tibialis anterior (P < 0.01), indicating an earlier activation for these muscles in beginners compared to elites (range: −13.2 to −3.8% of the swimming cycle). Three muscle synergies were identified for both beginners and elites. Although their composition was similar between populations, the third synergy exhibited a high within-group variability. Moderate to high indices of similarity were found for the shape of synergy activation coefficients (range: 0.63 to 0.88) but there was a significant backward shift (−8.4% of the swimming cycle) in synergy #2 for beginners compared to elites. This time shift suggested differences in the global arm-to-leg coordination. These results indicate that the synergistic organisation of muscle coordination during breaststroke swimming is not profoundly affected by expertise. However, specific timing adjustments were observed between lower and upper limbs.

Phonological and morphophonological effects on grammatical development in children with specific language impairment.

Five-year-olds with specific language impairment (SLI) often struggle with mastering grammatical morphemes. It has been proposed that verbal morphology is particularly problematic in this respect. Previous research has also shown that in young typically developing children grammatical markers appear later in more phonologically challenging contexts. The main aim was to explore whether grammatical deficits in children with SLI are morphosyntactic in nature, or whether phonological factors also explain some of the variability in morpheme production. The analysis considered the effects of the same phonological factors on the production of three different morphemes: two verbal (past tense -ed; third-person singular -s) and one nominal morpheme (possessive -s). The participants were 30 children with SLI (21 boys) aged 4;6-5;11 years (mean = 5;1). The data were collected during grammar test sessions, which consisted of question/answer elicitations of target forms involving picture props. A total of 2301 items were analysed using binary logistic regression; the predictors included: (1) utterance position of the target word, (2) phonological complexity of its coda, (3) voicing of the final stem consonant, (4) syllabicity (allomorph type) and (5) participant accounting for the individual differences in the responses. The results showed a robust effect of syllabicity on the correct morpheme production. Specifically, syllabic allomorphs (e.g., She dresses) were significantly more challenging than the segmental ones (e.g., He runs) for all three morphemes. The effects of other factors were observed only for a single morpheme: coda complexity and voicing helped explain variability in past tense production, and utterance position significantly affected children's performance with the possessive. The participant factor also had a significant effect, indicating high within-group variability--often observed in SLI population. The systematic effect of syllabicity across both verbal and nominal morphemes suggests morphophonological influences in the grammatical development of children with SLI that cannot be fully explained by syntactic deficits. Poorer performance in producing syllabic allomorphs can be accounted for by much lower overall frequency of these forms, and by the 'tongue-twisting' effect of producing similar segments in succession, as in added [aedəd], washes [wɒʃəz]. Interestingly, the greater acoustic salience of the syllabic allomorphs (an extra syllable) does not enhance children's abilities to produce them. These findings suggest that the interconnections between different levels of language have a stronger effect on the grammatical development of children with SLI than might be expected. Allomorphy should, therefore, be taken into account when designing language assessments and speech therapy, ensuring that children receive sufficient practice with the entire set of allomorphic variants.

Recently Deglaciated High-Altitude Soils of the Himalaya: Diverse Environments, Heterogenous Bacterial Communities and Long-Range Dust Inputs from the Upper Troposphere

BackgroundThe Himalaya with its altitude and geographical position forms a barrier to atmospheric transport, which produces much aqueous-particle monsoon precipitation and makes it the largest continuous ice-covered area outside polar regions. There is a paucity of data on high-altitude microbial communities, their native environments and responses to environmental-spatial variables relative to seasonal and deglaciation events.Methodology/Principal FindingsSoils were sampled along altitude transects from 5000 m to 6000 m to determine environmental, spatial and seasonal factors structuring bacterial communities characterized by 16 S rRNA gene deep sequencing. Dust traps and fresh-snow samples were used to assess dust abundance and viability, community structure and abundance of dust associated microbial communities. Significantly different habitats among the altitude-transect samples corresponded to both phylogenetically distant and closely-related communities at distances as short as 50 m showing high community spatial divergence. High within-group variability that was related to an order of magnitude higher dust deposition obscured seasonal and temporal rearrangements in microbial communities. Although dust particle and associated cell deposition rates were highly correlated, seasonal dust communities of bacteria were distinct and differed significantly from recipient soil communities. Analysis of closest relatives to dust OTUs, HYSPLIT back-calculation of airmass trajectories and small dust particle size (4–12 µm) suggested that the deposited dust and microbes came from distant continental, lacustrine and marine sources, e.g. Sahara, India, Caspian Sea and Tibetan plateau. Cyanobacteria represented less than 0.5% of microbial communities suggesting that the microbial communities benefitted from (co)deposited carbon which was reflected in the psychrotolerant nature of dust-particle associated bacteria.Conclusions/SignificanceThe spatial, environmental and temporal complexity of the high-altitude soils of the Himalaya generates ongoing disturbance and colonization events that subject heterogeneous microniches to stochastic colonization by far away dust associated microbes and result in the observed spatially divergent bacterial communities.

Improved Statistical Modeling of Tumor Growth and Treatment Effect in Preclinical Animal Studies with Highly Heterogeneous Responses In Vivo

Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated. We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework. The framework is implemented and distributed as an R package, which enables model estimation and statistical inference, as well as statistical power and precision analyses. When applied to four tumor growth experiments, the modeling framework was shown to (i) improve the detection of subtle treatment effects in the presence of high within-group tumor variability; (ii) reveal hidden tumor subgroups associated with established or novel biomarkers, such as ERβ expression in a MCF-7 breast cancer model, which remained undetected with standard statistical analysis; (iii) provide guidance on the selection of sufficient sample sizes and most informative treatment periods; and (iv) offer flexibility to various cancer models, experimental designs, and treatment options. Model-based testing of treatment effect on the tumor growth rate (or slope) was shown as particularly informative in the preclinical assessment of treatment alternatives based on dietary interventions. In general, the modeling framework enables identification of such biologically significant differences in tumor growth profiles that would have gone undetected or had required considerably higher number of animals when using traditional statistical methods.

Influence of advanced prosthetic knee joints on perceived performance and everyday life activity level of low-functional persons with a transfemoral amputation or knee disarticulation

To assess the effects of two types of microprocessor-controlled prosthetic knee joints (MPKs) on perceived performance and everyday life activity level. Randomized cross-over trial. Thirty persons with a unilateral above-knee amputation or knee disarticulation classified as Medicare Functional Classification Level-2. Participants were measured in 3 conditions, i.e. using a mechanically controlled prosthesis, an MPK featuring a microprocessor-controlled stance and swing phase (MPKA), and an MPK featuring a microprocessor-controlled stance phase (MPKB). Subjects' perceived performance regarding prosthesis use was measured with the Prosthesis Evaluation Questionnaire. Subjects' activity level was quantified using accelerometry. As high within-group variability regarding subjects' functional performance was expected to impede detection of possible effects of an MPK, data were analysed for the total group and for 3 subgroups of participants. Participants' perception regarding ambulation, residual limb health, utility, and satisfaction with walking were significantly higher in the MPKA condition compared with the mechanical knee joint condition. Participants' activity level was similar in all knee joint conditions. Although Medicare Functional Classification Level-2 amputees report benefitting in terms of their performance from using an MPK, this is not reflected in their actual daily activity level after one week of using an MPK.

Improved cryopreservation of human hepatocytes using a new xeno free cryoprotectant solution

To optimize a xeno-free cryopreservation protocol for primary human hepatocytes. The demand for cryopreserved hepatocytes is increasing for both clinical and research purposes. Despite several hepatocyte cryopreservation protocols being available, improvements are urgently needed. We first compared controlled rate freezing to polystyrene box freezing and did not find any significant change between the groups. Using the polystyrene box freezing, we compared two xeno-free freezing solutions for freezing of primary human hepatocytes: a new medium (STEM-CELLBANKER, CB), which contains dimethylsulphoxide (DMSO) and anhydrous dextrose, both permeating and non-permeating cryoprotectants, and the frequently used DMSO - University of Wisconsin (DMSO-UW) medium. The viability of the hepatocytes was assessed by the trypan blue exclusion method as well as a calcein-esterase based live-dead assay before and after cryopreservation. The function of the hepatocytes was evaluated before and after cryopreservation by assessing enzymatic activity of 6 major cytochrome P450 isoforms (CYPs): CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A7. The new cryoprotectant combination preserved hepatocyte viability significantly better than the standard DMSO-UW protocol (P < 0.01). There was no significant difference in viability estimation between both the trypan blue (TB) and the Live-Dead Assay methods. There was a correlation between viability of fresh hepatocytes and the difference in cell viability between CB and DMSO protocols (r(2) = 0.69) using the TB method. However, due to high within-group variability in the activities of the major CYPs, any statistical between-group differences were precluded. Cryopreservation of human hepatocytes using the cryoprotectant combination was a simple and xeno-free procedure yielding better hepatocyte viability. Thus, it may be a better alternative to the standard DMSO-UW protocol. Estimating CYP activities did not seem to be a relevant way to compare hepatocyte function between different groups due to high normal variability between different liver samples. The cryoprotectant combination may be a better alternative to the standard DMSO-UW protocol in primary human hepatocyte cryopreservation.

Landing Patterns of Phloem- and Wood-feeding Coleoptera on Black Spruce of Different Physiological and Decay States

We examined landing patterns of phloeophagous and xylophagous Coleoptera among trees and snags of different physiological and decay states in a pure open-canopy black spruce stand in boreal Canada to study prelanding host selection mechanisms in the absence of nonhost volatiles. Sticky traps were used to capture insects landing on high- and low-density natural snags (i.e., wood density), girdled trees, living trees, and stovepipe controls. Patterns were generally weak, with high within-group variability in species composition and landing rates. Within-group variability differed between groups, with highest variations in living trees and recent snags. Despite this evidence of frequent landing on suboptimal or inappropriate hosts, affinities were detected in most common taxa. Cerambycidae showed preferences for girdled trees. Common species of Scolytinae showed divergent preferences, because Crypturgus borealis Swaine and Dryocoetes autographus (Ratzeburg) were captured more often on high-density natural snags, Polygraphus rufipennis (Kirby) on girdled trees, and Orthotomicus latidens (LeConte) on living trees. These observed landing patterns are broadly consistent with current knowledge on the ecology of these species. Although preferences, and thus prelanding assessment of hosts based on volatiles, were detected in several species, the numerous landings observed on inappropriate hosts suggest that random landing at close range may be as common in pure stands as what was previously observed in mixed stands.

Chemical Exposures: Cats as Sentinel Species

Pet cats may be like canaries in coal mines when it comes to evaluating the health impacts of polybrominated diphenyl ethers (PBDEs), persistent chemicals used in carpet pads, furniture, and electronics. Chronic PBDE exposure may partly explain an epidemic of hyperthyroid disease in older cats, says Janice Dye, a U.S. EPA research biologist. In turn, studying the effects of chronic PBDE exposure in cats could offer clues as to the effects in their human counterparts. Veterinarians first noticed a dramatic surge in feline hyperthyroidism (FH) in the 1980s, coinciding with the use of PBDEs as flame retardants in consumer products. FH, the most common endocrine disorder in cats, causes rapid weight loss due to increased concentrations of thyroxine. Histologic changes in FH mirror those seen in older humans experiencing toxic nodular goiter (TNG), in which an enlarged thyroid gland overproduces thyroxine. The causes of FH and TNG remain unknown. Dye looked at whether hyperthyroidal cats had greater body burdens of PBDEs. She and her colleagues measured numerous PBDE congeners in serum samples collected from 23 cats, 11 of which were positive for FH. They report in the 15 September 2007 Environmental Science & Technology that total average PBDE levels were three times higher in older cats with FH than in younger cats without FH, but the difference was not statistically significant because of high within-group variability. “All cats are high [compared with humans], and some cats are incredibly high,” Dye notes. She also found that cat food, particularly canned fish-flavored brands, contains high levels of PBDEs. Cats swallow PBDEs in food and by licking PBDE-laden house dust from their fur. PBDE congeners contain bromine atoms that mimic the iodine in thyroxine. PBDEs may interact with thyroid-binding proteins to displace thyroxine, and chronic exposure may lead to sustained increases in secretion of thyroid-stimulating hormone and thyroid hyperplasia. “When that happens,” says Dye, “it’s pedal to the metal, and the cat’s thyroid makes too much thyroxine.” The potential link between FH and PBDEs suggests that house cats may be sentinels for chronic indoor PBDE exposure in people. By understanding more completely how PBDEs alter thyroid hormone levels in cat sentinels, “we can assess whether comparable risk exists for exposed people, especially children,” Dye says. Like cats, toddlers may be inordinately exposed to PBDEs in dust by crawling on floors and placing objects in their mouths. A case study of one family, described in the October 2006 EHP, found that a toddler had PBDE levels up to 10 times higher than those of his parents. “We don’t know what PBDEs do to children during critical stages of development,” says Dye, but cats offer hints about “where chronic exposure may lead.” People in the United States have the highest PBDE levels reported worldwide, according to a meta-analysis published in the 15 February 2004 Environmental Science & Technology. Heather Stapleton, an environmental chemist at Duke University, points out that the link between PBDEs and health problems in cats is reminiscent of the revelation 25 years ago that children ingesting lead in household dust experienced learning problems. Says Stapleton, “It’s important to understand the effects of exposure to these brominated flame retardants in humans.”

Identification of individuals with elevated cholesterol in family physicians' offices

Guidelines for screening for elevated serum cholesterol have been published in both Canada and the United States. Preventive practices have been difficult to integrate into episodic care. This study was designed to test the impact of an educational intervention to increase physicians' screening for elevated cholesterol in their practices. It was hypothesized that physicians who participated in the intervention would demonstrate higher rates of appropriate screening. A three-group randomized controlled trial of an educational intervention was conducted over 10 months in family physicians' private offices throughout Nova Scotia. Invitation letters were mailed to full-time family physicians with 5 or more years in practice. Fifty-nine (27.2% of 217 eligible) physicians entered and 51 completed the study. The study group physicians attended a half-day workshop emphasizing information regarding, and approaches to, screening. The primary outcome measure was of physician screening in their practice. The baseline preworkshop screening rate averaged 51.7% for all groups. The groups were similar in this regard (p = .14). Physicians in the two study groups who attended the workshop had higher postworkshop screening rates than the control group (p = .08). The lack of strongly statistically significant effects of the intervention may be deceiving when the high base screening rate and the high physician within-group variability are considered. Attempts to evaluate the impact of interventions must take into account the very large amount of information directed at physicians and the public regarding elevated cholesterol.