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PubMed2000

Modeling protein density of states: additive hydrophobic effects are insufficient for calorimetric two-state cooperativity.

A well-established experimental criterion for two-state thermodynamic cooperativity in protein folding is that the van't Hoff enthalpy DeltaH(vH) around the transition midpoint is equal, or very nearly so, to the calorimetric enthalpy DeltaH(cal) of the entire transition. This condition is satisfied by many small proteins. We use simple lattice models to provide a statistical mechanical framework to elucidate how this calorimetric two-state picture may be reconciled with the hierarchical multistate scenario emerging from recent hydrogen exchange experiments. We investigate the feasibility of using inverse Laplace transforms to recover the underlying density of states (i.e., enthalpy distribution) from calorimetric data. We find that the constraint imposed by DeltaH(vH)/DeltaH(cal) approximately 1 on densities of states of proteins is often more stringent than other "two-state" criteria proposed in recent theoretical studies. In conjunction with reasonable assumptions, the calorimetric two-state condition implies a narrow distribution of denatured-state enthalpies relative to the overall enthalpy difference between the native and the denatured conformations. This requirement does not always correlate with simple definitions of "sharpness" of a transition and has important ramifications for theoretical modeling. We find that protein models that assume capillarity cooperativity can exhibit overall calorimetric two-state-like behaviors. However, common heteropolymer models based on additive hydrophobic-like interactions, including highly specific two-dimensional Gō models, fail to produce proteinlike DeltaH(vH)/DeltaH(cal) approximately 1. A simple model is constructed to illustrate a proposed scenario in which physically plausible local and nonlocal cooperative terms, which mimic helical cooperativity and environment-dependent hydrogen bonding strength, can lead to thermodynamic behaviors closer to experiment. Our results suggest that proteinlike thermodynamic cooperativity may require a cooperative interplay between local and nonlocal interactions. The prospect of using calorimetric data to constrain Z-scores of knowledge-based potentials is discussed.

Calorimetry↗

PubMed2003

A prospective evaluation of bone mineral density measurement in females who have fallen.

BACKGROUND: The National Service Framework for Older Persons recognises the relationship between falls and osteoporosis; however, the best method for the evaluation of bone mineral density measurement in fallers is unclear. Dual energy X-ray absorptiometry of lumbar spine and hip is the gold standard for bone mineral density measurement, but is time consuming and may not be readily available. A cheaper, more portable alternative is peripheral dual energy X-ray absorptiometry of the heel. This predicts overall fracture risk as effectively as dual X-ray at the spine and hip, although site specific measurements provide the best estimate of fracture risk at a particular location. AIMS: 1. To validate peripheral dual energy X-ray in fallers by comparing heel bone mineral density measurement with measurements obtained at the lumbar spine and hip. 2. To determine the prevalence of osteoporosis in an unselected cohort of fallers. METHODS: 118 consecutive females over 50 attending for investigation of falls had heel bone mineral density measurement measured using peripheral dual energy X-ray (PIXI, Lunar). A representative sample of 52 (44%) also attended for bone mineral density measurement at the hip and lumbar spine using Hologic QDR 4500. Bone mineral density (g/cm(2)) measurements were compared with mean values for young adults and age-related normals giving T (number of standard deviation units above or below the mean for normal young adults) and Z (number of standard deviations above or below the age-related normal mean) scores. RESULTS: In the total group [n = 118 mean (SD) age 74 (11)] heel bone mineral density was 0.4 (0.1), T score--1.1 (1.6) and Z score--0.1 (1.5). The relationship between absolute bone mineral density measurements taken at heel, total hip and lumbar spine were compared and the correlation coefficients show a strong positive relationship between all measurements (all r values > 0.54, P < 0.0001) with a particularly strong relationship between hip and heel (r = 0.74). Those with two or more risk factors for falls were significantly more likely to have lower bone mineral density. DISCUSSION: This study has shown that peripheral dual energy X-ray is a reliable method of assessment, applicable to use within a Falls Unit. In addition, although the prevalence of osteoporosis is not increased in unselected fallers, those with two or more risk factors for falls are at increased risk of osteoporosis and limited resources may be more appropriately targeted toward this group.

Absorptiometry, Photon↗

PubMed2026

Evaluation of population-specific polygenic risk scores for blood lipids: insights from Taiwanese cohorts and multiancestry meta-analysis.

BACKGROUND: Blood lipids are heritable risk factors for cardiovascular disease (CVD), a leading cause of mortality worldwide. However, the genetic architecture of lipid traits and the performance of polygenic risk scores (PRSs) remain underexplored in East Asian (EAS) populations, including Taiwanese Han individuals. METHODS: We conducted genome-wide association studies and PRS analyses for five lipid traits: total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and the ratio of low-density lipoprotein cholesterol to total cholesterol. Lipid profile data were obtained from the China Medical University Hospital cohort. PRSs were evaluated on the basis of their correlations with measured lipid levels. To evaluate trans-ancestry PRS transferability, localized models were systematically compared against models derived from discovery-stage GWAS meta-analyses incorporating five ancestry groups from the Global Lipids Genetics Consortium. The performance of the PRS models in predicting lipid-related diseases was evaluated through receiver operating characteristic curve analyses. RESULTS: The population-specific PRS models explained 11%-40% of the variance in lipid levels within the target cohort. Models leveraging global multiancestry GWAS meta-analysis weights revealed limited predictive performance (r 2 = 0.04-0.19), whereas analyses incorporating EAS-specific data yielded higher correlations (r 2 = 0.13-0.30), although these correlations did not exceed those derived from the hospital-based cohort alone. When combined with age and sex, the PRS models demonstrated strong predictive performance for coronary artery disease, atherosclerosis, and ischemic stroke, with area under the curve values of 0.910, 0.926, and 0.854, respectively. CONCLUSION: Population-specific PRS models derived from a Taiwanese population outperformed meta-analysis-derived frameworks in predicting lipid levels and demonstrated substantial potential for predicting CVD risk, indicating the importance of ancestry-matched genetic studies in precision medicine.

LDL-C/TC ratio↗

PubMedDate not supplied

A biological oscillator system and the development of sleep-waking behavior during early infancy.

The sleep-waking behavior of a male infant, normal with respect to pregnancy, delivery and Apgar score, was observed continuously from birth till the first 4 months of life. The infant was allowed to sleep and awake according to his own schedule and was fed only if his behavior could be judged as a feeding demand. Using several methods of computerized analysis it could be demonstrated that the spontaneous sleep-waking behavior was mainly driven by two endogenous rhythms, an ultradian cycle and a circadian one. While the ultradian rhythm was already established at term showing a mean period of 4 h, the circadian variation developed during the first 3 months of life. So far our results support earlier studies (KLEITMAN and ENGELMANN; PARMELEE; HELLBRUGGE,). The present paper, however, gives further evidence that both rhythms do not run independently, but seem to constitute a system of connected oscillators. As soon as the circadian rhythm is manifestly developed, the period of the ultradian rhythm seems to be modulated according to circadian variations. More specifically, during the nocturnal phase of the circadian rhythm the ultradian rhythm decelerated. By contrast, during the diurnal phase the ultradian cycle was accelerated. Using circadian frequency modulation of the ultradian cycle as the underlying principle, a computerized model of both connected oscillators was developed. The theoretically predicted sleep-waking behavior was compared to the behavior actually observed in the infant of this study. During postnatal development the coupled rhythms cause characteristic periodicities of the sleep-waking pattern. Since the infant experiences his world within a basic framework of sleep and waking spans, the different periodicities may be considered as a structure timing the information process in the developing brain.

Biological Clocks↗

PubMed2026

Cell Type-Resolved Causal Inference and Spatial Transcriptomic Integration Reveal Immune-Specific Genetic Drivers of Autoimmune and Malignant Thyroid Disease.

BACKGROUND: Thyroid diseases, including autoimmune thyroid disease (AITD) and thyroid cancer, are characterized by immune dysregulation, yet the cell type-specific genetic mechanisms underlying these conditions remain poorly understood. Most genome-wide association studies (GWAS) have relied on bulk tissue expression quantitative trait loci (eQTL), which cannot resolve the heterogeneity of immune cell populations. METHODS: We performed two-sample Mendelian randomization (MR) analyses using single-cell cis-eQTLs from 14 immune cell subtypes (OneK1K cohort) as instrumental variables against GWAS summary statistics for four thyroid outcomes: autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid cancer and autoimmune thyroiditis. Causal associations were validated through Bayesian colocalization, phenome-wide association analysis (PheWAS) and multi-layered transcriptomic validation encompassing spatial transcriptomics of AITD tissue (GSE248205), bulk RNA-seq of thyroid cancer (GSE3678) and single-cell RNA-seq of thyroid tumours (GSE250521). gsMap spatial LD score regression was applied to map disease heritability onto spatial tissue architecture. RESULTS: We identified six Bonferroni-significant causal gene-cell type pairs for autoimmune hyperthyroidism, including protective effects of ABHD16A in naïve/immature B cells (OR = 0.440), HIST1H3H in CD8 NC T cells (OR = 0.324), HMGN4 in NK recruiting cells (OR = 0.556) and ZKSCAN4 in CD8 S100B T cells (OR = 0.427), with five pairs showing strong colocalization (PP.H4 ≥ 86%). Three pairs reached significance for autoimmune hypothyroidism, including a risk association of HLA-F in CD4 NC T cells (OR = 1.139). For autoimmune thyroiditis, FAM134B/RETREG1 showed consistent suggestive protective associations across both CD4 and CD8 NC T cells (PP.H4 ≥ 90% for both), suggesting a possible involvement of ER phagy regulation in thyroiditis susceptibility. Thyroid cancer showed a suggestive association with HLA-G in classical monocytes (OR = 1.899, PP.H4 = 53%). Spatial transcriptomic validation demonstrated progressive immune infiltration from control tissue to Graves' disease to Hashimoto's thyroiditis (7.7%-15.7%, 46.1%-54.1%, respectively) and strong spatial correlation between target gene expression and corresponding cell type enrichment (e.g., plasma cell-HLA-DQB1: r = 0.491, p < 10-300). HLA-G was independently validated in thyroid cancer bulk (log2fc = 0.542, p = 9.51 × 10-3, AUC = 0.857) and single-cell datasets. PheWAS revealed no significant associations detected for the core candidates. gsMap identified significant enrichment of autoimmune hypothyroidism heritability in gastrointestinal tract, adrenal gland and adipose tissue (all Bonferroni p < 0.002). CONCLUSIONS: This study establishes a multi-scale analytical framework integrating cell type-resolved genetic inference with spatial tissue validation, revealing distinct immunogenetic architectures underlying autoimmune versus malignant thyroid disease. Protective genetic programs in autoimmune hyperthyroidism converge on chromatin remodelling (HIST1H3H, HMGN4, ZKSCAN4) and lipid metabolism (ABHD16A) across lymphocyte subsets, whereas thyroid cancer risk involves immune escape mediated by HLA-G in myeloid cells. The ER-phagy receptor RETREG1 represents a candidate pathway warranting further investigation in autoimmune thyroiditis. These findings provide genetically supported, cell type-specific therapeutic targets and demonstrate a generalizable strategy for dissecting the immune-mediated mechanisms of complex thyroid diseases.

Mendelian randomization↗

PubMed1985

[Pattern changes in the framework of cesarean sections in 1980/83 as compared to 1974/76 in the University Women's Clinic in Jena].

In a comparative study on Caesarean section problems-based on investigations from 1974/76 and 1980/83-conducted at the Gynaecological and Obstetrical Hospital of Jena University, changes are apparent in the indication for Caesarean section and in maternal morbidity. The evident decrease in statistically uncorrected perinatal mortality as well as in uncorrected intra-and postnatal mortality during this period (difference statistically significant at p less than 0.05) was not due to a further increase in Caesarean sections from 8.23% (period 1974/76) to 9.27% (period 1980/83), but to other factors (improved medical care for pregnant women and improved neonatal check-up). In comparison with uncorrected intra-and postnatal mortality, perinatal Caesarean section lethality even showed a 2,46-fold relative increase. As late morbidity among high-risk children related to the immediate stage of labour is still poorly understood, "extended" indication for Caesarean section is maintained-in spite of high infection morbidity among mothers. General perioperative antibiotic prophylaxis for these women is recommended because of the statistically significant poor situation of secondary Caesarean sections as far as maternal morbidity is concerned.

Apgar Score↗

PubMed2001

Vulnerability to health problems in female informal caregivers of persons with HIV/AIDS and age-related dementias.

The health of informal caregivers is often studied from the perspective of caregivers' and care receivers' personal and interpersonal characteristics. This study offers an alternative explanation based on a vulnerable populations framework and considers the role of resource availability to the health status of informal caregivers (n=76). Caregivers in a convenience sample were females of diverse ethnicity and socioeconomic status, and care recipients were diagnosed with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) or age-related dementias (ARD). Personal interviews using structured instruments were conducted with caregivers who were attending outpatient clinics at a public hospital and a VA hospital. Instruments included the Center for Epidemiologic Studies Depression-Scale (CES-D), the Global Health Assessment (GHA), the Activities of Daily Living Scale (ADL), the Memory and Behavior Problems Checklist (MBPC) and items from the Symptom Checklist-90 (SCL-90) measuring anger, anxiety and loneliness. Caregivers were experiencing both physical and mental health problems. Regression analyses were used to examine the relationships among resources available to caregivers, conditions that put caregivers at risk for poorer health, and health status itself. Analyses were conducted for each group of caregivers separately (HIV and ARD) and for the total group, using depressive symptoms and perception of physical health as dependent variables. In caregivers of people with HIV/AIDS (PWHIV), caregiver distress over care recipient symptoms, anxiety and education were related to depressive symptoms. Depressive symptoms, anger and functional status of the PWHIV were related to caregivers' perception of poorer physical health. In caregivers of people with ARD, there were no significant predictors for depressive symptoms or perception of physical health. In the total group of caregivers, lower income and more anger were related to depressive symptom score. When perception of physical health was the dependent variable, minority ethnicity and depressive mood were related to worse perception of physical health. These findings support the relationship of a lack of resources to health status. A community-based programme of resources and health care services for the caregiver-care receiver dyad is recommended.

Adult↗

PubMed2006

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura.

Epidemiological studies indicate that migraine with typical aura (MA) has a major genetic component but the genes for MA have not been identified. However, the autosomal dominantly inherited familial hemiplegic migraine (FHM) is often caused by mutations in the CACNA1A or ATP1A2 genes. The aim of the study was to investigate if the CACNA1A or ATP1A2 genes are involved in MA with an apparently autosomal dominant mode of inheritance. From a clinic population diagnosed by a trained physician we recruited 34 extended families (comprising 174 MA patients) with an apparently autosomal dominant mode of inheritance of MA. We performed a linkage analysis of 161 of 174 MA patients and 79 unaffected relatives using a framework marker set of 44 markers for chromosome 1 and 22 markers for chromosome 19. Linkage analysis was made with a non-parametric or autosomal dominant parametric model, either allowing for heterogeneity or not, using an affected only analysis. We identified no linkage to CACNA1A and ATP1A2 loci on chromosome 19 or 1, respectively. Additionally, at least two patients from each family and 92 healthy, unrelated controls were selected for a sequence analysis. We sequenced the 48 exons of CACNA1A and the 23 exons of ATP1A2, including promoter and flanking intron sequences. No polymorphism was identified in the CACNA1A or ATP1A2 genes with a strong correlation to MA. Our study shows that the CACNA1A or ATP1A2 genes are probably not involved in MA. To identify the genes involved in the common forms of migraine, future genetic studies should focus on MA and migraine without aura (MO) and not FHM.

Calcium Channels↗

PubMed2000

Estimates of the daily phase and amplitude of the endogenous component of the circadian rhythm of core temperature in sedentary humans living nychthemerally.

Fifteen healthy female subjects were studied for eight days while living conventionally. Subjects were free to choose the ways they spent their time within a framework of regular times of retiring and rising; in practice, much of the waking time was spent in sedentary activities. Nine of the subjects were aware of the natural light-dark cycle, this approximating to a 12:12 L:D schedule at the time of year when the study took place. Before the study, subjects were assessed for their degree of "morningness" by questionnaire; throughout the study, they wore a rectal probe, and an activity meter on their non-dominant wrist. The timing (phase) and amplitude of the circadian rectal temperature rhythm were assessed on each day by cosinor analysis as well as by a method based on visual inspection of the data. These two parameters were also assessed after the temperature data for each day had been "purified" by a number of methods. From these results it was possible to investigate the effect of purification upon the amplitude of the circadian rhythm of temperature. Also, the day-by-day variability of phase, and the relationship between morningness and phase, were compared using these methods of phase estimation, and using cross-correlation between data sets from adjacent days; in all cases, raw and purified temperature data were used. There was a significantly greater amount of daily variation in phase using purified rather than raw data sets, and this difference was present with all methods of purification as well as with all methods for estimating phase. Purification decreased the amplitude of the circadian temperature rhythm by about 30%. Finally, there was a significant correlation between the morningness score of the subjects and the phase of the circadian temperature rhythm, the phase becoming earlier with increasing morningness; when this relationship was re-examined using purified data, it became more marked. These results reflect the masking effects exerted upon raw temperature data by lifestyle. The extent to which the purification methods enable the endogenous component of a circadian rhythm - and, by implication, the output of the endogenous circadian oscillator - to be estimated in subjects living normally is addressed.

Activities of Daily Living↗

PubMed2006

The use of macroalgal species richness and composition on intertidal rocky seashores in the assessment of ecological quality under the European Water Framework Directive.

The EC Water Framework Directive (WFD) suggests using abundance and species composition of intertidal seaweed communities for ecological quality classification of rocky seashores. There are two difficulties with this. According to WFD all sensitive species should be present on a shore. There is no accepted list of sensitive seaweed species and those which may be sensitive in one location may not be so in another. Second, natural successions can result in very large abundance changes of common species, e.g. from almost completely fucoid-dominated shores to almost totally barnacle-dominated shores, without any change in ecological quality. Studies have shown that numerical species richness, not the list of actual species present, is broadly constant in the absence of disturbance. The ephemeral species, possibly the sensitive members of the community, change regularly in such a way as to conserve species richness. It is proposed that species richness on a defined length of shore be used as a criterion of ecological quality. A database of species found on over 300 shores in the British Isles, under strictly controlled sampling conditions, has given ranges of values of species richness to be expected and has allowed for variations in these values due to sub-habitat variability, wave exposure and turbidity to be factored in. A major problem in applying such a tool is the lack of expertise of many workers in critical identification of seaweed species. A reduced species list has been extracted from the database using species commonly present and identifiable with reasonable certainty. A numerical index of ecological quality is proposed based on scores for various aspects of the physical nature of the habitat combined with a score for species richness which may be based on the reduced species list. The scoring system also uses further aspects of community structure, such as ecological status groups and the proportions of rhodophyta, chlorophyta and opportunist species. For this system to be effective there has to be close control of the way in which sampling is carried out to ensure a uniform level of thoroughness.

Databases, Factual↗

PubMed2005

Development and validation of the Chinese Quality of Life Instrument.

BACKGROUND: This paper describes the development of the Chinese Quality of Life Instrument (ChQOL) which is a self-report health status instrument. Chinese Medicine relies very much on asking subjective feelings of patients in the process of diagnosis and monitoring of treatment. For thousands of years, Chinese Medicine practitioners have accumulated a good wealth of experiences in asking questions about health of their patients based on the concept of health in Chinese Medicine. These experiences were then transformed into questions for the ChQOL. It is believed that ChQOL can contribute to the existing Patient Report Outcome measures. This paper outlines the concept of health and disease in Traditional Chinese Medicine, the building of the conceptual framework of the ChQOL, the steps of drafting, selecting and validating the items, and the psychometric properties of the ChQOL. METHODS: The development of the ChQOL was based on the concept of health in Traditional Chinese Medicine with a theory driven approach. Based on the results of literature review, the research team developed an initial model of health which encompassed the concept of health in TCM. An expert panel was then invited to comment and give suggestions for improvement of the initial model. According to their suggestions, the model was refined and a set of initial items for the ChQOL was drafted. The refined model, together with the key domains, facets and initial items of the ChQOL were then mailed to a sample of about 100 Chinese medicine practitioners throughout Mainland China for their comments and advice. A revised set of items were developed for linguistic testing by a convenience sample consisting of both healthy people and people who attended Chinese Medicine treatment. After that, an item pool was developed for field-testing. Field test was conducted on a convenience sample of healthy and patient subjects to determine the construct validity and psychometric properties of the ChQOL. RESULTS: Construct validity was established by various methods, i.e. the internal consistency in all facets and domains were good; the correlation between facets to domain, and domains to overall ChQOL correlation were high; confirmatory factor analysis showed that the structure fitness of all facets, domain and overall structure were good with CFI > 0.9. Test-retest reliability was also good, especially in the domain scores with ICC value ranging from 0.83 to 0.90. No ceiling or floor effect was noted which indicated that ChQOL can be applied to subjects with a wide range of health status. Most facet scores, domain scores and the overall CHQOL scores were able to discriminate groups of subjects with known differences in health status. The ChQOL had mild positive convergence with the other generic health related QOL measures, i.e. the WHOQOL-100 and the SF-36, with moderate correlations. CONCLUSION: In conclusion, the study indicated that the ChQOL is conceptually valid with satisfactory psychometric properties. It can provide additional information on health and QOL on top of the existing generic health related QOL measures. Furthermore, it forms basis for further testing and applications in clinical trials.

Adolescent↗

PubMed2005

Development of a reliable and valid nutritional knowledge questionnaire for urban South African adolescents.

OBJECTIVES: We wanted to develop a valid and reliable nutritional knowledge test for urban South African adolescents who were participating in the Birth-to-Twenty cohort study. The questionnaire was intended for use every second year, from ages 13 to 14 y until age 20 y. METHODS: The initial steps involved the development of a conceptual framework and identification of nutritional concepts in collaboration with nutritional experts, and this defined the construct of the questionnaire. The South African national teaching curriculum objectives for nutritional education and other relevant issues were selected as the desired concepts, and most items were phrased in accordance with the recently developed South African Food-Based Dietary Guidelines. Thereafter, 140 items (questions) were developed and in turn assessed by an expert panel, and the result was that only 88 items remained. This was done to ensure content and face validity of the items. The 88 items were constructed into a questionnaire and piloted for appropriateness and understanding by adolescents, ages 13 to 14 y, as a means of assessing face validity by non-experts. The edited preliminary questionnaire (still with 88 items) was administered to a nutrition expert group (n = 71) versus a non-expert group (n = 82), referred to as sample 1, for the purposes of performing item analysis and assessing construct validity of the questionnaire. The result of the analysis, a 63-item questionnaire, was administered to adolescents at three school grade levels, 8 (n = 128), 10 (n = 143), and 12 (n = 98), referred to as sample 2, which was representative of the grades in which the Birth-to-Twenty group will be in when the questionnaire is administered. The questionnaire was administered to the sample to assess its content validity and internal consistency reliability. The final questionnaire had 60 items, and its construct, content, and internal consistency reliability were reassessed. RESULTS: The final 60-item questionnaire displayed a significant difference (P < 0.0001) in the mean scores of the expert and non-expert groups tested. It had internal consistencies (Cronbach's alpha) of 0.71, 0.79, and 0.82 for grades 8, 10, and 12 respectively, and an overall value of 0.77 for all groups combined. However, it was less than 0.7 for most grade 8 pupils and for all grades at a historically disadvantaged school. CONCLUSION: A nutritional knowledge questionnaire with construct, face, and content validities and internal consistency was developed for use in South African adolescents to evaluate their nutritional knowledge. Internal consistency was low in children at a disadvantaged school and those in grade 8 compared with multiracial groups at a multiracial school. It is recommended that pupils at disadvantaged schools be assisted by trained interviewers when taking the test.

Adolescent↗

PubMed2006

Genome BLAST distance phylogenies inferred from whole plastid and whole mitochondrion genome sequences.

BACKGROUND: Phylogenetic methods which do not rely on multiple sequence alignments are important tools in inferring trees directly from completely sequenced genomes. Here, we extend the recently described Genome BLAST Distance Phylogeny (GBDP) strategy to compute phylogenetic trees from all completely sequenced plastid genomes currently available and from a selection of mitochondrial genomes representing the major eukaryotic lineages. BLASTN, TBLASTX, or combinations of both are used to locate high-scoring segment pairs (HSPs) between two sequences from which pairwise similarities and distances are computed in different ways resulting in a total of 96 GBDP variants. The suitability of these distance formulae for phylogeny reconstruction is directly estimated by computing a recently described measure of "treelikeness", the so-called delta value, from the respective distance matrices. Additionally, we compare the trees inferred from these matrices using UPGMA, NJ, BIONJ, FastME, or STC, respectively, with the NCBI taxonomy tree of the taxa under study. RESULTS: Our results indicate that, at this taxonomic level, plastid genomes are much more valuable for inferring phylogenies than are mitochondrial genomes, and that distances based on breakpoints are of little use. Distances based on the proportion of "matched" HSP length to average genome length were best for tree estimation. Additionally we found that using TBLASTX instead of BLASTN and, particularly, combining TBLASTX and BLASTN leads to a small but significant increase in accuracy. Other factors do not significantly affect the phylogenetic outcome. The BIONJ algorithm results in phylogenies most in accordance with the current NCBI taxonomy, with NJ and FastME performing insignificantly worse, and STC performing as well if applied to high quality distance matrices. delta values are found to be a reliable predictor of phylogenetic accuracy. CONCLUSION: Using the most treelike distance matrices, as judged by their delta values, distance methods are able to recover all major plant lineages, and are more in accordance with Apicomplexa organelles being derived from "green" plastids than from plastids of the "red" type. GBDP-like methods can be used to reliably infer phylogenies from different kinds of genomic data. A framework is established to further develop and improve such methods. delta values are a topology-independent tool of general use for the development and assessment of distance methods for phylogenetic inference.

Algorithms↗

PubMedDate not supplied

Efficient detection of unusual words.

Words that are, by some measure, over- or underrepresented in the context of larger sequences have been variously implicated in biological functions and mechanisms. In most approaches to such anomaly detections, the words (up to a certain length) are enumerated more or less exhaustively and are individually checked in terms of observed and expected frequencies, variances, and scores of discrepancy and significance thereof. Here we take the global approach of annotating the suffix tree of a sequence with some such values and scores, having in mind to use it as a collective detector of all unexpected behaviors, or perhaps just as a preliminary filter for words suspicious enough to undergo a more accurate scrutiny. We consider in depth the simple probabilistic model in which sequences are produced by a random source emitting symbols from a known alphabet independently and according to a given distribution. Our main result consists of showing that, within this model, full tree annotations can be carried out in a time-and-space optimal fashion for the mean, variance and some of the adopted measures of significance. This result is achieved by an ad hoc embedding in statistical expressions of the combinatorial structure of the periods of a string. Specifically, we show that the expected value and variance of all substrings in a given sequence of n symbols can be computed and stored in (optimal) O(n2) overall worst-case, O (n log n) expected time and space. The O (n2) time bound constitutes an improvement by a linear factor over direct methods. Moreover, we show that under several accepted measures of deviation from expected frequency, the candidates over- or underrepresented words are restricted to the O(n) words that end at internal nodes of a compact suffix tree, as opposed to the theta(n2) possible substrings. This surprising fact is a consequence of properties in the form that if a word that ends in the middle of an arc is, say, overrepresented, then its extension to the nearest node of the tree is even more so. Based on this, we design global detectors of favored and unfavored words for our probabilistic framework in overall linear time and space, discuss related software implementations and display the results of preliminary experiments.

Algorithms↗

PubMed2006

Practice size and quality attainment under the new GMS contract: a cross-sectional analysis.

BACKGROUND: The Quality and Outcomes Framework (QOF) of the new General Medical Services contract, for the first time, incentivises certain areas of general practice workload over others. The ability of practices to deliver high quality care may be related to the size of the practice itself. AIM: To explore the relationship between practice size and points attained in the QOF. DESIGN OF STUDY: Cross-sectional analyses of routinely available data. SETTING: Urban general practice in mainland Scotland. METHOD: QOF points and disease prevalence were obtained for all urban general practices in Scotland (n = 638) and linked to data on the practice, GP and patient population. The relationship between QOF point attainment, disease prevalence and practice size was examined using univariate statistical analyses. RESULTS: Smaller practices were more likely to be located in areas of socioeconomic deprivation; had patients with poorer health; and were less likely to participate in voluntary practice-based quality schemes. Overall, smaller practices received fewer QOF points compared to larger practices (P = 0.003), due to lower point attainment in the organisational domain (P = 0.002). There were no differences across practice size in the other domains of the QOF, including clinical care. Smaller practices reported higher levels of chronic obstructive pulmonary disease (COPD) and mental health conditions and lower levels of asthma, epilepsy and hypothyroidism. There was no difference in the reported prevalence of hypertension or coronary heart disease (CHD) across practices, in contrast to CHD mortality for patients aged under 70 years, where the mortality rate was 40% greater for single-handed practices compared with large practices. CONCLUSIONS: Although smaller practices obtained fewer points than larger practices under the QOF, this was due to lower scores in the organisational domain of the contract rather than to lower scores for clinical care. Single-handed practices, in common with larger practices serving more deprived populations, reported lower than expected CHD prevalence in their practice populations. Our results suggest that smaller practices continue to provide clinical care of comparable quality to larger practices but that they may need increased resources or support, particularly in the organisational domain, to address unmet need or more demanding QOF criteria.

Adult↗

PubMed2026

Using the OPTIMAL Theory to Optimize Aerodynamics in Respiratory Training for Healthy Adults and Individuals With Parkinson's Disease.

BACKGROUND: The OPTIMAL (Optimizing Performance Through Intrinsic Motivation and Attention for Learning) theory is a motor learning framework proposing that optimizing intrinsic motivation enhances motor performance and learning. The theory identifies three key components-Enhanced Expectancies (EE), Autonomy Support (AS) and External Focus of Attention (EF)-which facilitate more efficient, goal-directed movement. These components have been shown to improve motor outcomes in limb-based tasks; however, their application to respiratory training, particularly in clinical contexts such as voice and swallowing therapy in patients with Parkinson's disease (pwPD), has not yet been systematically explored. AIMS: This study aimed to investigate whether implementing OPTIMAL theory strategies during a respiratory muscle strength training (RMST) task improves immediate respiratory motor performance in healthy adults and pwPD. Additionally, we aimed to examine the effects of these strategies on motivation and cognitive engagement. METHODS: This quasi-randomized, single-session trial included 47 participants: Healthy CONTROL (n = 17), Healthy OPTIMAL (n = 16) and PD OPTIMAL (n = 14). Healthy participants were quasi-randomly assigned to either intervention or control conditions, whereas pwPD completed the intervention only. All participants completed a single respiratory session that included baseline, practice and retention phases. Outcome measures included peak expiratory flow, cough peak expiratory flow, cognitive engagement (EEG-based Cognitive Engagement Index) and self-administered motivation questionnaire. OUTCOMES AND RESULTS: Exhalation force improved from baseline to retention in the Healthy OPTIMAL group (baseline: M = 296 L/min; retention: M = 338 L/min; p < 0.001) and the PD OPTIMAL group (baseline: M = 315 L/min; retention: M = 370 L/min; p < 0.0001), but not in the Healthy CONTROL group (p > 0.05). No significant changes in cough strength were observed in any group. No correlations were found between cognitive engagement and exhalation force or motivation scores. However, motivation increased more in the Healthy OPTIMAL group (Questionnaire 1: M = 57.2; Questionnaire 2: M = 60.7) and the PD OPTIMAL group (Questionnaire 1: M = 60.1; Questionnaire 2: M = 62.8) than in the Healthy CONTROL group (Questionnaire 1: M = 61.1; Questionnaire 2: M = 62.5). CONCLUSIONS AND IMPLICATIONS: Implementing the OPTIMAL theory enhances immediate respiratory motor performance in both healthy participants and pwPD. OPTIMAL theory has clinical value in voice and swallowing therapy, although further research is needed to establish long-term efficacy and clinical impact. WHAT THIS PAPER ADDS: What is already known on the subject Motivation is a critical factor in rehabilitation. The OPTIMAL theory has been shown to improve both motivation and motor performance in limb-based tasks. Its impact on respiratory training, however, has not been previously examined. What this paper adds to the existing knowledge This study shows that applying OPTIMAL strategies during a respiratory muscle strength training task significantly improved peak expiratory flow in both healthy adults and people with Parkinson's disease. What are the potential or clinical implications of this work? Integrating the OPTIMAL theory principles into respiratory therapy may enhance motor outcomes, supporting voice, swallowing and cough rehabilitation.

Humans↗

PubMed2026

Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.

Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.

common variants↗

PubMed1998

Socioeconomic factors, perceived control and self-reported health in Russia. A cross-sectional survey.

Russia has the lowest life expectancy among industrialised countries, but little is known about other health outcomes and determinants of health in the Russian population. Here we report a cross-sectional study in a national sample of the Russian population of social and psychosocial determinants of two self-reported health indicators: self-rated health (shown to predict mortality in prospective studies) and physical functioning (validated against more objective health measures). A multi-stage sample of the Russian population aged 18 years and more was interviewed (n=1599, response rate 66%). The questionnaire included political attitudes, social and economic circumstances, psychosocial factors, smoking, alcohol consumption, self-rated health and physical functioning (from the SF36 instrument). Scores of perceived control over life and over one's health were calculated from 6 and 3 questions, respectively. Data were analysed in logistic regression for two dichotomised outcomes: poor self-rated health (worse than average) and low physical functioning (less than 60% of maximum). Overall, 25% of subjects rated their health as worse than average; this is substantially more than in western countries. Perceived control over life was strongly related to both outcomes; age- and sex-adjusted OR for 1 standard deviation increase in control were 0.60 (95% CI 0.52-0.69) for poor self-rated health and 0.67 (0.57-0.81) for low physical functioning. Adjustment for a battery of other factors reduced these estimates only slightly. Associations between control over one's health and both outcomes were also significant, but weaker and attenuated in multivariate models. Material deprivation was also strongly related to both outcomes. Education was inversely related to self-rated health, and unmarried men reported poor physical functioning substantially more often. Subjects not approving the economic changes reported poorer health but this association was removed by adjustment for socioeconomic factors and control. Subjects who could not rely on informal social structures when in problems reported worse health; this effect largely persisted in multivariate analyses. These results are consistent with the hypothesis that poor health status in Russia is related to dysfunction of social structures, socioeconomic deprivation, and lack of perceived control. The absence of informal social networks, vital for maintaining general welfare, seems to affect adversely self-rated health. Deprivation and low perceived control may be important mediators between the broad social environment and health in populations undergoing transition and can provide a useful framework for many biological and behavioural factors. Prospective studies are needed to address the issue of temporality and reporting bias, the major problems in interpreting these findings.

Activities of Daily Living↗