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BACKGROUND: How the biophysics of electrical conductivity measures relate to brain activity is poorly understood. The sedative, ethanol, reduces metabolic activity but its impact on brain electrical conductivity is unknown. PURPOSE: To investigate whether ethanol reduces brain electrical tissue conductivity. STUDY TYPE: Prospective. SUBJECTS: Fifty-two healthy volunteers (aged 18-37 years, 22 females, 30 males). FIELD STRENGTH/SEQUENCE: 3 T, T1-weighted, multi-shot, turbo-field echo (TFE); 3D balanced fast-field echo (bFFE). ASSESSMENT: Brain gray and white matter tissue conductivity measured with phase-based magnetic resonance electrical properties tomography (MREPT) compared before and 20 minutes after ethanol consumption (0.7 g/kg body weight). Differential conductivity whole brain maps were generated for three subgroups: those with strong ( ∆ σ max $$ \Delta {\sigma}_{\mathrm{max}} $$ > 0.1 S/m; N = 33), weak (0.02 S/m ≤ ∆ σ max $$ \Delta {\sigma}_{\mathrm{max}} $$ ≤ 0.1 S/m; N = 9) conductivity decrease, and no significant response ( ∆ σ max $$ \Delta {\sigma}_{\mathrm{max}} $$ < 0.02 S/m, N = 10). Maps were compared in the strong response group where breath alcohol rose between scans, vs. those where it fell. STATISTICAL TESTS: Average breath alcohol levels were compared to the differential conductivity maps using linear regression. T-maps were generated (threshold P < 0.05 and P < 0.001; minimum cluster 48 mm3). Differential conductivity maps were compared with ANOVA. RESULTS: Whole-group analysis showed decreased conductivity that did not survive statistical thresholding. Strong responders (N = 33) showed a consistent pattern of significantly decreased conductivity ( ∆ σ max $$ \Delta {\sigma}_{\mathrm{max}} $$ > 0.1 S/m) in frontal/occipital and cerebellar white matter. The weak response group (N = 9) showed a similar pattern of conductivity decrease (0.02 S/m ≤ ∆ σ max $$ \Delta {\sigma}_{\mathrm{max}} $$ ≤ 0.1 S/m). There was no significant relationship with breath alcohol levels, alcohol use, age, ethnicity, or sex. The strong responders' regional response was different between ascending (N = 12) or descending (N = 20) alcohol during the scan. DATA CONCLUSION: Ethanol reduces brain tissue conductivity in a participant-dependent and spatially dependent fashion. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
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OBJECTIVES: We examined longitudinal changes in cognitive and physical function and associations between change in function and falls in people with and without mild cognitive impairment (MCI). DESIGN: Prospective cohort study with assessments every 2 years (for up to 6 years). SETTING: Community, Sydney, Australia. PARTICIPANTS: Four hundred and eighty one people were classified into three groups: those with MCI at baseline and MCI or dementia at follow-up assessments (n = 92); those who fluctuated between cognitively normal and MCI throughout follow-up (cognitively fluctuating) (n = 157), and those who were cognitively normal at baseline and all reassessments (n = 232). MEASUREMENTS: Cognitive and physical function measured over 2-6 years follow-up. Falls in the year following participants' final assessment. RESULTS: In summary, 27.4%, 38.5%, and 34.1% of participants completed 2, 4, and 6 years follow-up of cognitive and physical performance, respectively. The MCI and cognitive fluctuating groups demonstrated cognitive decline, whereas the cognitively normal group did not. The MCI group had worse physical function than the cognitively normal group at baseline but decline over time in physical performance was similar across all groups. Decline in global cognitive function and sensorimotor performance were associated with multiple falls in the cognitively normal group and decline in mobility (timed-up-and-go test) was associated with multiple falls across the whole sample. CONCLUSIONS: Cognitive declines were not associated with falls in people with MCI and fluctuating cognition. Declines in physical function were similar between groups and decline in mobility was associated with falls in the whole sample. As exercise has multiple health benefits including maintaining physical function, it should be recommended for all older people. Programs aimed at mitigating cognitive decline should be encouraged in people with MCI.
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Acidentes por Quedas , Disfunção Cognitiva , Humanos , Idoso , Estudos Longitudinais , Estudos Prospectivos , Acidentes por Quedas/prevenção & controle , Equilíbrio Postural , Estudos de Tempo e Movimento , Disfunção Cognitiva/complicações , CogniçãoRESUMO
STUDY DESIGN: Natural experiment OBJECTIVES: To determine whether COVID-19 restrictions were associated with changes in the incidence of traumatic spinal cord injury (TSCI) in Scotland. SETTING: The Queen Elizabeth National Spinal Injuries Unit (QENSIU), the sole provider of treatment for TSCI in Scotland. METHODS: Time series analysis of all admissions for TSCI between 1st January 2015 and 31st August 2022. RESULTS: Over the 8-year study period, 745 patients were admitted to the QENSIU with a TSCI. Interrupted time series analysis showed that level 3 and 4 COVID-19 lockdown restrictions (the most severe levels) were associated with lower incidence of TSCI (RR 0.63, CI% CI 0.47, 0.82, p < 0.001). The associations were stronger in people aged over 45 (additive interaction p = 0.001), males (additive interaction p = 0.01) and non-tetraplegia (additive interaction p = 0.002). The incidence of TSCI due to deliberate self-harm was higher (0.41 versus 0.23 per month) during restrictions. CONCLUSIONS: Overall, TSCI incidence reduced in Scotland when lockdowns were implemented, presumably due to lower engagement in risky activities. The increase in TSCI due to deliberate self-harm may reflect increased mental health problems and social isolation and should be anticipated and targeted in future pandemics. The change in incidence during the COVID-19 pandemic may have an economic impact and see a temporary reduction in the burden on health and social care. The results of this study will be useful for resource planning in future pandemics.
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COVID-19 , Traumatismos da Medula Espinal , Traumatismos da Coluna Vertebral , Masculino , Humanos , Idoso , Traumatismos da Medula Espinal/complicações , Pandemias/prevenção & controle , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/complicações , Controle de Doenças Transmissíveis , Incidência , Projetos de PesquisaRESUMO
The objective of this analysis was to investigate the relationship between pain and quality of life and physical activity as a mediator in the relationship between pain and quality of life. This study utilised a combination of questionnaire data from 503 community-living people aged 70-years and over concerning quality of life, pain, and physical activity. Participants with higher levels of pain intensity experienced lower quality of life and engaged in lessphysical activity (P < 0.05). Physical activity was a mediator in the relationship between pain and quality of life(6.5 %). This study confirms an association between pain and quality of life and highlights physical activ-ity as an essential component of this relationship; further research is needed to understand the mechanism of this relationship.
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AIMS: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. METHODS AND RESULTS: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4â mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. CONCLUSION: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. CLASSIFICATION OF EVIDENCE: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.
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Demência , Hipertensão , Acidente Vascular Cerebral , Humanos , Pressão Sanguínea , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Demência/epidemiologia , Demência/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The Dominantly Inherited Alzheimer Network (DIAN) is a longitudinal observational study that collects data on cognition, blood pressure (BP), and other variables from autosomal-dominant Alzheimer's disease mutation carriers (MCs) and non-carrier (NC) family members in early to mid-adulthood, providing a unique opportunity to evaluate BP and cognition relationships in these populations. METHOD: We examined cross-sectional and longitudinal relationships between systolic and diastolic BP and cognition in DIAN MC and NC. RESULTS: Data were available from 528 participants, who had a mean age of 38 (SD = 11) and were 42% male and 61% MCs, at a median follow-up of 2 years. Linear-multilevel models found only cross-sectional associations in the MC group between higher systolic BP and poorer performance on language (ß = -0.181 [-0.318, -0.044]), episodic memory (-0.212 [-0.375, -0.049]), and a composite cognitive measure (-0.146 [-0.276, -0.015]). In NCs, the relationship was cross-sectional only and present for language alone. DISCUSSION: Higher systolic BP was cross-sectionally but not longitudinally associated with poorer cognition, particularly in MCs. BP may influence cognition gradually, but further longitudinal research is needed.
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Doença de Alzheimer , Humanos , Masculino , Adulto , Feminino , Estudos Transversais , Pressão Sanguínea , Cognição , Mutação/genéticaRESUMO
Motivation: Reliance on mapping to a single reference haplotype currently limits accurate estimation of allele or haplotype-specific expression using RNA-sequencing, notably in highly polymorphic regions such as the major histocompatibility complex. Results: We present AltHapAlignR, a method incorporating alternate reference haplotypes to generate gene- and haplotype-level estimates of transcript abundance for any genomic region where such information is available. We validate using simulated and experimental data to quantify input allelic ratios for major histocompatibility complex haplotypes, demonstrating significantly improved correlation with ground truth estimates of gene counts compared to standard single reference mapping. We apply AltHapAlignR to RNA-seq data from 462 individuals, showing how significant underestimation of expression of the majority of classical human leukocyte antigen genes using conventional mapping can be corrected using AltHapAlignR to allow more accurate quantification of gene expression for individual alleles and haplotypes. Availability and implementation: Source code freely available at https://github.com/jknightlab/AltHapAlignR. Supplementary information: Supplementary data are available at Bioinformatics online.
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Perfilação da Expressão Gênica/métodos , Expressão Gênica , Haplótipos , RNA/genética , Análise de Sequência de RNA/métodos , Software , Alelos , Humanos , Antígenos Comuns de Leucócito/genéticaRESUMO
Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.
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Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mosaicismo , Mutação , Neoplasias Ovarianas/genética , Fosfoproteínas Fosfatases/genética , Alelos , Análise por Conglomerados , Éxons , Feminino , Humanos , Isoenzimas/genética , Linfócitos/metabolismo , Proteína Fosfatase 2C , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/metabolismoRESUMO
RATIONALE: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity. OBJECTIVES: To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community-acquired pneumonia. METHODS: We performed genome-wide gene expression profiling in peripheral blood leukocytes of adult patients admitted to intensive care with sepsis due to fecal peritonitis (n = 117) or community-acquired pneumonia (n = 126), and of control subjects without sepsis (n = 10). MEASUREMENTS AND MAIN RESULTS: A substantial portion of the transcribed genome (18%) was differentially expressed compared with that of control subjects, independent of source of infection, with eukaryotic initiation factor 2 signaling being the most enriched canonical pathway. We identified two sepsis response signature (SRS) subgroups in fecal peritonitis associated with early mortality (P = 0.01; hazard ratio, 4.78). We defined gene sets predictive of SRS group, and serial sampling demonstrated that subgroup membership is dynamic during intensive care unit admission. We found that SRS is the major predictor of transcriptomic variation; a small number of genes (n = 263) were differentially regulated according to the source of infection, enriched for IFN signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation as well as natural killer cell and IL-3 signaling. CONCLUSIONS: The majority of the sepsis transcriptomic response is independent of the source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.
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Peritonite/genética , Pneumonia/genética , Sepse/genética , Transcriptoma/genética , Idoso , Infecções Comunitárias Adquiridas/sangue , Infecções Comunitárias Adquiridas/genética , Fezes , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Peritonite/sangue , Pneumonia/sangue , Estudos Prospectivos , Sepse/sangueRESUMO
Pain hypersensitivity is present in some people with acute low back pain (LBP) and thought to be involved in the development of chronic LBP. Early evidence suggests that pain hypersensitivity in acute LBP precedes poor long-term outcome. We aimed to examine whether the presence of pain hypersensitivity in acute LBP influenced recovery status at 6 months and differentiated how pain and disability changed over time. Participants with acute nonspecific LBP (<6 weeks after pain onset, N = 118) were included in this longitudinal study. Quantitative sensory testing, including pressure and heat pain thresholds, and conditioned pain modulation and questionnaires were compared at baseline and longitudinally (at 3 and 6 months) between recovered and unrecovered participants. Using k-means clustering, we identified subgroups based on baseline sensory measures alone, and in combination with psychological factors, and compared pain and disability outcomes between subgroups. Sensory measures did not differ at baseline or longitudinally between recovered (N = 50) and unrecovered (N = 68) participants. Subgrouping based on baseline sensory measures alone did not differentiate pain or disability outcomes at any timepoint. Participants with high psychological distress at baseline (N = 19) had greater disability, but not pain, at all timepoints than those with low psychological distress, regardless of the degrees of pain sensitivity. Our findings suggest that pain hypersensitivity in acute LBP does not precede poor recovery at 6 months or differentiate how pain and disability change over time. High psychological distress during acute LBP is associated with unremitting and pronounced disability, while pain severity is unaffected. PERSPECTIVE: Pain hypersensitivity is thought to be involved in the transition to chronic LBP. Contradictory to prevailing hypothesis, our findings suggest pain hypersensitivity alone in acute LBP does not precede poor recovery. High psychological distress in acute LBP has a stronger influence than pain hypersensitivity on long-term disability, but not pain outcomes.
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BACKGROUND: Early evidence suggests human assumed central sensitization (HACS) is present in some people with acute low back pain (LBP). Factors influencing individual variation in HACS during acute LBP have not been fully explored. We aimed to examine the evidence for HACS in acute LBP and the contribution of brain-derived neurotrophic factor (BDNF), clinical, psychological and demographic factors to HACS. METHODS: Participants with acute LBP (<6 weeks after pain onset, N = 118) and pain-free controls (N = 57) from a longitudinal trial were included. Quantitative sensory testing including pressure and heat pain thresholds and conditioned pain modulation, BDNF serum concentration and genotype and questionnaires were assessed. RESULTS: There were no signs of HACS during acute LBP at group level when compared with controls. Sensory measures did not differ when compared between controls and LBP participants with different BDNF genotypes. Two LBP subgroups with distinct sensory profiles were identified. Although one subgroup (N = 60) demonstrated features of HACS including pressure/heat pain hypersensitivity at a remote site and deficient conditioned pain modulation, pain severity and disability did not differ between the two subgroups. Variation in sensory measures (~33%) was partially explained by BDNF genotype, sex, age and psychological factors. CONCLUSIONS: This study confirms that HACS is present in some people with acute LBP, but this was not associated with pain or disability. Further, no relationship was observed between BDNF and HACS in acute LBP. More research is needed to understand factors contributing to individual variation in sensory measures in LBP. SIGNIFICANCE: Human assumed central sensitization (HACS) is present in acute low back pain (LBP) but factors contributing to individual variation are not fully explored. This study investigated the relationship between factors such as brain derived neurotrophic factor (BDNF) and HACS in acute LBP. Our findings indicate that HACS was present in specific LBP subgroups but BDNF was unrelated to HACS. Combinations of BDNF genotype, demographic and psychological factors explained a small proportion of the variation in sensory measures during acute LBP.
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Dor Aguda , Dor Lombar , Humanos , Fator Neurotrófico Derivado do Encéfalo , Sensibilização do Sistema Nervoso Central , Estudos Transversais , Dor Lombar/psicologia , Dor Aguda/psicologia , DemografiaRESUMO
Magnetic resonance electrical properties tomography (MREPT) is an emerging imaging modality to noninvasively measure tissue conductivity and permittivity. Implementation of MREPT in the clinic requires repeatable measurements at a short scan time and an appropriate protocol. The aim of this study was to investigate the repeatability of conductivity measurements using phase-based MREPT and the effects of compressed SENSE (CS), and RF shimming on the precision of conductivity measurements. Conductivity measurements using turbo spin echo (TSE) and three-dimensional balanced fast field echo (bFFE) with CS factors were repeatable. Conductivity measurement using bFFE phase showed smaller mean and variance that those measured by TSE. The conductivity measurements using bFFE showed minimal deviation with CS factors up to 8, with deviation increasing at CS factors > 8. Subcortical structures produced less consistent measurements than cortical parcellations at higher CS factors. RF shimming using full slice coverage 2D dual refocusing echo acquisition mode (DREAM) and full coverage 3D dual TR approaches further improved measurement precision. BFFE is a more optimal sequence than TSE for phase-based MREPT in brain. Depending on the area of the brain being measured, the scan can be safely accelerated with compressed SENSE without sacrifice of precision, offering the potential to employ MREPT in clinical research and applications. RF shimming with better field mapping further improves precision of the conductivity measures.
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Imageamento por Ressonância Magnética , Tomografia , Imageamento por Ressonância Magnética/métodos , Tomografia/métodos , Espectroscopia de Ressonância Magnética , Encéfalo/diagnóstico por imagem , Condutividade ElétricaRESUMO
OBJECTIVES: Pro-inflammatory molecules are thought to underpin the development of chronic low back pain (LBP). Although research has begun to explore the association between pro-inflammatory molecules in acute LBP and long-term outcome, no study has explored the role of anti-inflammatory molecules. We aimed to explore whether levels of systemic pro- and anti-inflammatory molecules 1) changed over a period of six months from the onset of acute LBP; 2) differed between people who were recovered (N = 11) and unrecovered (N = 24) from their episode of LBP at six months; 3) baseline psychological factors were related to inflammatory molecule serum concentrations at baseline, three and six months. METHODS: We retrospectively included participants with acute LBP included from a larger prospective trial and examined blood samples for the measurement of pro- and anti-inflammatory molecules and measures of pain, disability, and psychological factors at baseline, three and six months. RESULTS: The serum concentrations of pro- and anti-inflammatory molecules did not differ over time when compared between participants who recovered and those who did not recover at six-month follow-up. At three months, the unrecovered group had higher interleukin (IL)-8 and IL-10 serum concentrations than the recovered group. Baseline psychological factors were not related to inflammatory molecules at any time point. DISCUSSION: This exploratory study showed that levels of systemic inflammatory molecules did not change over the course of LBP, irrespective of whether people were recovered or unrecovered at six months. There was no relationship between acute-stage psychological factors and systemic inflammatory molecules. Further investigation is needed to elucidate the contribution of pro- and anti-inflammatory molecules to long-term LBP outcome.
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Dor Aguda , Dor Lombar , Humanos , Dor Lombar/terapia , Estudos Longitudinais , Estudos Prospectivos , Estudos Retrospectivos , Anti-Inflamatórios/uso terapêuticoRESUMO
The molecular processes driving the transition from acute to chronic low back pain (LBP) remain poorly understood and are likely to be sexually dimorphic. This study aimed to explore sex differences in the serum proteomic profile of people experiencing an acute LBP episode and determine if serum protein concentrations were associated with three-month outcome. Serum samples were collected through venepuncture from 30 female and 29 male participants experiencing an acute LBP episode. Serum samples underwent trypsin digestion and fractionation using hydrophobic interaction chromatography and were then analysed using mass-spectrometry. Mass-spectrometry spectra were searched in the Swissprot database for protein identification. Sex differences in protein abundance changes were evident upon inspection of fold changes. Multivariable data analysis identified 21 serum proteins during the acute episode that correctly classified 93% of males and 23 serum proteins that correctly classified 90% of females with ongoing LBP at 3 months. Pathway analysis suggested the differentially expressed proteins during acute LBP were frequently involved in immune, inflammatory, complement, or coagulation responses. This data provides preliminary evidence that biological processes during an acute LBP episode may contribute to the resolution, or persistence, of LBP symptoms at 3 months, however, these processes differ between males and females. PERSPECTIVE: Differential expression of serum proteins was observed between male and female participants during an acute LBP episode. This preliminary work provides a foundation for future research targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP.
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ABSTRACT: Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N = 120) participated in a prospective cohort study with 6-month follow-up. Candidate predictors were selected from the neurobiological (eg, sensorimotor cortical excitability assessed by sensory and motor-evoked potentials and brain-derived neurotrophic factor genotype), psychological (eg, depression and anxiety), symptom-related (eg, LBP history), and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with the presence of LBP at 6 months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress, and pain catastrophizing were the strongest predictors ( R2 = 0.47) of pain intensity at 6 months. Older age and higher pain catastrophizing were the strongest predictors ( R2 = 0.30) of disability at 6 months. When the LBP outcome was dichotomised, sensory cortex and corticomotor excitability, brain-derived neurotrophic factor genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at 6 months (C-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in the 6-month pain intensity.
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Dor Aguda , Dor Lombar , Humanos , Dor Lombar/psicologia , Fator Neurotrófico Derivado do Encéfalo , Prognóstico , Estudos Prospectivos , Ansiedade/psicologia , Dor Aguda/complicações , Avaliação da Deficiência , Inquéritos e QuestionáriosRESUMO
Chronic lymphocytic leukaemia (CLL) cells can express unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain (IGHV) genes with differing clinical behaviours, variable B cell receptor (BCR) signalling capacity and distinct transcriptional profiles. As it remains unclear how these differences reflect the tumour cells' innate pre/post germinal centre origin or their BCR signalling competence, we applied mRNA/miRNA sequencing to 38 CLL cases categorised into three subsets by IGHV mutational status and BCR signalling capacity. We identified 492 mRNAs and 38 miRNAs differentially expressed between U-CLL and M-CLL, but only 9 mRNAs and 0 miRNAs associated with BCR competence within M-CLL. Of the IGHV-associated miRNAs, (14/38 (37%)) derived from chr14q32 clusters where all miRNAs were co-expressed with the MEG3 lncRNA from a cancer associated imprinted locus. Integrative analysis of miRNA/mRNA data revealed pronounced regulatory potential for the 14q32 miRNAs, potentially accounting for up to 25% of the IGHV-related transcriptome signature. GAB1, a positive regulator of BCR signalling, was potentially regulated by five 14q32 miRNAs and we confirmed that two of these (miR-409-3p and miR-411-3p) significantly repressed activity of the GAB1 3'UTR. Our analysis demonstrates a potential key role of the 14q32 miRNA locus in the regulation of CLL-related gene regulation.
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Leucemia Linfocítica Crônica de Células B , MicroRNAs , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , MicroRNAs/genética , Mutação , RNA Mensageiro/genéticaRESUMO
In many road crashes the human body is exposed to high forces, commonly resulting in multiple injuries. This study of linked road crash data aimed to identify co-occurring injuries in multiple injured road users by using a novel application of a data mining technique commonly used in Market Basket Analysis. We expected that some injuries are statistically associated with each other and form Individual-Based Injury Patterns (IBIPs) and further that specific road users are associated with certain IBIPs. First, a new injury taxonomy was developed through a four-step process to allow the use of injury data recorded from either of the two major dictionaries used to document anatomical injury. Then data from the Swedish Traffic Accident Data Acquisition, which includes crash circumstances from the police and injury information from hospitals, was analysed for the years 2011 to 2017. The injury data was analysed using the Apriori algorithm to identify statistical association between injuries (IBIP). Each IBIP were then used as the outcome variable in logistic regression modelling to identify associations between specific road user types and IBIPs. A total of 48,544 individuals were included in the analysis of which 36,480 (75.1%) had a single injury category recorded and 12,064 (24.9%) were considered multiply injured. The data mining analysis identified 77 IBIPs in the multiply injured sample and 16 of these were associated with only one road user type. IBIPs and their relation to road user type are one step on the journey towards developing a tool to better understand and quantify injury severity and thereby improve the evidence-base supporting prioritisation of road safety countermeasures.
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Traumatismo Múltiplo , Ferimentos e Lesões , Acidentes de Trânsito , Mineração de Dados , Humanos , Modelos Logísticos , Polícia , Ferimentos e Lesões/epidemiologiaRESUMO
STUDY OBJECTIVES: To characterize how mandibular advancement enlarges the upper airway via posterior tongue advancement in people with obstructive sleep apnea (OSA) and whether this is associated with mandibular advancement splint (MAS) treatment outcome. METHODS: One-hundred and one untreated people with OSA underwent a 3T magnetic resonance (MRI) scan. Dynamic mid-sagittal posterior tongue and mandible movements during passive jaw advancement were measured with tagged MRI. Upper airway cross-sectional areas were measured with the mandible in a neutral position and advanced to 70% of maximum advancement. Treatment outcome was determined after a minimum of 9 weeks of therapy. RESULTS: Seventy-one participants completed the study: 33 were responders (AHI<5 or AHI≤10 events/hr with >50% AHI reduction), 11 were partial responders (>50% AHI reduction but AHI>10 events/hr), and 27 nonresponders (AHI reduction<50% and AHI≥10 events/hr). Responders had the greatest naso- and oropharyngeal tongue anterior movement (0.40 ± 0.08 and 0.47 ± 0.13 mm, respectively) and oropharyngeal cross-sectional area enlargement (6.41 ± 2.12%) per millimeter of mandibular advancement. A multivariate model that included tongue movement and percentage of airway enlargement per millimeter of mandibular advancement along with baseline AHI correctly classified 69.2% (5-fold cross-validated 62.5%, n = 39) of participants in response categories when the jaw was advanced in the range that would usually be regarded as sufficient for clinical efficacy (> 4 mm). In comparison, a model using only baseline AHI correctly classified 50.0% of patients (5-fold cross-validated 52.5%, n = 40). CONCLUSIONS: Tongue advancement and upper airway enlargement with mandibular advancement in conjunction with baseline AHI improve treatment response categorization to a satisfactory level (69.2%, 5-fold cross-validated 62.5%).
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Avanço Mandibular , Apneia Obstrutiva do Sono , Humanos , Polissonografia , Apneia Obstrutiva do Sono/patologia , Apneia Obstrutiva do Sono/cirurgia , Língua , Resultado do TratamentoRESUMO
BACKGROUND: The use of high-throughput sequencing in combination with chromatin immunoprecipitation (ChIP-seq) has enabled the study of genome-wide protein binding at high resolution. While the amount of data generated from such experiments is steadily increasing, the methods available for their analysis remain limited. Although several algorithms for the analysis of ChIP-seq data have been published they focus almost exclusively on transcription factor studies and are usually not well suited for the analysis of other types of experiments. RESULTS: Here we present ChIPseqR, an algorithm for the analysis of nucleosome positioning and histone modification ChIP-seq experiments. The performance of this novel method is studied on short read sequencing data of Arabidopsis thaliana mononucleosomes as well as on simulated data. CONCLUSIONS: ChIPseqR is shown to improve sensitivity and spatial resolution over existing methods while maintaining high specificity. Further analysis of predicted nucleosomes reveals characteristic patterns in nucleosome sequences and placement.
Assuntos
Algoritmos , Imunoprecipitação da Cromatina/métodos , Nucleossomos/genética , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Sítios de Ligação , Biologia Computacional/métodos , DNA de Plantas/genética , Genoma de Planta , Histonas/genética , Modelos Estatísticos , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodosRESUMO
OBJECTIVES: A widely used measure of emotion dysregulation, the Difficulties in Emotion Regulation Scale (DERS), may insufficiently cover a number of potentially important aspects of emotional dysregulation. A new measure of emotional dysregulation, the Emotional Dysregulation Questionnaire (EDQ) was therefore developed based upon an eight-factor model of the construct. DESIGN AND METHOD: The DERS and the EDQ were administered to a community sample (N = 362; 183 female, 179 male), along with a number of measures of psychopathology associated with emotional dysregulation. The capacity of the EDQ and the DERS to account for the emotional dysregulation associated with these different types of psychopathology was then compared. RESULTS: In several of the psychopathologies examined, the EDQ could account for more variation than the DERS, suggesting that it more comprehensively assessed the emotion regulation deficits associated with these issues. CONCLUSIONS: Results suggest the EDQ possesses several advantages relative to the DERS, allowing for a more comprehensive and accurate assessment of emotional dysregulation. PRACTITIONER POINTS: Emotional dysregulation is a common component of many psychological disorders. The Difficulties in Emotion Regulation Scale is one of the primary self-report measures used to asses these difficulties, however, concerns exist that it may not comprehensively assess the construct of emotional dysregulation. A new self-report measure of comparable length, the Emotional Dysregulation Questionnaire has been developed, with this new measure possessing several advantages relative to the DERS with regard to the assessment of emotional dysregulation. The use of this measure in clinical practice may more accurately identify the emotion regulation deficits present in clients.