RESUMO
Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense variant resource by harmonizing multiple data sets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extendable to other model organisms. The result is a web- and programmatically accessible data service called GenomeMUSter, comprising single-nucleotide variants covering 657 strains at 106.8 million segregating sites. Interoperation with phenotype databases, analytic tools, and other resources enable a wealth of applications, including multitrait, multipopulation meta-analysis. We show this in cross-species comparisons of type 2 diabetes and substance use disorder meta-analyses, leveraging mouse data to characterize the likely role of human variant effects in disease. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.
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Diabetes Mellitus Tipo 2 , Humanos , Camundongos , Animais , Filogenia , Genótipo , Camundongos Endogâmicos , Fenótipo , Mutação , Variação GenéticaRESUMO
MYB plays a key role in gene regulation throughout the hematopoietic hierarchy and is critical for the maintenance of normal hematopoietic stem cells (HSC). Acquired genetic dysregulation of MYB is involved in the etiology of a number of leukemias, although inherited noncoding variants of the MYB gene are a susceptibility factor for many hematological conditions, including myeloproliferative neoplasms (MPN). The mechanisms that connect variations in MYB levels to disease predisposition, especially concerning age dependency in disease initiation, are completely unknown. Here, we describe a model of Myb insufficiency in mice that leads to MPN, myelodysplasia, and leukemia in later life, mirroring the age profile of equivalent human diseases. We show that this age dependency is intrinsic to HSC, involving a combination of an initial defective cellular state resulting from small effects on the expression of multiple genes and a progressive accumulation of further subtle changes. Similar to previous studies showing the importance of proteostasis in HSC maintenance, we observed altered proteasomal activity and elevated proliferation indicators, followed by elevated ribosome activity in young Myb-insufficient mice. We propose that these alterations combine to cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation.
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Leucemia , Transtornos Mieloproliferativos , Animais , Camundongos , Humanos , Proteostase , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Regulação da Expressão Gênica , Leucemia/metabolismo , Transtornos Mieloproliferativos/metabolismoRESUMO
The Mouse Phenome Database (MPD; https://phenome.jax.org; RRID:SCR_003212), supported by the US National Institutes of Health, is a Biomedical Data Repository listed in the Trans-NIH Biomedical Informatics Coordinating Committee registry. As an increasingly FAIR-compliant and TRUST-worthy data repository, MPD accepts phenotype and genotype data from mouse experiments and curates, organizes, integrates, archives, and distributes those data using community standards. Data are accompanied by rich metadata, including widely used ontologies and detailed protocols. Data are from all over the world and represent genetic, behavioral, morphological, and physiological disease-related characteristics in mice at baseline or those exposed to drugs or other treatments. MPD houses data from over 6000 strains and populations, representing many reproducible strain types and heterogenous populations such as the Diversity Outbred where each mouse is unique but can be genotyped throughout the genome. A suite of analysis tools is available to aggregate, visualize, and analyze these data within and across studies and populations in an increasingly traceable and reproducible manner. We have refined existing resources and developed new tools to continue to provide users with access to consistent, high-quality data that has translational relevance in a modernized infrastructure that enables interaction with a suite of bioinformatics analytic and data services.
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Bases de Dados Genéticas , Fenômica , Camundongos , Animais , Camundongos Endogâmicos , Fenótipo , GenótipoRESUMO
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for >2.4 h. They inhibit SERT transport-associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.SIGNIFICANCE STATEMENT Selective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to SERT, which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2-6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands engage their therapeutic target(s).
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Transtorno Depressivo Maior , Inibidores Seletivos de Recaptação de Serotonina , Animais , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fluoxetina/farmacologia , Escitalopram , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Retículo Endoplasmático/metabolismo , Citalopram/farmacologia , MamíferosRESUMO
Nature-based interventions (NBIs) are activities, strategies, or programs taking place in natural settings, such as exercising in greenspaces, to improve the health and well-being of people by integrating the benefits of nature exposure with healthy behaviours. Current reviews on NBIs do not report the effects on different groups of physical health conditions. The purpose of this systematic review and meta-analysis was to identify and synthesize the evidence of the effect of NBIs on physical health outcomes and biomarkers of physical health conditions. Overall, 20,201 studies were identified through searching MEDLINE, Embase, CINAHL, SPORTDiscus, and CENTRAL databases up to June 7, 2024. Inclusion criteria were: 1) randomized controlled intervention studies; 2) population with a physical health condition; 3) NBIs vs. different intervention or no intervention; and 4) measuring physical health outcomes and/or biomarkers. Twenty-six studies were included in the review, 15 of which contributed to the meta-analysis. Compared to control groups, NBIs groups showed significant improvements in: diastolic blood pressure (MD -3.73 mmHg [-7.46 to -0.00], I2 = 62%) and heart rate (MD -7.44 bpm [-14.81 to -0.06], I2 = 0%) for cardiovascular conditions, fatigue (SMD -0.50 [-0.82 to -0.18], I2 = 16%) for central nervous system conditions, and body fat percentage (MD -3.61% [-5.05 to -2.17], I2 = 0%) for endocrine conditions. High effect heterogeneity was found in several analyses and the included studies had moderate-to-high risk of bias (RoB). The non-significant outcomes showed a direction of effect in favour of NBI groups for cardiovascular, central nervous system, endocrine, musculoskeletal, and respiratory conditions. This review found some beneficial effects in favour of NBIs for health outcomes in at least three condition groups though RoB and inconsistent effects limited some interpretations. NBIs are promising therapies that healthcare professionals can consider integrating into clinical practice.
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Nível de Saúde , Humanos , Natureza , Exercício FísicoRESUMO
BACKGROUND: A network meta-analysis aims to help clinicians make clinical decisions on the most effective treatment for a certain condition. Neck pain is multifactorial, with various classification systems and treatment options. Classifying patients and grouping interventions in clinically relevant treatment nodes for a NMA is essential, but this process is poorly defined. OBJECTIVE: Our aim is to obtain consensus among experts on neck pain classifications and the grouping of interventions into nodes for a future network meta-analysis. DESIGN: A Delphi consensus study involving neck pain experts worldwide. METHODS: We invited authors of neck pain clinical practice guidelines published from 2014 onwards. The Delphi baseline questionnaire was developed based on the findings of a scoping review, including four items on classifications and 19 nodes. Participants were asked to record their level of agreement on a seven-point Likert scale or using Yes/No/Not sure answer options for the various statements. We used descriptive analysis to summarise the responses on each statement with content analysis of the free-text comments. RESULTS: In total, 18/80 experts (22.5%) agreed to participate in one or more Delphi rounds. We needed three rounds to reach consensus for two classification of neck pain: one based on aetiology and one on duration. In addition, we also reached consensus on the grouping of interventions, including a definition of each node, with the number of nodes reduced to 17. CONCLUSION: With this consensus we clinically validated two neck pain classifications and grouped conservative treatments into 17 well-defined and clinically relevant nodes.
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Tratamento Conservador , Cervicalgia , Humanos , Técnica Delphi , Cervicalgia/diagnóstico , Cervicalgia/terapia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
The Mouse Phenome Database continues to serve as a curated repository and analysis suite for measured attributes of members of diverse mouse populations. The repository includes annotation to community standard ontologies and guidelines, a database of allelic states for 657 mouse strains, a collection of protocols, and analysis tools for flexible, interactive, user directed analyses that increasingly integrates data across traits and populations. The database has grown from its initial focus on a standard set of inbred strains to include heterogeneous mouse populations such as the Diversity Outbred and mapping crosses and well as Collaborative Cross, Hybrid Mouse Diversity Panel, and recombinant inbred strains. Most recently the system has expanded to include data from the International Mouse Phenotyping Consortium. Collectively these data are accessible by API and provided with an interactive tool suite that enables users' persistent selection, storage, and operation on collections of measures. The tool suite allows basic analyses, advanced functions with dynamic visualization including multi-population meta-analysis, multivariate outlier detection, trait pattern matching, correlation analyses and other functions. The data resources and analysis suite provide users a flexible environment in which to explore the basis of phenotypic variation in health and disease across the lifespan.
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Fenômica , Camundongos , Animais , Camundongos Endogâmicos , FenótipoRESUMO
Existing phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focussed measurable trait data. The integration of trait and biological attribute information with an ever increasing body of chemical, environmental and biological data greatly facilitates computational analyses and it is also highly relevant to biomedical and clinical applications. The Ontology of Biological Attributes (OBA) is a formalised, species-independent collection of interoperable phenotypic trait categories that is intended to fulfil a data integration role. OBA is a standardised representational framework for observable attributes that are characteristics of biological entities, organisms, or parts of organisms. OBA has a modular design which provides several benefits for users and data integrators, including an automated and meaningful classification of trait terms computed on the basis of logical inferences drawn from domain-specific ontologies for cells, anatomical and other relevant entities. The logical axioms in OBA also provide a previously missing bridge that can computationally link Mendelian phenotypes with GWAS and quantitative traits. The term components in OBA provide semantic links and enable knowledge and data integration across specialised research community boundaries, thereby breaking silos.
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Ontologias Biológicas , Disciplinas das Ciências Biológicas , Estudo de Associação Genômica Ampla , FenótipoRESUMO
PURPOSE: The aim of this study was to conduct a systematic review of the psychometric properties of Pressure Pain Detection Threshold (PPDT) measures in people with hand or wrist injuries. STUDY DESIGN AND METHODS: MEDLINE, Embase, and CINAHL databases were searched to identify eligible studies evaluating psychometric properties of PPDT in samples composed of at least 50% of people with hand or wrist injury. The Consensus-based Standards for the Measurement of Health Instruments' risk of bias checklist was used to critically appraise the included studies, and qualitative synthesis was performed by pooling the results of all studies that presented the same measurement property using Grading of Recommendations, Assessment, Development, and Evaluation. RESULTS: From 415 studies, 11 relevant studies were identified. Of the 11 studies, four hand or wrist injuries were represented; carpal tunnel syndrome, distal radius fractures, osteoarthritis, and complex regional pain syndrome. Intra-rater reliability was considered sufficient (intraclass correlation coefficient 0.64-0.94), with small reported standard error of the mean values (5.3-39.2 kPa). Results of validity and responsiveness could not be synthesized due to heterogeneity. Risk of bias for reliability and measurement error was assessed as very good or adequate, whereas validity and responsiveness were doubtful or inadequate. Overall quality of evidence was low or very low for all measurement properties. CONCLUSIONS: Inconsistent results and low quality evidence provide little confidence in the overall measurement properties of PPDT in a hand or wrist injury population. No criterion standard for pain further highlights complexities around pain measurement such that the results obtained from PPDT measures in clinical practice cannot be compared to a gold standard measure.
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Limiar da Dor , Traumatismos do Punho , Humanos , Psicometria , Reprodutibilidade dos Testes , Extremidade Superior , Traumatismos do Punho/complicações , Traumatismos do Punho/diagnósticoRESUMO
The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely accessed and highly functional data repository housing primary phenotype data for the laboratory mouse accessible via APIs and providing tools to analyze and visualize those data. Data come from investigators around the world and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses rigorously curated per-animal data with detailed protocols. Public ontologies and controlled vocabularies are used for annotation. In addition to phenotype tools, genetic analysis tools enable users to integrate and interpret genome-phenome relations across the database. Strain types and populations include inbred, recombinant inbred, F1 hybrid, transgenic, targeted mutants, chromosome substitution, Collaborative Cross, Diversity Outbred and other mapping populations. Our new analysis tools allow users to apply selected data in an integrated fashion to address problems in trait associations, reproducibility, polygenic syndrome model selection and multi-trait modeling. As we refine these tools and approaches, we will continue to provide users a means to identify consistent, quality studies that have high translational relevance.
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Biologia Computacional/métodos , Bases de Dados Genéticas , Genoma , Fenômica , Fenótipo , Algoritmos , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Mutação , Linguagens de Programação , Ferramenta de Busca , Software , Especificidade da Espécie , NavegadorRESUMO
The mechanisms underlying chronic pain development following musculoskeletal trauma are complex and multifactorial. In their search, some researchers are turning to the subchondral bone as a potential contributor to pain due to its vascularity, using a depth-specific imaging technique. However, this technique has been mainly used in the knee. We propose the use of a quantitative computed tomography (QCT) depth-specific analysis to measure subchondral bone following wrist trauma. Ten participants (n = 5 post-trauma; n = 5 healthy) underwent bilateral computed tomography scans of their wrist accompanied by a calibration phantom with known densities. Average subchondral volumetric bone mineral density (vBMD) was studied at three depths from the subchondral surface (0-2.5, 2.5-5, 5-7.5 mm) according to radial articular surface contact in both wrists of each participant. Percentage differences and Cohen's d effect sizes were calculated to analyze bilateral vBMD and vBMD differences between groups. This image-based tool demonstrated subject-specific, depth-specific, and joint-specific measures of vBMD within the wrist. This methodology highlighted the differences between depth-specific vBMD in healthy people and people who have experienced wrist trauma. Overall, the healthy cohort demonstrated higher vBMD across all three depths and both articular surfaces. This imaging technique further distinguished between subchondral cortical and trabecular bones, wherein clinical implications can be drawn from these distinctions in future work. Our study therefore supports the utility of a QCT imaging technique in detecting differences in depth-specific vBMD in the wrist.
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Densidade Óssea , Punho , Osso Esponjoso , Humanos , Dor , Tomografia Computadorizada por Raios X/métodos , Punho/diagnóstico por imagemRESUMO
BACKGROUND: Psychological factors have been shown to be consistent predictors of chronic pain in people with musculoskeletal injuries. However, few prognostic studies have considered multiple risk factors including peritraumatic distress. In addition, previous research has not considered that the associations between peritraumatic distress and pain levels can vary across pain outcomes. QUESTION/PURPOSE: To determine whether an easily measurable level of baseline distress is associated with pain levels 1 year after noncatastrophic traumatic injuries when the outcome to be assessed is not normally distributed. METHODS: This was a prospective cohort study. The data were captured from two cohorts in London, Ontario, Canada, and Chicago, IL, USA. Participants were adults with acute noncatastrophic (that is, not treated with surgery or hospitalization) musculoskeletal injuries of any etiology with various injury locations (60% [145 of 241] spinal and 40% [96 of 241] peripheral) that presented to local urgent care centers. Other inclusion criteria included English/French speakers and having no other disorder that would affect their pain levels. In total, between the years 2015 and 2018, 241 participants were recruited based on the inclusion criteria. Ninety-three percent (225 of 241) of participants provided baseline data, and of these, 48% (109 of 225) were lost to follow-up in 1 year. Based on a complete case approach, this study included 116 participants who ranged in age from 18 to 66 years and 69% (80) of whom were women. The Traumatic Injuries Distress Scale (TIDS) was used to evaluate distress at baseline (within 4 weeks of injury). The TIDS is a validated, reliable 12-item risk prognosis screening tool that takes less than 3 minutes to complete with questions regarding uncontrolled pain, negative affect, and intrusion/hyperarousal. The minimum and maximum possible scores are 0 and 24, with higher scores indicating higher levels of distress. The Numeric Pain Rating Scale (NPRS) was used to assess the pain level at baseline and again 12 months postinjury. To complete the NPRS, participants rate the severity of their pain on a scale of 0 to 10, with 0 indicating no pain and 10 indicating the worst pain imaginable. NPRS scores of 1 to 3 indicate mild pain, 4 to 6 indicate moderate pain and 7 or higher indicate severe pain. As a preliminary analysis, to assess whether the participants as a group experienced recovery, a paired samples t-test was used to compare NPRS scores at baseline and 12 months. In all, 52% (60 of 116) of participants reported no pain (NPRS = 0), and mean pain intensity scores improved from 4.8 ± 2.1 at baseline to 1.6 ± 1.6 at 12-month follow-up (p < 0.001). Quantile regression was used to describe the association between baseline distress and pain levels 1 year after the injury. This technique was used because it reveals the relationships at different quantiles of the pain outcome distribution. RESULTS: The results indicate some people (52% [60 of 116]) recovered regardless of their baseline level of distress (30th quantile of the NPRS: ß = 0). However, in those with persisting pain, higher levels of baseline distress are associated with greater levels of pain 12 months after the injury (50th quantile of the NPRS: ß = 0.11; p = 0.01; 70th quantile of the NPRS: ß = 0.27; p < 0.001; 90th quantile of the NPRS: ß = 0.31; p = 0.01). According to this model, with a baseline TIDS score of 5, there is 10% probability that patients will report moderate or greater levels of pain (4 or higher of 10) 12 months later. This probability then increases as the TIDS score increases. For instance, at a score of 13 on the TIDS, the probability of a patient reporting moderate or higher levels of pain increases to 30%, and the probability of reporting severe pain (higher than 6 of 10) is 10%. CONCLUSION: Clinicians and surgeons in orthopaedic settings can screen for the presence of peritraumatic distress using the TIDS, which is an easily administered tool that does not require extensive knowledge of psychology, and by using it they can identify those with higher levels of distress who are more likely to have persistent, long-term pain. A score of 4 or less indicates a low risk of persistent pain, a score between 5 and 12 (endpoints included) indicates moderate risk, and a score of 13 or higher indicates high risk. Future studies should investigate whether certain immediate interventions for peritraumatic distress in the aftermath of trauma can decrease the likelihood that a patient will develop chronic pain after injury. As an analysis technique, quantile regression is useful to assess complex associations in many orthopaedic settings in which a certain outcome is expected to occur in most patients leading to non-normally distributed data. LEVEL OF EVIDENCE: Level II, therapeutic study.
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Manejo da Dor/métodos , Manejo da Dor/psicologia , Medição da Dor , Transtornos de Estresse Pós-Traumáticos/psicologia , Ferimentos e Lesões/psicologia , Ferimentos e Lesões/terapia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Previous neck-specific patient-reported outcome measures (PROMs) have tended to measure both symptoms and disability. This multi-staged study developed and evaluated a neck-specific PROM focusing on functional disability. METHODS: This study integrated findings from systematic reviews on neck-specific outcome measures, patient interviews, qualitative studies on neck disability, and iterative item testing to develop a 10-item measure of neck-related disability (ND10). Content validity was assessed by classifying items using the International Classification of Functioning, Disability and Health (ICF) and perspective linking. Patients (n = 78) with neck pain completed cognitive interviews, exploring items of the Neck Disability Index (NDI) and ND10, and completed structured questions related to literacy and relevance. Test-retest reliability and internal consistency were evaluated using intraclass correlation coefficients, Bland Altman graphs, and Cronbach's alpha. Concurrent convergent validity was evaluated by comparing the ND10 to the NDI, Single Assessment Numeric Evaluation (SANE), and Disabilities of the Arm, Shoulder and Hand (DASH). Known group validity was determined by comparing ND10 scores from patients, who rated their neck as more or less than 1/2 of "normal" on the SANE, using t-tests. RESULTS: The ND10 requires respondents to make rational judgements about their neck-related body function and disability. It has high internal consistency (0.94) and re-test reliability (0.87; SEM = 3.2/100; MDC = 7.5); and no re-test bias (mean re-test difference of 0.6). It followed expected correlation patterns, being highly correlated with related multi-item PROMs (r = 0.85-0.91), and moderately correlated to the single-item SANE. More patients agreed that the ND10 was easily readable than did so for the NDI (84% vs 68%; p < 0.05). All the PROMs distinguished the patients who perceived themselves as being abnormal/normal defined by a dichotomized SANE (p < 0.01). CONCLUSION: The ND10 is reliable and valid for measuring neck-related functional disability. Longitudinal and cross-cultural translation studies are needed to support future use.
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Avaliação da Deficiência , Traduções , Comparação Transcultural , Humanos , Cervicalgia , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
PURPOSE: Radial head arthroplasty (RHA) is commonly performed to manage comminuted unreconstructible radial head fractures. Although the outcomes of RHA are often satisfactory, revisions are usually considered when pain intensity is higher than expected. Therefore, it is important to investigate the recovery trajectories of patients following RHA over an extended period and the characteristics that may lead to unfavorable outcomes. METHODS: The Patient-Rated Elbow Evaluation (PREE) was used to assess recovery in 94 patients at baseline (within 2-7 days after surgery); 3 and 6 months; and 1, 2, 3, 4, 5, and 8 years after RHA. Lower PREE values indicate lower pain and disability. Latent growth curve analysis was used to determine classes of recovery. The characteristics of the participants in the identified recovery trajectory classes were then compared. RESULTS: Two distinct recovery trajectories were identified: optimal and suboptimal recoveries. Most patients (84%) belonged to the optimal recovery class, which exhibited significantly lower baseline PREE scores, a consistent pattern of recovery, and a relatively high rate of change. Patients in the suboptimal recovery class (16%) had significantly higher baseline PREE scores and continued to experience relatively higher levels of pain and disability for the duration of the study; their rate of recovery was much slower. Patients belonging to the 2 recovery trajectories did not differ based on age or sex. Although we had low power in other variables, a qualitative exploration showed that the number of current or previous smokers was higher in the suboptimal recovery trajectory class. CONCLUSIONS: In this longitudinal cohort study, we show that high postsurgical pain and disability, and potentially smoking, may adversely affect the recovery trajectory following RHA. Clinicians are recommended to assess these potential factors while considering revision surgeries. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.
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Purpose This cross-sectional study aimed to determine if age and perceived job exertion (PJE) moderate the effect of gender on upper extremity (UE) disorders in injured workers. Methods We sampled a consecutive cohort of patients attending a specialty clinic for injured workers with UE musculoskeletal problems. We measured UE disability and pain using the Quick Disability of the Arm, Shoulder, and Hand (QDASH). Participants reported their PJE on a Global Rating of Change scale ranging from 1 (minimal perceived exertion) to 15 (maximal perceived exertion). Linear regression was used to explore the effect of gender on QDASH. We probed the moderating role of age and PJE using floodlight regression and identified the Johnson-Neyman (JN) region of age and PJE, where the effect of gender on QDASH becomes significant at the 95% level. Results We analyzed 418 participants, of whom 44% were women. The effect of gender on QDASH was significant for women aged 49 or younger (JN-region border: Age = 48.5, effect = 4.4, SE = 2.2, p = 0.05). Women workers with UE disorders younger than 49 years old report higher levels of pain and disability than do men. After the age of 49 years, both men and women workers experience a similar worsening of UE pain and disability with increasing age. Pain and disability increase with increased perceived job demands similarly for both men and women workers. Conclusions Women younger than 49 years had higher levels of UE pain and disorders than men. Both men and women workers reported higher UE disability with an increase in their PJE.
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Sistema Musculoesquelético , Esforço Físico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor , Extremidade SuperiorRESUMO
Emerging adulthood (ages 18-25) is a critical period for neurobiological development and the maturation of the hypothalamic-pituitary-adrenal axis. Recent findings also suggest that a natural perturbation of the gut microbiota (GM), combined with other factors, may create a unique vulnerability during this period of life. The GM of emerging adults is thought to be simpler, less diverse, and more unstable than either younger or older people. We postulate that this plasticity in the GM suggests a role in the rising mental health issues seen in westernized societies today via the gut-brain-microbiota axis. Studies have paid particular attention to the diversity of the microbiota, the specific function and abundance of bacteria, and the production of metabolites. In this narrative review, we focus specifically on diet, physical activity/exercise, substance use, and sleep in the context of the emerging adult. We propose that this is a crucial period for establishing a stable and more resilient microbiome for optimal health into adulthood. Recommendations will be made about future research into possible behavioral adjustments that may be beneficial to endorse during this critical period to reduce the probability of a "dysbiotic" GM and the emergence and severity of mental health concerns.
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Microbioma Gastrointestinal , Adolescente , Adulto , Idoso , Encéfalo , Humanos , Sistema Hipotálamo-Hipofisário , Saúde Mental , Sistema Hipófise-Suprarrenal , Adulto JovemRESUMO
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a significant neurodevelopment disorder among children and adolescents, with 5 % prevalence. Bone fractures account for 25 % of accidents and injuries among all children and adolescents. Considering the characteristics of inattention, hyperactivity, and impulsivity in children with ADHD, it is critical to examine bone fractures among these children. The objective of our meta-analysis was to determine the prevalence of bone fractures among children and adolescents with ADHD. METHODS: We completed a systematic review and meta-analysis using an electronic search of the following databases: CINAHL, EMBASE, PsycINFO, PubMed, and Scopus. The search terms used were: "attention deficit hyperactivity disorder OR attention deficit disorder" and "bone fracture*." We included studies examining patients 18 years or younger who were diagnosed with ADHD and tracked (prospectively or retrospectively) for five or more years. Effect size (es), using a random effects model, was calculated. We registered the review protocol with PROSPERO (CRD42019119527). RESULTS: From 445 records retrieved, 31 full text articles were reviewed and 5 articles met inclusion criteria for meta-analysis. The summary es revealed the prevalence of bone fractures among children and adolescents with ADHD to be 4.83 % (95 % CI: 3.07-6.58 %). The location of bone fractures, using a subset of data, showed a distribution of 69.62 %, 22.85 %, and 7.53 % in the upper limbs, lower limbs, and other anatomical regions, respectively. Another subset of studies revealed a 2.55-fold increase in the prevalence of fractures among the children with ADHD compared to their counterparts. CONCLUSIONS: Awareness of these findings is critical to physicians, parents, and policy makers to create safe environments and provide supports in order to optimize the health and safety of children and adolescents with ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade , Fraturas Ósseas , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Humanos , Pais , Prevalência , Estudos RetrospectivosRESUMO
During neural development, self-avoidance ensures that a neuron's processes arborize to evenly fill a particular spatial domain. At the individual cell level, self-avoidance is promoted by genes encoding cell-surface molecules capable of generating thousands of diverse isoforms, such as Dscam1 (Down syndrome cell adhesion molecule 1) in Drosophila Isoform choice differs between neighboring cells, allowing neurons to distinguish "self" from "nonself". In the mouse retina, Dscam promotes self-avoidance at the level of cell types, but without extreme isoform diversity. Therefore, we hypothesize that DSCAM is a general self-avoidance cue that "masks" other cell type-specific adhesion systems to prevent overly exuberant adhesion. Here, we provide in vivo and in vitro evidence that DSCAM masks the functions of members of the cadherin superfamily, supporting this hypothesis. Thus, unlike the isoform-rich molecules tasked with self-avoidance at the individual cell level, here the diversity resides on the adhesive side, positioning DSCAM as a generalized modulator of cell adhesion during neural development.
Assuntos
Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Retina/metabolismo , Animais , Adesão Celular/fisiologia , Linhagem Celular , Membrana Celular/metabolismo , Comportamento de Escolha/fisiologia , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Células HEK293 , Humanos , Camundongos , Moléculas de Adesão de Célula Nervosa/metabolismo , Neuritos/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismoRESUMO
PURPOSE: To review information pertaining to glaucoma following infant lensectomy surgery and to provide evidence to support the responsible mechanism of this condition. METHODS AND RESULTS: Described risk factors and proposed mechanisms for infantile aphakic glaucoma were assessed. The clinical evidence observed in affected glaucoma patients was analyzed, and evidence of postoperative anterior chamber fibrosis was reviewed and interpreted. CONCLUSION: The review and assessment of laboratory and clinical evidence support the proposal that infantile aphakic glaucoma is caused, in part, by postoperative anterior chamber fibroization related to lens cell dispersion and active epithelial-mesenchymal transition with resultant filtration angle tissue injury and loss of function.
Assuntos
Afacia Pós-Catarata , Extração de Catarata , Catarata , Glaucoma , Afacia Pós-Catarata/etiologia , Afacia Pós-Catarata/cirurgia , Glaucoma/etiologia , Glaucoma/cirurgia , Humanos , Lactente , Pressão Intraocular , Estudos RetrospectivosRESUMO
BACKGROUND: The Pain Catastrophizing Scale (PCS) is a widely used self-report tool to evaluate pain related catastrophizing. The PCS was developed using classical test theory and has been shown to be psychometrically sound among various populations. However, it's current three subscales are rarely used in clinical practice, offering potential for an abbreviated version that reduces administrative burden and can be used to estimate full scale scores, yet is not bound by the inclusion of items from each subscale. Hence, the aim of the current study was to develop a unidimensional abbreviated version of the PCS through findings from qualitative, classical test theory, and newer Rasch analysis. METHODS: The current cross-sectional study used data from the Quebec Pain Registry (n = 5646) to obtain PCS scores of people seeking care at tertiary chronic pain centres. To develop an abbreviated unidimensional tool, items were removed based on triangulation of qualitative review of each item and response, corrected item-total correlations, and Rasch analysis. Confirmatory factor analysis was conducted on the final remaining items to confirm the tool was assessing a single latent construct (catastrophizing). Fit was assessed using the cumulative fit index (CFI), Tucker Lewis Index (TLI), and root-mean-squared error of approximation (RMSEA). RESULTS: After triangulation, a final abbreviated 4-item scale showed adequate model fit with a strong correlation (r > 0.95) with the original scale and properties that were stable across age, sex, cause, and medicolegal status. Additionally, the brief version addressed some problematic wording on some items on the original scale. Both the original and new abbreviated tool were associated with the Beck Depression Inventory and the Brief Pain Inventory at the same magnitude. CONCLUSION: The abbreviated scale may allow for a decrease in administrator burden and greater clinical uptake when a quick screen for exaggerated negative orientation towards pain is needed.