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1.
Haemophilia ; 30(2): 306-319, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38239180

RESUMO

AIM: For people with haemophilia A (PwHA), bleeding in the joints leads to joint damage and haemophilia-related arthropathy, impacting range of motion and life expectancy. Existing guidelines for managing haemophilia A support healthcare professionals (HCPs) and PwHA in their efforts to preserve joint health. However, such guidance should be reviewed, considering emerging evidence and consensus as presented in this manuscript. METHODS: Fifteen HCPs experienced in the management of PwHA in the UK participated in a three-round Delphi panel. Consensus was defined at ≥70% of panellists agreeing or disagreeing for Likert-scale questions, and ≥70% selecting the same option for multiple- or single-choice questions. Questions not reaching consensus were revised for the next round. RESULTS: 26.8% (11/41), 44.8% (13/29) and 93.3% (14/15) of statements reached consensus in Rounds 1, 2 and 3, respectively. HCPs agreed that prophylaxis should be offered to patients with a baseline factor VIII (FVIII) level of ≤5 IU/dL and that, where there is no treatment burden, the aim of prophylaxis should be to achieve a trough FVIII level ≥15 IU/dL and maintain a longer period with FVIII levels of ≥20-30 IU/dL to provide better bleed protection. The aspirational goal for PwHA is to prevent all joint bleeds, which may be achieved by maintaining normalised (50-150 IU/dL) FVIII levels. CONCLUSION: The panel of experts were largely aligned on approaches to preserving joint health in PwHA, and this consensus may help guide HCPs.


Assuntos
Hemofilia A , Humanos , Hemofilia A/tratamento farmacológico , Fator VIII/uso terapêutico , Consenso , Hemartrose/prevenção & controle , Hemorragia/prevenção & controle , Reino Unido
2.
J Pediatr Orthop ; 43(4): 193-197, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36728260

RESUMO

BACKGROUND: The Grit Scale is used to measure grit, defined by Duckworth and colleagues as the disposition to show perseverance and passion for long-term goals. It has been shown that psychological factors like motivation, coachability, and coping with adversity are correlated with faster readiness for return to sport (RTS) in patients undergoing anterior cruciate ligament reconstruction (ACLR). This study investigates the association between pediatric patients' baseline grit scores and; preoperative Patient-reported Outcomes Measurement Information System (PROMIS) Pain scores and the recovery of range of motion (ROM) after ACLR. The investigators hypothesized that higher preoperative grit scores would predict lower preoperative pain scores and earlier return of knee ROM in patients undergoing ACLR. METHODS: This is a retrospective cohort study. Pediatric patients who underwent primary ACLR were assigned the pediatric Grit Scale. Patients were subdivided by meniscal procedures due to differences in postoperative protocols. ACLR alone or with meniscectomy (ACLR ± meniscectomy) were grouped together and ACLR with meniscal repair (ACLR + meniscus repair) represented the other cohort. Patients above the 50th grit percentile were considered "high grit". Patients below the 50th percentile were considered "low grit". Baseline PROMIS pain intensity and interference were collected. ROM was compared by grit cohort using the Mann-Whitney U test with a significance threshold of P ≤ 0.05. RESULTS: A total of 58 patients undergoing ACLR were analyzed: 20 ACLR ± meniscectomy and 38 ACLR + meniscus repair. The mean age was 15.0 ± 2.1 years with 41.4% of participants identifying as females. No significant difference was noted between baseline PROMIS pain intensity and interference and grit score ( P = 0.82, P = 0.91, respectively). Three months postoperatively, for those in the ACLR + meniscus repair cohort, low grit ROM was 130 degrees (interquartile range = 10 degrees), whereas high grit ROM was 135 degrees (interquartile range = 8 degrees) ( P = 0.006). CONCLUSIONS: This study found no differences in pain scores at presentation between grit cohorts but found that patients with grit scores below the 50th percentile undergoing ACLR + meniscus repair have 5 degrees less total ROM at 3 months compared with those with high grit scores. Quicker ROM recovery in patients with high grit may be a leading indicator of these patients' likelihood to achieve other postoperative milestones and meet criteria for RTS more quickly; the relationship between grit and readiness for RTS should be further investigated. LEVEL OF EVIDENCE: Level IV; retrospective cohort study.


Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Menisco , Lesões do Menisco Tibial , Feminino , Humanos , Criança , Adolescente , Estudos Retrospectivos , Lesões do Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/complicações , Lesões do Menisco Tibial/complicações , Articulação do Joelho/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , Menisco/cirurgia , Dor/cirurgia
3.
Blood ; 136(17): 1956-1967, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32693407

RESUMO

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.


Assuntos
Grânulos Citoplasmáticos/patologia , Heterogeneidade Genética , Síndrome da Plaqueta Cinza , Sistema Imunitário/patologia , Fenótipo , Biópsia , Proteínas Sanguíneas/genética , Estudos de Casos e Controles , Estudos de Coortes , Grânulos Citoplasmáticos/metabolismo , Diagnóstico Diferencial , Frequência do Gene , Estudos de Associação Genética , Síndrome da Plaqueta Cinza/classificação , Síndrome da Plaqueta Cinza/genética , Síndrome da Plaqueta Cinza/imunologia , Síndrome da Plaqueta Cinza/patologia , Humanos , Sistema Imunitário/fisiologia , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Mutação
4.
Clin Orthop Relat Res ; 479(12): 2576-2586, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34587147

RESUMO

BACKGROUND: Grit has been defined as "perseverance and passion for long-term goals" and is characterized by maintaining focus and motivation toward a challenging ambition despite setbacks. There are limited data on the impact of grit on burnout and psychologic well-being in orthopaedic surgery, as well as on which factors may be associated with these variables. QUESTIONS/PURPOSES: (1) Is grit inversely correlated with burnout in orthopaedic resident and faculty physicians? (2) Is grit positively correlated with psychologic well-being in orthopaedic resident and faculty physicians? (3) Which demographic characteristics are associated with grit in orthopaedic resident and faculty physicians? (4) Which demographic characteristics are associated with burnout and psychologic well-being in orthopaedic resident and faculty physicians? METHODS: This study was an institutional review board-approved interim analysis from the first year of a 5-year longitudinal study of grit, burnout, and psychologic well-being in order to assess baseline relationships between these variables before analyzing how they may change over time. Orthopaedic residents, fellows, and faculty from 14 academic medical centers were enrolled, and 30% (335 of 1129) responded. We analyzed for the potential of response bias and found no important differences between sites in low versus high response rates, nor between early and late responders. Participants completed an email-based survey consisting of the Duckworth Short Grit Scale, Maslach Burnout Inventory-Human Services (Medical Personnel) Survey, and Dupuy Psychological Well-being Index. The Short Grit Scale has been validated with regard to internal consistency, consensual and predictive validity, and test-retest stability. The Psychological Well-being Index has similarly been validated with regard to reliability, test-retest stability, and internal consistency, and the Maslach Burnout Inventory has been validated with regard to internal consistency, reliability, test-retest stability, and convergent validity. The survey also obtained basic demographic information such as survey participants' age, gender, race, ethnicity, marital status, current year of training or year in practice (as applicable), and region of practice. The studied population consisted of 166 faculty, 150 residents, and 19 fellows. Beyond the expected age differences between sub-populations, the fellow population had a higher proportion of women than the faculty and resident populations did. Pearson correlations and standardized ß coefficients were used to assess the relationships of grit, burnout, psychologic well-being, and continuous participant characteristics. RESULTS: We found moderate, negative relationships between grit and emotional exhaustion (r = -0.30; 95% CI -0.38 to -0.21; p < 0.001), depersonalization (r = -0.34; 95% CI -0.44 to -0.23; p < 0.001), and the overall burnout score (r = -0.39; 95% CI -0.48 to -0.31; p < 0.001). The results also showed a positive correlation between grit and personal accomplishment (r = 0.39; 95% CI 0.29 to 0.48; p < 0.001). We also found a moderate, positive relationship between grit and psychologic well-being (r = 0.39; 95% CI 0.30 to 0.49; p < 0.001). Orthopaedic surgeons with 21 years or more of practice had higher grit scores than physicians with 10 to 20 years of practice. Orthopaedic surgeons in practice for 21 years or more also had lower burnout scores than those in practice for 10 to 20 years. Married physicians had higher psychologic well-being than unmarried physicians did. CONCLUSION: Among orthopaedic residents, fellows, and faculty, grit is inversely related to burnout, with lower scores for emotional exhaustion and depersonalization and higher scores for personal accomplishment as grit increases. CLINICAL RELEVANCE: The results suggest that grit could be targeted as an intervention for reducing burnout and promoting psychologic well-being among orthopaedic surgeons. Other research has suggested that grit is influenced by internal characteristics, life experiences, and the external environment, suggesting that there is potential to increase one's grit. Residency programs and faculty development initiatives might consider measuring grit to assess for the risk of burnout, as well as offering curricula or training to promote this psychologic characteristic.


Assuntos
Esgotamento Profissional/psicologia , Docentes de Medicina/psicologia , Corpo Clínico Hospitalar/psicologia , Ortopedia/educação , Local de Trabalho/psicologia , Logro , Adulto , Feminino , Objetivos , Humanos , Internato e Residência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica
5.
Blood ; 130(2): 214-220, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28487294

RESUMO

The effect of variation in platelet function in platelet donors on patient outcome following platelet transfusion is unknown. This trial assessed the hypothesis that platelets collected from donors with highly responsive platelets to agonists in vitro assessed by flow cytometry (high-responder donors) are cleared more quickly from the circulation than those from low-responder donors, resulting in lower platelet count increments following transfusion. This parallel group, semirandomized double-blinded trial was conducted in a single center in the United Kingdom. Eligible patients were those 16 or older with thrombocytopenia secondary to bone marrow failure, requiring prophylactic platelet transfusion. Patients were randomly assigned to receive a platelet donation from a high- or low-responder donor when both were available, or when only 1 type of platelet was available, patients received that. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary end point was the platelet count increment 10 to 90 minutes following transfusion. Analysis was by intention to treat. Fifty-one patients were assigned to receive platelets from low-responder donors, and 49 from high-responder donors (47 of which were randomized and 53 nonrandomized). There was no significant difference in platelet count increment 10 to 90 minutes following transfusion in patients receiving platelets from high-responder (mean, 21.0 × 109/L; 95% confidence interval [CI], 4.9-37.2) or low-responder (mean, 23.3 × 109/L; 95% CI, 7.8-38.9) donors (mean difference, 2.3; 95% CI, -1.1 to 5.7; P = .18). These results support the current policy of not selecting platelet donors on the basis of platelet function for prophylactic platelet transfusion.


Assuntos
Hemorragia/prevenção & controle , Transfusão de Plaquetas , Trombocitopenia/terapia , Doadores de Tecidos/classificação , Adulto , Idoso , Anemia Aplástica/sangue , Anemia Aplástica/complicações , Anemia Aplástica/patologia , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Doenças da Medula Óssea/sangue , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea , Método Duplo-Cego , Feminino , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/patologia , Hemorragia/sangue , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Fator de Ativação de Plaquetas/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Testes de Função Plaquetária , Trombocitopenia/sangue , Trombocitopenia/etiologia , Trombocitopenia/patologia
6.
Blood ; 129(4): 520-524, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28064200

RESUMO

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibß, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB.


Assuntos
Plaquetas/metabolismo , Hemorragia/genética , Mutação , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Trombocitopenia/genética , Alelos , Plaquetas/patologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genes Dominantes , Genoma Humano , Hemorragia/diagnóstico , Hemorragia/metabolismo , Hemorragia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Contagem de Plaquetas , Trombocitopenia/diagnóstico , Trombocitopenia/metabolismo , Trombocitopenia/patologia
7.
Blood ; 127(23): 2903-14, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-26912466

RESUMO

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Perda Auditiva/genética , Mutação , Trombocitopenia/genética , Células A549 , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Criança , Feminino , Forminas , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Perda Auditiva/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Síndrome , Trombocitopenia/complicações , Adulto Jovem
8.
Blood ; 127(23): 2791-803, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27084890

RESUMO

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.


Assuntos
Transtornos Plaquetários/genética , Predisposição Genética para Doença , Hemorragia/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Trombose/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
9.
J Shoulder Elbow Surg ; 26(2): 331-336, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27720415

RESUMO

BACKGROUND: The purpose of this study was to determine the relative amount of load that is transmitted through the superior portion of the subscapularis during activities of daily living as compared with the load that is transmitted through the middle and inferior portions in a normal shoulder and in a shoulder with a supraspinatus tear. METHODS: By use of the Newcastle shoulder model, the subscapularis was modeled with 3 lines of action encircling the humeral head. The load was measured in the entire subscapularis, and the percentage of this load in each of the 3 tendinous bands was calculated. Subsequently, a supraspinatus tear was simulated, and the forces generated by the subscapularis and glenohumeral joint contact forces were measured. RESULTS: The maximum force produced by the entire subscapularis muscle for the various activities ranged from 3 to 43 N. Load sharing between the 3 subscapularis bands showed that the superior band bore the largest percentage of the total load of the muscle (95% ± 2%). The load in the subscapularis, particularly in the superior band, increased significantly when a supraspinatus tear was simulated (P < .0001). CONCLUSION: The superior band of the subscapularis tendon bears the highest percentage of load compared with the middle or inferior band. The load in the subscapularis increased significantly in the presence of a simulated supraspinatus tear. Because a disproportionate amount of force is transmitted through the superior subscapularis, more clinical research is warranted to determine whether tears in this region should be routinely repaired.


Assuntos
Lesões do Manguito Rotador/fisiopatologia , Manguito Rotador/fisiologia , Traumatismos dos Tendões/fisiopatologia , Atividades Cotidianas , Fenômenos Biomecânicos , Cadáver , Humanos , Modelos Biológicos , Amplitude de Movimento Articular
10.
Nucleic Acids Res ; 42(Database issue): D966-74, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24217912

RESUMO

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.


Assuntos
Ontologias Biológicas , Bases de Dados Factuais , Doenças Genéticas Inatas/genética , Fenótipo , Animais , Doenças Genéticas Inatas/diagnóstico , Genômica , Humanos , Internet , Camundongos
12.
Transfusion ; 54(4): 1166-79, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24117481

RESUMO

BACKGROUND: Relatively minor bleeding (e.g., bruising and/or petechiae) may cause patient distress. This systematic review's objective was to assess whether bleeding affects health-related quality of life (HRQoL) or illness perceptions or representations (IPs) in patients with hematologic malignancies or myelodysplasia (MDS). STUDY DESIGN AND METHODS: We searched, in full, 12 electronic databases (including CENTRAL, MEDLINE, and EMBASE) up to January 7, 2013, for eligible randomized controlled trials (RCTs), prospective cohort studies, and cross-sectional studies. RESULTS: A total of 6247 studies were initially identified; 5945 studies were excluded on the basis of the abstract. A total of 302 full-text articles were evaluated independently by two reviewers; of these, six studies within seven citations were eligible for inclusion. Two studies are still in progress, four studies within five citations were included in this review (one RCT, one prospective observational study, one interview study, and one Web-based survey). None of the included studies were designed to assess the impact bleeding had on HRQoL or IPs. The Web-based survey and observational study used two new patient-reported outcome scales which specifically assessed patient distress or concern due to bleeding. The majority of patients within these two studies either did not experience bleeding or did not have severe thrombocytopenia. CONCLUSION: There is insufficient evidence to demonstrate whether bleeding is a significant clinical problem that affects patients' HRQoL or IPs in either patients with MDS or patients with hematologic malignancies. Rigorously designed studies to assess the scale of this problem in both of these groups of patients are required.


Assuntos
Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/diagnóstico , Hemorragia/complicações , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Autorrelato , Estudos de Coortes , Estudos Transversais , Neoplasias Hematológicas/epidemiologia , Hemorragia/diagnóstico , Hemorragia/epidemiologia , Humanos , Síndromes Mielodisplásicas/epidemiologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Autoimagem
13.
EMBO Mol Med ; 16(10): 2560-2582, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39198715

RESUMO

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.


Assuntos
Disceratose Congênita , Proteínas de Ligação a Telômeros , Telômero , Disceratose Congênita/genética , Humanos , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Telômero/genética , Telômero/metabolismo , Masculino , Complexo Shelterina , Feminino , Mutação , Criança
14.
HSS J ; 19(1): 107-112, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36776513

RESUMO

Background: Symptomatic pediatric patients referred for magnetic resonance imaging (MRI) commonly present with traumatic bone marrow edema (BME) patterns. Purpose: We sought to associate discrete MRI patterns of BME with specific injury mechanisms in pediatric knee injuries to classify injury patterns by anatomical location of the BME. We aimed to group these into 6 patterns: patellar dislocation, extensor mechanism overload, hyperextension, single compartment impaction, ligament avulsion/translation, and direct contusion. Methods: We retrospectively reviewed 314 MRIs performed with a standard protocol on symptomatic patients aged 3 to 18 years at 1 institution. Our analysis included images, reports, and traumatic BME patterns. A musculoskeletal radiologist and orthopedic surgeon independently assigned 1 of the 6 injury patterns to each scan. Results: After exclusion criteria were applied to the 314 MRIs, 62 (19.7%) remained, 40 boys and 22 girls. The average age was of 12.2 years. The most frequent injury patterns were patellar dislocation (n = 22, 35%) and extensor mechanism overload (n = 14, 22%). κ value associated with pattern determination was .766, indicating substantial concordance. Bone marrow edema signal intensity on fat-suppressed sequences was classified as severe in 92% of cases. Conclusions: The strength of pediatric knee ligaments and tendons relative to epiphyseal bone may contribute to a high rate of BME injury patterns seen on MRI in symptomatic pediatric patients. We found that pediatric BME could be classified into 6 specific injury patterns, which might be useful to clinicians in recognizing mechanisms of injury. Further clinical studies are needed to assess the clinical differences in both short-term and long-term outcomes of the BME patterns described.

16.
Cureus ; 13(9): e17706, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34650880

RESUMO

Epstein-Barr virus (EBV) infections have variable presentations ranging from asymptomatic to the triad of fever, pharyngitis, and adenopathy in infectious mononucleosis. Although haematological abnormalities are commonly seen in EBV infections, severe EBV-associated thrombocytopenia is a rare presentation, complicating clinical diagnosis and requiring appropriate management. Here we describe a case of a 14-year-old female with severe thrombocytopenia (platelet count of 5 x109/L) and spontaneous haemorrhage, accompanied by periorbital oedema, an uncommon symptom in EBV-associated infectious mononucleosis. She was treated with intravenous immunoglobulins and a four-day course of methylprednisolone. Treatment resulted in progressive platelet count recovery, and the patient was discharged seven days post-admission with a platelet count of 143 x109/L. The case highlights the need to consider EBV infection as a differential diagnosis in patients presenting with acute severe thrombocytopenia.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34506368

RESUMO

INTRODUCTION: The purpose of this study was to determine the proportion of students matching in orthopaedic surgery after a structured, early-exposure mentored research program and what factors were associated with those students compared with participants who matched in other specialties. METHODS: Program data were reviewed from 2007 to 2015. Multivariable binary logistic regression analysis was used to evaluate student and research factors associated with orthopaedic surgery match. RESULTS: Of 174 students, 117 (67%) matched into surgical residency programs, with 49% (n = 85) matching into orthopaedic surgery. The percentage of women matching into orthopaedic surgery (37%) was less than that of men (53%), which, however, increased over the study period. Students who matched in orthopaedic surgery had greater numbers of publications (3.55 [range 0 to 17] average publications) compared with students who matched in other specialties (1.98 (range 0 to 11) average publications). The average number of publications per student increased from 0.79 (±1.44, range 0 to 10, 40%) preprogram to 1.95 (±2.28, range 0 to 11, 71%) postprogram. Measured factors associated with orthopaedic surgery match were publications with program mentor, postprogram first authorship, and total publications. DISCUSSION: Approximately half of the participants matched into orthopaedic surgery. Analysis showed that research productivity increased after program participation and was statistically associated with increased likelihood of orthopaedic surgery match.


Assuntos
Internato e Residência , Procedimentos Ortopédicos , Ortopedia , Estudantes de Medicina , Feminino , Humanos , Masculino , Mentores , Ortopedia/educação
18.
Med Acupunct ; 33(4): 286-294, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471447

RESUMO

Objective: Demand for complementary medicine, in particular, acupuncture, has increased over the past few years but widespread acceptance has been limited, in part, by the lack of high-quality studies, including lack of blinding. Acupuncture studies traditionally have difficulty with blinding as sham acupuncture can have up to a 40%-50% analgesic effect. This study randomized patients between Acupuncture and No Acupuncture (standard of care) without using sham needles. The primary outcome was adequate blinding of electro-auricular acupuncture in the intraoperative setting with secondary outcomes of pain/nausea control. Materials and Methods: Forty patients undergoing anterior cruciate ligament reconstruction were enrolled. Subjects were randomly assigned to receive acupuncture (Enhanced Electro-Auricular Trauma Protocol) or No Acupuncture during their surgeries. All patients received spinal anesthesia and intravenous midazolam, ketamine, and propofol for sedation. 1000 mg of intravenous (IV) acetaminophen and up to 30 mg of IV ketorolac were given at closure. No opioids or peripheral nerve blocks were administered intraoperatively. Results: Bang's Blinding indices were 0.2 (95% confidence interval [CI]: -0.02, 0.42) in the Acupuncture group, and 0.11 (95% CI: -0.10, 0.31) in the No Acupuncture group on postoperative day 1. Both groups had adequate blinding. There were no differences in pain scores, nausea/vomiting incidence, opioid consumption 0-24 hours, or patient satisfaction. Five patients in the No Acupuncture group received rescue blocks, while no patients in the Acupuncture group needed a rescue block (Fisher's exact test: p = 0.047). Conclusions: This study proved the primary hypothesis that adequate blinding of intraoperative acupuncture can be performed when patients are under sedation and neuraxial anesthesia. This research is registered at ClinicalTrials.gov as Clinical Trial Registration #: NCT03711734.

19.
JBJS Case Connect ; 10(2): e19.00462, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649151

RESUMO

CASE: Two firefighters developed Parsonage-Turner syndrome (PTS) shortly after sustaining episodes of heat stroke. Patient 1 was a 40-year-old man who presented with shoulder pain and supraspinatus and infraspinatus weakness. Patient 2 was a 35-year-old man who presented with shoulder pain and absent external rotation strength. Both had electrodiagnostic testing and magnetic resonance imaging findings consistent with PTS. Both demonstrated partial but incomplete recovery at 1- and 2.5-year follow-ups, respectively. CONCLUSIONS: PTS should remain on the differential diagnosis for any patient presenting with sudden onset shoulder pain and neurological deficits after an episode of heat-related illness.


Assuntos
Neurite do Plexo Braquial/etiologia , Bombeiros , Golpe de Calor/complicações , Adulto , Neurite do Plexo Braquial/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino
20.
J Am Acad Orthop Surg ; 27(5): e227-e234, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247313

RESUMO

INTRODUCTION: The purpose of this study was to identify objective predictors of grit, self-control, and conscientiousness in orthopaedic surgery residency applicants. METHODS: The following attributes were assessed in 455 applicants: grit, self-control, conscientiousness, consistency of interest, perseverance of effort, and ambition. These measures were correlated with standard, objective demographics obtained during the application process. RESULTS: Alpha Omega Alpha status, additional degrees, and number of publications did not predict any of the studied attributes. Grit increased with age (P < 0.001) but decreased with increasing board scores (P = 0.004). Former collegiate athletes demonstrated greater grit (P < 0.001), consistency of interest (P = 0.007), perseverance (P = 0.006), and self-control (P = 0.019). Female applicants demonstrated more grit (P = 0.044), consistency of interest (P = 0.003), and conscientiousness (P = 0.029) than males. Applicants with military experience had increased ambition (P = 0.033) and conscientiousness (P = 0.001). CONCLUSION: Overall, orthopaedics applicants possess increased grit compared with the general public, and a number of objective variables reliably predicted the studied attributes. LEVEL OF EVIDENCE: Level III, Cross-sectional study.


Assuntos
Consciência , Identificação Psicológica , Internato e Residência , Motivação , Cirurgiões Ortopédicos/psicologia , Ortopedia/educação , Autocontrole , Adulto , Fatores Etários , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
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