RESUMO
Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling (RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8-associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2. However, laterality defects are present in nearly half of those with MEGF8-associated CRPT2, but are rare in RAB23-associated CRPT1. Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1. No patient to date has carried two MEGF8 gene alterations that are both predicted to lead to complete loss-of-function, suggesting that a variable degree of residual MEGF8 activity may be essential for viability and potentially contributing to variable phenotypic severity. These data refine the phenotypic spectrum of CRPT2 in comparison to CRPT1 and more than double the number of likely pathogenic MEGF8 variants in this rare disorder.
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Acrocefalossindactilia , Fenótipo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Acrocefalossindactilia/genética , Acrocefalossindactilia/patologia , Proteínas de Membrana/genética , Mutação , Linhagem , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Substance misuse, obesity, mental health conditions, type 1 diabetes, cancers, and cardiovascular and chronic respiratory diseases together account for 41% of disability-adjusted life years linked to noncommunicable diseases (NCDs) among children and adolescents worldwide. However, the evidence on risk factors and interventions for this age group is scarce. Here we searched four databases to generate an evidence gap map of existing interventions and research gaps for these risk factors and NCDs. We mapped 159 reviews with 2,611 primary studies; most (96.2%) were conducted in high-income countries, and only 100 studies (3.8%) were from low- and middle-income countries (LMICs). The efficacy of therapeutic interventions on biomarkers and adverse events for NCDs appears to be well evidenced. Interventions for mental health conditions appear to be moderately evidenced, while interventions for obesity and substance misuse appear to be moderate to very low evidenced. Priority areas for future research include evaluating digital health platforms to support primary NCD prevention and management, and evaluating the impact of policy changes on the prevalence of obesity and substance misuse. Our findings highlight the wide disparity of evidence between high-income countries and LMICs. There is an urgent need for increased, targeted financing to address the research gaps in LMICs.
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Doenças não Transmissíveis , Transtornos Relacionados ao Uso de Substâncias , Criança , Humanos , Adolescente , Doenças não Transmissíveis/epidemiologia , Doenças não Transmissíveis/terapia , Lacunas de Evidências , Países em Desenvolvimento , Fatores de Risco , Obesidade/epidemiologia , Obesidade/terapiaRESUMO
Aims: The aim of this study was to capture 12-month outcomes from a representative multicentre cohort of patients undergoing total ankle arthroplasty (TAA), describe the pattern of patient-reported outcome measures (PROMs) at 12 months, and identify predictors of these outcome measures. Methods: Patients listed for a primary TAA at 19 NHS hospitals between February 2016 and October 2017 were eligible. PROMs data were collected preoperatively and at six and 12 months including: Manchester-Oxford Foot and Ankle Questionnaire (MOXFQ (foot and ankle)) and the EuroQol five-dimension five-level questionnaire (EQ-5D-5L). Radiological pre- and postoperative data included Kellgren-Lawrence score and implant position measurement. This was supplemented by data from the National Joint Registry through record linkage to determine: American Society of Anesthesiologists (ASA) grade at index procedure; indication for surgery, index ankle previous fracture; tibial hind foot alignment; additional surgery at the time of TAA; and implant type. Multivariate regression models assessed outcomes, and the relationship between MOXFQ and EQ-5D-5L outcomes, with patient characteristics. Results: Data from 238 patients were analyzed. There were significant improvements in MOXFQ and EQ-5D-5L among people who underwent TAA at six- and 12-month assessments compared with preoperative scores (p < 0.001). Most improvement occurred between preoperative and six months, with little further improvement at 12 months. A greater improvement in MOXFQ outcome postoperatively was associated with older age and more advanced radiological signs of ankle osteoarthritis at baseline. Conclusion: TAA significantly benefits patients with end-stage ankle disease. The lack of substantial further overall change between six and 12 months suggests that capturing PROMs at six months is sufficient to assess the success of the procedure. Older patients and those with advanced radiological disease had the greater gains. These outcome predictors can be used to counsel younger patients and those with earlier ankle disease on the expectations of TAA.
Assuntos
Tornozelo , Artroplastia de Substituição do Tornozelo , Humanos , Tornozelo/cirurgia , Resultado do Tratamento , Artroplastia de Substituição do Tornozelo/métodos , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/cirurgia , Avaliação de Resultados em Cuidados de SaúdeRESUMO
CONTEXT: Pain is a major symptom in adults with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) and response to current treatments, including bisphosphonates and standard analgesics (nonsteroidal anti-inflammatory drugs and opiates) is unpredictable. No studies have explored whether the type of pain is variable in this patient group. OBJECTIVE: To determine the frequency of neuropathic-like pain in patients with FD/MAS. DESIGN: Retrospective, dual registry study. SETTING: Community. PATIENTS: FD/MAS online registries: the US-based Familial Dysautonomia Foundation (FDF) and the UK-based Rare and Undiagnosed Diseases (RUDY) study. INTERVENTION: Subjects completed questionnaires to evaluate the presence of features of neuropathic-like pain (painDETECT) and the impact on sleep quality (Pittsburgh Sleep Quality Index) and mental health (Hospital Anxiety and Depression Scale). Descriptive statistics were used to characterize the prevalence and associated burden of neuropathic-like pain. MAIN OUTCOME MEASURES: Incidence of neuropathic, nociceptive, and unclear pain. RESULTS: Of 249 participants, one third experienced neuropathic-like pain. This group had statistically significantly (Pâ <â 0.001) worse mental well-being and sleep in comparison to those with predominately nociceptive pain. CONCLUSIONS: Neuropathic-like pain is common in patients with FD/MAS and associated with worse quality of life. Evaluation of pain in patients with FD/MAS should include assessment of neuropathic-like pain to guide personalized approaches to treatment and inform future research.
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Displasia Fibrosa Óssea , Displasia Fibrosa Poliostótica , Doenças do Sistema Nervoso Periférico , Adulto , Displasia Fibrosa Poliostótica/complicações , Displasia Fibrosa Poliostótica/tratamento farmacológico , Displasia Fibrosa Poliostótica/epidemiologia , Humanos , Dor/epidemiologia , Dor/etiologia , Qualidade de Vida , Estudos RetrospectivosRESUMO
BACKGROUND: Osteogenesis imperfecta, fibrous dysplasia/McCune-Albright syndrome and X-linked hypophosphatemia are three rare musculoskeletal diseases characterised by bone deformities, frequent fractures and pain. Little high-quality research exists on appropriate treatment and long-term management of these conditions in adults. This is further worsened by limited research funding in rare diseases and a general mismatch between the existing research priorities and those of the patients. This partnership adopted the James Lind Alliance approach to identify the top 10 research priorities for rare musculoskeletal diseases in adults through joint patient, carer and healthcare professional collaboration. RESULTS: The initial survey for question collection recruited 198 respondents, submitting a total of 988 questions. 77% of the respondents were patients with a rare musculoskeletal disease. Following out-of-scope question exclusion, repeating query grouping and scientific literature check for answers, 39 questions on treatment and long-term management remained. In the second public survey, 220 respondents, of whom 85% were patients with a rare musculoskeletal disease, their carers, relatives or friends, prioritised these uncertainties, which allowed selection of the top 25. In the last stage, patients, carers and healthcare professionals gathered for a priority setting workshop to reach a consensus on the final top 10 research priorities. These focus on the uncertainties surrounding appropriate treatment and holistic long-term disease management, highlighting several aspects indirect to abnormal bone metabolism, such as extra-skeletal symptoms, psychological care of both patients and their families and disease course through ageing. CONCLUSIONS: This James Lind Alliance priority setting partnership is the first to investigate rare bone diseases. The priorities identified here were developed jointly by patients, carers and healthcare professionals. We encourage researchers, funding bodies and other stakeholders to use these priorities in guiding future research for those affected by rare musculoskeletal disorders.
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Pesquisa Biomédica , Doenças Musculoesqueléticas , Adulto , Cuidadores , Prioridades em Saúde , Humanos , Doenças Musculoesqueléticas/terapia , Doenças Raras , PesquisaRESUMO
Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693 GG homozygotes actually had significantly worse BASDAI (mean 4.2, 95% CI: 4-4.5) than AA homozygotes (mean 3.8, 95% CI: 3.7-4) in both the unadjusted (difference = 0.4, p = 0.006) and adjusted analyses (difference = 0.2-0.5, p = 0.002-0.04 depending on the adjustment model). We found no evidence that rs1900693 predicted functional status (BASFI) or global disease scores (BAS-G), and it exerted no influence on either the intention to treat with or efficacy of anti-TNF treatment.
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Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Espondilite Anquilosante/genética , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Produtos Biológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/tratamento farmacológicoRESUMO
Osteoarthritis is a major cause of disability and there is no current pharmaceutical treatment which can prevent the disease or slow its progression. Dietary advice or supplementation is clearly an attractive option since it has low toxicity and ease of implementation on a population level. We have previously demonstrated that sulforaphane, a dietary isothiocyanate derived from its glucosinolate precursor which is found in broccoli, can prevent cartilage destruction in cells, in in vitro and in vivo models of osteoarthritis. As the next phase of this research, we enrolled 40 patients with knee osteoarthritis undergoing total knee replacement into a proof-of-principle trial. Patients were randomised to either a low or high glucosinolate diet for 14 days prior to surgery. We detected ITCs in the synovial fluid of the high glucosinolate group, but not the low glucosinolate group. This was mirrored by an increase in ITCs and specifically sulforaphane in the plasma. Proteomic analysis of synovial fluid showed significantly distinct profiles between groups with 125 differentially expressed proteins. The functional consequence of this diet will now be tested in a clinical trial.
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Biomarcadores/metabolismo , Brassica/efeitos adversos , Isotiocianatos/metabolismo , Articulação do Joelho/fisiopatologia , Osteoartrite do Joelho/etiologia , Líquido Sinovial/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , ProteômicaRESUMO
BACKGROUND: Health-related quality of life of adults with osteogenesis imperfecta (OI), fibrous dysplasia (FD) and X-linked hypophosphatemia (XLH) remains poorly described. The aim of this study was to describe the HRQoL of adults with osteogenesis imperfecta, fibrous dysplasia and X-linked hypophophataemia and perform a cost-utility simulation to calculate the maximum cost that a health care system would be willing to pay for a hypothetical treatment of a rare bone disease. RESULTS: Participants completed the EQ-5D-5 L questionnaire between September 2014 and March 2016. For the economic simulation, we considered a hypothetical treatment that would be applied to OI participants in the lower tertile of the health utility score. A total of 109 study participants fully completed the EQ-5D-5 L questionnaire (response rate 63%). Pain/discomfort was the most problematic domain for participants with all three diseases (FD 31%, XLH 25%, OI 16%). The economic simulation identified an expected treatment impact of +2.5 QALYs gained per person during the 10-year period, which led to a willing to pay of £14,355 annually for a health care system willing to pay up to £50,000 for each additional QALY gained by an intervention. CONCLUSIONS: This is the first study to quantitatively measure and compare the HRQoL of adults with OI, FD and XLH and the first to use such data to conduct an economic simulation leading to healthcare system willingness-to-pay estimates for treatment of musculoskeletal rare diseases at various cost-effectiveness thresholds.
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Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Displasia Fibrosa Poliostótica/fisiopatologia , Osteogênese Imperfeita/fisiopatologia , Qualidade de Vida , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido , Adulto JovemRESUMO
Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10-anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the thioesterase (TE) domain of FASN. Inhibition of recombinant TE activity, inhibition of cellular FASN, and cytotoxicity in human prostate cancer cell lines and normal fibroblasts, is shown for the most potent inhibitors. Collectively, the data illustrate the novel inhibitory capacity of the 1,4-quinone and 9,10-anthraquinone pharmacophores against FASN.
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Esterases/antagonistas & inibidores , Ácido Graxo Sintases/antagonistas & inibidores , Compostos de Sulfidrila/química , Esterases/química , Esterases/metabolismo , Ácido Graxo Sintases/metabolismo , HumanosRESUMO
"Each year over 25,000 people die from Venous Thromboembolism (VTE) contracted in hospital. This is more than the combined total of deaths from breast cancer, AIDS and traffic accidents". (1) Orthopaedic patients are at particular risk of VTE. In 2011, the project team carried out an audit into compliance with national VTE assessment guidelines on all acute trauma and orthopaedic admissions during a two week period at a District General Hospital. The study demonstrated that compliance was initially low, but showed a large improvement following the implementation of simple measures. The measures included: asking consultants to remind junior doctors, putting posters up in the trauma doctors office, asking nursing staff to check for a VTE assessment on admission to the ward, and putting reminders on the patient name board. The project team subsequently recommended an alteration to the hospital's computer system to incorporate a check of VTE assessment and prophylaxis. A second assessment using the same methodology sought to assess whether the previous improvements were sustained and the impact of this computer system alteration. Overall, compliance with national VTE guidance improved further.
RESUMO
Positron emission tomography (PET) is a molecular imaging modality that provides the opportunity to rapidly and non-invasively visualize tumors derived from multiple organs. In order to do so, PET utilizes radiotracers, such as ¹8F-FDG and ¹¹C-acetate, whose uptake coincides with altered metabolic pathways within tumors. Increased expression and activity of enzymes in the fatty acid synthesis pathway is a frequent hallmark of cancer cells. As a result, this pathway has become a prime target for therapeutic intervention. Although multiple drugs have been developed that both directly and indirectly interfere with fatty acid synthesis, an optimal means to assess their efficacy is lacking. Given that ¹¹Cacetate is directly linked to the fatty acid synthesis pathway, this probe provides a unique opportunity to monitor lipogenic tumors by PET. Herein, we review the relevance of the fatty acid synthesis pathway in cancer. Furthermore, we address the potential utility of ¹¹C-acetate PET in imaging tumors, especially those that are not FDG-avid. Last, we discuss several therapeutic interventions that could benefit from ¹¹C-acetate PET to monitor therapeutic response in patients with certain types of cancers.
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Ácidos Graxos/metabolismo , Neoplasias/metabolismo , Ácido Acético , Isótopos de Carbono , Ácido Graxo Sintases/metabolismo , Humanos , Neoplasias/diagnóstico , Tomografia por Emissão de PósitronsRESUMO
The activation of protein kinases is one of the primary mechanisms whereby T cell receptors (TCR) propagate intracellular signals. To date, the majority of kinases known to be involved in the early stages of TCR signaling are protein-tyrosine kinases such as Lck, Fyn, and ZAP-70. Here we report a constitutive association between the TCR and a serine/threonine kinase, which was mediated through the membrane-proximal portion of CD3 epsilon. Mass spectrometry analysis of CD3 epsilon-associated proteins identified G protein-coupled receptor kinase 2 (GRK2) as a candidate Ser/Thr kinase. Transient transfection assays and Western blot analysis verified the ability of GRK2 to interact with the cytoplasmic domain of CD3 epsilon within a cell. These findings are consistent with recent reports demonstrating the ability of certain G protein-coupled receptors (GPCR) and G proteins to physically associate with the alpha/beta TCR. Because GRK2 is primarily involved in arresting GPCR signals, its interaction with CD3 epsilon may provide a novel means whereby the TCR can negatively regulate signals generated through GPCRs.