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Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identified Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs. Elevated ß-catenin and JunD level in CRC facilitates chromatin interaction between hTERT promoter and T-INT2 that is necessary to turn on hTERTexpression. Pharmacological screens uncovered salinomycin, which inhibits JunD mediated hTERT-T-INT2 interaction that is required for the formation of a stable transcription complex on the hTERT promoter. Our results showed for the first time how known CRC alterations, such as APC, lead to WT-hTERT promoter reactivation during stepwise-tumorigenesis and provide a new perspective for developing cancer-specific drugs.
Healthy and cancer cells harbor the same DNA sequence, but reactivation of the Human Telomerase Reverse Transcriptase (hTERT) gene is observed only in cancer cells. How does that happen was not known for over three decades of research? This study identifies a specific DNA structure that forms only in cancer cells and brings the necessary molecular machinery into the correct position to activate the hTERT gene. The detailed mechanism of hTERT activation provided in this study will be instrumental in designing cancer cell-specific hTERT inhibitors, especially since all the other ways of inhibiting telomerase failed in the clinic.
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Neoplasias Colorretais , Telomerase , Humanos , Carcinogênese , Cromatina/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Regiões Promotoras Genéticas , Telomerase/antagonistas & inibidores , Telomerase/genética , Transcrição GênicaRESUMO
BACKGROUND: The TANDEM multicentre, pragmatic, randomised controlled trial evaluated whether a tailored psychological intervention based on a cognitive behavioural approach for people with COPD and symptoms of anxiety and/or depression improved anxiety or depression compared with usual care (control). METHODS: People with COPD and moderate to very severe airways obstruction and Hospital Anxiety and Depression Scale subscale scores indicating mild to moderate anxiety (HADS-A) and/or depression (HADS-D) were randomised 1.25:1 (242 intervention and 181 control). Respiratory health professionals delivered the intervention face-to-face over 6-8â weeks. Co-primary outcomes were HADS-A and HADS-D measured 6â months post-randomisation. Secondary outcomes at 6 and 12â months included: HADS-A and HADS-D (12â months), Beck Depression Inventory II, Beck Anxiety Inventory, St George's Respiratory Questionnaire, social engagement, the EuroQol instrument five-level version (EQ-5D-5L), smoking status, completion of pulmonary rehabilitation, and health and social care resource use. RESULTS: The intervention did not improve anxiety (HADS-A mean difference -0.60, 95% CI -1.40-0.21) or depression (HADS-D mean difference -0.66, 95% CI -1.39-0.07) at 6â months. The intervention did not improve any secondary outcomes at either time-point, nor did it influence completion of pulmonary rehabilitation or healthcare resource use. Deaths in the intervention arm (13/242; 5%) exceeded those in the control arm (3/181; 2%), but none were associated with the intervention. Health economic analysis found the intervention highly unlikely to be cost-effective. CONCLUSION: This trial has shown, beyond reasonable doubt, that this cognitive behavioural intervention delivered by trained and supervised respiratory health professionals does not improve psychological comorbidity in people with advanced COPD and depression or anxiety.
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Depressão , Doença Pulmonar Obstrutiva Crônica , Humanos , Depressão/terapia , Intervenção Psicossocial , Ansiedade/terapia , Transtornos de Ansiedade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/terapia , Qualidade de VidaRESUMO
Reactivation of telomerase is a major hallmark observed in 90% of all cancers. Yet paradoxically, enhanced telomerase activity does not correlate with telomere length and cancers often possess short telomeres; suggestive of supplementary non-canonical roles that telomerase might play in the development of cancer. Moreover, studies have shown that aberrant expression of shelterin proteins coupled with their release from shortening telomeres can further promote cancer by mechanisms independent of their telomeric role. While targeting telomerase activity appears to be an attractive therapeutic option, this approach has failed in clinical trials due to undesirable cytotoxic effects on stem cells. To circumvent this concern, an alternative strategy could be to target the molecules involved in the non-canonical functions of telomeric proteins. In this review, we will focus on emerging evidence that has demonstrated the non-canonical roles of telomeric proteins and their impact on tumorigenesis. Furthermore, we aim to address current knowledge gaps in telomeric protein functions and propose future research approaches that can be undertaken to achieve this.
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Neoplasias/patologia , Proteínas de Ligação a Telômeros/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Disceratose Congênita/genética , Disceratose Congênita/patologia , Humanos , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Ribonucleoproteínas Nucleolares Pequenas/genética , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo , Proteínas de Ligação a Telômeros/química , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .
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Pré-Eclâmpsia/diagnóstico , Complicações na Gravidez/diagnóstico , Feminino , Humanos , Gravidez , Prognóstico , Reprodutibilidade dos Testes , Projetos de Pesquisa , Medição de RiscoRESUMO
Existing assays of social interaction are suboptimal, and none measures propinquity, the tendency of rodents to maintain close physical proximity. These assays are ubiquitously performed using inbred mouse strains and mutations placed on inbred genetic backgrounds. We developed the automatable tube cooccupancy test (TCOT) based on propinquity, the tendency of freely mobile rodents to maintain close physical proximity, and assessed TCOT behavior on a variety of genotypes and social and environmental conditions. In outbred mice and rats, familiarity determined willingness to cooccupy the tube, with siblings and/or cagemates of both sexes exhibiting higher cooccupancy behavior than strangers. Subsequent testing using multiple genotypes revealed that inbred strain siblings do not cooccupy at higher rates than strangers, in marked contrast to both outbred and rederived wild mice. Mutant mouse strains with "autistic-like" phenotypes (Fmr1-/y and Eif4e Ser209Ala) displayed significantly decreased cooccupancy.
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Endogamia , Comportamento Social , Animais , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos , Ratos Sprague-Dawley , Estresse PsicológicoRESUMO
Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow progressing and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy.
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Neurônios Dopaminérgicos/transplante , Doença de Parkinson/metabolismo , Doença de Parkinson/cirurgia , Putamen/cirurgia , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Doença de Parkinson/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
PURPOSE: PARP4 has been proposed as a candidate breast cancer susceptibility gene. However, its function and involvement in breast carcinogenesis is unclear. We sought to determine the variant frequency of PARP4 in BRCA-negative women referred for genetic testing from Singapore and to perform functional analyses of PARP4. METHODS: Next-generation sequencing of PARP4 was conducted for 198 BRCA-negative cases from Singapore. Three independent case-control association analyses of PARP4 were performed for (1) our Singaporean cohort, (2) three dbGaP datasets, and (3) cases from TCGA, with controls from the Exome Aggregation Consortium (ExAC). PARP4 knockout cells were generated utilizing the CRISPR-Cas9 approach in MDA-MB-231 (breast cancer) and MCF10A (normal breast) cell lines, and colony formation, cell proliferation, and migration assays carried out. RESULTS: Candidate variants in PARP4 were identified in 5.5% (11/198) of our Singapore cohort. Case-control association studies for our cases and the dbGaP datasets showed no significant association. However, a significant association was observed for PARP4 variants when comparing 988 breast cancer cases from the TCGA provisional data and 53,105 controls from ExAC (ALL) (OR 0.249, 95% CI 0.139-0.414, P = 2.86 × 10-11). PARP4 knockout did not affect the clonogenicity, proliferation rate, and migration of normal breast cells, but appeared to decrease the proliferation rate and clonogenicity of breast cancer cells. CONCLUSIONS: Taken together, our results do not support that PARP4 functions as a cancer susceptibility gene. This study highlights the importance of performing functional analyses for candidate cancer predisposition genes.
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Biomarcadores Tumorais , Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional , Feminino , Técnicas de Silenciamento de Genes , Estudos de Associação Genética/métodos , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Medição de Risco , Fatores de Risco , Singapura , Ensaio Tumoral de Célula-Tronco , Adulto JovemRESUMO
PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data. METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry. RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent. CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.
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Genes da Neurofibromatose 1 , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Adulto , Idoso , Biomarcadores Tumorais , Análise Mutacional de DNA , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Neurofibromatose 1/epidemiologia , Neurofibromatose 1/mortalidadeRESUMO
BACKGROUND: There is a lack of research in forensic settings examining therapeutic relationships. A structured communication approach, placing patients' perspectives at the heart of discussions about their care, was used to improve patients' quality of life in secure settings. The objectives were to: ⢠Establish the feasibility of the trial design ⢠Determine the variability of the outcomes of interest ⢠Estimate the costs of the intervention ⢠If necessary, refine the intervention METHODS: A pilot cluster randomised controlled trial was conducted. Data was collected from July 2012 to January 2015 from participants in 6 medium secure in-patient services in London and Southern England. 55 patients and 47 nurses were in the intervention group with 57 patients and 45 nurses in the control group. The intervention comprised 6 nurse-patient meetings over a 6 month period. Patients rated their satisfaction with a range of domains followed by discussions on improving patient identified problems. Assessments took place at baseline, 6 months, and 12 months. Participants were not blind to their allocated group. The primary outcome was self-reported quality of life collected by a researcher blind to participants' allocation status. RESULTS: The randomisation procedures and intervention approach functioned well. The measures used were understood by the participants and gave relevant outcome information. The response rates were good with low patient withdrawal rates. The quality of life estimated treatment effect was 0.2 (95 % CI: -0.4 to 0.8) at 6 months and 0.4 (95 % CI: -0.3 to 1.1) indicating the likely extreme boundaries of effect in the main trial. The estimated treatment effect of the primary outcome is clinically important, and a positive effect of the intervention is not ruled out. The estimate of the ICC for the primary outcome at 6 and 12 months was 0.04 (0.00 to 0.17) and 0.05 (0.00 to 0.18). The cost of the intervention was £529 per patient. CONCLUSIONS: The trial design was viable as the basis for a full-scale trial. A full trial is justified to estimate the effect of the intervention with greater certainty. The variability of the outcomes could be used to calculate numbers needed for a full-scale trial. Ratings of need for therapeutic security may be useful in any future study. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34145189 . Retrospectively registered 22 June 2012.
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OBJECTIVE: To describe the first reported case of bacteremia and empyema caused by Shewanella algae and summarize the existing literature on Shewanella human infection. CASE SUMMARY: A 25-year-old healthy male was shot through the chest into the abdomen and fled into an adjacent body of seawater. He underwent surgical repair of his injuries, including pleural decortication. Leukocytosis, bandemia, and copious yellow bronchorrhea led to cultures; piperacillin/tazobactam and vancomycin were started for broad-spectrum empiric management based on the local intensive care unit antibiogram. Blood and pleural fluid cultures revealed S algae. Sputum cultures grew methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. He was successfully managed with an empiric and then tailored antibiotic regimen. DISCUSSION: Shewanella algae is a rare Gram-negative bacillus that has infrequently been reported to cause infection. It is found predominantly in men. Shewanella algae infections span bacteremia to necrotizing soft tissue infection and are associated with injury and seawater exposure. Shewanella is susceptible to the majority of third- and fourth-generation cephalosporins, aminoglycosides, chloramphenicol, erythromycin, aztreonam, and fluoroquinolones, but are less predictably susceptible to tetracycline and trimethoprim/sulfamethoxazole and carbapenem agents. Shewanella infection is associated with medical comorbidities, in particular, renal failure and cardiovascular disease. CONCLUSIONS: To our knowledge, this is the first case report of bacteremia and empyema caused by S algae. Such a case involving a young healthy individual should encourage health care providers to be aware of the potential infections caused by unusual pathogens, and to employ appropriate empiric antibiotic therapy based on reported sensitivity profiles. Based on available susceptibilities, we recommend using a third or fourth-generation cephalosporin as first-line pharmacologic management with regimen de-escalation based on culture-derived data.
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Bacteriemia/microbiologia , Empiema Pleural/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Shewanella , Adulto , Bacteriemia/tratamento farmacológico , Cefalosporinas/uso terapêutico , Empiema Pleural/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Lesão Pulmonar , Masculino , Ferimentos por Arma de FogoRESUMO
Background: People with chronic obstructive pulmonary disease have high levels of anxiety and depression, which is associated with increased morbidity and poor uptake of effective treatments, such as pulmonary rehabilitation. Cognitive-behavioural therapy improves mental health of people with long-term conditions and could potentially increase uptake of pulmonary rehabilitation, enabling synergies that could enhance the mental health of people with chronic obstructive pulmonary disease. Aim: Our aim was to develop and evaluate the clinical effectiveness and cost effectiveness of a tailored cognitive-behavioural approach intervention, which links into, and optimises the benefits of, routine pulmonary rehabilitation. Design: We carried out a pragmatic multicentre randomised controlled trial using a 1.25 : 1 ratio (intervention : control) with a parallel process evaluation, including assessment of fidelity. Setting: Twelve NHS trusts and five Clinical Commissioning Groups in England were recruited into the study. The intervention was delivered in participant's own home or at a local NHS facility, and by telephone. Participants: Between July 2017 and March 2020 we recruited adults with moderate/very severe chronic obstructive pulmonary disease and mild/moderate anxiety and/or depression, meeting eligibility criteria for assessment for pulmonary rehabilitation. Carers of participants were invited to participate. Intervention: The cognitive-behavioural approach intervention (i.e. six to eight 40- to 60-minute sessions plus telephone support throughout pulmonary rehabilitation) was delivered by 31 trained respiratory healthcare professionals to participants prior to commencing pulmonary rehabilitation. Usual care included routine pulmonary rehabilitation referral. Main outcome measures: Co-primary outcomes were Hospital Anxiety and Depression Scale - anxiety and Hospital Anxiety and Depression Scale - depression at 6 months post randomisation. Secondary outcomes at 6 and 12 months included health-related quality of life, smoking status, uptake of pulmonary rehabilitation and healthcare use. Results: We analysed results from 423 randomised participants (intervention, n = 242; control, n = 181). Forty-three carers participated. Follow-up at 6 and 12 months was 93% and 82%, respectively. Despite good fidelity for intervention delivery, mean between-group differences in Hospital Anxiety and Depression Scale at 6 months ruled out clinically important effects (Hospital Anxiety and Depression Scale - anxiety mean difference -0.60, 95% confidence interval -1.40 to 0.21; Hospital Anxiety and Depression Scale - depression mean difference -0.66, 95% confidence interval -1.39 to 0.07), with similar results at 12 months. There were no between-group differences in any of the secondary outcomes. Sensitivity analyses did not alter these conclusions. More adverse events were reported for intervention participants than for control participants, but none related to the trial. The intervention did not generate quality-of-life improvements to justify the additional cost (adjusted mean difference £770.24, 95% confidence interval -£27.91 to £1568.39) to the NHS. The intervention was well received and many participants described positive affects on their quality of life. Facilitators highlighted the complexity of participants' lives and considered the intervention to be of potential valuable; however, the intervention would be difficult to integrate within routine clinical services. Our well-powered trial delivered a theoretically designed intervention with good fidelity. The respiratory-experienced facilitators were trained to deliver a low-intensity cognitive-behavioural approach intervention, but high-intensity cognitive-behavioural therapy might have been more effective. Our broad inclusion criteria specified objectively assessed anxiety and/or depression, but participants were likely to favour talking therapies. Randomisation was concealed and blinding of outcome assessment was breached in only 15 participants. Conclusions: The tailored cognitive-behavioural approach intervention delivered with fidelity by trained respiratory healthcare professionals to people with chronic obstructive pulmonary disease was neither clinically effective nor cost-effective. Alternative approaches that are integrated with routine long-term condition care are needed to address the unmet, complex clinical and psychosocial needs of this group of patients. Trial registration: This trial is registered as ISRCTN59537391. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/146/02) and is published in full in Health Technology Assessment; Vol. 28, No. 1. See the NIHR Funding and Awards website for further award information.
People with long-standing lung problems, such as chronic obstructive pulmonary disease, often also have anxiety and depression, which further reduces their quality of life. Two existing treatments could help. Pulmonary rehabilitation (a programme of exercise and education) improves both the physical and mental health of people with chronic obstructive pulmonary disease. Cognitivebehavioural therapy (a talking therapy) may reduce anxiety and depression. The TANDEM [Tailored intervention for Anxiety and Depression Management in chronic obstructive pulmonary disease (COPD)] intervention linked these two treatments by providing talking therapy based on cognitivebehavioural therapy during the waiting time following referral for pulmonary rehabilitation. The TANDEM treatment was delivered by respiratory healthcare professionals (e.g. nurses or physiotherapists) trained to deliver the talking therapy in six to eight weekly sessions. The sessions were conducted in the participant's home (or another convenient location), with brief telephone support during the pulmonary rehabilitation. Of 423 participants recruited to the study, 242 participants received TANDEM talking therapy and 181 participants received usual care (including a referral to pulmonary rehabilitation). We measured mental health, quality of life, social life, attendance at pulmonary rehabilitation and healthcare use in both groups at 6 and 12 months. Forty-three carers joined the study and we assessed their mental well-being. We interviewed patients, carers and health professionals to find out their views and experience of the TANDEM treatment. We also examined whether or not the TANDEM treatment was good value for money. The TANDEM treatment did not improve the mental or the physical health of people with chronic obstructive pulmonary disease. In addition, the TANDEM treatment cost the NHS an extra £770 per patient, which was not good value for money. The TANDEM treatment was well received, and many participants told us how it had helped them. Heath-care professionals noted how participants did not just have chronic obstructive pulmonary disease, but were coping with many physical, mental and social problems. The TANDEM intervention was not effective and, therefore, other strategies will be needed to help people with chronic obstructive pulmonary disease and mental health problems live with their condition.
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Depressão , Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Depressão/terapia , Qualidade de Vida , Intervenção Psicossocial , Ansiedade/terapia , Doença Pulmonar Obstrutiva Crônica/terapia , Análise Custo-BenefícioRESUMO
In 2016, we published a conceptual framework outlining the conclusions of our work in defining pilot and feasibility studies. Since then, the CONSORT extension to randomised pilot and feasibility trials has been published and there have been further developments in the pilot study landscape. In this paper, we revisit and extend our framework to incorporate the various feasibility pathways open to researchers, which include internal pilot studies. We consider, with examples, when different approaches to feasibility and pilot studies are more effective and efficient, taking into account the pragmatic decisions that may need to be made. The ethical issues involved in pilot studies are discussed. We end with a consideration of the funders' perspective in making difficult resource decisions to include feasibility work and the policy implications of these; throughout, we provide examples of the uncertainties and compromises that researchers have to navigate to make progress in the most efficient way.
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Individuals with autism spectrum disorder (ASD) have altered sensory processing but may ineffectively communicate their experiences. Here, we used a battery of nociceptive behavioral tests to assess sensory alterations in two commonly used mouse models of ASD, BTBR T+ Itpr3tf /J (BTBR), and fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also asked whether emotional contagion, a primitive form of empathy, was altered in BTBR and Fmr1 KO mice when experiencing pain with a social partner. BTBR mice demonstrated mixed nociceptive responses with hyporesponsivity to mechanical/thermal stimuli and intraplantar injections of formalin and capsaicin while displaying hypersensitivity on the acetic acid test. Fmr1-KO mice were hyposensitive to mechanical stimuli and intraplantar injections of capsaicin and formalin. BTBR and Fmr1-KO mice developed significantly less mechanical allodynia following intraplantar injections of complete Freund's adjuvant, while BTBR mice developed slightly more thermal hyperalgesia. Finally, as measured by the formalin and acetic acid writhing tests, BTBR and Fmr1-KO mice did not show emotional contagion of pain. In sum, our findings indicate that depending on the sensation, pain responses may be mixed, which reflects findings in ASD individuals.
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Comunicação Animal , Transtorno Autístico/fisiopatologia , Nociceptividade , Percepção da Dor , Animais , Transtorno Autístico/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND OBJECTIVE: Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be designed with either a pragmatic or explanatory mindset. Whereas pragmatic trials aim to inform the choice between different care options and thus, are designed to resemble conditions outside of a clinical trial environment, explanatory trials examine the benefit of a treatment under more controlled conditions. There is existing guidance for designing feasibility studies, but none that explicitly considers the goals of pragmatic designs. We aimed to identify unique areas of uncertainty that are relevant to planning a pragmatic trial. RESULTS: We identified ten relevant domains, partly based on the pragmatic-explanatory continuum indicator summary-2 (PRECIS-2) framework, and describe potential questions of uncertainty within each: intervention development, research ethics, participant identification and eligibility, recruitment of individuals, setting, organization, flexibility of delivery, flexibility of adherence, follow-up, and importance of primary outcome to patients and decision-makers. We present examples to illustrate how uncertainty in these domains might be addressed within a feasibility study. CONCLUSION: Researchers planning a feasibility study in advance of a pragmatic trial should consider feasibility objectives specifically relevant to areas of uncertainty for pragmatic trials.
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Pesquisa Biomédica/estatística & dados numéricos , Pesquisa Biomédica/normas , Ensaios Clínicos Pragmáticos como Assunto/estatística & dados numéricos , Ensaios Clínicos Pragmáticos como Assunto/normas , Projetos de Pesquisa/estatística & dados numéricos , Projetos de Pesquisa/normas , Incerteza , Estudos de Viabilidade , Guias como Assunto , Humanos , Projetos PilotoRESUMO
BACKGROUND: Pilot and feasibility studies (PAFS) often have complex objectives aimed at assessing feasibility of conducting a larger study. These may not be clear to participants in pilot studies. METHODS: Here, we aimed to assess the transparency of informed consent in PAFS by investigating whether researchers communicate, through patient information leaflets and consent forms, key features of the studies. We collected this data from original versions of these documents submitted for ethics approval and the final approved documents for PAFS submitted to the Hamilton Integrated Research Ethics Board, Canada. RESULTS: One hundred eighty-four PAFS, submitted for ethics approval from 2004 to 2020, were included, and we found that of the approved consent documents which were provided to participants, 83.2% (153) stated the terms "pilot" or "feasibility" in their title, 12% (22) stated the definition of a pilot/feasibility study, 42.4% (78) of the studies stated their intent to assess feasibility, 19.6% (36) stated the specific feasibility objectives, 1.6% (3) stated the criteria for success of the pilot study, and 0.5% (1) stated all five of these criteria. After ethics review, a small increase in transparency occurred, ranging from 1.6 to 2.8% depending on the criteria. By extracting data from the protocols of the PAFS, we found that 73.9% (136) stated intent to assess feasibility, 71.2% (131) stated specific feasibility objectives, and 33.7% (62) stated criteria for success of the study to lead to a larger study. CONCLUSION: The transparency of informed consent in PAFS is inadequate and needs to be specifically addressed by research ethics guidelines. Research ethics boards and researchers ought to be made aware and mindful of best practices of informed consent in the context of PAFS.
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BACKGROUND: The aim of the TANDEM trial is to evaluate whether a tailored, psychological cognitive behavioural approach intervention, which links into, and optimises the effects of routine pulmonary rehabilitation (PR), leads to a reduction in mild/moderate anxiety and/or depression in people with moderate, severe or very severe chronic obstructive pulmonary disease. METHODS AND DESIGN: TANDEM is a multi-centre, two-arm, parallel group, pragmatic, individually randomised controlled, superiority trial including an internal pilot. Participants are randomised to receive either the intervention (a tailored psychological intervention plus usual care including referral to PR) or the control (usual care including referral to PR). The designed randomisation ratio is 1.25:1 in favour of the intervention. The multiple-primary outcomes are participant depression and anxiety at 6 months, measured using the Hospital Anxiety and Depression Scale (HADS) depression and anxiety subscales. RESULTS: This article describes the statistical analysis plan (SAP) for the TANDEM trial. In particular, we describe the general analysis principles, how we will handle missing data, the primary and secondary outcomes and how these will be analysed, sensitivity analyses for the multiple-primary outcomes, and any other analyses and data summaries. The SAP was developed and published prior to completion of follow-up of the last participant. TRIAL REGISTRATION: ISRCTN registry ISRCTN59537391. Registered on 20 March 2017.
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Depressão , Doença Pulmonar Obstrutiva Crônica , Ansiedade/diagnóstico , Ansiedade/terapia , Análise Custo-Benefício , Depressão/diagnóstico , Depressão/terapia , Humanos , Intervenção Psicossocial , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Qualidade de VidaRESUMO
BACKGROUND: Congenital cytomegalovirus (CCMV) accounts for high rates of infant morbidity and mortality. Neutropenia is a common finding in CCMV infection, of which the age of presentation overlaps with autoimmune neutropenia (AIN). AIN represents one of the most common forms of chronic neutropenia in childhood. METHODS: A literature search exploring biologic associations between CCMV and AIN was conducted: PubMed (MEDLINE), Ovid and Web of Science. We further describe 2 cases of concurrent CCMV and AIN. Both cases were confirmed with the indirect granulocyte immunofluorescence test and alternative etiologies for neutropenia excluded. RESULTS: Our 2 patients represent confirmed cases of AIN in infants with CCMV. One patient demonstrated neutropenia while undergoing treatment with Valganciclovir, while the other was never treated. With interruption of Valganciclovir in infant A, neutrophil counts (ANC) did not improve and upon resumption of treatment ANC remained static. CONCLUSIONS: Further studies examining a possible biologic link between CCMV and AIN are advocated for. We encourage clinicians to actively consider AIN in the differential diagnosis of all infants with CCMV presenting with neutropenia.
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Doenças Autoimunes/etiologia , Infecções por Citomegalovirus/congênito , Neutropenia/etiologia , Anticorpos/imunologia , Infecções por Citomegalovirus/complicações , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Troca Materno-Fetal/imunologia , Neutropenia/imunologia , Neutrófilos/imunologia , GravidezRESUMO
BACKGROUND: The evidence shows that WAT-based interventions enhance the physical activity (PA) levels of young people by sustainably delivering behavior change techniques (BCTs). These results may not be replicable among older adults. This paper aims to evaluate the effectiveness of WAT-based interventions in improving PA levels in sedentary older adults. METHODS: Eight electronic databases were searched for randomized controlled trials published January 2008 to December 2018. BCTs delivered by WAT aimed at increasing PA levels using step counts or time spent on moderate-to-vigorous (MVPA) exercise as an outcome were eligible for inclusion. RESULTS: In nine out of the ten included studies, higher PA levels were seen in the intervention group than in the control group. One study where the participants' mean age was 80+ showed no significant increase in PA levels. Significant effects were also demonstrated from the meta-analysis, which included four studies using a passive control (i.e., the usual care or health information) on step counts (n = 207, Hedges g = 1.27, 95 % CI = 0.51-2.04, p = 0.001) and two studies on MVPA (n = 83, Hedge's g = 1.23, 95 % CI = 0.75-1.70, p < 0.001). A non-significant effect was found on step counts (n = 201, Hedge's g = 0.22, 95 % CI = -0.62 to 1.06, p = 0.61) in three studies that used an active control comparison group (i.e., traditional pedometer). CONCLUSIONS: A WAT-based intervention is effective at improving PA levels among older adults over the short term when compared with the usual care or health information. However, when compared with a traditional pedometer or when used among old-old adults, the results were inconclusive.
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INTRODUCTION: Pilot/feasibility studies assess the feasibility of conducting a larger study. Although researchers ought to communicate the feasibility objectives to their participants, many research ethics guidelines do not comment on how informed consent applies to pilot studies. It is unclear whether researchers and research ethics boards clearly communicate the purpose of pilot studies to participants consenting.The primary objective of this study is to assess whether pilot/feasibility studies submitted for ethics approval to a research ethics board transparently communicate the purpose of the study to participants through their informed consent practice. A highly transparent consent practice entails the consent documents communicate: (1) the term 'pilot' or 'feasibility' in the title; (2) the definition of a pilot/feasibility study; (3) the primary objectives of the study are to assess feasibility; (4) the specific feasibility objectives; and (5) the criteria for the study to successfully lead to the main study. The secondary objectives are to assess whether there is a difference between submitted and revised versions of the consent documents (revisions are made to obtain research ethics approval), to determine factors associated with transparent consent practices and to assess the consistency with which pilot and feasibility studies assess feasibility outcomes as their primary objectives. METHODS AND ANALYSIS: This is a retrospective review of informed consent information for pilot/feasibility studies submitted to the Hamilton integrated Research Ethics Board, Canada. We will look at submitted and revised consent documents for pilot/feasibility studies submitted over a 14-year period. We will use descriptive statistics to summarise data, reporting results as percentages with 95% CIs, and conduct logistic regression to determine characteristics associated with transparent consent practices. ETHICS AND DISSEMINATION: The study protocol was approved by the Hamilton integrated Research Ethics Board, and the results of this study will be submitted for publication in a peer-reviewed journal.
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Consentimento Livre e Esclarecido/normas , Garantia da Qualidade dos Cuidados de Saúde , Estudos de Viabilidade , Humanos , Projetos Piloto , Estudos RetrospectivosRESUMO
BACKGROUND: People with chronic obstructive pulmonary disease (COPD) are at increased risk of depression and anxiety, which greatly reduces their quality of life and is associated with worse outcomes; but these psychological co-morbidities are under-recognised and undertreated in COPD patients. Pulmonary rehabilitation (PR) improves mood for up to 6 months but health practitioners under-refer, and patients commonly fail to attend/complete PR. Research suggests that complex non-pharmacological interventions, including both psychological and exercise components, may reduce anxiety and depression in COPD. We have developed a tailored, cognitive behavioural approach (CBA) intervention for patients with COPD and co-morbid anxiety and/or depression ('TANDEM'), which precedes and optimises the benefits of currently offered PR. We hypothesise that such a psychological intervention, delivered by supervised, trained respiratory healthcare professionals, will improve mood in patients with mild to moderate anxiety and/or depression and encourage uptake and completion of PR. METHODS: We will conduct a multi-centre, pragmatic, randomised controlled trial of the TANDEM intervention compared to usual care across the Midlands, London, the South East and Bristol, UK. We will train healthcare professionals familiar with COPD to deliver the manualised, tailored, face-to-face, one-to-one intervention weekly for 6-8 weeks. We will recruit 430 participants from primary, community and secondary care with confirmed COPD and moderate to very severe airflow limitation, who are eligible for assessment for PR, and who screen positive for symptoms of mild/moderate depression and/or anxiety using the Hospital Anxiety and Depression scale (HADS). Participants will be randomised 1.25:1 (intervention: usual care). The co-primary outcomes are the HADS anxiety and depression subscale scores at 6 months; participants will be followed up to 12 months. Secondary outcomes include uptake and completion of PR and healthcare resource use. There will be a parallel process evaluation and a health economic evaluation. DISCUSSION: The TANDEM intervention has the potential to optimise the unrealised synergy between a psychological intervention and PR. The CBA sessions will precede PR and target individuals' cognitions, behaviours and symptoms associated with anxiety and depression to decrease psychological morbidity and increase effective self-management amongst patients with COPD. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN59537391. Registered on 20 March 2017. Protocol version 6.0, 22 April 2018.