RESUMO
Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.
Assuntos
Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Mutação , Neoplasias Pancreáticas/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Education has been highlighted as fundamental in equipping healthcare professionals with essential knowledge and skills to provide good end-of-life care. Multiprofessional educational programmes have a positive influence on knowledge, attitude and confidence but few have sought to understand the longer term impact on care delivery. The European Certificate in Essential Palliative Care is an 8-week home-study-based programme for healthcare professionals and is currently run in nine centres. Successful candidates have undertaken the course from their own countries around the world. This article describes the evaluation of the European Certificate in Essential Palliative Care which has been evolving over 15 years. AIMS: To evaluate the impact an educational intervention has on participants' confidence in palliative care, to determine whether this is sustained over time and explore participants' perception of the influence of the course on confidence. DESIGN: A mixed-method longitudinal approach. SETTING/PARTICIPANTS: A survey using a self-efficacy scale was emailed to 342 candidates who received an educational intervention and semi-structured interviews to a sub-sample of 15 candidates at baseline, 3 and 6 months. RESULTS: At 3 months, candidates had almost 20 times higher odds of being above any given level of confidence than at baseline which was sustained at 6 months. Qualitative analysis identified examples of increased competence and confidence improving palliative care delivery. CONCLUSION: Findings suggest that the European Certificate in Essential Palliative Care improves confidence in palliative care and that this is sustained over time with evidence of confidence in symptom control, communication and a holistic approach in clinical practice.
Assuntos
Pessoal de Saúde/educação , Cuidados Paliativos , Autoeficácia , Assistência Terminal , Adulto , Feminino , Humanos , Entrevistas como Assunto , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
Importance: Eradication of systemic tuberculosis (TB) has been limited by neglected populations and the HIV pandemic. Whereas ocular TB often presents as uveitis without any prior evidence of systemic TB, the existing uncertainty in the diagnosis of TB uveitis may perpetuate missed opportunities to address systemic TB. Objective: To examine the clinical features of TB uveitis and the associations with response to antitubercular therapy (ATT). Design, Setting, and Participants: This retrospective multinational cohort study included patients from 25 ophthalmology referral centers diagnosed with TB uveitis and treated with ATT from January 1, 2004, through December 31, 2014, with a minimum follow-up of 1 year. Main Outcomes and Measures: Treatment failure, defined as a persistence or recurrence of inflammation within 6 months of completing ATT, inability to taper oral corticosteroids to less than 10 mg/d or topical corticosteroid drops to less than 2 drops daily, and/or recalcitrant inflammation necessitating corticosteroid-sparing immunosuppressive therapy. Results: A total of 801 patients (1272 eyes) were studied (mean [SD] age, 40.5 [14.8] years; 413 [51.6%] male and 388 [48.4%] female; 577 [73.6%] Asian). Most patients had no known history (498 of 661 [75.3%]) of systemic TB. Most patients had bilateral involvement (471 of 801 [58.8%]). Common clinical signs reported include vitreous haze (523 of 1153 [45.4%]), retinal vasculitis (374 of 874 [42.8%]), and choroidal involvement (419 of 651 [64.4%]). Treatment failure developed in 102 of the 801 patients (12.7%). On univariate regression analysis, the hazard ratios (HRs) associated with intermediate uveitis (HR, 2.21; 95% CI, 1.07-4.55; P = .03), anterior uveitis (HR, 2.68; 95% CI, 1.32-2.35; P = .006), and panuveitis (HR, 3.28; 95% CI, 1.89-5.67; P < .001) were significantly higher compared with posterior distribution. The presence of vitreous haze had a statistically significant association (HR, 1.95; 95% CI, 1.26-3.02; P = .003) compared with absence of vitreous haze. Bilaterality had an associated HR of 1.50 (95% CI, 0.96-2.35) compared with unilaterality (HR, 1 [reference]), although this finding was not statistically significant (P = .07). On multivariate Cox proportional hazards regression analysis, the presence of vitreous haze had an adjusted HR of 2.98 (95% CI, 1.50-5.94; P = .002), presence of snow banking had an adjusted HR of 3.71 (95% CI, 1.18-11.62; P = .02), and presence of choroidal involvement had an adjusted HR of 2.88 (95% CI, 1.22-6.78; P = .02). Conclusions and Relevance: A low treatment failure rate occurred in patients with TB uveitis treated with ATT. Phenotypes and test results are studied whereby patients with panuveitis having vitreous and choroidal involvement had a higher risk of treatment failure. These findings are limited by retrospective methods. A prospectively derived composite clinical risk score might address this diagnostic uncertainty through holistic and standardized assessment of the combinations of clinical features and investigation results that may warrant diagnosis of TB uveitis and treatment with ATT.
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Antituberculosos/uso terapêutico , Tuberculose Ocular/diagnóstico , Tuberculose Ocular/tratamento farmacológico , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento , Corpo Vítreo/patologiaRESUMO
BACKGROUND: To examine whether SMOFlipid prevents progression of intestinal failure-associated liver disease (IFALD) in parenteral nutrition (PN)-dependent infants with early IFALD (conjugated bilirubin 17-50 µmol/L, 1-3 mg/dL). STUDY DESIGN: Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin. RESULTS: Twenty-four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment ( P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, -59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups. CONCLUSIONS: Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.
Assuntos
Emulsões Gordurosas Intravenosas/uso terapêutico , Enteropatias/terapia , Hepatopatias/terapia , Fosfolipídeos/uso terapêutico , Óleo de Soja/uso terapêutico , Bilirrubina/sangue , Emulsões/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Enteropatias/complicações , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Hepatopatias/complicações , Masculino , Nutrição Parenteral Total , Projetos Piloto , Resultado do TratamentoRESUMO
OBJECTIVES: To test the feasibility of conducting a controlled trial into the effectiveness of a self-management programme integrated into stroke rehabilitation. DESIGN: A feasibility cluster-randomised design was utilised with stroke rehabilitation teams as units of randomisation. SETTING: Community-based stroke rehabilitation teams in London. PARTICIPANTS: 78 patients with a diagnosis of stroke requiring community based rehabilitation. INTERVENTION: The intervention consisted of an individualised approach to self-management based on self-efficacy. Clinicians were trained to integrate defined self-management principles into scheduled rehabilitation sessions, supported by a patient-held workbook. MAIN OUTCOMES MEASURES: Patient measures of quality of life, mood, self-efficacy and functional capacity, and health and social care utilisation, were carried out by blinded assessors at baseline, 6 weeks and 12 weeks. Fidelity and acceptability of the delivery were evaluated by observation and interviews. RESULTS: 4 community stroke rehabilitation teams were recruited, and received a total of 317 stroke referrals over 14 months. Of these, 138 met trial eligibility criteria and 78 participants were finally recruited (56.5%). Demographic and baseline outcome measures were similar between intervention and control arms, with the exception of age. All outcome measures were feasible to use and clinical data at 12 weeks were completed for 66/78 participants (85%; 95% CI 75% to 92%). There was no significant difference in any of the outcomes between the arms of the trial, but measures of functional capacity and self-efficacy showed responsiveness to the intervention. Observation and interview data confirmed acceptability and fidelity of delivery according to predetermined criteria. Costs varied by site. CONCLUSIONS: It was feasible to integrate a stroke self-management programme into community rehabilitation, using key principles. Some data were lost to follow-up, but overall results support the need for conducting further research in this area and provide data to support the design of a definitive trial. TRIAL REGISTRATION NUMBER: ISRCTN42534180.
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Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Autocuidado/métodos , Reabilitação do Acidente Vascular Cerebral , Afeto , Idoso , Análise por Conglomerados , Prestação Integrada de Cuidados de Saúde , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Qualidade de Vida , Autoeficácia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Pre-exposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate is used to prevent the sexual acquisition of HIV in groups at high risk such as transgender women. We used data from the iPrEx study to assess PrEP efficacy, effectiveness, and adherence in transgender women. METHODS: The iPrEx trial was a randomised controlled trial of PrEP with oral emtricitabine plus tenofovir disoproxil fumarate compared with placebo in men who have sex with men (MSM) and transgender women, followed by an open-label extension. Drug concentrations were measured in blood by liquid chromatography and tandem mass spectroscopy. We did unplanned exploratory analyses to investigate differences in PrEP outcomes among transgender women and between transgender women and MSM. FINDINGS: Of the 2499 participants enrolled in the randomised controlled trial, 29 (1%) identified as women, 296 (12%) identified as trans, 14 (1%) identified as men but reported use of feminising hormones, such that 339 (14%) reported one or more characteristics and are classified as transgender women for the purpose of this study. Compared with MSM, transgender women more frequently reported transactional sex, receptive anal intercourse without a condom, or more than five partners in the past 3 months. Among transgender women, there were 11 HIV infections in the PrEP group and ten in the placebo group (hazard ratio 1·1, 95% CI 0·5-2·7). In the PrEP group, drug was detected in none of the transgender women at the seroconversion visit, six (18%) of 33 seronegative transgender women (p=0·31), and 58 (52%) of 111 seronegative MSM (p<0·0001). PrEP use was not linked to behavioural indicators of HIV risk among transgender women, whereas MSM at highest risk were more adherent. INTERPRETATION: PrEP seems to be effective in preventing HIV acquisition in transgender women when taken, but there seem to be barriers to adherence, particularly among those at the most risk. Studies of PrEP use in transgender women populations should be designed and tailored specifically for this population, rather than adapted from or subsumed into studies of MSM. FUNDING: US National Institutes of Health and the Bill & Melinda Gates Foundation.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Preservativos/estatística & dados numéricos , Emtricitabina/administração & dosagem , Infecções por HIV/prevenção & controle , Adesão à Medicação/psicologia , Profilaxia Pré-Exposição , Tenofovir/administração & dosagem , Pessoas Transgênero , Adulto , Brasil/epidemiologia , Ensaios Clínicos Fase III como Assunto , Prestação Integrada de Cuidados de Saúde , Aconselhamento Diretivo/métodos , Equador/epidemiologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Homossexualidade Masculina , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Peru/epidemiologia , Parceiros Sexuais/psicologia , África do Sul/epidemiologia , Tailândia/epidemiologia , Pessoas Transgênero/psicologia , Estados Unidos/epidemiologiaRESUMO
PURPOSE: The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. PATIENTS AND METHODS: Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. RESULTS: Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P=.02, P<.001, and P=.05, respectively). However, the majority of the BRCA mutation-positive patients did not actually meet these genetic testing criteria. CONCLUSION: Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/genética , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/etnologia , Carcinoma Ductal Pancreático/patologia , Análise Mutacional de DNA/métodos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Hereditariedade , Humanos , Incidência , Judeus/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Ontário/epidemiologia , Neoplasias Pancreáticas/etnologia , Neoplasias Pancreáticas/patologia , Linhagem , Fenótipo , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
OBJECTIVE: Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons. DESIGN AND METHODS: The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft-Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy. RESULTS: There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: -2.4 vs. -1.1 ml/min; P=0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P=0.02), and resolved after stopping pre-exposure prophylaxis (mean change: -0.1 vs. 0.0 ml/min; P=0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy. CONCLUSIONS: In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Quimioprevenção/métodos , Desoxicitidina/análogos & derivados , Infecções por HIV/prevenção & controle , Testes de Função Renal , Rim/fisiologia , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Quimioprevenção/efeitos adversos , Creatinina/sangue , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Emtricitabina , Feminino , Humanos , Rim/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Fósforo/sangue , Placebos/administração & dosagem , Tenofovir , Adulto JovemRESUMO
OBJECTIVE: To determine expert beliefs regarding the probability of intestinal failure-associated liver disease (IFALD) with novel lipid-based approaches (lipid minimization/ω-3 lipids) in managing IFALD to facilitate Bayesian analyses of clinical trials of these therapies. STUDY DESIGN: Structured interviews were conducted using a validated approach to belief elicitation with 60 intestinal failure (IF) experts from across North America. Participants were asked to estimate, in an average population of infants referred for management of IF with early IFALD, the probability of advanced IFALD at 3 months following referral in each of 3 scenarios: (1) conventional lipid, (2) ω-3 lipids, and (3) lipid minimization. Probability distributions of the risk of advanced IFALD with each strategy were developed. Distributions of the elicited treatment effect for the novel approaches, relative to conventional lipid, were calculated. RESULTS: Median duration of experience of participants managing patients with IF was 8.5 (range, 2-35) years. The median probability of advanced IFALD using conventional lipid was 32.5%; ω-3 lipids, 17.5%; and lipid minimization, 13%. The median of the elicited treatment effects relative to conventional lipid was a relative risk of 0.53 for the ω-3 lipid and 0.45 for lipid minimization. CONCLUSIONS: There was consistent expert opinion that the novel lipid-based approaches are superior to conventional therapy, with similar estimates of treatment efficacy for the 2 approaches. The distributions of the elicited treatment effects can be used as prior distributions in Bayesian analyses of clinical trials of these novel strategies.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Enteropatias/terapia , Falência Hepática/terapia , Teorema de Bayes , Emulsões Gordurosas Intravenosas/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Humanos , Lactente , Enteropatias/complicações , Falência Hepática/complicações , Masculino , América do Norte , Nutrição Parenteral/métodosRESUMO
After disappointing results from all efficacy trials conducted to date, the field of microbicides research now faces substantial challenges. Poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies have hampered progress and created mistrust about the use of microbicides as a method to prevent HIV-1 sexual transmission. Although new promising strategies are available, there will need to be serious reappraisals of how decisions are made to advance the next generations of candidates into clinical trials, and the use of appropriate animal models in this process will be critical.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Polímeros/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Doenças Vaginais/prevenção & controle , Administração Intravaginal , Animais , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos Locais/uso terapêutico , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Humanos , Masculino , Cooperação do Paciente , Polieletrólitos , Polímeros/farmacologia , Polímeros/uso terapêutico , Primatas , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Doenças Vaginais/tratamento farmacológicoRESUMO
Prior studies have indicated that dehydroepiandrosterone (DHEA) may have immunomodulatory properties as well as positive effects on mood, quality of life, and body composition. Preliminary data suggest that DHEA inhibits expression of human immunodeficiency virus 1 (HIV) in latently infected cells; thus, it might be a potential adjunct to currently available antiretroviral therapy. The objective was to determine DHEA's impact on latent HIV infection, persistent viral replication, immunity, and nonimmune aspects of health restoration. A randomized, double-blind, placebo-controlled 24-week outpatient intervention included 40 subjects with suppressed HIV viremia on a stable antiretroviral regimen. Participants were randomized with equal probability to receive either DHEA or placebo for 12 weeks, followed by open-label DHEA for an additional 12 weeks. Intensive virologic monitoring included plasma viral load assays (lower limits of detection 50 copies/ml and 2.5 copies/ml) and quantitative cultures of replication-competent virus reservoirs in blood cells. A full battery of immunologic measurements was performed. Measurements of hormones, body weight, and body composition were obtained. Quality of life was assessed using validated questionnaires. DHEA was bioavailable as ascertained by increased levels of DHEA, DHEA(S), and androstenedione in recipients' plasma compared to the control group. The titers of infectious HIV culturable from blood trended upward in the DHEA arm although there was no significant change in plasma HIV RNA level. No significant immune effects were observed with DHEA. There appeared to be no benefit with regard to lean muscle mass or bone density in the DHEA recipients. DHEA treatment had a positive impact on overall quality of life. DHEA supplementation in fully suppressed HIV patients was associated with an improvement in quality of life but appeared to have no beneficial antiviral, immunomodulatory, hormonal, or body composition effects, suggesting that it not be routinely used as an adjunctive therapy in this population.