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Creatine transporter deficiency has been described with normal or uninformative levels of creatine and creatinine in plasma, while urine has been the preferred specimen type for biochemical diagnosis. We report a cohort of untreated patients with creatine transporter deficiency and abnormal plasma creatine panel results, characterized mainly by markedly decreased plasma creatinine. We conclude that plasma should be considered a viable specimen type for the biochemical diagnosis of this disorder, and abnormal results should be followed up with further confirmatory testing.
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Encefalopatias Metabólicas Congênitas , Creatina , Creatina/deficiência , Creatinina , Deficiência Intelectual Ligada ao Cromossomo X , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Humanos , Creatina/sangue , Creatina/urina , Creatinina/sangue , Creatinina/urina , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/sangue , Masculino , Feminino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Criança , Pré-Escolar , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/deficiência , Lactente , Adolescente , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/sangue , AdultoRESUMO
BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. FUNDING: USAID and Janssen Research & Development.
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Infecções por HIV , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Contagem de Linfócito CD4 , Quimioterapia Combinada , Infecções por HIV/epidemiologiaRESUMO
BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).
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Antituberculosos/administração & dosagem , Moxifloxacina/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Adulto , Antituberculosos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Moxifloxacina/efeitos adversos , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos/mortalidadeRESUMO
BACKGROUND: Graduate medical education is centered in hospitals despite a care system where patients mostly receive their care in an outpatient setting. Such gaps may exist because of inadequate funding for residency positions in community and hospital-based clinics. OBJECTIVE: Determine if physician residents' contribution to outpatient workload offsets their costs for supervision, salary, and fringe benefits as residents acquire skills to become independent practitioners. RESEARCH DESIGN: VA's electronic patient records from 2005 through 2018 were analyzed using generalized linear mixed models to estimate resident and staff contributions to workload in relative value units. MEASURES: Resident participation rate is resident contributed workload net of supervision as a percent of total clinic workload. Productivity is per diem resident workload as a percent of per diem staff workload. Efficiency is per dollar resident workload as a percent of per dollar staff workload. Progressive independence is annual rate of change in resident productivity. RESULTS: Average participation rates varied by specialty from 6% to 22%, with 11% (primary care) and 13% (psychiatry). Productivity rates ranged from 21% to 94%, with 57% (primary care) and 61% (psychiatry). Efficiency rates varied from 0.63 to 3.81, with 1.69 (primary care), 1.89 (psychiatry). Progressive independence rates varied from 2.7%/year (psychiatry) to 39.7%/year (specialty care). CONCLUSIONS: Although residents rotating through most VA clinics generate revenue to cover their direct costs as they learn, some federal subsidies may be necessary to encourage hospital- and community-based clinics to accept residents from the less profitable primary care and mental health specialties.
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Internato e Residência , Médicos , Educação de Pós-Graduação em Medicina , Humanos , Pacientes Ambulatoriais , Carga de TrabalhoRESUMO
BACKGROUND: Managing patients during the coronavirus disease-2019 (COVID-19) pandemic, and the associated severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) in particular, required the nimble responsiveness for which WOC nurses are known. Problem-solving skills were needed to continue the level of WOC nursing services expected by patients, families, and professional colleagues, while reducing the hours we were physically present at our clinical facility. In order to respond to these demands, our team realized it must create an innovative approach to provide efficient, cost-effective consultations during this global crisis. This Challenges in Practice article summarizes our experience with use of telemedicine technologies to perform remote consultations within the acute care setting. CASES: Case 1 was a 52-year-old woman with a history of paraplegia. She had several pressure injuries but had not received topical care for these wounds prior to admission. A consultation for the WOC nurse was requested and performed via telehealth services on a day our team was working off-site. This case illustrates the process our team used to perform a virtual consultation and demonstrates how the use of images placed in the electronic medical record aided in developing an effective plan of care. Case 2 was a 48-year-old man who tested positive for COVID-19. He developed bilateral unstageable pressure injuries on his cheeks after being placed in the prone position for a prolonged period while critically ill. This case describes multiple technologic platforms used for telemedicine consults in a patient with COVID-19 requiring isolation. CONCLUSIONS: Remote consultation by WOC nurses was possible in our healthcare system because of previous experience using telemedicine technology and well-established collaborative relationships with providers and bedside nurses. By expanding our use of telemedicine technology, we were able to provide ongoing care to a patient without COVID-19 who had WOC consultation needs, and a patient with strict isolation demands due to COVID-19.
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Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Úlcera por Pressão/terapia , Consulta Remota/organização & administração , COVID-19 , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Úlcera por Pressão/etiologia , Úlcera por Pressão/patologia , SARS-CoV-2RESUMO
Exploring the tendon proteome is a challenging but important task for understanding the mechanisms of physiological/pathological processes during ageing and disease and for the development of new treatments. Several extraction methods have been utilised for tendon mass spectrometry, however different extraction methods have not been simultaneously compared. In the present study we compared protein extraction in tendon with two chaotropic agents, guanidine hydrochloride (GnHCl) and urea, a detergent, RapiGest™, and their combinations for shotgun mass spectrometry. An initial proteomic analysis was performed following urea, GnHCl, and RapiGest™ extraction of equine superficial digital flexor tendon (SDFT) tissue. Subsequently, another proteomic analysis was performed following extraction with GnHCl, Rapigest™, and their combinations. Between the two chaotropic agents, GnHCl extracted more proteins, whilst a greater number of proteins were solely identified after Rapigest™ extraction. Protein extraction with a combination of GnHCl followed by RapiGest™ on the insoluble pellet demonstrated, after label-free quantification, increased abundance of identified collagen proteins and low sample to sample variability. In contrast, GnHCl extraction on its own showed increased abundance of identified proteoglycans and cellular proteins. Therefore, the selection of protein extraction method for tendon tissue for mass spectrometry analysis should reflect the focus of the study.
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Detergentes/química , Proteínas/isolamento & purificação , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Tendões/metabolismo , Animais , Guanidina/química , Cavalos , Proteínas/análise , Proteínas/metabolismo , Ureia/química , Fluxo de TrabalhoRESUMO
Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and structural characterization of a high affinity inactivator of PAI-1. This molecule binds to PAI-1 reversibly and acts through an allosteric mechanism that inhibits PAI-1 binding to proteases and to its cofactor vitronectin. The binding site is identified by X-ray crystallography and mutagenesis as a pocket at the interface of ß-sheets B and C and α-helix H. A similar pocket is present on other serpins, suggesting that this site could be a common target in this structurally conserved protein family.
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Inibidor 1 de Ativador de Plasminogênio/química , Regulação Alostérica , Cristalografia por Raios X , Humanos , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Vitronectina/química , Vitronectina/genética , Vitronectina/metabolismoRESUMO
BACKGROUND: Newborn screening (NBS) for Krabbe disease (KD) in New York and Missouri is conducted by measuring galactocerebrosidase (GALC) activity using tandem mass spectrometry (MS/MS). These NBS efforts have shown that the incidence of KD is unexpectedly low (1:400,000) while many individuals (ca. 1:6000) with reduced GALC activity and genotypes of uncertain significance are detected and subjected to follow up testing. Psychosine (PSY) is a putative marker of KD progression and can be measured in dried blood spots (DBS). We sought to determine the role that PSY levels play in NBS for KD, follow up, and treatment monitoring. METHODS: PSY was eluted from DBS with methanol containing N,N-dimethyl-D-erythro-sphingosine as internal standard (IS). Liquid chromatography-MS/MS was conducted over 17 minutes in the multiple reaction monitoring positive mode to follow the precursor to product species transitions for PSY and IS. Separation of the structural isomers PSY and glucosylsphingosine was accomplished by hydrophilic interaction liquid chromatography. RESULTS: Pre-analytical and analytical factors were studied and revealed satisfactory results. PSY was also measured in DBS collected from controls (range: <8 nmol/L, N = 220), KD patients at various disease stages (range: 8-112, N = 26), and GALC mutation carriers (range: <15 nmol/L, N = 18). CONCLUSIONS: PSY measurement in DBS could serve as a 2nd tier assay in NBS for KD, simplify and reduce the cost of follow up protocols, help determine disease progression, and be used to monitor KD patients following hematopoietic stem cell transplantation. However, additional chronological measurements of PSY in KD patients are required to confirm these possibilities.
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Teste em Amostras de Sangue Seco , Leucodistrofia de Células Globoides/diagnóstico , Triagem Neonatal/métodos , Psicosina/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Teste em Amostras de Sangue Seco/normas , Humanos , Lactente , Recém-Nascido , Leucodistrofia de Células Globoides/sangue , Limite de Detecção , Pessoa de Meia-Idade , Triagem Neonatal/normas , Psicosina/análise , Melhoria de Qualidade , Valores de Referência , Reprodutibilidade dos Testes , Adulto JovemAssuntos
Medicina Militar/história , Militares/educação , Militares/história , Sistemas Automatizados de Assistência Junto ao Leito/história , Sistemas Automatizados de Assistência Junto ao Leito/organização & administração , Adulto , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Estados UnidosRESUMO
In the mid-twentieth century, the social movement of death revivalism sought to resist the medicalisation of dying and grief through promotion of the dying person retaining autonomy, and societal openness toward death and bereavement. Despite this advocacy, present-day dying in high income countries is largely institutionalised, with value placed on control over the body and emotions. These phenomena are at odds with the ambitions of death revivalism, and demonstrate the re-medicalisation of dying and grief. Furthermore, contemporary society is continually advancing into the post-digital age, reflected in digital technologies being a tacit part of human existence. Within this framework, this study aims to investigate how people living with life-limiting illness and their loved ones experience, negotiate, and resist medicalisation of dying and grief through online internet forums. We collected posts through web-scraping and utilised Natural Language Processing techniques to select 7048 forum posts from 2003 to 2020, and initially categorise data, before utilising Inductive Thematic Analysis, which generated two major themes. The theme of 'Comfort' describes online forums facilitating psychosocial support which was often used to compensate for systemic deficiencies, especially during the Covid-19 pandemic. Common sources of comfort included animal companions and spirituality, in stark contrast with the medicalised model. The theme of 'Capability' describes online forums acting as solutions for people facing disempowering care systems, including providing information on legal rights and benefits which may not be otherwise easily available, and facilitating collective advocacy. Our findings indicate that community-led online forums can play an effective and sustainable role in democratising care and retaining agency when facing life-limiting illness and grief. Future palliative and bereavement care research must focus on how online forums can be integrated into existing systems, made transparent and accessible, be adequately funded and structured, and be optimised, including compensating for service disruption encountered during future pandemics.
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Pesar , Processamento de Linguagem Natural , Pesquisa Qualitativa , Humanos , Medicalização , COVID-19/psicologia , Atitude Frente a Morte , Internet , Apoio SocialRESUMO
Introduction: Health systems like the Veterans Health Administration (VA) face challenges in recruiting and retaining a primary care physician workforce. This cross-sectional study of recent or current VA medical residents sought to identify determinants of intent to pursue primary care practice in VA after residency training. Methods: Residents were identified from administrative data between 2020 and 2021 and recruited via an emailed self-administered survey. Multivariable logistic regression, accounting for survey non-response, was applied to examine the association between intent to pursue VA practice and two sets of measures: VA training experiences and individual preferences for work conditions. Results: Of 268 responses received, 141 (56%) of the sample reported inclination to consider VA employment post-residency. Experiences with training in VA were rated more positively in the VA-inclined group compared to the not-inclined group. In the multivariable model, intent to practice primary care was the strongest predictor (OR 4.04, p < 0001). Preceptors' modeling of work-life balance (OR 3.23, p = 0.009) and perceptions of quality of clinical staff and services (OR 2.64, p = 0.004), ability to get patients the care they need (OR 2.51, p = 0.017), and quality of patient care (OR 2.30, p = 0.075) were independent predictors of being in the VA inclined group. Conclusion: Overall, we found that intent to practice primary care and the quality of VA training experiences are important determinants of inclination to consider VA for employment. These results provide an important perspective relevant to medical education, the hiring and retention of the United States (U.S). primary care workforce.
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Background Despite the increased use of telemedicine, the evidence base on virtual supervision in graduate medical education (GME) is not well described. Objective To systematically review the impact of virtual supervision on trainee education, patient care, and patient satisfaction in Accreditation Council for Graduate Medical Education (ACGME)-accredited specialties. Methods Two databases (PubMed, EMBASE) were searched from database inception to December 2022. Inclusion criteria were peer-reviewed, full-text, English-language articles reporting the use of virtual supervision in GME in ACGME-accredited specialties. Exclusion criteria were studies involving direct supervision, supervisors who were not credentialed physicians, or non-GME trainees. Two investigators independently extracted data and appraised the methodological quality of each study using the Mixed Methods Appraisal Tool (MMAT). The reporting of this systematic review was guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Results Of 5278 records identified, 26 studies met the eligibility criteria. Virtual supervision was predominantly utilized in operating rooms and inpatient settings, facilitating clinical examinations or surgical procedures through videoconferencing software in specialties such as dermatology, neurosurgery, and orthopedics. However, some studies reported technical challenges that hindered effective teaching and communication. Based on self-reported surveys, supervisor and trainee satisfaction with virtual supervision was mixed, while patient satisfaction with the care was generally high. The MMAT ratings suggested limitations in sampling strategy, outcome measurement, and confounding factors. Conclusions Virtual supervision was applicable to various specialties and settings, facilitating communication between supervisors and trainees, although there were some technological challenges.
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Educação de Pós-Graduação em Medicina , Internato e Residência , Humanos , Telemedicina , Competência Clínica , Comunicação por Videoconferência , Satisfação do PacienteRESUMO
Background: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. Methods: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. Findings: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period. Interpretation: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. Funding: The National Institute for Health Research Health Technology Assessment programme.
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Sometimes being on the front lines involves caring for our colleagues. "Assisting nurses to nurture and heal themselves" is a defined role of holistic nursing practice (AHNA & ANA, 2013, p. 8). Nothing can be more catastrophic for a nurse's career than the loss of her/his license to practice. In this dark hour a nurse will often need extra support and someone to walk alongside her/him in the healing process. This article describes a holistic nurse in North Carolina who is helping nurses in her region find the courage to rise up from the ashes and start anew.
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Esgotamento Profissional/prevenção & controle , Licenciamento em Enfermagem/legislação & jurisprudência , Erros Médicos/prevenção & controle , Recursos Humanos de Enfermagem Hospitalar/legislação & jurisprudência , Má Conduta Profissional/legislação & jurisprudência , Esgotamento Profissional/enfermagem , Humanos , Relações Interprofissionais , Erros Médicos/enfermagem , Papel do Profissional de Enfermagem , Local de Trabalho/legislação & jurisprudênciaRESUMO
BACKGROUND: Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). METHODS: Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. FINDINGS: 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. INTERPRETATION: Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. FUNDING: Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).
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Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/terapia , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Celecoxib , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , OrquiectomiaRESUMO
BACKGROUND: Design and implementation of multi-country clinical trials for multidrug-resistant tuberculosis (MDR-TB) are complex for several reasons, including trial duration, varying levels of experience and infrastructure across settings, and different regulatory requirements. STREAM was an MDR-TB clinical trial that recruited over 1000 participants. We documented challenges and best practices/lessons learned from the site perspective to improve implementation of future trials. METHODS: We conducted a voluntary survey of trial staff at all sites to obtain information on challenges encountered and best practices/lessons learned from implementation of the STREAM trial. Respondents were asked to identify substantive aspects of trial implementation from a list that included: trial administration, laboratory strengthening/infrastructure, pharmacy and supply chain management, community engagement, regulatory and ethics requirements, health economics, and other (respondent designated) about which a practical guide would be useful to improve future trial implementation. For each aspect of trial implementation selected, respondents were asked to report challenges and best practices/lessons learned during STREAM. Lastly, respondents were asked to list up to three things they would do differently when implementing future trials. Summary statistics were generated for quantitative data and thematic analysis was undertaken for qualitative data. RESULTS: Of 67 responses received from 13 of 15 sites, 47 (70%) were included in the analyses, after excluding duplicate or incomplete responses. Approximately half the respondents were investigators or trial coordinators. The top three aspects of trial implementation identified for a best practices/lessons learned practical guide to improve future trial implementation were: trial administration, community engagement, and laboratory strengthening/infrastructure. For both challenges and best practices/lessons learned, three common themes were identified across different aspects of trial implementation. Investment in capacity building and ongoing monitoring; investment in infrastructure and well-designed trial processes; and communication and coordination between staff and meaningful engagement of stakeholders were all thought to be critical to successful trial implementation. CONCLUSIONS: Existing practices for clinical trial implementation should be reevaluated. Sponsors should consider the local context and the need to increase upfront investment in the cross-cutting thematic areas identified to improve trial implementation.
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Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Inquéritos e QuestionáriosRESUMO
Objectives: It is common for relatives to feel uncertain about what to expect at the bedside of a dying loved one. The Centre for the Art of Dying Well together with clinical, academic and communications experts created a 'Deathbed Etiquette' guide offering information and reassurance to relatives. This study explores the views of practitioners with experience in end-of-life care on the guide and how it might be used. Methods: Three online focus groups and nine individual interviews were conducted with a purposive sample of 21 participants involved in end-of-life care. Participants were recruited through hospices and social media. Data were analysed using thematic analysis. Results: Discussions highlighted the importance of effective communication that normalises experiences of being by the bedside of a dying loved one. Tensions around the use of the words 'death' and 'dying' were identified. Most participants also expressed reservations about the title, with the word 'deathbed' found to be old-fashioned and the word 'etiquette' not capturing the varied experiences of being by the bedside. Overall, however, participants agreed that the guide is useful for 'mythbusting' death and dying. Conclusion: There is a need for communication resources that can support practitioners in having honest and compassionate conversations with relatives in end-of-life care. The 'Deathbed Etiquette' guide is a promising resource to support relatives and healthcare practitioners by providing them with suitable information and helpful phrases. More research is needed on how to implement the guide in healthcare settings.
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Objective: Using health records from the Department of Veterans Affairs (VA), the largest healthcare training platform in the United States, we estimated independent associations between the intensity of attending supervision of surgical residents and 30-day postoperation patient outcomes. Background: Academic leaders do not agree on the level of autonomy from supervision to grant surgery residents to best prepare them to enter independent practice without risking patient outcomes. Methods: Secondary data came from a national, systematic 1:8 sample of n = 862,425 teaching encounters where residents were listed as primary surgeon at 122 VA medical centers from July 1, 2004, through September 30, 2019. Independent associations between whether attendings had scrubbed or not scrubbed on patient 30-day all-cause mortality, complications, and 30-day readmission were estimated using generalized linear-mixed models. Estimates were tested for any residual confounding biases, robustness to different regression models, stability over time, and validated using moderator and secondary factors analyses. Results: After accounting for potential confounding factors, residents supervised by scrubbed attendings in 733,997 nonemergency surgery encounters had fewer deaths within 30 days of the operation by 14.2% [0.3%, 29.9%], fewer case complications by 7.9% [2.0%, 14.0%], and fewer readmissions by 17.5% [11.2%, 24.2%] than had attendings not scrubbed. Over the 15 study years, scrubbed surgery attendings may have averted an estimated 13,700 deaths, 43,600 cases with complications, and 73,800 readmissions. Conclusions: VA policies on attending surgeon supervision have protected patient safety while allowing residents in selected teaching encounters to have limited autonomy from supervision.
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BACKGROUND: Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. METHODS: Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. RESULTS: Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). INTERPRETATION: The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer. FUNDING: Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.
Assuntos
Adenocarcinoma/terapia , Antagonistas de Androgênios/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Neoplasias da Próstata/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/efeitos adversos , Terapia Combinada , Humanos , Masculino , Orquiectomia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/radioterapia , Qualidade de Vida , Radioterapia/efeitos adversos , Taxa de SobrevidaRESUMO
Background: The US Department of Veterans Affairs (VA) conducts the largest health professions education program in the country in partnership with academic medical, nursing, and associated health programs across the nation. After World War II, the VA was pressed to meet the increasing population of veterans needing health care and faced challenges in recruiting clinicians. Observations: The passage of 2 legislative actions, the Servicemen's Readjustment Act and Public Law 79-293, and a key policy memorandum set the foundation for the partnership between the VA and academic medical centers that led to improved medical care for veterans and expansion of health professions education for the VA and the nation. Conclusions: Since passage of these actions, the VA-academic health professions education partnership has grown to involve 113,000 trainees rotating through 150 VA medical centers annually from more than 1400 colleges and universities.