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AmiA and AmiB are peptidoglycan-hydrolyzing enzymes from Escherichia coli that are required to break the peptidoglycan layer during bacterial cell division and maintain integrity of the cell envelope. In vivo, the activity of AmiA and AmiB is tightly controlled through their interactions with the membrane-bound FtsEX-EnvC complex. Activation of AmiA and AmiB requires access to a groove in the amidase-activating LytM domain of EnvC which is gated by ATP-driven conformational changes in FtsEX-EnvC complex. Here, we present a high-resolution structure of the isolated AmiA protein, confirming that it is autoinhibited in the same manner as AmiB and AmiC, and a complex of the AmiB enzymatic domain bound to the activating EnvC LytM domain. In isolation, the active site of AmiA is blocked by an autoinhibitory helix that binds directly to the catalytic zinc and fills the volume expected to accommodate peptidoglycan binding. In the complex, binding of the EnvC LytM domain induces a conformational change that displaces the amidase autoinhibitory helix and reorganizes the active site for activity. Our structures, together with complementary mutagenesis work, defines the conformational changes required to activate AmiA and/or AmiB through their interaction with their cognate activator EnvC.
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Proteínas de Escherichia coli , Proteínas de Escherichia coli/metabolismo , Peptidoglicano/metabolismo , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Escherichia coli/metabolismo , Amidoidrolases/metabolismo , Proteínas de Bactérias/metabolismoRESUMO
Emerging infectious diseases with zoonotic potential often have complex socioecological dynamics and limited ecological data, requiring integration of epidemiological modeling with surveillance. Although our understanding of SARS-CoV-2 has advanced considerably since its detection in late 2019, the factors influencing its introduction and transmission in wildlife hosts, particularly white-tailed deer (Odocoileus virginianus), remain poorly understood. We use a Susceptible-Infected-Recovered-Susceptible epidemiological model to investigate the spillover risk and transmission dynamics of SARS-CoV-2 in wild and captive white-tailed deer populations across various simulated scenarios. We found that captive scenarios pose a higher risk of SARS-CoV-2 introduction from humans into deer herds and subsequent transmission among deer, compared to wild herds. However, even in wild herds, the transmission risk is often substantial enough to sustain infections. Furthermore, we demonstrate that the strength of introduction from humans influences outbreak characteristics only to a certain extent. Transmission among deer was frequently sufficient for widespread outbreaks in deer populations, regardless of the initial level of introduction. We also explore the potential for fence line interactions between captive and wild deer to elevate outbreak metrics in wild herds that have the lowest risk of introduction and sustained transmission. Our results indicate that SARS-CoV-2 could be introduced and maintained in deer herds across a range of circumstances based on testing a range of introduction and transmission risks in various captive and wild scenarios. Our approach and findings will aid One Health strategies that mitigate persistent SARS-CoV-2 outbreaks in white-tailed deer populations and potential spillback to humans.
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COVID-19 , Cervos , SARS-CoV-2 , Animais , Cervos/virologia , COVID-19/transmissão , COVID-19/epidemiologia , COVID-19/veterinária , COVID-19/virologia , Humanos , Modelos Epidemiológicos , Animais Selvagens/virologia , Biologia Computacional , Surtos de Doenças/veterinária , Surtos de Doenças/estatística & dados numéricos , Zoonoses/transmissão , Zoonoses/epidemiologia , Zoonoses/virologiaRESUMO
BACKGROUND & AIMS: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. METHODS: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). RESULTS: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p <0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. CONCLUSION: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease. IMPACT AND IMPLICATIONS: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease.
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COVID-19 , Doenças do Sistema Digestório , Hepatite Autoimune , Hepatopatias , Transplante de Fígado , Humanos , Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinação , Cirrose Hepática , Anticorpos , Imunidade , Anticorpos Antivirais , TransplantadosRESUMO
Contemporary wildlife disease management is complex because managers need to respond to a wide range of stakeholders, multiple uncertainties, and difficult trade-offs that characterize the interconnected challenges of today. Despite general acknowledgment of these complexities, managing wildlife disease tends to be framed as a scientific problem, in which the major challenge is lack of knowledge. The complex and multifactorial process of decision-making is collapsed into a scientific endeavor to reduce uncertainty. As a result, contemporary decision-making may be oversimplified, rely on simple heuristics, and fail to account for the broader legal, social, and economic context in which the decisions are made. Concurrently, scientific research on wildlife disease may be distant from this decision context, resulting in information that may not be directly relevant to the pertinent management questions. We propose reframing wildlife disease management challenges as decision problems and addressing them with decision analytical tools to divide the complex problems into more cognitively manageable elements. In particular, structured decision-making has the potential to improve the quality, rigor, and transparency of decisions about wildlife disease in a variety of systems. Examples of management of severe acute respiratory syndrome coronavirus 2, white-nose syndrome, avian influenza, and chytridiomycosis illustrate the most common impediments to decision-making, including competing objectives, risks, prediction uncertainty, and limited resources.
Replanteamiento del manejo de problemas por enfermedades de fauna mediante el análisis de decisiones Resumen El manejo actual de las enfermedades de la fauna es complejo debido a que los gestores necesitan responder a una amplia gama de actores, varias incertidumbres y compensaciones difíciles que caracterizan los retos interconectados del día de hoy. A pesar de que en general se reconocen estas complejidades, el manejo de las enfermedades tiende a plantearse como un problema científico en el que el principal obstáculo es la falta de conocimiento. El proceso complejo y multifactorial de la toma decisiones está colapsado dentro de un esfuerzo científico para reducir la incertidumbre. Como resultado de esto, las decisiones contemporáneas pueden estar simplificadas en exceso, depender de métodos heurísticos simples y no considerar el contexto legal, social y económico más amplio en el que se toman las decisiones. De manera paralela, las investigaciones científicas sobre las enfermedades de la fauna pueden estar lejos de este contexto de decisiones, lo que deriva en información que puede no ser directamente relevante para las preguntas pertinentes de manejo. Proponemos replantear los obstáculos para el manejo de enfermedades de fauna como problemas de decisión y abordarlos con herramientas analíticas de decisión para dividir los problemas complejos en elementos más manejables de manera cognitiva. En particular, las decisiones estructuradas tienen el potencial de mejorar la calidad, el rigor y la transparencia de las decisiones sobre las enfermedades de la fauna en una variedad de sistemas. Ejemplos como el manejo del coronavirus del síndrome de respiración agudo tipo 2, el síndrome de nariz blanca, la influenza aviar y la quitridiomicosis ilustran los impedimentos más comunes para la toma de decisiones, incluyendo los objetivos en competencia, riesgos, incertidumbre en las predicciones y recursos limitados.
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Animais Selvagens , Conservação dos Recursos Naturais , Tomada de Decisões , Técnicas de Apoio para a Decisão , Animais , Conservação dos Recursos Naturais/métodos , COVID-19/epidemiologia , SARS-CoV-2 , IncertezaRESUMO
BACKGROUND: Effective alcohol and other drugs (AODs) treatment has been proven to increase productivity and reduce costs to the community. Telehealth has previously been proven effective at delivering AOD treatment in the right settings. Yet, Australia's current Medicare funding restricts telephone consultations. AIM: We hypothesise that treatment modality influences attendance rates. Specifically, telephone consultations can remove barriers to accessing treatment and, therefore, can increase attendance. METHODS: We conducted a retrospective audit on our addiction medicine specialist outpatient service from 1 July 2022 to 30 June 2023. A mixed-effects logistic regression model was used to analyse factors associated with attendance rates. RESULTS: There were 576 participants in the study, and 3354 appointments were booked over the 12-month study period. Of these, 2695 were face-to-face, 541 were telephone and 118 were video. The unadjusted raw attendance rate was highest in the telephone group (87.24%), followed by face-to-face (73.02%) and video (44.92%). After adjusting for covariates, telephone consultation was associated with significantly increased odds of attending compared to face-to-face (odds ratio (OR) = 2.60, 95% confidence interval (CI) = 1.90-3.54, P < 0.001). Video consultation was associated with a 69% reduction in the odds of attending compared to face-to-face (OR = 0.31, 95% CI = 0.019-0.49, P < 0.001). CONCLUSIONS: While physical attendance may be required for specific clinical care, telephone consultations are associated with increased attendance and can form an important adjunct to delivering addiction treatment. Given the substantial costs of substance use disorders, this could inform government policies and funding priorities to further improve access and treatment outcomes.
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BACKGROUND: Reconstruction of lower lip defects is challenging because of the functional and aesthetic demands of the lower face. We review the functional and aesthetic outcomes of the Karapandzic-type flaps for reconstructing lower lip defects. METHODS: A retrospective review of patients who underwent repair using Karapandzic-type flaps. RESULTS: Fifty patients with lower lip defects ranging from 20% to 95% (mean 59.2% ± 20%) were included. Eighteen patients (36%) were repaired using a bilateral flap, and 32 (64%) were reconstructed using a unilateral flap design. All patients had preservation of oral competency and a satisfactory aesthetic result. No patient complained of microstomia. A complication rate of 8% was noted ( n = 4) with postoperative wound infection and small areas of dehiscence. There was no statistically significant difference in complication rates in patients older than 75 years, in patients with a history of head/neck radiation, or in defects greater than 70% of lower lip breadth. CONCLUSION: Karapandzic-type flaps are versatile and reliable for the reconstruction of a broad range of lower lip defects. This one-stage procedure can produce superior functional and aesthetic results as compared with other local and distant flaps with minimal risk of functional microstomia.
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Neoplasias Labiais , Procedimentos de Cirurgia Plástica , Retalhos Cirúrgicos , Humanos , Estudos Retrospectivos , Masculino , Feminino , Idoso , Retalhos Cirúrgicos/transplante , Retalhos Cirúrgicos/efeitos adversos , Pessoa de Meia-Idade , Procedimentos de Cirurgia Plástica/métodos , Procedimentos de Cirurgia Plástica/efeitos adversos , Neoplasias Labiais/cirurgia , Idoso de 80 Anos ou mais , Estética , Lábio/cirurgia , Adulto , Resultado do TratamentoRESUMO
Rotator cuff repair has a substantial failure rate despite various attempts to improve outcome and prevent a retear. Patch augmentation is an intuitively appealing approach to seek to reduce failure rate and improve outcomes for patients. Two main augmentation approaches are used: "on-lay" and "bridging." The literature is heterogeneous, and the best approach is uncertain. The evidence on patch augmentation for rotator cuff repair is both disparate and weak. Large randomized trials and registry data are required to move the field, ensure patient safety, and avoid wasting precious resources.
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Lesões do Manguito Rotador , Manguito Rotador , Humanos , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/cirurgia , Artroplastia , Resultado do Tratamento , ArtroscopiaRESUMO
BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. METHODS: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. FINDINGS: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. INTERPRETATION: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. FUNDING: The UK National Institute for Health Research Health Technology Assessment Programme.
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Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Traumatismos do Joelho , Lesões do Ligamento Cruzado Anterior/diagnóstico , Lesões do Ligamento Cruzado Anterior/etiologia , Lesões do Ligamento Cruzado Anterior/cirurgia , Reconstrução do Ligamento Cruzado Anterior/efeitos adversos , Reconstrução do Ligamento Cruzado Anterior/métodos , Humanos , Traumatismos do Joelho/etiologia , Traumatismos do Joelho/reabilitação , Traumatismos do Joelho/cirurgia , Articulação do Joelho/cirurgia , Medicina Estatal , Resultado do TratamentoRESUMO
BACKGROUND: Hand trauma, comprising injuries to both the hand and wrist, affects over five million people per year in the NHS, resulting in 250 000 operations each year. Surgical site infection (SSI) following hand trauma surgery leads to significant morbidity. Triclosan-coated sutures may reduce SSI in major abdominal surgery but have never been tested in hand trauma. Feasibility needs to be ascertained before a definitive trial can be delivered in hand trauma. METHODS: A multicentre feasibility RCT of antimicrobial sutures versus standard sutures involving adults undergoing surgery for hand trauma to evaluate feasibility for a definitive trial. Secondary objectives were incidence of SSI in both groups, hand function measured with patient-reported outcome measures, health-related quality of life and change in employment. Randomization was performed on a 1:1 basis, stratified by age of the patient and whether the injury was open or closed, using a secure, centralized, online randomization service. Participants were blinded to allocation. RESULTS: 116 participants were recruited and randomized (60 intervention, 56 control). Of 227 screened, most were eligible (89.5 per cent), and most who were approached agreed to be included in the study (84.7 per cent). Retention was low: 57.5 per cent at 30 days, 52 per cent at 90 days and 45.1 per cent at 6 months. Incidence of SSI was >20 per cent in both groups. Hand function deteriorated after injury but recovered to near pre-injury levels during the study period. CONCLUSIONS: Risk of SSI after hand trauma is high. A definitive RCT of antimicrobial sutures in hand trauma surgery is feasible, if retention is improved. TRIAL REGISTRATION: ISRCTN10771059.
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Anti-Infecciosos Locais , Anti-Infecciosos , Traumatismos da Mão , Adulto , Humanos , Anti-Infecciosos Locais/uso terapêutico , Punho/cirurgia , Qualidade de Vida , Havaí , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/etiologia , Traumatismos da Mão/cirurgiaRESUMO
BACKGROUND: Surgery for nail bed injuries in children is common. One of the key surgical decisions is whether to replace the nail plate following nail bed repair. The aim of this RCT was to assess the clinical effectiveness and cost-effectiveness of nail bed repair with fingernail replacement/substitution compared with repair without fingernail replacement. METHODS: A two-arm 1 : 1 parallel-group open multicentre superiority RCT was performed across 20 secondary-care hospitals in the UK. The co-primary outcomes were surgical-site infection at around 7 days after surgery and cosmetic appearance summary score at a minimum of 4 months. RESULTS: Some 451 children presenting with a suspected nail bed injury were recruited between July 2018 and July 2019; 224 were allocated to the nail-discarded arm, and 227 to the nail-replaced arm. There was no difference in the number of surgical-site infections at around 7 days between the two interventions or in cosmetic appearance. The mean total healthcare cost over the 4 months after surgery was 84 (95 per cent c.i. 34 to 140) lower for the nail-discarded arm than the nail-replaced arm (P < 0.001). CONCLUSION: After nail bed repair, discarding the fingernail was associated with similar rates of infection and cosmesis ratings as replacement of the finger nail, but was cost saving. Registration number: ISRCTN44551796 (http://www.controlled-trials.com).
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Unhas , Infecção da Ferida Cirúrgica , Humanos , Criança , Unhas/cirurgia , Unhas/lesões , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Resultado do Tratamento , Custos de Cuidados de Saúde , Análise Custo-BenefícioRESUMO
FtsEX is a bacterial ABC transporter that regulates the activity of periplasmic peptidoglycan amidases via its interaction with the murein hydrolase activator, EnvC. In Escherichia coli, FtsEX is required to separate daughter cells after cell division and for viability in low-osmolarity media. Both the ATPase activity of FtsEX and its periplasmic interaction with EnvC are required for amidase activation, but the process itself is poorly understood. Here we present the 2.1 Å structure of the FtsX periplasmic domain in complex with its periplasmic partner, EnvC. The EnvC-FtsX periplasmic domain complex has a 1-to-2 stoichiometry with two distinct FtsX-binding sites located within an antiparallel coiled coil domain of EnvC. Residues involved in amidase activation map to a previously identified groove in the EnvC LytM domain that is here found to be occluded by a "restraining arm" suggesting a self-inhibition mechanism. Mutational analysis, combined with bacterial two-hybrid screens and in vivo functional assays, verifies the FtsEX residues required for EnvC binding and experimentally test a proposed mechanism for amidase activation. We also define a predicted link between FtsEX and integrity of the outer membrane. Both the ATPase activity of FtsEX and its periplasmic interaction with EnvC are required for resistance to membrane-attacking antibiotics and detergents to which E. coli would usually be considered intrinsically resistant. These structural and functional data provide compelling mechanistic insight into FtsEX-mediated regulation of EnvC and its downstream control of periplasmic peptidoglycan amidases.
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Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Ciclo Celular/química , Divisão Celular/fisiologia , Endopeptidases/química , Periplasma/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Membrana Celular/metabolismo , Cristalografia por Raios X , Análise Mutacional de DNA , Endopeptidases/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli , Modelos Moleculares , Mutação , N-Acetil-Muramil-L-Alanina Amidase/genética , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Periplasma/química , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Domínios e Motivos de Interação entre ProteínasRESUMO
BACKGROUND: Traditional invasive suture suspension techniques have proven efficacy and durability. A previously described percutaneous placement of a neck suspension suture with light guidance has transformed this into a minimally invasive technique. This novel technique provides a major advance for minimally invasive neck rejuvenation. OBJECTIVES: The authors sought to describe their experience with light-guided percutaneous neck rejuvenation over the past 4.5 years, including technique, patient selection, safety profile, and expected outcomes. METHODS: Data were retrospectively reviewed for all patients who underwent the procedure with 5 surgeons across 4 aesthetic plastic surgery practices from January 2018 through May 2022. Inclusion criteria were mild to moderate neck laxity, prominent anterior platysma bands, and desire to improve neck contour. Patients undergoing concurrent skin incision >5 mm (ie, open rhytidectomy or platysmaplasty) were excluded. RESULTS: A total of 391 patients meeting criteria were identified during the study period. No hematomas were documented. Four patients (1%) developed infection at the suture site, 1 resolving on antibiotics and 3 requiring suture removal. Eighteen (4.6%) developed recurrent platysmal bands, and 7 (1.8%) had residual loose skin. Four (1%) experienced transient marginal mandibular neuropraxia. Mean length of follow-up time was 240 days. CONCLUSIONS: Light-guided percutaneous suture suspension is a safe and viable option for improving neck contours. Although it does not address extensive skin laxity or excess submental fat, it can be combined with energy-based tissue tightening, submental liposuction, or skin excision. In selected patients, this minimally invasive procedure provides predictable results with a low risk of complications.
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Procedimentos de Cirurgia Plástica , Ritidoplastia , Humanos , Estudos Retrospectivos , Rejuvenescimento , Pescoço/cirurgia , Ritidoplastia/efeitos adversos , Ritidoplastia/métodos , SuturasRESUMO
Standardized assessment measures are important for accurate diagnosis of mental health problems and for treatment planning and evaluation. However, little is known about youth mental health providers' typical use of standardized measures across disciplines and outside the context of evidence-based practice initiatives. A multidisciplinary national survey examined the frequency with which 674 youth mental health providers administer standardized and unstandardized measures, and the extent to which organizational (i.e., implementation climate, rigid hierarchical organizational structure) and provider (i.e., attitudes toward standardized assessment measures, highest degree, practice setting) characteristics are associated with standardized measure use. Providers used unstandardized measures far more frequently than standardized measures. Providers' perceptions (a) that standardized measures are practical or feasible, (b) that their organization supports and values evidence-based practices, and (c) that their organization has a rigid hierarchical structure predicted greater use of standardized measures. Working in schools predicted less frequent SMU, while working in higher education and other professional settings predicted more frequent SMU. Standardized measures were not routinely used in this community-based sample. A rigid hierarchical organizational structure may be conducive to more frequent administration of standardized measures, but it is unclear whether such providers actually utilize these measures for clinical decision-making. Alternative strategies to promote standardized measure use may include promoting organizational cultures that value empirical data and encouraging use of standardized measures and training providers to use pragmatic standardized measures for clinical decision making.
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Serviços Comunitários de Saúde Mental , Saúde Mental , Humanos , Adolescente , Atenção à Saúde , Prática Clínica Baseada em Evidências , Modelos EstruturaisRESUMO
BACKGROUND: Use of patient-reported outcomes (PROs) and patient and public engagement are critical ingredients of pragmatic trials, which are intended to be patient centered. Engagement of patients and members of the public in selecting the primary trial outcome and determining the target difference can better ensure that the trial is designed to inform the decisions of those who ultimately stand to benefit. However, to the best of our knowledge, the use and reporting of PROs and patient and public engagement in pragmatic trials have not been described. The objectives of this study were to review a sample of pragmatic trials to describe (1) the prevalence of reporting patient and public engagement; (2) the prevalence and types of PROs used; (3) how its use varies across trial characteristics; and (4) how sample sizes and target differences are determined for trials with primary PROs. METHODS AND FINDINGS: This was a methodological review of primary reports of pragmatic trials. We used a published electronic search filter in MEDLINE to identify pragmatic trials, published in English between January 1, 2014 and April 3, 2019; we identified the subset that were registered in ClinicalTrials.gov and explicitly labeled as pragmatic. Trial descriptors were downloaded from ClinicalTrials.gov; information about PROs and sample size calculations were extracted from the manuscript. Chi-squared, Cochran-Armitage, and Wilcoxon rank sum tests were used to examine associations between trial characteristics and use of PROs. Among 4,337 identified primary trial reports, 1,988 were registered in CT.gov, of which 415 were explicitly labeled as pragmatic. Use of patient and public engagement was identified in 39 (9.4%). PROs were measured in 235 (56.6%): 144 (34.7%) used PROs as primary outcomes and 91 (21.9%) as only secondary outcomes. Primary PROs were symptoms (64; 44%), health behaviors (36; 25.0%), quality of life (17; 11.8%), functional status (16; 11.1%), and patient experience (10; 6.9%). Trial characteristics with lower prevalence of use of PROs included being conducted exclusively in children or adults over age 65 years, cluster randomization, recruitment in low- and middle-income countries, and primary purpose of prevention; trials conducted in Europe had the highest prevalence of PROs. For the 144 trials with a primary PRO, 117 (81.3%) reported a sample size calculation for that outcome; of these, 71 (60.7%) justified the choice of target difference, most commonly, using estimates from pilot studies (31; 26.5%), standardized effect sizes (20; 17.1%), or evidence reviews (16; 13.7%); patient or stakeholder opinions were used to justify the target difference in 8 (6.8%). Limitations of this study are the need for trials to be registered in ClinicalTrials.gov, which may have reduced generalizability, and extracting information only from the primary trial report. CONCLUSIONS: In this study, we observed that pragmatic trials rarely report patient and public engagement and do not commonly use PROs as primary outcomes. When provided, target differences are often not justified and rarely informed by patients and stakeholders. Research funders, scientific journals, and institutions should support trialists to incorporate patient engagement to fulfill the mandate of pragmatic trials to be patient centered.
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Participação do Paciente/métodos , Medidas de Resultados Relatados pelo Paciente , Ensaios Clínicos Pragmáticos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Estudos Transversais , Bases de Dados Factuais/tendências , Humanos , Participação do Paciente/tendênciasRESUMO
Sample size calculations from high-profile surgical RCTs that used a patient-reported outcome measure as primary outcome were reviewed systematically against Difference ELicitation in TriAls (DELTA2) standards, with a focus on target differences. In this sample of trials, there was frequent use of suboptimal methods to determine the target difference, and sample size calculations were generally not reported to DELTA2 standards. This risks over-recruitment and/or erroneous trial conclusions, which clinicians should be aware of when interpreting published trials.
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Medidas de Resultados Relatados pelo Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Tamanho da Amostra , Procedimentos Cirúrgicos Operatórios , Estudos de Equivalência como Asunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/economia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Apoio à Pesquisa como AssuntoRESUMO
OBJECTIVES: To test the feasibility of randomisation to radical prostatectomy (RP) plus pelvic lymphadenectomy in addition to standard-of-care (SOC) systemic therapy in men with newly diagnosed oligo-metastatic prostate cancer. PATIENTS AND METHODS: A prospective, randomised, non-blinded, feasibility clinical trial with an embedded QuinteT Recruitment Intervention (QRI) to optimise recruitment was conducted in nine nationwide tertiary care centres undertaking high-volume robotic surgery. We aimed to randomise 50 men with synchronous oligo-metastatic prostate cancer within an 18-month recruitment period to SOC systemic therapy vs SOC plus RP (intervention arm). The main outcome measures were: ability to randomise patients, optimised by a QRI; EuroQoL five Dimensions five Levels (EQ-5D-5L) questionnaires to capture quality-of-life (QoL) data at baseline and 3 months post-randomisation; routine clinicopathological assessment to capture adverse events and prostate-specific antigen in both arms, plus standard perioperative parameters in the surgical arm. RESULTS: A total of 51 men were randomised within 14 months (one was subsequently deemed ineligible), with 60-83% accrual rate in centres that recruited at least two patients. All patients completed the trial follow-up; one patient in the intervention arm subsequently did not undergo the surgical intervention and one in the SOC arm refused all therapies. The QRI positively impacted recruitment. QoL data showed similarly high functioning in both study arms. Surgery for men with oligo-metastatic prostate cancer was found to be safe and had similar impact on early functional outcomes as surgery for standard indication. CONCLUSION: It is feasible to randomise men with synchronous oligo-metastatic prostate cancer to a surgical intervention in addition to standard systemic therapies. While surgery appeared safe with no substantial impact on QoL in this feasibility study, a large randomised controlled trial is now warranted to examine treatment effectiveness of this additional component in the multimodality management of oligo-metastatic prostate cancer.
Assuntos
Neoplasias da Próstata , Qualidade de Vida , Estudos de Viabilidade , Humanos , Masculino , Estudos Prospectivos , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.
Assuntos
Futilidade Médica , Registros , Coleta de Dados , Estudos de Viabilidade , Humanos , Tamanho da AmostraRESUMO
BACKGROUND: ADHD in adults is a common and debilitating neurodevelopmental mental health condition. Yet, diagnosis, clinical management and monitoring are frequently constrained by scarce resources, low capacity in specialist services and limited awareness or training in both primary and secondary care. As a result, many people with ADHD experience serious barriers in accessing the care they need. METHODS: Professionals across primary, secondary, and tertiary care met to discuss adult ADHD clinical care in the United Kingdom. Discussions identified constraints in service provision, and service delivery models with potential to improve healthcare access and delivery. The group aimed to provide a roadmap for improving access to ADHD treatment, identifying avenues for improving provision under current constraints, and innovating provision in the longer-term. National Institute for Health and Care Excellence (NICE) guidelines were used as a benchmark in discussions. RESULTS: The group identified three interrelated constraints. First, inconsistent interpretation of what constitutes a 'specialist' in the context of delivering ADHD care. Second, restriction of service delivery to limited capacity secondary or tertiary care services. Third, financial limitations or conflicts which reduce capacity and render transfer of care between healthcare sectors difficult. The group recommended the development of ADHD specialism within primary care, along with the transfer of routine and straightforward treatment monitoring to primary care services. Longer term, ADHD care pathways should be brought into line with those for other common mental health disorders, including treatment initiation by appropriately qualified clinicians in primary care, and referral to secondary mental health or tertiary services for more complex cases. Long-term plans in the NHS for more joined up and flexible provision, using a primary care network approach, could invest in developing shared ADHD specialist resources. CONCLUSIONS: The relegation of adult ADHD diagnosis, treatment and monitoring to specialist tertiary and secondary services is at odds with its high prevalence and chronic course. To enable the cost-effective and at-scale access to ADHD treatment that is needed, general adult mental health and primary care must be empowered to play a key role in the delivery of quality services for adults with ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Acessibilidade aos Serviços de Saúde , Humanos , Atenção Primária à Saúde , Encaminhamento e Consulta , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Hip fractures are a major healthcare problem, presenting a considerable challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising rapidly. The majority of intracapsular hip fractures are treated surgically. OBJECTIVES: To assess the relative effects (benefits and harms) of all surgical treatments used in the management of intracapsular hip fractures in older adults, using a network meta-analysis of randomised trials, and to generate a hierarchy of interventions according to their outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Web of Science, and five other databases in July 2020. We also searched clinical trials databases, conference proceedings, reference lists of retrieved articles and conducted backward-citation searches. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing different treatments for fragility intracapsular hip fractures in older adults. We included total hip arthroplasties (THAs), hemiarthroplasties (HAs), internal fixation, and non-operative treatments. We excluded studies of people with hip fracture with specific pathologies other than osteoporosis or resulting from high-energy trauma. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. One review author completed data extraction which was checked by a second review author. We collected data for three outcomes at different time points: mortality and health-related quality of life (HRQoL) - both reported within 4 months, at 12 months, and after 24 months of surgery, and unplanned return to theatre (at end of study follow-up). We performed a network meta-analysis (NMA) with Stata software, using frequentist methods, and calculated the differences between treatments using risk ratios (RRs) and standardised mean differences (SMDs) and their corresponding 95% confidence intervals (CIs). We also performed direct comparisons using the same codes. MAIN RESULTS: We included 119 studies (102 RCTS, 17 quasi-RCTs) with 17,653 participants with 17,669 intracapsular fractures in the review; 83% of fractures were displaced. The mean participant age ranged from 60 to 87 years and 73% were women. After discussion with clinical experts, we selected 12 nodes that represented the best balance between clinical plausibility and efficiency of the networks: cemented modern unipolar HA, dynamic fixed angle plate, uncemented first-generation bipolar HA, uncemented modern bipolar HA, cemented modern bipolar HA, uncemented first-generation unipolar HA, uncemented modern unipolar HA, THA with single articulation, dual-mobility THA, pins, screws, and non-operative treatment. Seventy-five studies (with 11,855 participants) with data for at least two of these treatments contributed to the NMA. We selected cemented modern unipolar HA as a reference treatment against which other treatments were compared. This was a common treatment in the networks, providing a clinically appropriate comparison. In order to provide a concise summary of the results, we report only network estimates when there was evidence of difference between treatments. We downgraded the certainty of the evidence for serious and very serious risks of bias and when estimates included possible transitivity, particularly for internal fixation which included more undisplaced fractures. We also downgraded for incoherence, or inconsistency in indirect estimates, although this affected few estimates. Most estimates included the possibility of benefits and harms, and we downgraded the evidence for these treatments for imprecision. We found that cemented modern unipolar HA, dynamic fixed angle plate and pins seemed to have the greatest likelihood of reducing mortality at 12 months. Overall, 23.5% of participants who received the reference treatment died within 12 months of surgery. Uncemented modern bipolar HA had higher mortality than the reference treatment (RR 1.37, 95% CI 1.02 to 1.85; derived only from indirect evidence; low-certainty evidence), and THA with single articulation also had higher mortality (network estimate RR 1.62, 95% CI 1.13 to 2.32; derived from direct evidence from 2 studies with 225 participants, and indirect evidence; very low-certainty evidence). In the remaining treatments, the certainty of the evidence ranged from low to very low, and we noted no evidence of any differences in mortality at 12 months. We found that THA (single articulation), cemented modern bipolar HA and uncemented modern bipolar HA seemed to have the greatest likelihood of improving HRQoL at 12 months. This network was comparatively sparse compared to other outcomes and the certainty of the evidence of differences between treatments was very low. We noted no evidence of any differences in HRQoL at 12 months, although estimates were imprecise. We found that arthroplasty treatments seemed to have a greater likelihood of reducing unplanned return to theatre than internal fixation and non-operative treatment. We estimated that 4.3% of participants who received the reference treatment returned to theatre during the study follow-up. Compared to this treatment, we found low-certainty evidence that more participants returned to theatre if they were treated with a dynamic fixed angle plate (network estimate RR 4.63, 95% CI 2.94 to 7.30; from direct evidence from 1 study with 190 participants, and indirect evidence). We found very low-certainty evidence that more participants returned to theatre when treated with pins (RR 4.16, 95% CI 2.53 to 6.84; only from indirect evidence), screws (network estimate RR 5.04, 95% CI 3.25 to 7.82; from direct evidence from 2 studies with 278 participants, and indirect evidence), and non-operative treatment (RR 5.41, 95% CI 1.80 to 16.26; only from indirect evidence). There was very low-certainty evidence of a tendency for an increased risk of unplanned return to theatre for all of the arthroplasty treatments, and in particular for THA, compared with cemented modern unipolar HA, with little evidence to suggest the size of this difference varied strongly between the arthroplasty treatments. AUTHORS' CONCLUSIONS: There was considerable variability in the ranking of each treatment such that there was no one outstanding, or subset of outstanding, superior treatments. However, cemented modern arthroplasties tended to more often yield better outcomes than alternative treatments and may be a more successful approach than internal fixation. There is no evidence of a difference between THA (single articulation) and cemented modern unipolar HA in the outcomes measured in this review. THA may be an appropriate treatment for a subset of people with intracapsular fracture but we have not explored this further.
Assuntos
Fraturas do Quadril , Idoso , Idoso de 80 Anos ou mais , Pinos Ortopédicos , Placas Ósseas , Feminino , Fixação Interna de Fraturas , Fraturas do Quadril/cirurgia , Humanos , Pessoa de Meia-Idade , Metanálise em RedeRESUMO
BACKGROUND: Hip fractures are a major healthcare problem, presenting a huge challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising rapidly. The majority of hip fractures are treated surgically. This review evaluates evidence for types of arthroplasty: hemiarthroplasties (HAs), which replace part of the hip joint; and total hip arthroplasties (THAs), which replace all of it. OBJECTIVES: To determine the effects of different designs, articulations, and fixation techniques of arthroplasties for treating hip fractures in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, seven other databases and one trials register in July 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing different arthroplasties for treating fragility intracapsular hip fractures in older adults. We included THAs and HAs inserted with or without cement, and comparisons between different articulations, sizes, and types of prostheses. We excluded studies of people with specific pathologies other than osteoporosis and with hip fractures resulting from high-energy trauma. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We collected data for seven outcomes: activities of daily living, functional status, health-related quality of life, mobility (all early: within four months of surgery), early mortality and at 12 months after surgery, delirium, and unplanned return to theatre at the end of follow-up. MAIN RESULTS: We included 58 studies (50 RCTs, 8 quasi-RCTs) with 10,654 participants with 10,662 fractures. All studies reported intracapsular fractures, except one study of extracapsular fractures. The mean age of participants in the studies ranged from 63 years to 87 years, and 71% were women. We report here the findings of three comparisons that represent the most substantial body of evidence in the review. Other comparisons were also reported, but with many fewer participants. All studies had unclear risks of bias in at least one domain and were at high risk of detection bias. We downgraded the certainty of many outcomes for imprecision, and for risks of bias where sensitivity analysis indicated that bias sometimes influenced the size or direction of the effect estimate. HA: cemented versus uncemented (17 studies, 3644 participants) There was moderate-certainty evidence of a benefit with cemented HA consistent with clinically small to large differences in health-related quality of life (HRQoL) (standardised mean difference (SMD) 0.20, 95% CI 0.07 to 0.34; 3 studies, 1122 participants), and reduction in the risk of mortality at 12 months (RR 0.86, 95% CI 0.78 to 0.96; 15 studies, 3727 participants). We found moderate-certainty evidence of little or no difference in performance of activities of daily living (ADL) (SMD -0.03, 95% CI -0.21 to 0.16; 4 studies, 1275 participants), and independent mobility (RR 1.04, 95% CI 0.95 to 1.14; 3 studies, 980 participants). We found low-certainty evidence of little or no difference in delirium (RR 1.06, 95% CI 0.55 to 2.06; 2 studies, 800 participants), early mortality (RR 0.95, 95% CI 0.80 to 1.13; 12 studies, 3136 participants) or unplanned return to theatre (RR 0.70, 95% CI 0.45 to 1.10; 6 studies, 2336 participants). For functional status, there was very low-certainty evidence showing no clinically important differences. The risks of most adverse events were similar. However, cemented HAs led to less periprosthetic fractures intraoperatively (RR 0.20, 95% CI 0.08 to 0.46; 7 studies, 1669 participants) and postoperatively (RR 0.29, 95% CI 0.14 to 0.57; 6 studies, 2819 participants), but had a higher risk of pulmonary embolus (RR 3.56, 95% CI 1.26 to 10.11, 6 studies, 2499 participants). Bipolar HA versus unipolar HA (13 studies, 1499 participants) We found low-certainty evidence of little or no difference between bipolar and unipolar HAs in early mortality (RR 0.94, 95% CI 0.54 to 1.64; 4 studies, 573 participants) and 12-month mortality (RR 1.17, 95% CI 0.89 to 1.53; 8 studies, 839 participants). We are unsure of the effect for delirium, HRQoL, and unplanned return to theatre, which all indicated little or no difference between articulation, because the certainty of the evidence was very low. No studies reported on early ADL, functional status and mobility. The overall risk of adverse events was similar. The absolute risk of dislocation was low (approximately 1.6%) and there was no evidence of any difference between treatments. THA versus HA (17 studies, 3232 participants) The difference in the risk of mortality at 12 months was consistent with clinically relevant benefits and harms (RR 1.00, 95% CI 0.83 to 1.22; 11 studies, 2667 participants; moderate-certainty evidence). There was no evidence of a difference in unplanned return to theatre, but this effect estimate includes clinically relevant benefits of THA (RR 0.63, 95% CI 0.37 to 1.07, favours THA; 10 studies, 2594 participants; low-certainty evidence). We found low-certainty evidence of little or no difference between THA and HA in delirium (RR 1.41, 95% CI 0.60 to 3.33; 2 studies, 357 participants), and mobility (MD -0.40, 95% CI -0.96 to 0.16, favours THA; 1 study, 83 participants). We are unsure of the effect for early functional status, ADL, HRQoL, and mortality, which indicated little or no difference between interventions, because the certainty of the evidence was very low. The overall risks of adverse events were similar. There was an increased risk of dislocation with THA (RR 1.96, 95% CI 1.17 to 3.27; 12 studies, 2719 participants) and no evidence of a difference in deep infection. AUTHORS' CONCLUSIONS: For people undergoing HA for intracapsular hip fracture, it is likely that a cemented prosthesis will yield an improved global outcome, particularly in terms of HRQoL and mortality. There is no evidence to suggest a bipolar HA is superior to a unipolar prosthesis. Any benefit of THA compared with hemiarthroplasty is likely to be small and not clinically appreciable. We encourage researchers to focus on alternative implants in current clinical practice, such as dual-mobility bearings, for which there is limited available evidence.