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Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPOmod) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPOmod decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPOmod in hematology research and clinical HSC transplantation.
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Receptores de Trombopoyetina , Trombopoyetina , Animales , Humanos , Ratones , Ciclo Celular , Microscopía por Crioelectrón , Receptores de Trombopoyetina/genética , Trombopoyesis , Metilación de ADNRESUMEN
PURPOSE: Acute cough in children has a significant impact on the child and family. Relevant quality of life (QoL) instruments are essential for high-quality clinical research. This study aimed to (1) revalidate the 16-item Parent-proxy Children's Acute Cough-specific QoL questionnaire (PAC-QoL16) using a different dataset (i.e., different children), (2) confirm the minimally important difference (MID), and (3) develop and validate a short form. METHODS: Three datasets from two sources were utilized, comprising of 332 children with acute cough (< 2 weeks duration); the first dataset (n = 83, 54 boys; median age 2.04 years, IQR 1.08-4.06 years) was used for revalidation, the second dataset (n = 238, 141 boys; median age 2.17 years, IQR 1.21-4.21 years) was used to develop the short form, and the third dataset (n = 94, 62 boys; median age, 1.75 years, IQR 0.90-3.63 years) was used to confirm the short form. Psychometric properties were investigated. RESULTS: Six items were found to account for 96.4% of the variance in the PAC-QoL16. The PAC-QoL16 and short form (PAC-QoL6) scales correlated with cough scores (rs ≤ - 0.40, p < 0.001), were internally consistent (Cronbach α = 0.94 and 0.87, respectively) and demonstrated sensitivity to change over time. A MID of 0.71 to 1.11 is recommended. CONCLUSION: Both the PAC-QoL16 and newly developed short form (PAC-QoL6) are reliable and valid outcome measures that assess children's acute cough-specific QoL at a given time point, are easy to interpret and reflect changes over time. The new short form addresses the need for outcome measures to be as time effective as possible without loss of information.
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Tos , Calidad de Vida , Niño , Preescolar , Enfermedad Crónica , Humanos , Lactante , Masculino , Psicometría , Encuestas y CuestionariosRESUMEN
AIM: In children presenting to an emergency department (ED) with an acute coughing illness, the aims of this study were to: (i) describe the frequency of doctor visits and medication use; and (ii) describe management and relate it to current evidence-based guidelines. METHODS: This was a cross-sectional study in ED of a major teaching hospital (Royal Children's Hospital, Brisbane, Australia). Participants included 537 children (<15 years) presenting with acute (<2 weeks) cough, with a median age of 2.2 years (interquartile range 1.0-4.0); 61.5% were boys. Hospitalised children and those with asthma, pneumonia or chronic illnesses were excluded. Main outcome measures were: (i) frequency of pre-ED doctor visits and medication use; and (ii) comparison of management to current evidence-based recommendations related to four discharge diagnoses: bronchiolitis, 'wheeze/reactive airway disease (RAD)', croup and 'non-specific acute respiratory illness'. RESULTS: A total of 300 children (55.9%) had seen a doctor prior to their ED presentation, and use of medications pre-ED was high (53.4%). While 93.4% of children with croup were treated in accordance with guidelines, concordance was lower for children with bronchiolitis or 'wheeze/RAD'. The majority of children with a discharge diagnosis of 'wheeze/RAD' (95.6%) received bronchodilators, and 72.7% also received oral corticosteroids but were not diagnosed with asthma. More than half (55.1%) of the children with non-specific acute respiratory illness received medication(s) either prior to or during their ED presentation. CONCLUSIONS: The burden of acute cough-related illnesses in children is high, and there is a need for improved uptake of evidence-based guidelines. In addition, the large number of children diagnosed with 'wheeze/RAD' suggests asthma is likely under-diagnosed in this setting.
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Costo de Enfermedad , Tos/fisiopatología , Tos/terapia , Servicio de Urgencia en Hospital , Adolescente , Niño , Salud Infantil , Preescolar , Tos/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Queensland/epidemiología , Ruidos Respiratorios/diagnósticoRESUMEN
PURPOSE: Acute respiratory infections (ARIs), and associated symptoms such as cough, are frequently experienced among children and impose a burden on families (e.g., use of medical resources and time off work/school). However, there are little data on changes in, and predictors of, quality of life (QoL) over the duration of an ARI with cough (ARIwC) episode. We therefore aimed to determine cough-specific QoL and identify its influencing factors among children with ARIwC, at the time of presentation to a pediatric emergency department (ED), and over the following 4 weeks. METHODS: Data from 283 children aged < 15 years were included in our analyses. We used the validated parent-proxy children's acute cough-specific QoL questionnaire (PAC-QoL) at each time-point. Linear regression and mixed effect modeling were used to identify factors influencing QoL at baseline and over the follow-up period. RESULTS: Median PAC-QoL at baseline was 2.7 (IQR 2.1-3.6) and significantly improved by Day-7 (4.9, IQR 3.8-6.1) and Day-14 (6.59, IQR 5.1-7.0), both p < 0.001. The improvements in median PAC-QoL between Days-14, -21, and -28 were not significant. Regression modeling identified that day-cough severity, night-cough severity, and financial concerns had the highest impact on both baseline, and follow-up, PAC-QoL scores. There were five additional independent significant factors at baseline and six at follow-up. CONCLUSIONS: Quality of life is considerably impaired at presentation to ED, but improves significantly by Days-7 and -14. As cough severity and financial concerns had the highest impact on QoL, effectively managing cough to reduce the clinical and financial burden on children and families is important.
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Enfermedad Aguda/psicología , Tos/psicología , Calidad de Vida/psicología , Infecciones del Sistema Respiratorio/psicología , Adulto , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Patient-relevant outcome measures are essential for high-quality clinical research, and quality-of-life (QoL) tools are the current standard. Currently, there is no validated children's acute cough-specific QoL questionnaire. OBJECTIVE: The objective of this study was to develop and validate the Parent-proxy Children's Acute Cough-specific QoL Questionnaire (PAC-QoL). METHODS: Using focus groups, a 48-item PAC-QoL questionnaire was developed and later reduced to 16 items by using the clinical impact method. Parents of children with a current acute cough (<2 weeks) at enrollment completed 2 validated cough score measures, the preliminary 48-item PAC-QoL, and 3 other questionnaires (the State Trait Anxiety Inventory [STAI], the Short-Form 8-item 24-hour recall Health Survey [SF-8], and the Depression, Anxiety, and Stress 21-item Scale [DASS21]). All measures were repeated on days 3 and 14. RESULTS: The median age of the 155 children enrolled was 2.3 years (interquartile range, 1.3-4.6). Median cough duration at enrollment was 3 days (interquartile range, 2-5). The reduced 16-item scale had high internal consistency (Cronbach α = 0.95). Evidence for repeatability and criterion validity was shown by significant correlations between the domains and total PAC-QoL scores and the SF-8 (r = -0.36 and -0.51), STAI (r = -0.27 and -0.39), and DASS21 (r = -0.32 and -0.41) scales on days 0 and 3, respectively. The final PAC-QoL questionnaire was sensitive to change over time, with changes significantly relating to changes in cough score measures (P < .001). CONCLUSION: The 16-item PAC-QoL is a reliable and valid outcome measure that assesses QoL related to childhood acute cough at a given time point and reflects changes in acute cough-specific QoL over time.
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Tos/epidemiología , Calidad de Vida , Enfermedad Aguda , Adolescente , Niño , Preescolar , Femenino , Encuestas Epidemiológicas , Humanos , Lactante , Masculino , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Trained for decades to analyze risks, benefits, unique body compositions, and complex medical scenarios, healthcare providers are now faced with one of medicine's most trying obstacles: how to practice medicine when new abortion bans contradict best practice standards. Drawn from qualitative interviews with medical providers in Tennessee, USA conducted between October 2022 and December 2022, this study shows how medical providers often must make medical decisions based on legal risks as opposed to standards of care. This is particularly significant as malpractice insurance does not cover criminal charges. In states with abortion bans, often hastily implemented and subject to changes by lawmakers, medical providers are now practicing a new kind of defensive medicine in an effort to protect themselves from legal threats. We call this hesitant medicine, where providers often experience a tension between their own legal protection and the well-being of their patients, making them hesitant to provide necessary abortion care. This has serious, far-reaching consequences. We focus on three distinct arenas impacted by this new form of defensive medicine, specifically: providers' decision-making around patient care, impacts on patient relationships, and finally, what we call the ultimate defense, leaving states with abortion bans to move to states with fewer legal risks. We conclude with commentary on potential ways to reduce the negative impacts of these trends.
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Aborto Inducido , Humanos , Femenino , Tennessee , Embarazo , Aborto Inducido/legislación & jurisprudencia , Investigación Cualitativa , Medicina Defensiva , Personal de Salud/psicología , Toma de Decisiones , Aborto Legal/legislación & jurisprudenciaRESUMEN
OBJECTIVES: This project aimed to determine where health technology can support best-practice perioperative care for patients waiting for surgery. METHODS: An exploratory codesign process used personas and journey mapping in three interprofessional workshops to identify key challenges in perioperative care across four health districts in Sydney, Australia. Through participatory methodology, the research inquiry directly involved perioperative clinicians. In three facilitated workshops, clinician and patient participants codesigned potential digital interventions to support perioperative pathways. Workshop output was coded and thematically analysed, using design principles. RESULTS: Codesign workshops, involving 51 participants, were conducted October to November 2022. Participants designed seven patient personas, with consumer representatives confirming acceptability and diversity. Interprofessional team members and consumers mapped key clinical moments, feelings and barriers for each persona during a hypothetical perioperative journey. Six key themes were identified: 'preventative care', 'personalised care', 'integrated communication', 'shared decision-making', 'care transitions' and 'partnership'. Twenty potential solutions were proposed, with top priorities a digital dashboard and virtual care coordination. DISCUSSION: Our findings emphasise the importance of interprofessional collaboration, patient and family engagement and supporting health technology infrastructure. Through user-based codesign, participants identified potential opportunities where health technology could improve system efficiencies and enhance care quality for patients waiting for surgical procedures. The codesign approach embedded users in the development of locally-driven, contextually oriented policies to address current perioperative service challenges, such as prolonged waiting times and care fragmentation. CONCLUSION: Health technology innovation provides opportunities to improve perioperative care and integrate clinical information. Future research will prototype priority solutions for further implementation and evaluation.
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Comunicación , Listas de Espera , Humanos , Tecnología Biomédica , Atención Perioperativa , AustraliaRESUMEN
OBJECTIVES: Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies. STUDY DESIGN AND SETTING: Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with postrandomization consent for the intervention group and no specific postrandomization consent for the usual care control group. Information from identified TwiCs was extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to nonuptake of interventions and informed consent procedure. RESULTS: We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46; 17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46; 100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for nonuptake of the intervention, anticipating a median nonuptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for nonuptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%). CONCLUSION: Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial nonuptake of the intervention warrants further research to guide the planning, implementation, and analysis of TwiCs.
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Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.
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BACKGROUND: Cough is the most common symptom presenting to primary healthcare services. Cough in children is associated with significant morbidity for both children and their parents. While inhaled corticosteroids (ICS) can potentially reduce cough associated with airway inflammation and airway hyper-reactivity, use of ICS in children is not without potential adverse effects. Therefore, it would be beneficial to clinical practice to evaluate the evidence for the efficacy of ICS in reducing the severity of cough in children with subacute cough (defined as cough duration of two to four weeks) systematically. OBJECTIVES: To evaluate the efficacy of ICS in reducing the severity of cough in children with subacute cough. SEARCH METHODS: The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE, review articles and reference lists of relevant articles were searched. The latest searches were performed in November 2011. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing ICS with a control group in children with subacute cough were considered for inclusion. DATA COLLECTION AND ANALYSIS: Search results were reviewed against pre-determined criteria for inclusion. Two sets of review authors independently selected, extracted and assessed the data for inclusion. Study authors were contacted for further information where required. Data were analysed as 'intention to treat'. MAIN RESULTS: The search identified 1178 potentially relevant titles; however, there were no published studies that were specifically designed to answer this question. Two studies met criteria for inclusion in the review and 98 children were included in the meta-analysis. There was no significant difference between groups in the proportion of children 'not cured' at follow-up (primary outcome measure), with a pooled odds ratio (OR) of 0.61 (95% confidence interval (CI) 0.24 to 1.55). However, the included studies were limited in their ability to answer the review question by the fact that all participants were infants, post acute bronchiolitis illness, and cough duration at the start of study medication was ill-defined. AUTHORS' CONCLUSIONS: There is currently no evidence to support the use of ICS for treatment of subacute cough in children. However, this systematic review is limited by the small number of studies available for analysis and the size, quality and design of these studies. Further well-designed RCTs are required to support or refute the efficacy of treatment with ICS in children with subacute cough.
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Corticoesteroides/administración & dosificación , Tos/tratamiento farmacológico , Enfermedad Aguda , Administración por Inhalación , Humanos , Lactante , Resultado del TratamientoRESUMEN
AIMS: Olecranon fractures are usually caused by falling directly on to the olecranon or following a fall on to an outstretched arm. Displaced fractures of the olecranon with a stable ulnohumeral joint are commonly managed by open reduction and internal fixation. The current predominant method of management of simple displaced fractures with ulnohumeral stability (Mayo grade IIA) in the UK and internationally is a low-cost technique using tension band wiring. Suture or suture anchor techniques have been described with the aim of reducing the hardware related complications and reoperation. An all-suture technique has been developed to fix the fracture using strong synthetic sutures alone. The aim of this trial is to investigate the clinical and cost-effectiveness of tension suture repair versus traditional tension band wiring for the surgical fixation of Mayo grade IIA fractures of the olecranon. METHODS: SOFFT is a multicentre, pragmatic, two-arm parallel-group, non-inferiority, randomized controlled trial. Participants will be assigned 1:1 to receive either tension suture fixation or tension band wiring. 280 adult participants will be recruited. The primary outcome will be the Disabilities of the Arm, Shoulder and Hand (DASH) score at four months post-randomization. Secondary outcome measures include DASH (at 12, 18, and 24 months), pain, Net Promotor Score (patient satisfaction), EuroQol five-dimension five-level score (EQ-5D-5L), radiological union, complications, elbow range of motion, and re-operations related to the injury or to remove metalwork. An economic evaluation will assess the cost-effectiveness of treatments. DISCUSSION: There is currently no high-quality evidence comparing the clinical and cost effectiveness of the tension suture repair to the traditional tension band wiring currently offered for the internal fixation of displaced fractures of the olecranon. The Simple Olecranon Fracture Fixation Trial (SOFFT) is a randomized controlled trial with sufficient power and design rigour to provide this evidence for the subtype of Mayo grade IIA fractures.Cite this article: Bone Jt Open 2023;4(1):27-37.
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BACKGROUND: Prescribing of potentially inappropriate medications and under-prescribing of guideline-recommended medications for cardiovascular risk modification have both been associated with negative outcomes in older adults. Hospitalisation represents an important opportunity to optimise medication use and may be achieved through geriatrician-led interventions. OBJECTIVE: We aimed to evaluate whether implementation of a novel model of care called Geriatric Comanagement of older Vascular (GeriCO-V) surgery patients is associated with improvements in medication prescribing. METHODS: We used a prospective pre-post study design. The intervention was a geriatric co-management model, where a geriatrician delivered comprehensive geriatric assessment-based interventions including a routine medication review. We included consecutively admitted patients to the vascular surgery unit at a tertiary academic centre aged ≥ 65 years with an expected length of stay of ≥ 2 days and who were discharged from hospital. Outcomes of interest were the prevalence of at least one potentially inappropriate medication as defined by the Beers Criteria at admission and discharge, and rates of cessation of at least one potentially inappropriate medication present on admission. In the subgroup of patients with peripheral arterial disease, the prevalence of guideline-recommended medications on discharge was determined. RESULTS: There were 137 patients in the pre-intervention group (median [interquartile range] age: 80.0 [74.0-85.0] years, 83 [60.6%] with peripheral arterial disease) and 132 patients in the post-intervention group (median [interquartile range] age: 79.0 (73.0-84.0) years, 75 [56.8%] with peripheral arterial disease). There was no change in the prevalence of potentially inappropriate medication use from admission to discharge in either group (pre-intervention: 74.5% on admission vs 75.2% on discharge; post-intervention: 72.0% vs 72.7%, p = 0.65). Forty-five percent of pre-intervention group patients had at least one potentially inappropriate medication present on admission ceased, compared with 36% of post-intervention group patients (p = 0.11). A higher number of patients with peripheral arterial disease in the post-intervention group were discharged on antiplatelet agent therapy (63 [84.0%] vs 53 [63.9%], p = 0.004) and lipid-lowering therapy (58 [77.3%] vs 55 [66.3%], p = 0.12). CONCLUSIONS: Geriatric co-management was associated with an improvement in guideline-recommended antiplatelet agent prescribing aimed at cardiovascular risk modification for older vascular surgery patients. The prevalence of potentially inappropriate medications was high in this population, and was not reduced with geriatric co-management.
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Prescripción Inadecuada , Enfermedad Arterial Periférica , Humanos , Anciano , Anciano de 80 o más Años , Estudios Prospectivos , Inhibidores de Agregación Plaquetaria , Hospitalización , Lista de Medicamentos Potencialmente Inapropiados , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugíaRESUMEN
Chronic osteomyelitis (COM) of the lower limb in adults can be surgically managed by either limb reconstruction or amputation. This scoping review aims to map the outcomes used in studies surgically managing COM in order to aid future development of a core outcome set. A total of 11 databases were searched. A subset of studies published between 1 October 2020 and 1 January 2011 from a larger review mapping research on limb reconstruction and limb amputation for the management of lower limb COM were eligible. All outcomes were extracted and recorded verbatim. Outcomes were grouped and categorized as per the revised Williamson and Clarke taxonomy. A total of 3,303 records were screened, of which 99 studies were included. Most studies were case series (77/99; 78%) and assessed one method of reconstruction (68/99; 69%). A total of 511 outcomes were reported, which were grouped into 58 distinct outcomes. Overall, 143/511 of all outcomes (28%) were provided with a clear, in-text definition, and 231 outcomes (45%) had details reported of how and when they were measured. The most commonly reported outcome was 'recurrence of osteomyelitis' (62; 12%). The single-most patient-reported outcome measure was 'pain'. This study has highlighted significant inconsistencies in the defining, reporting, and measuring of outcomes across studies investigating surgical management for chronic osteomyelitis of the lower limb in adults. Future studies should clearly report complete details of how outcomes are defined and measured, including timing. The development of a standardized core outcome set would be of significant benefit in order to allow evidence synthesis and comparison across studies.
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Background: RCTs often face issues such as slow recruitment, poor intervention adherence and high attrition, however the 2020/2021 COVID-19 pandemic intensified these challenges. Strategies employed by the DISC trial to overcome pandemic-related barriers to recruitment, treatment delivery and retention may be useful to help overcome routine problems. Methods: A structured survey and teleconference with sites was undertaken. Key performance indicators in relation to recruitment, treatment delivery and retention were compared descriptively before and after the pandemic started. This was situated also in relation to qualitative opinions of research staff. Results: Prior to the pandemic, retention was 93.6%. Increased support from the central trial management team and remote data collection methods kept retention rates high at 81.2% in the first 6 months of the pandemic, rising to 89.8% in the subsequent 6 months. Advertising the study to patients resulted in 12.8 patients/month enquiring about participation, however only six were referred to recruiting sites. Sites reported increased support from junior doctors resolved research nurse capacity issues. One site avoided long delays by using theatre space in a private hospital. Conclusions: Recruitment post-pandemic could be improved by identification of barriers, increased support from junior doctors through the NIHR associate PI scheme and advertising. Remote back-up options for data collection can keep retention high while reducing patient and site burden. To future proof studies against similar disruptions and provide more flexibility for participants, we recommend that RCTs have a back-up option of remote recruitment, a back-up location for surgeries and flexible approaches to collecting data.
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Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.
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Leucemia Mieloide Aguda , Manosa , Humanos , Muerte Celular , Citarabina/farmacología , Línea Celular Tumoral , Leucemia Mieloide Aguda/metabolismo , Apoptosis , Tirosina Quinasa 3 Similar a fmsRESUMEN
OBJECTIVE: To determine bronchoalveolar lavage (BAL) levels of 3 innate immunity components (human ß-defensin-2 [hBD2], mannose-binding lectin [MBL], and surfactant protein-A [SP-A]), the relationship with airway neutrophilia and infection, and cytokine production of stimulated BAL cells in children with current protracted bacterial bronchitis (PBB), children with resolved PBB (PBB well), and controls. STUDY DESIGN: BAL of 102 children (mean age 2.8 years) fulfilling predefined criteria of current PBB (n = 61), PBB well (n = 20), and controls (n = 21) was cultured (quantitative bacteriology) and viruses examined by polymerase chain reaction. hBD2, MBL, and SP-A were measured, and cytokine production by lipopolysaccharide-stimulated BAL cells was determined. RESULTS: Median hBD2 and MBL levels were significantly higher in the current PBB group (hBD2 = 164.4, IQR 0-435.5 pg/mL; MBL = 1.7, 0.4-4 ng/mL) than in the PBB well group (hBD2 = 0, IQR 0-85.2; MBL = 0.6, IQR 0.03-2.9) and controls (hBD2 = 3.6, IQR 0-126; MBL = 0.4, IQR 0.02-79). hBD2 was significantly higher in children with airway infection (n = 54; median 76.9, IQR 0-397.3) compared with those without (n = 48; 0, IQR 0-236.3), P= .04. SP-A levels and cytokine production of stimulated BAL cells were similar between groups. CONCLUSION: In children's airways, hBD2, but not MBL and SP-A, relates to inflammation and infection. In children with PBB, mechanisms involving airway hBD2 and MBL are augmented. These pulmonary innate immunity components and the ability of BAL cells to respond to stimuli are unlikely to be deficient.
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Líquido del Lavado Bronquioalveolar/química , Lectina de Unión a Manosa/análisis , Proteína A Asociada a Surfactante Pulmonar/análisis , beta-Defensinas/análisis , Bronquitis Crónica , Broncoscopía , Preescolar , Femenino , Humanos , Inmunidad Innata , Lactante , MasculinoRESUMEN
BACKGROUND: Chronic respiratory illnesses are the most common group of childhood chronic health conditions and are overrepresented in socially isolated groups. OBJECTIVE: To conduct a randomized controlled pilot trial to evaluate the efficacy of Breathe Easier Online (BEO), an Internet-based problem-solving program with minimal facilitator involvement to improve psychosocial well-being in children and adolescents with a chronic respiratory condition. METHODS: We randomly assigned 42 socially isolated children and adolescents (18 males), aged between 10 and 17 years to either a BEO (final n = 19) or a wait-list control (final n = 20) condition. In total, 3 participants (2 from BEO and 1 from control) did not complete the intervention. Psychosocial well-being was operationalized through self-reported scores on depression symptoms and social problem solving. Secondary outcome measures included self-reported attitudes toward their illness and spirometry results. Paper-and-pencil questionnaires were completed at the hospital when participants attended a briefing session at baseline (time 1) and in their homes after the intervention for the BEO group or a matched 9-week time period for the wait-list group (time 2). RESULTS: The two groups were comparable at baseline across all demographic measures (all F < 1). For the primary outcome measures, there were no significant group differences on depression (P = .17) or social problem solving (P = .61). However, following the online intervention, those in the BEO group reported significantly lower depression (P = .04), less impulsive/careless problem solving (P = .01), and an improvement in positive attitude toward their illness (P = .04) compared with baseline. The wait-list group did not show these differences. Children in the BEO group and their parents rated the online modules very favorably. CONCLUSIONS: Although there were no significant group differences on primary outcome measures, our pilot data provide tentative support for the feasibility (acceptability and user satisfaction) and initial efficacy of an Internet-based intervention for improving well-being in children and adolescents with a chronic respiratory condition. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number: ACTRN12610000214033; http://www.anzctr.org.au/trial_view.aspx?ID=308074 (Archived by WebCite at http://www.webcitation.org/63BL55mXH).
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Internet , Enfermedades Respiratorias/terapia , Adolescente , Niño , Enfermedad Crónica , Femenino , Humanos , Masculino , Proyectos Piloto , Enfermedades Respiratorias/fisiopatología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Dupuytren's contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment; however, recent studies have indicated that an alternative to surgery-collagenase clostridium histolyticum (collagenase)-is better than a placebo in the treatment of Dupuytren's contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of collagenase compared with limited fasciectomy surgery. Dupuytren's intervention surgery vs collagenase trial (DISC) trial was therefore designed to fill this evidence gap. METHODS/DESIGN: The DISC trial is a multi-centre pragmatic two-arm parallel-group, randomised controlled trial. Participants will be assigned 1:1 to receive either collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren's contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported patient evaluation measure assessed 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost-effectiveness of treatments, and a qualitative sub-study will assess participants' experiences and preferences of the treatments. DISCUSSION: The DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost-effectiveness of collagenase compared to limited fasciectomy surgery for patients with Dupuytren's contracture. TRIAL REGISTRATION: Clinical.Trials.gov ISRCTN18254597 . Registered on April 11, 2017.
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Contractura de Dupuytren , Recurrencia Local de Neoplasia , Adulto , Colagenasas/efectos adversos , Contractura de Dupuytren/diagnóstico , Contractura de Dupuytren/tratamiento farmacológico , Contractura de Dupuytren/cirugía , Fasciotomía , Humanos , Masculino , Colagenasa Microbiana/efectos adversos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Background: Postal questionnaires are frequently used in randomised controlled trials to collect outcome data on participants; however, poor response can introduce bias, affect generalisability and validity, and reduce statistical power. The objective of this study was to assess whether a pen and/or social incentive text cover letter sent with a postal follow-up questionnaire increased response rates in a trial. Method: A two-by-two factorial randomised controlled trial was embedded within the OTIS host trial. Participants due their 12-month (final) follow-up questionnaire were randomised to be sent: a pen; a social incentive text cover letter; both; or neither. The primary outcome measure was the proportion of participants in each group who returned the questionnaire. Secondary outcomes were: time to return, completeness of the questionnaire, necessity of a reminder letter, and the cost effectiveness. Results: The overall 12-month questionnaire response rate was 721 out of 755 (95.5%). Neither the pen nor social incentive cover letter had a statistically significant effect on response rate: pen 95.2% vs. no pen 95.8%, adjusted OR 0.90 (95% CI 0.45 to 1.80; p=0.77); social incentive cover letter 95.2% vs. no social incentive cover letter 95.8%, adjusted OR 0.84 (95% CI 0.42 to 1.69, p=0.63). No statistically significant differences were observed between either of the intervention groups on time to response, need for a reminder or completeness. Therefore, neither intervention was cost-effective. Conclusions: We found no evidence of a difference in response rates associated with the inclusion of a pen and/or social incentive cover letter with the final follow-up postal questionnaire of the host trial. However, when these results are combined with previous SWATs, the meta-analysis evidence remains that including a pen increases response rates. The social incentive cover letter warrants further investigation to determine effectiveness. Trial registration: ISRCTN22202133 (21st June 2020).