Sample size determination for external pilot cluster randomised trials with binary feasibility outcomes:a tutorial

Abstract Justifying sample size for a pilot trial is a reporting requirement, but few pilot trials report a clear rationale for their chosen sample size. Unlike full-scale trials, pilot trials should not be designed to test effectiveness, and so, conventional sample size justification approaches do not apply. Rather, pilot trials typically specify a range of primary and secondary feasibility objectives. Often, these objectives relate to estimation of parameters that inform the sample size justification for the full-scale trial, many of which are binary. These binary outcomes are referred to as “feasibility outcomes” and include expected prevalence of the primary trial outcome, primary outcome availability, or recruitment or retention proportions. For pilot cluster trials, sample size calculations depend on the number of clusters, the cluster sizes, the anticipated intra-cluster correlation coefficient for the feasibility outcome and the anticipated proportion for that outcome. Of key importance is the intra-cluster correlation coefficient for the feasibility outcome. It has been suggested that correlations for feasibility outcomes are larger than for clinical outcomes measuring effectiveness. Yet, there is a dearth of information on realised values for these correlations. In this tutorial, we demonstrate how to justify sample size in external pilot cluster trials where the objective is to estimate a binary feasibility outcome. We provide sample size calculation formulae for a variety of scenarios, make available an R Shiny app for implementation, and compile a report of intra-cluster correlations for feasibility outcomes from a convenience sample. We demonstrate that unless correlations are very low, external pilot cluster trials can be made more efficient by including more clusters and fewer observations per cluster

Antenatal preventative pelvic floor muscle exercise intervention led by midwives to reduce postnatal urinary incontinence (APPEAL): protocol for a feasibility and pilot cluster randomised controlled trial

Background: Antenatal pelvic floor muscle exercises (PFME) in women without prior urinary incontinence (UI) are effective in reducing postnatal UI; however, UK midwives often do not provide advice and information to women on undertaking PFME, with evidence that among women who do receive advice, many do not perform PFME. Methods: The primary aim of this feasibility and pilot cluster randomised controlled trial is to provide a potential assessment of the feasibility of undertaking a future definitive trial of a midwifery-led antenatal intervention to support women to perform PFME in pregnancy and reduce UI postnatally. Community midwifery teams in participating NHS sites comprise trial clusters (n = 17). Midwives in teams randomised to the intervention will be trained on how to teach PFME to women and how to support them in undertaking PFME in pregnancy. Women whose community midwifery teams are allocated to control will receive standard antenatal care only. All pregnant women who give birth over a pre-selected sample month who receive antenatal care from participating community midwifery teams (clusters) will be sent a questionnaire at 10–12 weeks postpartum (around 1400–1500 women). Process evaluation data will include interviews with midwives to assess if the intervention could be implemented as planned. Interviews with women in both trial arms will explore their experiences of support from midwives to perform PFME during pregnancy. Data will be stored securely at the Universities of Birmingham and Exeter. Results will be disseminated through publications aimed at maternity service users, clinicians, and academics and inform a potential definitive trial of effectiveness. The West Midlands–Edgbaston Research Ethics Committee approved the study protocol. Discussion: Trial outcomes will determine if criteria to progress to a definitive cluster trial are met. These include women’s questionnaire return rates, prevalence of UI, and other health outcomes as reported by women at 10–12 weeks postpartum. Progress to a definitive trial however is likely to be prevented in the UK context by new perinatal pelvic health service, although this may be possible elsewhere. Trial registration: https://doi.org/10.1186/ISRCTN10833250. Registered 09/03/202

Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

BACKGROUND: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions. OBJECTIVES: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources. METHODS: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS). RESULTS: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices. CONCLUSIONS: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS

Cumulative incidence and risk factors for cutaneous squamous-cell carcinoma metastases in organ transplant recipients: the SCOPE-ITSCC metastases study, a prospective multi-center study.

Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous-cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. Of 514 SOTRs who presented with 623 primary cSCCs, 37 developed metastases with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size >2cm, clinical ulceration, poor differentiation grade, perineural invasion and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9% - 68.4%). SOTRs have a high risk of cSCC metastases and well-established clinical and histological risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis. [Abstract copyright: Copyright © 2024. Published by Elsevier Inc.

SN 2020zbf: A fast-rising hydrogen-poor superluminous supernova with strong carbon lines

SN 2020zbf is a hydrogen-poor superluminous supernova at $z = 0.1947$ that shows conspicuous C II features at early times, in contrast to the majority of H-poor SLSNe. Its peak magnitude is $M_{\rm g}$ = $-21.2$ mag and its rise time ($\lesssim 24$ days from first light) place SN 2020zbf among the fastest rising SLSNe-I. Spectra taken from ultraviolet (UV) to near-infrared wavelengths are used for the identification of spectral features. We pay particular attention to the C II lines as they present distinctive characteristics when compared to other events. We also analyze UV and optical photometric data, and model the light curves considering three different powering mechanisms: radioactive decay of Ni, magnetar spin-down and circumstellar material interaction (CSM). The spectra of SN 2020zbf match well with the model spectra of a C-rich low-mass magnetar model. This is consistent with our light curve modelling which supports a magnetar-powered explosion with a $M_{\rm ej}$ = 1.5 $M_\odot$. However, we cannot discard the CSM-interaction model as it also may reproduce the observed features. The interaction with H-poor, carbon-oxygen CSM near peak could explain the presence of C II emission lines. A short plateau in the light curve, around 30 - 40 days after peak, in combination with the presence of an emission line at 6580 \r{A} can also be interpreted as late interaction with an extended H-rich CSM. Both the magnetar and CSM interaction models of SN 2020zbf indicate that the progenitor mass at the time of explosion is between 2 - 5 $M_\odot$. Modelling the spectral energy distribution of the host reveals a host mass of 10$^{8.7}$ $M_\odot$, a star-formation rate of 0.24$^{+0.41}_{-0.12}$ $M_\odot$ yr$^{-1}$ and a metallicity of $\sim$ 0.4 $Z_\odot$.Comment: 26 pages, 22 figures, submitted to A&

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Density and Temperature of the Electron Core in the Inner Magnetosphere of Saturn from Cassini/RPWS Antennas (abstract). Planetary Radio Emissions| PLANETARY RADIO EMISSIONS VII 7|

We study the large scale structures of the electron core in the inner magnetosphere of Saturn (from the G-ring to Rhea orbit - i.e. 2.8 to 9 Rs). This study is deduced from the power spectra measurements acquired with the Cassini/RPWS electric dipole around the local plasma frequency (quasi-thermal noise spectroscopy), from July 2004 (SOI) to February 2010. We have especially investigated the radial diffusion and latitudinal confinement of the plasma torus towards Enceladus and Dione. We also discuss the longitudinal variations of the electron parameters using the recent SLS3 system. We will finally touch about the dust detection by using the RF power spectra measured on the monopole antenna and the possible effect of the dust on the observed electron parameters

Metabolism of 2-acylglycerol in rabbit and human platelets. Involvement of monoacylglycerol lipase and fatty acid amide hydrolase

The endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (N-arachidonoylethanolamine, AEA) are produced by neurons and other cells, including platelets, in a stimulus-dependent manner and act as signaling molecules; they are then inactivated through transport into cells followed by enzymatic degradation. A number of studies showed that monoacylglycerol lipase (MAGL) plays an important role in the degradation of 2-AG. In this study we investigated the enzymatic degradation of 2-acylglycerols in rabbit platelets and we characterized the responsible enzyme(s). [ 3H]2-AG and [ 3H]2-oleoylglycerol (2-OG) were both metabolized to [ 3H]glycerol and the respective fatty acid in a time and protein concentration-dependent manner, apparently by the action of MAGL activity. In the presence of the specific fatty acid amide hydrolase (FAAH) inhibitors URB597 and AM374, though, 2-OG hydrolysis was inhibited up to 55% in a concentration-dependent manner (Ic50 = 129.8 nM and 20.9 nM respectively). These results indicate the involvement of both MAGL and FAAH on 2-acylglycerol hydrolysis. MAGL was further characterized in the presence of URB597 and it was found that 2-monoacylglycerols were hydrolyzed in a time, pH and protein concentration-dependent manner and hydrolysis followed Michaelis-Menten kinetics, with an apparent KM of 0.11 μM and Vmax of 1.32 nmol/min*mg protein. Subcellular fractionation of platelet homogenate showed that MAGL activity was present in both the cytosolic and membrane fractions. In conclusion, the endocannabinoid 2-AG, as well as other 2-acylglycerols, are substrates of both FAAH and MAGL; the latter was characterized for the first time in platelets. In human platelets, under the same experimental conditions, the hydrolysis of 2-acylglycerols was higher and MAGL activity showed a different sensitivity against the inhibitors mentioned above. Finally, immunoblot analysis revealed the presence of MAGL, both in rabbit and human platelets, with a molecular mass of ∼ü33 kDa. © 2009 Informa UK Ltd All rights reserved