Publications by authors named "Jonathan Cook"

275 Publications

The challenge of equipoise in trials with a surgical and non-surgical comparison: a qualitative synthesis using meta-ethnography.

Trials 2021 Oct 7;22(1):678. Epub 2021 Oct 7.

Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Background: Randomised controlled trials in surgery can be a challenge to design and conduct, especially when including a non-surgical comparison. As few as half of initiated surgical trials reach their recruitment target, and failure to recruit is cited as the most frequent reason for premature closure of surgical RCTs. The aim of this qualitative evidence synthesis was to identify and synthesise findings from qualitative studies exploring the challenges in the design and conduct of trials directly comparing surgical and non-surgical interventions.

Methods: A qualitative evidence synthesis using meta-ethnography was conducted. Six electronic bibliographic databases (Medline, Central, Cinahl, Embase and PsycInfo) were searched up to the end of February 2018. Studies that explored patients' and health care professionals' experiences regarding participating in RCTs with a surgical and non-surgical comparison were included. The GRADE-CERQual framework was used to assess confidence in review findings.

Results: In total, 3697 abstracts and 49 full texts were screened and 26 published studies reporting experiences of patients and healthcare professionals were included. The focus of the studies (24/26) was primarily related to the challenge of recruitment. Two studies explored reasons for non-compliance to treatment allocation following randomisation. Five themes related to the challenges to these types of trials were identified: (1) radical choice between treatments; (2) patients' discomfort with randomisation: I want the best treatment for me as an individual; (3) challenge of equipoise: patients' a priori preferences for treatment; (4) challenge of equipoise: clinicians' a priori preferences for treatment and (5) imbalanced presentation of interventions.

Conclusion: The marked dichotomy between the surgical and non-surgical interventions was highlighted in this review as making recruitment to these types of trials particularly challenging. This review identified factors that increase our understanding of why patients and clinicians may find equipoise more challenging in these types of trials compared to other trial comparisons. Trialists may wish to consider exploring the balance of potential factors influencing patient and clinician preferences towards treatments before they start recruitment, to enable issues specific to a particular trial to be identified and addressed. This may enable trial teams to make more efficient considered design choices and benefit the delivery of such trials.
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http://dx.doi.org/10.1186/s13063-021-05403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495989PMC
October 2021

Psychological Science in the Wake of COVID-19: Social, Methodological, and Metascientific Considerations.

Perspect Psychol Sci 2021 Oct 1:1745691621999374. Epub 2021 Oct 1.

Department of Psychology, University of California, Davis.

The COVID-19 pandemic has extensively changed the state of psychological science from what research questions psychologists can ask to which methodologies psychologists can use to investigate them. In this article, we offer a perspective on how to optimize new research in the pandemic's wake. Because this pandemic is inherently a social phenomenon-an event that hinges on human-to-human contact-we focus on socially relevant subfields of psychology. We highlight specific psychological phenomena that have likely shifted as a result of the pandemic and discuss theoretical, methodological, and practical considerations of conducting research on these phenomena. After this discussion, we evaluate metascientific issues that have been amplified by the pandemic. We aim to demonstrate how theoretically grounded views on the COVID-19 pandemic can help make psychological science stronger-not weaker-in its wake.
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http://dx.doi.org/10.1177/1745691621999374DOI Listing
October 2021

Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop.

Health Technol Assess 2021 09;25(53):1-52

Editorial Department, The Lancet, London, UK.

Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges.

Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials.

Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout.

Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines.

Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect.

Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial.

Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS.

Future Work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.

Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme.
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http://dx.doi.org/10.3310/hta25530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450778PMC
September 2021

Findings from the patch augmented rotator cuff surgery (PARCS) feasibility study.

Pilot Feasibility Stud 2021 Aug 20;7(1):163. Epub 2021 Aug 20.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: A rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The patch augmented rotator cuff surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible.

Methods: A mixed methods feasibility study of conducing a subsequent RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder Society's (BESS) surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting.

Results: The BESS surgeons' survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting.

Conclusions: Randomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders.
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http://dx.doi.org/10.1186/s40814-021-00899-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377837PMC
August 2021

Early detection of neovascular age-related macular degeneration: an economic evaluation based on data from the EDNA study.

Br J Ophthalmol 2021 Aug 2. Epub 2021 Aug 2.

Health Economics Research Unit, University of Aberdeen, Aberdeen, UK

Background/aims: To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting.

Methods: A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon.

Results: SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient's subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient's subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%-99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000-£30 000) applied in the UK NHS.

Conclusions: Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.
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http://dx.doi.org/10.1136/bjophthalmol-2021-319506DOI Listing
August 2021

Diagnostic Accuracy of Monitoring Tests of Fellow Eyes in Patients with Unilateral Neovascular Age-Related Macular Degeneration: Early Detection of Neovascular Age-Related Macular Degeneration Study.

Ophthalmology 2021 Jul 28. Epub 2021 Jul 28.

Centre for Public Health, Queen's University Belfast, Belfast, Ireland. Electronic address:

Purpose: To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD).

Design: Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years.

Participants: Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD.

Methods: Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA.

Main Outcome Measures: Sensitivity and specificity of the 5 index tests.

Results: Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination.

Conclusions: Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.
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http://dx.doi.org/10.1016/j.ophtha.2021.07.025DOI Listing
July 2021

Geospatial analysis of pediatric surgical need and geographical access to care in Somaliland: a cross-sectional study.

BMJ Open 2021 07 21;11(7):e042969. Epub 2021 Jul 21.

Department of Public Health, Baylor University, Waco, Texas, USA

Background: The global burden of disease in children is large and disproportionally affects low-income and middle-income countries (LMICs). Geospatial analysis offers powerful tools to quantify and visualise disparities in surgical care in LMICs. Our study aims to analyse the geographical distribution of paediatric surgical conditions and to evaluate the geographical access to surgical care in Somaliland.

Methods: Using the Surgeons OverSeas Assessment of Surgical Need survey and a combined survey from the WHO's (WHO) Surgical Assessment Tool-Hospital Walkthrough and the Global Initiative for Children's Surgery Global Assessment in Paediatric Surgery, we collected data on surgical burden and access from 1503 children and 15 hospitals across Somaliland. We used several geospatial tools, including hotspot analysis, service area analysis, Voronoi diagrams, and Inverse Distance Weighted interpolation to estimate the geographical distribution of paediatric surgical conditions and access to care across Somaliland.

Results: Our analysis suggests less than 10% of children have timely access to care across Somaliland. Patients could travel up to 12 hours by public transportation and more than 2 days by foot to reach surgical care. There are wide geographical disparities in the prevalence of paediatric surgical conditions and access to surgical care across regions. Disparities are greater among children travelling by foot and living in rural areas, where the delay to receive surgery often exceeds 3 years. Overall, Sahil and Sool were the regions that combined the highest need and the poorest surgical care coverage.

Conclusion: Our study demonstrated wide disparities in the distribution of surgical disease and access to surgical care for children across Somaliland. Geospatial analysis offers powerful tools to identify critical areas and strategically allocate resources and interventions to efficiently scale-up surgical care for children in Somaliland.
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http://dx.doi.org/10.1136/bmjopen-2020-042969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296779PMC
July 2021

Risks posed by SARS-CoV-2 to North American bats during winter fieldwork.

Conserv Sci Pract 2021 Jun 30;3(6):e410. Epub 2021 Mar 30.

U.S. Geological Survey Patuxent Wildlife Research Center Laurel Maryland USA.

The virus that causes COVID-19 likely evolved in a mammalian host, possibly Old-World bats, before adapting to humans, raising the question of whether reverse zoonotic transmission to bats is possible. Wildlife management agencies in North America are concerned that the activities they authorize could lead to transmission of SARS-CoV-2 to bats from humans. A rapid risk assessment conducted in April 2020 suggested that there was a small but significant possibility that SARS-CoV-2 could be transmitted from humans to bats during summer fieldwork, absent precautions. Subsequent challenge studies in a laboratory setting have shed new information on these risks, as has more detailed information on human epidemiology and transmission. This inquiry focuses on the risk to bats from winter fieldwork, specifically surveys of winter roosts and handling of bats to test for white-nose syndrome or other research needs. We use an aerosol transmission model, with parameter estimates both from the literature and from formal expert judgment, to estimate the risk to three species of North American bats, as a function of several factors. We find that risks of transmission are lower than in the previous assessment and are notably affected by chamber volume and local prevalence of COVID-19. Use of facemasks with high filtration efficiency or a negative COVID-19 test before field surveys can reduce zoonotic risk by 65 to 88%.
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http://dx.doi.org/10.1111/csp2.410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250205PMC
June 2021

Evidence-Based Clinical Practice Guideline: Reconstruction after Skin Cancer Resection.

Dermatol Surg 2021 Jul;47(7):891-907

Farmington, Conn.; Winston-Salem, Durham, and Gastonia, N.C.; Cleveland, Ohio; Walnut Creek, Irvine, and Sacramento, Calif.; Arlington Heights and Chicago, Ill.; Chantilly, Va.; Washington, D.C.; St. Augustine, West Palm Beach, Tampa, and Orlando, Fla.; Philadelphia and Hershey, Pa.; Marlton, N.J.; Indianapolis, Ind.; Iowa City, Iowa; and New York, N.Y.

Summary: A multi-disciplinary work group involving stakeholders from various backgrounds and societies was convened to develop guidelines for the management of reconstruction after skin cancer resection. The goal was to identify areas of common ground and provide evidence-based recommendations to improve patient care. Given the heterogeneity of reconstructive techniques and clinical scenarios, investigation centered around common elements in the process. In some cases, a distinction was made between treatment options in the office-based setting as opposed to those in the facility setting. A systematic literature review was performed, and an established appraisal process was used to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology). Final recommendations are related to concepts concerning the timing of reconstruction, management of anticoagulation, use of antibiotics, methods of pain control, and follow-up assessment. At times, there was insufficient evidence to make high-level recommendations. The literature analysis highlights the need for additional methodologically robust studies in this area, to help guide clinical practice.
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http://dx.doi.org/10.1097/DSS.0000000000003115DOI Listing
July 2021

Intermittent short-arm centrifugation is a partially effective countermeasure against upright balance deterioration following 60-day head-down tilt bed rest.

J Appl Physiol (1985) 2021 08 1;131(2):689-701. Epub 2021 Jul 1.

Aerospace Medicine and Rehabilitation Laboratory, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.

This study investigated whether artificial gravity (AG), induced by short-radius centrifugation, mitigated deterioration in standing balance and anticipatory postural adjustments (APAs) of trunk muscles following 60-day head-down tilt bed rest. Twenty-four participants were allocated to one of three groups: control group ( = 8); 30-min continuous AG daily ( = 8); and intermittent 6 × 5 min AG daily ( = 8). Before and immediately after bed rest, standing balance was assessed in four conditions: eyes open and closed on both stable and foam surfaces. Measures including sway path, root mean square, and peak sway velocity, sway area, sway frequency power, and sway density curve were extracted from the center of pressure displacement. APAs were assessed during rapid arm movements using intramuscular or surface electromyography electrodes of the rectus abdominis; obliquus externus and internus abdominis; transversus abdominis; erector spinae at L1, L2, L3, and L4 vertebral levels; and deep lumbar multifidus muscles. The relative latency between the EMG onset of the deltoid and each of the trunk muscles was calculated. All three groups had poorer balance performance in most of the parameters (all < 0.05) and delayed APAs of the trunk muscles following bed rest (all < 0.05). Sway path and sway velocity were deteriorated, and sway frequency power was less in those who received intermittent AG than in the control group (all < 0.05), particularly in conditions with reduced proprioceptive feedback. These data highlight the potential of intermittent AG to mitigate deterioration of some aspects of postural control induced by gravitational unloading, but no protective effects on trunk muscle responses were observed. This study presents novel insights into the effect of artificial gravity (AG) on the deterioration of standing balance and anticipatory postural adjustments (APAs) of trunk muscles induced by 60-day strict head-down bed rest. The results indicated severe balance dysfunction and delayed APAs during rapid arm movement. AG partially mitigated the deterioration in standing balance and may thus be considered as a potential countermeasure for future planetary surface explorations. Optimization of AG protocols might enhance effects.
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http://dx.doi.org/10.1152/japplphysiol.00180.2021DOI Listing
August 2021

Letter to the editor regarding "Incomparability of treatment groups is often blindly ignored in randomised controlled trials - a post hoc analysis of baseline characteristic tables".

J Clin Epidemiol 2021 Jun 15. Epub 2021 Jun 15.

University of Oxford, Centre for Statistics in Medicine; Nuffield Dept of Orthopaedics Rheumatology an, Oxford, Oxfordshire, United Kingdom.

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http://dx.doi.org/10.1016/j.jclinepi.2021.04.022DOI Listing
June 2021

Need satisfaction in intergroup contact: A multinational study of pathways toward social change.

J Pers Soc Psychol 2021 Jun 17. Epub 2021 Jun 17.

Department of Psychology, University of Groningen.

What role does intergroup contact play in promoting support for social change toward greater social equality? Drawing on the needs-based model of reconciliation, we theorized that when inequality between groups is perceived as illegitimate, disadvantaged group members will experience a need for empowerment and advantaged group members a need for acceptance. When intergroup contact satisfies each group's needs, it should result in more mutual support for social change. Using four sets of survey data collected through the Zurich Intergroup Project in 23 countries, we tested several preregistered predictions, derived from the above reasoning, across a large variety of operationalizations. Two studies of disadvantaged groups (Ns = 689 ethnic minority members in Study 1 and 3,382 sexual/gender minorities in Study 2) support the hypothesis that, after accounting for the effects of intergroup contact and perceived illegitimacy, satisfying the need for empowerment (but not acceptance) during contact is positively related to support for social change. Two studies with advantaged groups (Ns = 2,937 ethnic majority members in Study 3 and 4,203 cis-heterosexual individuals in Study 4) showed that, after accounting for illegitimacy and intergroup contact, satisfying the need for acceptance (but also empowerment) is positively related to support for social change. Overall, findings suggest that intergroup contact is compatible with efforts to promote social change when group-specific needs are met. Thus, to encourage support for social change among both disadvantaged and advantaged group members, it is essential that, besides promoting mutual acceptance, intergroup contact interventions also give voice to and empower members of disadvantaged groups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pspi0000365DOI Listing
June 2021

Lumbar muscle atrophy and increased relative intramuscular lipid concentration are not mitigated by daily artificial gravity after 60-day head-down tilt bed rest.

J Appl Physiol (1985) 2021 07 3;131(1):356-368. Epub 2021 Jun 3.

Aerospace Medicine and Rehabilitation Laboratory, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.

Exposure to axial unloading induces adaptations in paraspinal muscles, as shown after spaceflights. This study investigated whether daily exposure to artificial gravity (AG) mitigated lumbar spine flattening and muscle atrophy associated with 60-day head-down tilt (HDT) bed rest (Earth-based space analog). Twenty-four healthy individuals participated in the study: 8 received 30-min continuous AG; 8 received 6 × 5-min AG interspersed with rest periods; and 8 received no AG exposure (control group). Magnetic resonance imaging (MRI) of the lumbopelvic region was conducted at baseline (BDC) and at day 59 of HDT (HDT59). Longitudinal relaxation time (T1)-weighted images were used to assess morphology of the lumbar spine (spinal length, intervertebral disk angles, disk area) and volumes of the lumbar multifidus (LM), lumbar erector spinae (LES), quadratus lumborum (QL), and psoas major (PM) muscles from L/L to L/S vertebral levels. A chemical shift-based two-point lipid/water Dixon sequence was used to evaluate muscle composition. Results showed that spinal length and disk area increased ( < 0.05); intervertebral disk angles ( < 0.05) and muscle volumes of LM, LES, and QL reduced ( < 0.01); and lipid-to-water ratio for the LM and LES muscles increased ( < 0.01) after HDT59 in all groups. Neither of the AG protocols mitigated the lumbar spinae deconditioning induced by HDT bed rest. The increase in lipid-to-water ratio in LM and LES muscles indicates an increased relative intramuscular lipid concentration. Altered muscle composition in atrophied muscles may impair lumbar spine function after body unloading, which could increase injury risk to vulnerable soft tissues. This relationship needs further investigation. This study presents novel insights into the morphological adaptations occurring in the lumbar spine after 60-day head-down bed rest and the potential role of artificial gravity (AG) to mitigate them. Results demonstrated no protective effect of AG protocols used in this study. In atrophied paraspinal muscles, the ratio of lipids versus intramuscular water increased in the postural lumbar muscles, which could impair muscle function during upright standing. These findings have relevance for future space explorations.
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http://dx.doi.org/10.1152/japplphysiol.00990.2020DOI Listing
July 2021

Multimodal imaging interpreted by graders to detect re-activation of diabetic eye disease in previously treated patients: the EMERALD diagnostic accuracy study.

Health Technol Assess 2021 05;25(32):1-104

Warwick Medical School, University of Warwick, Coventry, UK.

Background: Owing to the increasing prevalence of diabetes, the workload related to diabetic macular oedema and proliferative diabetic retinopathy is rising, making it difficult for hospital eye services to meet demands.

Objective: The objective was to evaluate the diagnostic performance, cost-effectiveness and acceptability of a new pathway using multimodal imaging interpreted by ophthalmic graders to detect reactivation of diabetic macular oedema/proliferative diabetic retinopathy in previously treated patients.

Design: This was a prospective, case-referent, cross-sectional diagnostic study.

Setting: The setting was ophthalmic clinics in 13 NHS hospitals.

Participants: Adults with type 1 or type 2 diabetes with previously successfully treated diabetic macular oedema/proliferative diabetic retinopathy in one/both eyes in whom, at the time of enrolment, diabetic macular oedema/proliferative diabetic retinopathy could be active or inactive.

Methods: For the ophthalmic grader pathway, review of the spectral domain optical coherence tomography scans to detect diabetic macular oedema, and seven-field Early Treatment Diabetic Retinopathy Study/ultra-wide field fundus images to detect proliferative diabetic retinopathy, by trained ophthalmic graders. For the current standard care pathway (reference standard), ophthalmologists examined patients face to face by slit-lamp biomicroscopy for proliferative diabetic retinopathy and, in addition, spectral domain optical coherence tomography imaging for diabetic macular oedema.

Outcome Measures: The primary outcome measure was sensitivity of the ophthalmic grader pathway to detect active diabetic macular oedema/proliferative diabetic retinopathy. The secondary outcomes were specificity, agreement between pathways, cost-consequences, acceptability and the proportion of patients requiring subsequent ophthalmologist assessment, unable to undergo imaging and with inadequate quality images/indeterminate findings. It was assumed for the main analysis that all patients in whom graders diagnosed active disease or were 'unsure' or images were 'ungradable' required examination by an ophthalmologist.

Results: Eligible participants with active and inactive diabetic macular oedema (152 and 120 participants, respectively) and active and inactive proliferative diabetic retinopathy (111 and 170 participants, respectively) were recruited. Under the main analysis, graders had a sensitivity of 97% (142/147) (95% confidence interval 92% to 99%) and specificity of 31% (35/113) (95% confidence interval 23% to 40%) to detect diabetic macular oedema. For proliferative diabetic retinopathy, graders had a similar sensitivity and specificity using seven-field Early Treatment Diabetic Retinopathy Study [sensitivity 85% (87/102), 95% confidence interval 77% to 91%; specificity 48% (77/160), 95% confidence interval 41% to 56%] or ultra-wide field imaging [sensitivity 83% (87/105), 95% confidence interval 75% to 89%; specificity 54% (86/160), 95% confidence interval 46% to 61%]. Participants attending focus groups expressed preference for face-to-face evaluations by ophthalmologists. In the ophthalmologists' absence, patients voiced the need for immediate feedback following grader's assessments, maintaining periodic evaluations by ophthalmologists. Graders and ophthalmologists were supportive of the new pathway. When compared with the reference standard (current standard pathway), the new grader pathway could save £1390 per 100 patients in the review of people with diabetic macular oedema and, depending on the imaging modality used, between £461 and £1189 per 100 patients in the review of people with proliferative diabetic retinopathy.

Conclusions: For people with diabetic macular oedema, the ophthalmic grader pathway appears safe and cost saving. The sensitivity of the new pathway to detect active proliferative diabetic retinopathy was lower, but may still be considered acceptable for patients with proliferative diabetic retinopathy previously treated with laser. Suggestions from focus group discussions should be taken into consideration if the new pathway is introduced to ensure its acceptability to users.

Limitations: Lack of fundus fluorescein angiography to confirm diagnosis of active proliferative diabetic retinopathy.

Future Work: Could refinement of the new pathway increase its sensitivity to detect proliferative diabetic retinopathy? Could artificial intelligence be used for automated reading of images in this previously treated population?

Trial Registration: Current Controlled Trials ISRCTN10856638 and ClinicalTrials.gov NCT03490318.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Vol. 25, No. 32. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200933PMC
May 2021

Snapshot of an influenza virus glycoprotein fusion intermediate.

Cell Rep 2021 May;35(7):109152

Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Enveloped virus entry requires the fusion of cellular and viral membranes, a process directed by their viral fusion glycoproteins. Our current knowledge of this process has been shaped by structural studies of the pre- and post-fusion conformations of these viral fusogens. These structural snapshots have revealed the start and end states necessary for fusion, but the dynamics of the intermediate conformations have remained unclear. Using the influenza C virus hemagglutinin-esterase-fusion glycoprotein as a model, we report the structural and biophysical characterization of a trapped intermediate. Crystallographic studies revealed a structural reorganization of the C terminus to create a second chain reversal region, resulting in the N and C termini being positioned in opposing directions. Intrinsic tryptophan fluorescence and bimane-induced quenching measurements suggest intermediate formation is mediated by conserved hydrophobic residues. Our study reveals a late-stage extended intermediate structural event. This work adds to our understanding of virus cell fusion.
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http://dx.doi.org/10.1016/j.celrep.2021.109152DOI Listing
May 2021

Evidence-based clinical practice guideline: Reconstruction after skin cancer resection.

J Am Acad Dermatol 2021 08 27;85(2):423-441. Epub 2021 Apr 27.

University of Connecticut; The Skin Surgery Center; University Hospitals Cleveland Medical Center/Case Western Reserve University; Kaiser Permanente; Duke University Medical Center; American Society of Plastic Surgeons; Galaria Plastic Surgery and Dermatology; Veterans Affairs Medical Center; Florida Center for Dermatology; Department of Dermatology, University of Pennsylvania Perelman School of Medicine; Private practice; Cooper Medical Center, Rowan University; University of South Florida; University of Central Florida; University of California, Irvine; Piedmont Plastic Surgery and Dermatology; Pennsylvania State University; Rush University Medical Center; University of Illinois at Chicago; R. L. Roudebush Veterans Affairs Medical Center; University of California, Davis, Medical Center; University of Iowa Hospitals & Clinics; Private practice; Northwestern University.

A multi-disciplinary work group involving stakeholders from various backgrounds and societies was convened to develop guidelines for the management of reconstruction after skin cancer resection. The goal was to identify areas of common ground and provide evidence-based recommendations to improve patient care. Given the heterogeneity of reconstructive techniques and clinical scenarios, investigation centered around common elements in the process. In some cases, a distinction was made between treatment options in the office-based setting as opposed to those in the facility setting. A systematic literature review was performed, and an established appraisal process was used to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology). Final recommendations are related to concepts concerning the timing of reconstruction, management of anticoagulation, use of antibiotics, methods of pain control, and follow-up assessment. At times, there was insufficient evidence to make high-level recommendations. The literature analysis highlights the need for additional methodologically robust studies in this area, to help guide clinical practice.
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http://dx.doi.org/10.1016/j.jaad.2021.03.015DOI Listing
August 2021

Evidence-Based Clinical Practice Guideline: Reconstruction after Skin Cancer Resection.

Plast Reconstr Surg 2021 May;147(5):812e-829e

From the University of Connecticut; The Skin Surgery Center; University Hospitals Cleveland Medical Center/Case Western Reserve University; Kaiser Permanente; Duke University Medical Center; American Society of Plastic Surgeons; Galaria Plastic Surgery and Dermatology; Veterans Affairs Medical Center; Florida Center for Dermatology; Department of Dermatology, University of Pennsylvania Perelman School of Medicine; private practice; Cooper Medical Center, Rowan University; University of South Florida; University of Central Florida; University of California, Irvine; Piedmont Plastic Surgery and Dermatology; Pennsylvania State University; Rush University Medical Center; University of Illinois at Chicago; R. L. Roudebush Veterans Affairs Medical Center; University of California, Davis, Medical Center; University of Iowa Hospitals & Clinics; private practice; and Northwestern University.

Summary: A multi-disciplinary work group involving stakeholders from various backgrounds and societies was convened to develop guidelines for the management of reconstruction after skin cancer resection. The goal was to identify areas of common ground and provide evidence-based recommendations to improve patient care. Given the heterogeneity of reconstructive techniques and clinical scenarios, investigation centered around common elements in the process. In some cases, a distinction was made between treatment options in the office-based setting as opposed to those in the facility setting. A systematic literature review was performed, and an established appraisal process was used to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology). Final recommendations are related to concepts concerning the timing of reconstruction, management of anticoagulation, use of antibiotics, methods of pain control, and follow-up assessment. At times, there was insufficient evidence to make high-level recommendations. The literature analysis highlights the need for additional methodologically robust studies in this area, to help guide clinical practice.
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http://dx.doi.org/10.1097/PRS.0000000000007789DOI Listing
May 2021

ENTPD1 (CD39) Expression Inhibits UVR-Induced DNA Damage Repair through Purinergic Signaling and Is Associated with Metastasis in Human Cutaneous Squamous Cell Carcinoma.

J Invest Dermatol 2021 Oct 20;141(10):2509-2520. Epub 2021 Apr 20.

Department of Duke Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Pinnell Center for Investigative Dermatology, Department of Duke Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA. Electronic address:

UVR and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells promote cSCC carcinogenesis, and in other solid tumors, infiltrating regulatory T cells and CD8 T cells express ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39), an ectoenzyme that catalyzes the rate-limiting step in converting extracellular adenosine triphosphate (ATP) to extracellular adenosine (ADO). We previously showed that extracellular purine nucleotides influence DNA damage repair. In this study, we investigate whether DNA damage repair is modulated through purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared with the expression on T cells from blood or nonlesional skin, and accordingly, concentrations of derivative extracellular adenosine diphosphate (ADP), adenosine monophosphate (AMP), and ADO are increased in tumors compared with those in normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize than in those that are nonmetastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL-27-dependent manner. Finally, increased extracellular ADO is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DNA damage repair secondary to UVR. Together, these data suggest a role for ENTPD1 expression on skin-resident T cells to regulate DNA damage repair through purinergic signaling to promote skin carcinogenesis and metastasis.
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http://dx.doi.org/10.1016/j.jid.2021.02.753DOI Listing
October 2021

Reamed intramedullary nailing versus circular frame external fixation for segmental tibial fractures (STIFF-F): a mixed methods feasibility study.

Pilot Feasibility Stud 2021 Apr 10;7(1):93. Epub 2021 Apr 10.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Segmental tibial fractures are fractures in two or more areas of the tibial diaphysis resulting in a separate intercalary segment of the bone. Surgical fixation is recommended for patients with segmental tibial fractures as non-operative treatment outcomes are poor. The most common surgical interventions are intramedullary nailing (IMN) and circular frame external fixation (CFEF), but evidence about which is better is of poor quality. An adequately powered randomised controlled trial (RCT) to determine optimum treatment is required. STIFF-F aimed to assess the feasibility of a multicentre RCT comparing IMN with CFEF for segmental tibial fracture.

Methods: STIFF-F was a mixed-methods feasibility study comprising a pilot RCT conducted at six UK Major Trauma Centres, qualitative interviews drawing on Phenomenology and an online survey of rehabilitation. The primary outcome was recruitment rate. Patients, 16 years and over, with a segmental tibial fracture (open or closed) deemed suitable for IMN or CFEF were eligible to participate. Randomisation was stratified by site using random permuted blocks of varying sizes. Participant or assessor blinding was not possible. Interviews were undertaken with patients about their experience of injury, treatment, recovery and participation. Staff were interviewed to identify contextual factors affecting trial processes, their experience of recruitment and the treatment pathway. An online survey was developed to understand the rehabilitation context of the treatments.

Results: Eleven patients were screened and three recruited to the pilot RCT. Nineteen staff and four patients participated in interviews, and 11 physiotherapists responded to the survey. This study found the following: (i) segmental tibial fractures were rarer than anticipated, (ii) the complexity of the injury, study setup times and surgeon treatment preferences impeded recruitment, (iii) recovery from a segmental tibial fracture is challenging, and rehabilitation protocols are inconsistent and (iv) despite the difficulty recruiting, staff valued this research question and strived to find a way forward.

Conclusion: The proposed multicentre RCT comparing IMN with CFEF is not feasible. This study highlighted the difficulty of recruiting patients to an RCT of a complex rare injury over a short time period.

Trial Registration: The study was registered with the International Standard Randomised Controlled Trials Number Registry: ISRCTN11229660.
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http://dx.doi.org/10.1186/s40814-021-00821-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035735PMC
April 2021

A feasibility study of standard dressings versus negative-pressure wound therapy in the treatment of adult patients having surgical incisions for hip fractures: the WHISH randomized controlled trial.

Bone Joint J 2021 04;103-B(4):755-761

Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Aims: This study sought to compare the rate of deep surgical site infection (SSI), as measured by the Centers for Disease Control and Prevention (CDC) definition, after surgery for a fracture of the hip between patients treated with standard dressings and those treated with incisional negative pressure wound therapy (iNPWT). Secondary objectives included determining the rate of recruitment and willingness to participate in the trial.

Methods: The study was a two-arm multicentre randomized controlled feasibility trial that was embedded in the World Hip Trauma Evaluation cohort study. Any patient aged > 65 years having surgery for hip fracture at five recruitment centres in the UK was considered to be eligible. They were randomly allocated to have either a standard dressing or iNPWT after closure of the wound. The primary outcome measure was deep SSI at 30 and 90 days, diagnosed according to the CDC criteria. Secondary outcomes were: rate of recruitment; further surgery within 120 days; health-related quality of life (HRQoL) using the EuroQol five-level five-dimension questionnaire (EQ-5D-5L); and related complications within 120 days as well as mobility and residential status at this time.

Results: A total of 462 valid randomizations were carried out (232 and 230 in the standard dressing and iNPWT groups, respectively). In the standard dressing group, 14 of 218 patients (6.4%) developed deep SSI. In the iNPWT group, four of 214 patients (1.9%) developed deep SSI. This gives a total rate of SSI of 4.2% (95% confidence interval (CI) 2.7% to 6.5%). Patients and surgeons were willing to participate in the study with 462 patients being recruited from a possible 749 (62.3%).

Conclusion: The rate of deep SSI 30 days after surgery for a fracture of the hip was 4%, which makes a study comparing the clinical effectiveness of standard dressings and iNPWT feasible. Cite this article:  2021;103-B(4):755-761.
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http://dx.doi.org/10.1302/0301-620X.103B4.BJJ-2020-1603.R1DOI Listing
April 2021

Invited Discussion on: A Prospective Study Determining Patient Satisfaction with Combined Cryolipolysis and Shockwave Therapy Treatment for Non-Invasive Body Contouring.

Aesthetic Plast Surg 2021 10 25;45(5):2326-2327. Epub 2021 Mar 25.

Sanctuary Plastic Surgery, 4800 N. Federal Highway, Suite c101, Boca Raton, FL, 33431, USA.

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October 2021

Internal fixation implants for intracapsular hip fractures in older adults.

Cochrane Database Syst Rev 2021 03 9;3:CD013409. Epub 2021 Mar 9.

Blizard Institute, Queen Mary University of London, London, UK.

Background: Hip fractures are a major healthcare problem, presenting a huge challenge and burden to patients, healthcare systems and society. The increased proportion of older adults in the world population means that the absolute number of hip fractures is rising rapidly across the globe. The majority of hip fractures are treated surgically. This review evaluates evidence for types of internal fixation implants used in joint-preserving surgery for intracapsular hip fractures.

Objectives: To determine the relative effects (benefits and harms) of different implants for the internal fixation of intracapsular hip fractures in older adults.

Search Methods: We searched CENTRAL, MEDLINE, Embase, Web of Science, Cochrane Database of Systematic Reviews, Epistemonikos, Proquest Dissertations and Theses, and National Technical Information Service 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 implants used for internal fixation of fragility intracapsular proximal femoral fractures in older adults. Types of implants were smooth pins (these include pins with fold-out hooks), screws, or fixed angle plates. We excluded studies in which all or most fractures were caused by specific pathologies other than osteoporosis or were the result of a high energy trauma.

Data Collection And Analysis: Two review authors independently assessed studies for inclusion. One review author extracted data and assessed risk of bias which was checked by a second review author. We collected data for seven outcomes: activities of daily living (ADL), delirium, functional status, health-related quality of life (HRQoL), mobility, mortality (reported within four months of surgery as early mortality, and at 12 months since surgery), and unplanned return to theatre for treating a complication resulting directly or indirectly from the primary procedure (such as deep infection or non-union). We assessed the certainty of the evidence for these outcomes using GRADE.

Main Results: We included 38 studies (32 RCTs, six quasi-RCTs) with 8585 participants with 8590 intracapsular fractures. The mean ages of participants in the studies ranged from 60 to 84 years; 73% were women, and 38% of fractures were undisplaced. We report here the findings of the four main comparisons, which were between different categories of implants. We downgraded the certainty of the outcomes for imprecision (when data were available from insufficient numbers of participants or the confidence interval (CI) was wide), study limitations (e.g. high or unclear risks of bias), and inconsistency (when we noted substantial levels of statistical heterogeneity). Smooth pins versus fixed angle plate (four studies, 1313 participants) We found very low-certainty evidence of little or no difference between the two implant types in independent mobility with no more than one walking stick (1 study, 112 participants), early mortality (1 study, 383 participants), mortality at 12 months (2 studies, 661 participants), and unplanned return to theatre (3 studies, 736 participants). No studies reported on ADL, delirium, functional status, or HRQoL. Screws versus fixed angle plates (11 studies, 2471 participants) We found low-certainty evidence of no clinically important differences between the two implant types in functional status using WOMAC (MD -3.18, 95% CI -6.35 to -0.01; 2 studies, 498 participants; range of scores from 0 to 96, lower values indicate better function), and HRQoL using EQ-5D (MD 0.03, 95% CI 0.00 to 0.06; 2 studies, 521 participants; range -0.654 (worst), 0 (dead), 1 (best)). We also found low-certainty evidence showing little or no difference between the two implant types in mortality at 12 months (RR 1.04, 95% CI 0.83 to 1.31; 7 studies, 1690 participants), and unplanned return to theatre (RR 1.10, 95% CI 0.95 to 1.26; 11 studies, 2321 participants). We found very low-certainty evidence of little or no difference between the two implant types in independent mobility (1 study, 70 participants), and early mortality (3 studies, 467 participants). No studies reported on ADL or delirium. Screws versus smooth pins (seven studies, 1119 participants) We found low-certainty evidence of no or little difference between the two implant types in mortality at 12 months (RR 1.07, 95% CI 0.85 to 1.35; 6 studies, 1005 participants; low-certainty evidence). We found very low-certainty evidence of little or no difference between the two implant types in early mortality (3 studies, 584 participants) and unplanned return to theatre (5 studies, 862 participants). No studies reported on ADL, delirium, functional status, HRQoL, or mobility. Screws or smooth pins versus fixed angle plates (15 studies, 3784 participants) In this comparison, we combined data from the first two comparison groups. We found low-certainty evidence of no or little difference between the two groups of implants in mortality at 12 months (RR 1.04, 95% CI.083 to 1.31; 7 studies, 1690 participants) and unplanned return to theatre (RR 1.02, 95% CI 0.88 to 1.18; 14 studies, 3057 participants). We found very low-certainty evidence of little or no difference between the two groups of implants in independent mobility (2 studies, 182 participants), and early mortality (4 studies, 850 participants). We found no additional evidence to support the findings for functional status or HRQoL as reported in 'Screws versus fixed angle plates'. No studies reported ADL or delirium.

Authors' Conclusions: There is low-certainty evidence that there may be little or no difference between screws and fixed angle plates in functional status, HRQoL, mortality at 12 months, or unplanned return to theatre; and between screws and pins in mortality at 12 months. The limited and very low-certainty evidence for the outcomes for which data were available for the smooth pins versus fixed angle plates comparison, as well as the other outcomes for which data were available for the screws and fixed angle plates, and screws and pins comparisons means we have very little confidence in the estimates of effect for these outcomes. Additional RCTs would increase the certainty of the evidence. We encourage such studies to report outcomes consistent with the core outcome set for hip fracture, including long-term quality of life indicators such as ADL and mobility.
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http://dx.doi.org/10.1002/14651858.CD013409.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092427PMC
March 2021

Patch augmentation surgery for rotator cuff repair: the PARCS mixed-methods feasibility study.

Health Technol Assess 2021 02;25(13):1-138

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: A rotator cuff tear is a common, disabling shoulder problem. Symptoms may include pain, weakness, lack of shoulder mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a need to improve the outcome of rotator cuff surgery, and the use of patch augmentation (on-lay or bridging) to provide support to the healing process and improve patient outcomes holds promise. Patches have been made using different materials (e.g. human/animal skin or tissue and synthetic materials) and processes (e.g. woven or mesh).

Objectives: The aim of the Patch Augmented Rotator Cuff Surgery (PARCS) feasibility study was to determine the design of a definitive randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible.

Design: A mixed-methods feasibility study of a randomised controlled trial.

Data Sources: MEDLINE, EMBASE and the Cochrane Library databases were searched between April 2006 and August 2018.

Methods: The project involved six stages: a systematic review of clinical evidence, a survey of the British Elbow and Shoulder Society's surgical membership, a survey of surgeon triallists, focus groups and interviews with stakeholders, a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. The various stakeholders (including patients, surgeons and industry representatives) were involved in stages 2-6.

Results: The systematic review comprised 52 studies; only 15 were comparative and, of these, 11 were observational (search conducted in August 2018). These studies were typically small (median number of participants 26, range 5-152 participants). There was some evidence to support the use of patches, although most comparative studies were at a serious risk of bias. Little to no published clinical evidence was available for a number of patches in clinical use. The membership survey of British Elbow and Shoulder surgeons [105 (21%) responses received] identified a variety of patches in use. Twenty-four surgeons (77%) completed the triallist survey relating to trial design. Four focus groups were conducted, involving 24 stakeholders. Differing views were held on a number of aspects of trial design, including the appropriate patient population (e.g. patient age) to participate. Agreement on the key research questions and the outline of two potential randomised controlled trials were achieved through the Delphi study [29 (67%)] and the consensus meeting that 22 participants attended.

Limitations: The main limitation was that the findings were influenced by the participants, who are not necessarily representative of the views of the relevant stakeholder groups.

Conclusion: The need for further clinical studies was clear, particularly given the range and number of different patches available.

Future Work: Randomised comparisons of on-lay patch use for completed rotator cuff repairs and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. These elements are included in the trial designs proposed in this study.

Study Registration: The systematic review is registered as PROSPERO CRD42017057908.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 13. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958078PMC
February 2021

Utilising benefit-risk assessments within clinical trials-a protocol for the BRAINS project.

Trials 2021 Jan 19;22(1):68. Epub 2021 Jan 19.

Clinical Trials Consulting & Training Limited, Buckingham, UK.

Background: Depending on the treatment to be investigated, a clinical trial could be designed to assess objectives of superiority, equivalence or non-inferiority. The design of the study is affected by many different elements including the control treatment, the primary outcome and associated relationships. In some studies, there could be more than one outcome of interest. In these situations, benefit-risk methodologies could be used to assess the outcomes simultaneously and consider the trade-off between the benefits against the risks of a treatment. Benefit-risk is used within the regulatory industry but seldom included within publicly funded clinical trials within the UK. This project aims to gain an expert consensus on how to select the appropriate trial design (e.g. superiority) and when to consider including benefit-risk methods.

Methods: The project will consist of four work packages: 1. A web-based survey to elicit current experiences and opinions, 2. A rapid literature review to assess any current recommendations, 3. A two-day consensus workshop to gain agreement on the recommendations, and 4. Production of a guidance document.

Discussion: The aim of the project is to provide a guideline for clinical researchers, grant funding bodies and reviewers for grant bodies for how to select the most appropriate trial design and when it is appropriate to consider using benefit-risk methods. The focus of the guideline will be on publicly funded trials however, the vision is that the work will be applicable across research settings and we will connect with other organisations and committees as appropriate.
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http://dx.doi.org/10.1186/s13063-021-05022-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814532PMC
January 2021

Effect on health-related quality of life of the X-Bolt dynamic plating system versus the sliding hip screw for the fixation of trochanteric fractures of the hip in adults: the WHiTE Four randomized clinical trial.

Bone Joint J 2021 Feb 3;103-B(2):256-263. Epub 2021 Jan 3.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Aims: Surgical treatment of hip fracture is challenging; the bone is porotic and fixation failure can be catastrophic. Novel implants are available which may yield superior clinical outcomes. This study compared the clinical effectiveness of the novel X-Bolt Hip System (XHS) with the sliding hip screw (SHS) for the treatment of fragility hip fractures.

Methods: We conducted a multicentre, superiority, randomized controlled trial. Patients aged 60 years and older with a trochanteric hip fracture were recruited in ten acute UK NHS hospitals. Participants were randomly allocated to fixation of their fracture with XHS or SHS. A total of 1,128 participants were randomized with 564 participants allocated to each group. Participants and outcome assessors were blind to treatment allocation. The primary outcome was the EuroQol five-dimension five-level health status (EQ-5D-5L) utility at four months. The minimum clinically important difference in utility was pre-specified at 0.075. Secondary outcomes were EQ-5D-5L utility at 12 months, mortality, residential status, mobility, revision surgery, and radiological measures.

Results: Overall, 437 and 443 participants were analyzed in the primary intention-to-treat analysis in XHS and SHS treatment groups respectively. There was a mean difference of 0.029 in adjusted utility index in favour of XHS with no evidence of a difference between treatment groups (95% confidence interval -0.013 to 0.070; p = 0.175). There was no evidence of any differences between treatment groups in any of the secondary outcomes. The pattern and overall risk of adverse events associated with both treatments was similar.

Conclusion: Any difference in four-month health-related quality of life between the XHS and SHS is small and not clinically important. There was no evidence of a difference in the safety profile of the two treatments; both were associated with lower risks of revision surgery than previously reported. Cite this article: 2021;103-B(2):256-263.
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http://dx.doi.org/10.1302/0301-620X.103B.BJJ-2020-1404.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954151PMC
February 2021

Bipolar Radiofrequency as an Adjunct to Face and Body Contouring: A 745-Patient Clinical Experience.

Aesthet Surg J 2021 05;41(6):685-694

Background: Radiofrequency (RF) technology has ushered in a new paradigm in body contouring for patients with mild to moderate skin laxity who desire fat removal without exacerbating skin laxity issues. A bipolar internal RF device, used as an adjunct to liposuction, has been found to be simpler and more accurate than previous technologies.

Objectives: The aim of this study was to review the authors' clinical experience with bipolar RF-assisted liposuction (RFAL).

Methods: We conducted a review of our large experience with bipolar RFAL, evaluating the nuances from appropriate patient selection and specific treatment areas. The review covered 745 patients treated from January 2017 to January 2020 at 2 centers. A retrospective chart review was performed of the first and last 50 patients treated at each center (for a total of 100 patients in each group) to assess trends in outcomes and adverse events.

Results: Results were generally excellent from physician evaluation, and overall patient satisfaction was high (96%). The two most common adverse events were temporary swelling (9%) and nodules (8.5%). Selected examples of a variety of cases are reviewed.

Conclusions: The ability to tighten skin with a minimally invasive tool adds much to the contemporary approach to the body-contouring patient with skin laxity. Adverse events were minimal and greatly decreased after an initial short learning curve. Bipolar RFAL is a strong addition to our surgical armamentarium and has become an essential tool for our practices.

Level Of Evidence: 4:
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May 2021

Hypothermia During Partial Nephrectomy for Patients with Renal Tumors: A Randomized Controlled Trial.

J Urol 2021 May 21;205(5):1303-1309. Epub 2020 Dec 21.

Division of Urology, Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.

Purpose: Surgeons induce renal hypothermia during partial nephrectomy to preserve kidney function, without strong evidence of benefit. This trial examined the effectiveness and safety of renal hypothermia during partial nephrectomy.

Materials And Methods: We conducted a parallel randomized controlled trial of hypothermia versus no hypothermia (control group) during partial nephrectomy at 6 academic hospitals. Eligible patients had a planned open partial nephrectomy for the treatment of a renal tumor. During surgery, after clamping the renal hilum, patients were randomized to the intervention or control arm in a 1:1 ratio using permuted blocks of variable lengths (2 and 4), stratified by institution, using a computer-based program. Surgeons and study coordinators were masked to treatment allocation until the renal hilum was clamped. Overall glomerular filtration rates were determined before, and 1-year after, surgery. The primary outcome was measured glomerular filtration rate (mGFR) assessed by the plasma clearance of Tc-DTPA. The trial (NCT01529658) was designed with 90% power to detect a minimal clinically important difference in mGFR of 10 ml/minute/1.73 m at a 5% significance level.

Results: Of the 184 patients randomized, hypothermia and control patients had similar baseline mean mGFR (87.1 vs 81.0 ml/minute/1.73 m). One hundred and sixty-one (79 hypothermia, 82 control) were alive with primary outcome data 1 year after surgery. The change in mGFR 1 year after surgery was -6.6 ml/minute/1.73 m in the hypothermia group and -7.8 ml/minute/1.73 m in the control group (mean difference 1.2 ml/minute/1.73 m, 95% CI -3.3 to 5.6). Operated-kidney change in mGFR was similar between groups (-5.8 vs -6.3 ml/minute/1.73 m; mean difference 0.5 ml/minute/1.73 m, 95% CI -2.9 to 3.8). No clinically significant difference in the mGFR was observed when patients were stratified by pre-planned subgroups. Renal hypothermia did not impact the secondary outcomes of surgical complications and patient reported quality of life.

Conclusions: Renal hypothermia during partial nephrectomy does not preserve kidney function in patients with normal or mildly impaired renal function.
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May 2021

Use of implantable meshes for augmented rotator cuff repair: a systematic review and meta-analysis.

BMJ Open 2020 12 7;10(12):e039552. Epub 2020 Dec 7.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, Oxfordshire, UK.

Objective: To appraise studies reporting on clinical effectiveness and safety of surgical meshes used to augment rotator cuff repairs (RCRs).

Design: Systematic review and meta-analysis.

Data Sources: MEDLINE, Embase and Cochrane databases were searched between April 2006 and April 2020.

Eligibility Criteria: All studies evaluating adults (≥18 years) undergoing RCR were considered. There were no language restrictions.

Data Extraction And Synthesis: Screening, data extraction and quality appraisal were conducted by two independent reviewers. Meta-analysis was conducted using a random-effects models if ≥2 comparative studies reported the same outcome measure. Risk of bias assessment was undertaken for randomised (RoB2, Cochrane) and comparative studies (ROBINS-I, Cochrane).

Results: We included 60 studies, consisting of 7 randomised controlled trials, 13 observational comparative studies and 40 observational case series. All comparative studies reported on shoulder-specific functional outcome scores, 18 on the radiographic occurrence of re-tear and 14 on pain score metrics. All studies contained some risk of bias.Compared with non-augmented repair, a small improvement in shoulder-specific function or pain scores was observed for synthetic patches with a mean improvement of 6.7 points on the University of California Los Angles (UCLA) shoulder score (95% CI 0.1 to 13.4) and 0.46 point reduction on the Visual Analogue Scale (95% CI -0.74 to -0.17), respectively. A reduced likelihood of radiologically observed re-tear was observed for synthetic (risk ratio (RR) 0.41, 95% CI 0.27 to 0.61) and allograft (RR 0.34, 95% CI 0.18 to 0.65) patches. A total of 49 studies reported on the occurrence of complications. Slightly higher crude complication rates were observed following patch-augmented repair (2.1%) than standard repair (1.6%).

Conclusions: While several studies suggest a decreased failure rate and small improvements in shoulder function and pain following augmented RCR, a paucity of rigorous clinical evaluation, for both effectiveness and safety, prevents firm recommendations.

Prospero Registration Number: CRD42017057908.
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http://dx.doi.org/10.1136/bmjopen-2020-039552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722806PMC
December 2020
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