Clinical Trial Quality Assessment in Adult Spinal Surgery: What Do Publication Status, Funding Source, and Result Reporting Tell Us?

Study Design Narrative Review Objectives The objective of this study was to compare publication status of clinical trials in adult spine surgery registered on ClinicalTrials.gov by funding source as well as to identify other trends in clinical trials in adult spine surgery. Methods All prospective, comparative, therapeutic (intervention-based) trials of adult spinal disease that were registered on ClinicalTrials.gov with a start date of January 1, 2000 and completion date before December 17, 2018 were included. Primary outcome was publication status of published or unpublished. A bivariate analysis was used to compare publication status to funding source of industry vs non-industry. Results Our search identified 107 clinical trials. The most common source of funding was industry (62 trials, 57.9% of total), followed by University funding (26 trials, 24.3%). The results of 76 trials (71.0%) were published, with industry-funded trials less likely to be published compared to non–industry-funded trials (62.9% compared to 82.2%, P = .03). Of the 31 unpublished studies, 13 did not report any results on ClinicalTrials.gov , and of those with reported results, none was a positive trial. Conclusions Clinician researchers in adult spine surgery should be aware that industry-funded trials are less likely to go on to publication compared to non–industry-funded trials, and that negative trials are frequently not published. Future opportunities include improvement in result reporting and in publishing negative studies.

Models of Research and Development Financing in the European Union: A Cluster Analysis

The paper aims to identify the different models of financing the expenditure on research and development in the European Union and define their characteristics through the application of the method of cluster analysis. The study shows the existence of four models within the EU, which are characterised by different ratios of R&D funding sources and have a specific geographical profile. Despite the differences, the private or public sector is defined as the funding source with the largest relative share in all models. The analysis shows that the model with the highest share of private sector funding provides the highest R&D expenditure as a percentage of GDP.

Clinical Guideline Highlights for the Hospitalist: Management of Upper Gastrointestinal and Ulcer Bleeding

GUIDELINE TITLE: American College of Gastroenterology: Upper Gastrointestinal and Ulcer Bleeding RELEASE DATE: May 1, 2021 PRIOR VERSION(S): March 1, 2012 DEVELOPER: American College of Gastroenterology Practice Parameters Committee FUNDING SOURCE: American College of Gastroenterology TARGET POPULATION: Adult patients with overt upper gastrointestinal bleeding

Symptoms reported in calls to emergency medical services 24 hours prior to out-of-hospital cardiac arrest

Background and purpose It remains unknown whether patients with out-of-hospital cardiac arrest (OHCA) experience prodromal symptoms. We aimed to investigate symptoms reported by patients with OHCA contacting emergency medical services (EMS) within 24 hours prior to arrest. Methods We linked OHCAs occurring from 2016 through 2018 to corresponding emergency calls occurring within 24 hours prior to arrest (defined as “pre-arrest calls”). These calls were included and evenly split and evaluated by authors. Results Among 4071 patients with OHCA, 481 patients (11.8%) had pre-arrest calls (59.9% males, median age 74 years) with a total of 539 calls. Figure 1 shows the reported symptoms across calls. The most commonly reported symptoms were breathing problems (59.4%), confusion (23.0%), unconsciousness (20.2%), chest pain (19.5%) and paleness (19.1%). The most common co-occurring symptom pairs were breathing problems in combination with paleness (14.5%), confusion (14.1%), unconsciousness (13.5%), sweating (13.0%) and chest pain (11.9%), respectively. An urgent response was dispatched in 68.7% of calls containing breathing problems compared to 83.0% of calls containing chest pain. Conclusion Among patients with OHCA, 11.8% had a call to EMS within 24 hours prior to arrest and breathing problems was the most commonly reported symptom occurring in 59.4% of calls. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Heart FoundationResearch Grant from Nordsjællands Hospital Figure 1

Comparative effectiveness and safety of edoxaban vs warfarin in patients with atrial fibrillation: a nationwide cohort study

Background and purpose The effectiveness and safety of edoxaban 60 mg and 30 mg for stroke prevention compared with warfarin in patients with atrial fibrillation (AF) has not been well-described in a nationwide cohort of Caucasian patients treated in standard clinical practice. Methods We used Danish nationwide registries to identify patients with AF during June 2016 and November 2018 who were treated with edoxaban or warfarin and computed rates per 100 person-years of thromboembolic, all-cause mortality, and bleeding events using an inverse probability of treatment weighting approach to account for baseline confounding. We used weighted pooled logistic regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing events between edoxaban 60 mg and warfarin users; edoxaban 30 mg was not included in formal comparisons. Results We identified 6451 AF patients, mean age was 72 years and 40% were females. A total of 1772 patients were treated with edoxaban 60 mg, 537 with edoxaban 30 mg, and 4142 with warfarin. The median CHA2DS2-VASc score was similar between warfarin and edoxaban 60 mg with a score of 3 (interquartile range [IQR] 2–4). In the inverse probability of treatment-weighted pseudo-population, the thromboembolic event rate for edoxaban 60 mg was 0.95 and 1.0 for warfarin, corresponding weighted HR of 1.00 (95% confidence intervals [CI] 0.59, 1.71); see Figure. Edoxaban 60 mg users were associated with lower rates of all-cause mortality (3.93) compared to warfarin (6.04), with a HR of 0.64 (95% CI 0.47 to 0.88). The event rates for bleeding were 3.36 and 3.14, respectively; HR 1.09 (95% CI 0.77, 1.57) Conclusion Edoxaban 60 mg is a safe and effective treatment compared with warfarin for stroke prevention in routine clinical care for white European patients with AF, with non-significantly different risks for stroke and clinically relevant bleeding, but lower all-cause mortality. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Daiichi-Sankyo Europe GmbH. This funding source had no role in the design of this study, its execution, analyses, interpretation of the data, or decision to submit results.

New insights into the development of radiation-induced cardiac damage using a mouse model

Background The improvement of anticancer-therapy results in a greater amount of long-term survivors after radiotherapy. Therefore, the understanding of cardiotoxicity after irradiation is of increasing importance. Long-term adverse cardiovascular events may become evident years or decades after radiotherapy. The relative contribution of irradiation in relation to other cancer treatments can often only be estimated. Recent experimental and clinical evidence suggests that cardiovascular symptoms, including exertional dyspnoea, may be caused by heart failure with preserved ejection fraction (HFpEF), which remains incompletely understood in patients after radiation therapy. Purpose We aim to characterize the development of radiation-induced cardiomyopathy and elucidate underlying patho-mechanisms. Methods Mice received a single dose of whole thorax irradiation (12.5 Gy) and were sacrificed at 1 and 3 days or 3, 6, 12, 16, 20 and 25–30 weeks. Endothelial cells and immune cells at different time points were quantified using flow cytometry (FACS). Structural changes and localization of endothelial cell damage was imaged using light-sheet fluorescence microscopy (LSFM) with CD31 staining. Development of fibrosis was determined using qRT-PCR (fibronectin and TGFβ), western blot (collagen-1,α-smooth muscle) and (immune-)histological analyses. Functional analyses were conducted using echocardiography and pressure-volume-(PV-)catheterization. Results Endothelial damage was determined by significant reduction of CD31 expression in mouse hearts 6 weeks after irradiation compared to sham-treated control mice using FACS analyses. LSFM showed structural changes especially in the edge zone of left ventricle presented as less densely CD31 stained regions. Additionally, we investigated cardiac immune cell response regarding innate and adaptive immunity, showing specific response to tissue damage at different time points. Invasion of monocytes started 6 weeks after irradiation and highest level of monocytes and macrophages was measured at 12 weeks. Regarding cardiac long-term damage, myocardial fibrosis was detected on RNA- and protein-level as well as in histological analyses with significant changes 20 weeks after chest irradiation. This could be correlated with echocardiographic parameters for diastolic dysfunction (elevated isovolumic relaxation time/mitral valve deceleration time). Also functional reserve of irradiated mice was reduced, investigated by measurement of cardiac output and stroke volume after dobutamine injection in PV-catheterization. Conclusion We described a novel time-dependent endothelial cell damage and immune cell response after thoracic irradiation in mice, which could also be imaged using LSFM. Characterization of long-term damage showed cardiac fibrosis correlating with diastolic dysfunction and reduced contractile reserve. Furthermore, therapeutic approaches will be investigated using the established mouse model. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Dr. S.M. Mrotzek acknowledges the following funding source: IFORES research grant from the Medical Faculty, University Duisburg-Essen, Germany.

Legal hunting for conservation of highly threatened species: The case of African rhinos

Legal hunting of highly threatened species – and especially the recreational practice of ‘trophy hunting’ – is controversial with selected ethical objections being increasingly voiced. Less attention has been paid to how hunting (even of threatened species) can be useful as a conservation tool, and likely outcomes if this was stopped. As case studies, we examine the regulated legal hunting in South Africa and Namibia of two African rhino species. Counter-intuitively, removing a small number of specific males can enhance population demography and genetic diversity, encourage range expansion, and generate meaningful socio-economic benefits to help fund effective conservation (facilitated by appropriate local institutional arrangements). Legal hunting of these species has been sustainable, as very small proportions of the populations of both species are hunted each year, and numbers of both today are higher in these countries than when controlled recreational hunting began. Terminating this management option and funding source could have negative consequences at a time when rhinos are being increasingly viewed as liabilities and COVID-19 has significantly impacted revenue generation for wildlife areas. Provided that there is appropriate governance and management, conservation of certain highly threatened species can be supported by cautiously selective and limited legal hunting.

Inconsistencies in fertility preservation for young people with cancer in the UK

ObjectiveTo assess the utilisation of and funding structure for fertility preservation for children diagnosed with cancer in the UK.DesignSurvey of paediatric oncologists/haematologists. Questionnaires were sent electronically with reminder notifications to non-responders.SettingUK Paediatric Oncology Principal Treatment Centres (PTCs).ParticipantsPaediatric oncologists/haematologists with an interest in the effects of treatment on fertility representing the 20 PTCs across the UK.Main outcome measuresReferral practices, sources and length of funding for storage of gametes or gonadal tissue for children diagnosed with cancer in the preceding 12 months.ResultsResponses were received from 18 PTCs (90%) with responses to 98.3% of questions. All centres had referred patients for fertility preservation: ovarian tissue collection/storage 100% (n=18 centres), sperm banking 100% (n=17; one centre was excluded due to the age range of their patients), testicular tissue storage 83% (n=15), mature oocyte collection 35% (n=6; one centre was excluded due to the age range of their patients). All centres with knowledge of their funding source reported sperm cryopreservation was NHS funded. Only 60% (n=9) centres reported the same for mature oocyte storage. Of the centres aware of their funding source, half reported that ovarian and testicular tissue storage was funded by charitable sources; this increased in England compared with the rest of the UK.ConclusionsInequality exists in provision of fertility preservation for children with cancer across the UK. There is lack of formalised government funding to support international guidelines, with resultant geographical variation in care. Centralised funding of fertility preservation for children and young adults is needed alongside establishment of a national advisory panel to support all PTCs.

Characteristics of the least-cited and most-cited articles in ophthalmology journals: A pilot study

Background: Limited research has examined differences between uncited papers and their most-cited counterparts. By comparing characteristics of each cohort, it is possible to better determine factors associated with increased citation count in the ophthalmology literature. Methods: We initially identified all research articles published in six popular general ophthalmology journals ( Ophthalmology, JAMA Ophthalmology, Investigative Ophthalmology and Visual Sciences, American Journal of Ophthalmology, British Journal of Ophthalmology, and Graefe’s Archive for Clinical and Experimental Ophthalmology) between 2001 and 2011. Forty-nine articles were identified as having accrued zero citations as of March 2021 and were compared with an equivalent number of articles with the highest number of citations published in the same journals and time period. Significance ( p < 0.05) for comparisons was determined using the Mann–Whitney U test and Fisher’s exact test. Results: Compared to the least-cited articles, the most-cited articles were significantly more likely to be clinical, multi-institutional, and multi-national in scope, report a statistically significant result, have a conflict of interest, state a funding source, and have higher sample sizes. These publications had significantly more words in the abstract and manuscript and more references. Overall, the first authors of the most-cited articles were significantly more likely to be female and report greater prior research productivity, as assessed by the relative citation ratio (RCR). Conclusion: Considering a small number of articles were uncited at least a decade after publication, it appears most research is useful for future investigations. However, there remain distinct differences between uncited articles and their most-cited equivalents in ophthalmology.