The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

Markt- und Potentialanalyse neuer integrierter Mobilitaetsdienstleistungen in Deutschland. Mit Materialband Schlussbericht

Published in two volumesAvailable from TIB Hannover: F02B1666: F02B1667 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman

Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

Purpose: This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. Methods: We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. Results: In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. Conclusion: Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome

Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: A cross-sectional web-based survey

Background Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. Patients, design and setting We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. Results Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54 female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31 and drug-induced TIN in 30 (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28 of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/ min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41 of patients (eGFR �90 mL/ min/1.73 m2), with only 3 having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80 of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18 (n=31) of patients, 21 of whom received mycophenolate mofetil. Conclusions Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88 of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

Free radicals and antioxidants at a glance using EPR spectroscopy

The delicate balance between the advantageous and detrimental effects of free radicals is one of the important aspects of human (patho)physiology. The controlled production of reactive oxygen and nitrogen species has an essential role in the regulation of various signaling switches. On the other hand, imbalanced generation of radicals is highly correlated with the pathogenesis of many diseases which require the application of selected antioxidants to regain the homeostasis. In the era of growing interest for redox processes, electron paramagnetic resonance (EPR) spectroscopy is arguably the best-suited technique for such research due to its ability to provide a unique insight into the world of free radicals and antioxidants. Herein, I present the principles of EPR spectroscopy and the applications of this method in assessing: (i) the oxidative status of biological systems, using endogenous long-lived free radicals (ascorbyl radical (Asc(center dot)), tocopheroxyl radical (TO center dot), melanin) as markers; (ii) the production of short-lived radicals (hydroxyl radical (OH center dot), superoxide radical anion (O-2(-)), sulfur-and carbon-centered radicals), which are implicated in both, oxidative stress and redox signaling; (iii) the metabolism of nitric oxide (NO center dot); (iv) the antioxidative properties of various drugs, compounds, and natural products; (v) other redox-relevant parameter. Besides giving a comprehensive survey of up-to-date literature, I also provide illustrative examples in sufficient detail to provide a means to exploit the potential of EPR in biochemical/physiological/medical research. The emphasis is on the features and characteristics (both positive and negative) relevant for EPR application in clinical sciences. My aim is to encourage fellow colleagues interested in free radicals and antioxidants to expand their base knowledge or methods used in their laboratories with data acquired by EPR or some of the EPR techniques outlined in this review, in order to boost up the exciting area of redox science