On the use of wearable sensors as mobility biomarkers in the marketing authorization of new drugs: A regulatory perspective.

The loss of mobility is a common trait in multiple health conditions (e.g., Parkinson's disease) and is associated with reduced quality of life. In this context, being able to monitor mobility in the real world, is important. Until recently, the technology was not mature enough for this; but today, miniaturized sensors and novel algorithms promise to monitor mobility accurately and continuously in the real world, also in pathological populations. However, before any such methodology can be employed to support the development and testing of new drugs in clinical trials, they need to be qualified by the competent regulatory agencies (e.g., European Medicines Agency). Nonetheless, to date, only very narrow scoped requests for regulatory qualification were successful. In this work, the Mobilise-D Consortium shares its positive experience with the European regulator, summarizing the two requests for Qualification Advice for the Mobilise-D methodologies submitted in October 2019 and June 2020, as well as the feedback received, which resulted in two Letters of Support publicly available for consultation on the website of the European Medicines Agency. Leveraging on this experience, we hereby propose a refined qualification strategy for the use of digital mobility outcome (DMO) measures as monitoring biomarkers for mobility in drug trials.

Comparison of arthroscopy versus percutaneous radiofrequency thermal ablation for the management of intra- and juxta-articular elbow osteoid osteoma: case series and a literature review.

BACKGROUND: Today, intra-articular and juxta-articular osteoid osteomas are treated with arthroscopy and radiofrequency thermal ablation. However, for the case of an elbow joint, arguments are made for the use of a minimally invasive technique to be the optimal choice. This study aims to analyse our experiences of arthroscopically treated elbow osteoid osteomas and to compare it with the published results of both techniques. METHODS: The retrospective study analyses the patients who underwent elbow arthroscopy ablation of an elbow osteoid osteoma at a single institution from January 2014 until March 2020. Clinical and diagnostic features, success and treatment failure rates, complications and tumour recurrence rates were all compared to 13 studies of intra-articular elbow osteoid osteoma arthroscopic ablation and 15 studies involving radiofrequency thermal ablation of intra-articular osteoid osteoma within different joints. RESULTS: Four males and two females, with a mean age of 19.3 years, were encompassed. All the patients had immediate postoperative pain relief and improved range of motion. No tumour recurrences were observed during a median of 21.7 months. The literature review yielded 86.4% success rate, 68.2% successful biopsies, one minor complication and no recurrences following the arthroscopic ablation of an elbow osteoid osteoma; while radiofrequency thermal ablation of an intra-articular elbow osteoid osteoma yielded 96.3% success rate, 33.3% successful biopsies, no complications and 3.7% recurrence rate. CONCLUSIONS: Our results are consistent with the published literature proving that arthroscopic ablation is an efficient method with low treatment failure rates and no recurrences in treating intra- and juxta-articular elbow osteoid osteomas. Advantages of arthroscopic ablation stem from the ability to visualise and safely deal with the lesion and the joint's reactive changes resulting in high biopsy rates, no recurrences and better postoperative elbow's range of motion. Still, the technique selection should be personalised considering the medical expertise of every institution.

Importance of Space-Occupying Anatomical Variations in Peroneal Tendoscopy.

BACKGROUND: We hypothesized that peroneal tendons disorders are more commonly associated with anatomical variations, which could overcrowd the retrofibular groove. METHODS: This single-center retrospective case study covered 84 consecutive cases that had undergone peroneal tendoscopy. Peroneal tendoscopy was performed on 82 patients, predominantly female (3:1) with a median age of 46 years. The preoperative evaluation and all the procedures were performed by a single surgeon using a standardized technique. RESULTS: Two patients required revision surgery 8 and 52 months after the index procedure due to persistent posterolateral ankle pain. Peroneal tendoscopy was performed as a solitary procedure in 45.1% (37/82) of cases, while the remaining cases involved peroneal tendoscopy as a supplementary procedure. Low-lying peroneus brevis muscle belly (LLMB) was the most common finding in this series in 53.7% (44/82) of cases. In 41.5% (34/82) of cases, longitudinal tears of the peroneus brevis tendon were noted. Some patients presented with more than 1 concomitant peroneal tendon pathology. The LLMB was observed in 23.5% (8/34) of cases with a longitudinal tear of the peroneus brevis tendon. CONCLUSION: Peroneal tendon anatomical variations, especially LLMB, were associated with the presence of peroneus brevis tendon ruptures and intrasheath peroneal tendon subluxations as well as posttraumatic posterolateral ankle pain. Due to high rates of undiagnosed and misdiagnosed cases of LLMB preoperatively, we believe special care should be taken to recognize it during tendoscopy. Peroneal tendoscopy is a high-efficiency, low-complication method to treat some peroneal tendon conditions. LEVEL OF EVIDENCE: Level IV, case series.

Accessory Soleus Muscle: Two Case Reports with a Completely Different Presentation Caused by the Same Entity.

Accessory soleus muscle (ASM) is a rare supernumerary anatomical variant that commonly presents as a posteromedial ankle swelling, which may become painful during physical activity. As it may mimic a soft tissue tumor, it is essential to differentiate this condition from ganglion, lipoma, hemangioma, synovioma, and sarcoma. However, ASM may also present with a painful syndrome, characterized by pain and paresthesia of the ankle and foot, mimicking the tarsal tunnel syndrome (TTS). Two cases of ASM are presented in this article. The first case had a typical presentation with painful posteromedial ankle swelling. After the initial assessment, the diagnosis was confirmed by magnetic resonance imaging (MRI), and ASM was treated by complete resection. The second case presented with pain and paresthesia in the right ankle and foot, but no swelling was noticeable. It was initially misdiagnosed by a rheumatologist and afterward overlooked on an MRI by a musculoskeletal radiology specialist and therefore mistreated by numerous physicians before being referred to our outpatient clinic. After further assessment, the diagnosis has been confirmed, and ASM was treated by complete resection combined with tarsal tunnel decompression. To the best of our knowledge, this is the first case reported in which ASM caused symptoms but presented without posteromedial swelling. This might be due to a proximally positioned belly of the ASM, followed by a tendinous insertion on the medial side of the calcaneus.

Specific and potent inhibition of NAD+-dependent DNA ligase by pyridochromanones.

Pyridochromanones were identified by high throughput screening as potent inhibitors of NAD+-dependent DNA ligase from Escherichia coli. Further characterization revealed that eubacterial DNA ligases from Gram-negative and Gram-positive sources were inhibited at nanomolar concentrations. In contrast, purified human DNA ligase I was not affected (IC50 > 75 microm), demonstrating remarkable specificity for the prokaryotic target. The binding mode is competitive with the eubacteria-specific cofactor NAD+, and no intercalation into DNA was detected. Accordingly, the compounds were bactericidal for the prominent human pathogen Staphylococcus aureus in the low microg/ml range, whereas eukaryotic cells were not affected up to 60 microg/ml. The hypothesis that inhibition of DNA ligase is the antibacterial principle was proven in studies with a temperature-sensitive ligase-deficient E. coli strain. This mutant was highly susceptible for pyridochromanones at elevated temperatures but was rescued by heterologous expression of human DNA ligase I. A physiological consequence of ligase inhibition in bacteria was massive DNA degradation, as visualized by fluorescence microscopy of labeled DNA. In summary, the pyridochromanones demonstrate that diverse eubacterial DNA ligases can be addressed by a single inhibitor without affecting eukaryotic ligases or other DNA-binding enzymes, which proves the value of DNA ligase as a novel target in antibacterial therapy.

Regulation of the glucose-specific phosphotransferase system (PTS) of Staphylococcus carnosus by the antiterminator protein GlcT.

The ptsG operon of Staphylococcus carnosus consists of two adjacent genes, glcA and glcB, encoding glucose- and glucoside-specific enzymes II, respectively, the sugar permeases of the phosphoenolpyruvate-dependent phosphotransferase system (PTS). The expression of the ptsG operon is glucose-inducible. Putative RAT (ribonucleic antiterminator) and terminator sequences localized in the promoter region of glcA suggest regulation via antitermination. The glcT gene was cloned and the putative antiterminator protein GlcT was purified. Activity of this protein was demonstrated in vivo in Escherichia coli and Bacillus subtilis. In vitro studies led to the assumption that phosphoenolpyruvate-dependent phosphorylation of residue His105 via the general PTS components enzyme I and HPr facilitates dimerization of GlcT and consequently activation. Because of the high similarity of the two ptsG-RAT sequences of B. subtilis and S. carnosus, in vivo studies were performed in B. subtilis. These indicated that GlcT of S. carnosus is able to recognize ptsG-RAT sequences of B. subtilis and to cause antitermination. The specific interaction between B. subtilis ptsG-RAT and S. carnosus GlcT demonstrated by surface plasmon resonance suggests that only the dimer of GlcT binds to the RAT sequence. HPr-dependent phosphorylation of GlcT facilitates dimer formation and may be a control device for the proper function of the general PTS components enzyme I and HPr necessary for glucose uptake and phosphorylation by the corresponding enzyme II.