Virtual Trauma Meeting as a Component of Undergraduate Orthopaedic Education.

INTRODUCTION: Virtual teaching has proven effective for medical students during the COVID-19 pandemic. This study is the first to describe an undergraduate orthopaedic teaching strategy in the format of virtual trauma meetings (VTM). METHODS: Clinical medical students from the Universities of Bristol and Cardiff were invited to attend five VTM between October and November 2020. These were delivered by consultants and speciality doctors via Zoom software. An 11-item feedback form was distributed after each session to assess the relevance of teaching material, student confidence in asking and answering questions, and if students would benefit from further sessions. Several open-ended questions were designed to evaluate aspects of the session that were most useful, which orthopaedic topics were of high priority and if they had any suggestions for improvement. Our initial aim was to assess student acceptance of the virtual format. Several months later pre-recorded material was uploaded onto YouTube and post hoc questionnaires were analysed. RESULTS: A total of 50 students attended, with a median of 11±6 attending per session, producing a total of 26 feedback responses. Among the responders, there were 10 males and nine females and 63% of the students were in their third year. 100% of students felt comfortable asking questions and 96% felt comfortable answering questions. X-ray interpretation and management of fractures were the highest priority subjects. The majority of students considered the interaction between senior and junior doctors most valuable, and the most common improvement suggested was the inclusion of polls or OSCE-styled questions. CONCLUSIONS: VTM could be a useful resource to enhance undergraduate trauma and orthopaedic (T&O) education by providing student-focused material in an open learning environment.

Adverse reaction to metal debris due to fretting corrosion between the acetabular components of modular dual-mobility constructs in total hip replacement: a systematic review and meta-analysis.

Modular dual-mobility (MDM) constructs can be used to reduce dislocation rates after total hip replacement (THR). However, there are concerns about adverse reaction to metal debris (ARMD) as a result of fretting corrosion between the metal liner and shell. This systematic review reports outcomes following THR using MDM components. It was registered with PROSPERO and conducted in line with Cochrane and PRISMA recommendations.Sixteen articles were included overall, with meta-analysis performed on relevant subsets using a random intercept logistic regression model. Estimated median incidence of ARMD requiring revision surgery within study follow-up period was 0.3% (95% CI 0.1 - 1.8%, from 11 cohort studies containing 1312 cases).Serum metal ion levels were mildly raised in 7.9% of cases, and significantly raised in 1.8%, but there was no correlation with worse clinical hip function scores within studies. Dislocation rate was 0.8%. Revision rate was 3.3%.There are mixed reports of wear on the backside of the metal liner from the acetabular shell and screw heads. Both implant design and component malseating are implicated, but currently it is unclear to what extent each factor is responsible.Studies were poor quality with high risk of confounding, especially from trunnion corrosion. We have made recommendations for further work. In the meantime, surgeons should be aware of the potential risk of ARMD when considering using an MDM prosthesis, and, if selecting one, must ensure proper seating of the liner and screws intraoperatively. Cite this article: EFORT Open Rev 2021;6:343-353. DOI: 10.1302/2058-5241.6.200146.

Use of Surgical Adhesive Tape to Maintain Tension on Intrafocal K-Wires for Easy Reduction and Fixation of Complex Intra-Articular Distal Radius Fractures.

Maintaining reduction during fixation of complex intra-articular distal radius fractures with dorsal comminution can be challenging. We describe an operative technique where reduction is achieved with temporary intrafocal Kirschner wires (K-wires), and held using surgical adhesive tape wrapped around the hand, whilst a volar plate is applied to achieve rigid fixation. This is a simple, inexpensive method used at our institutions which allows fixation of these fractures without the need for an operative assistant.

Digital pathology is a practical alternative to on-site intraoperative frozen section diagnosis in thoracic surgery.

AIMS: Telepathology uses digitised image transfer to allow off-site reporting of histopathology slides. This technology could facilitate the centralisation of pathology services, which may improve their quality and cost-effectiveness. The benefits may be most apparent in frozen section reporting, in which turnaround times (TATs) are vital. We moved from on-site to off-site telepathology reporting of thoracic surgery frozen section specimens in 2016. The aim of this study was to compare TATs before and after this service change. METHODS AND RESULTS: All thoracic frozen section specimens analysed 4 months prior and 4 months following the service change were included. Demographics, operation, sample type, time taken from theatre, time received by laboratory, time reported by laboratory, TAT, frozen section diagnosis, final histopathological diagnosis and final TNM staging were recorded. The results were analysed with spss statistical software version 24. In total, there were 65 samples from 59 patients; 34 before the change and 31 after the change. Specimens included 51 lung, six lymph node, three bronchial, three chest wall and two pleural biopsies. Before the change, the median TAT was 25 min [interquartile range (IQR) 20-33 min]. No diagnoses were deferred. No diagnoses were changed on subsequent paraffin analysis. After the change, with the use of digital pathology, the median TAT was 27.5 min (IQR 21.75-38.5 min). This difference was not significant (P = 0.581). Diagnosis was deferred in one case (3.23%). There was one (3.23%) mid-case technical failure resulting in the sample having to be transported by courier, resulting in a TAT of 106 min. No diagnoses were changed on subsequent paraffin analysis. CONCLUSIONS: There was no significant difference in reporting times between digital technology and an on-site service, although one sample was affected by a technical failure requiring physical transportation of the specimen for analysis. Our study was underpowered to detect differences in accuracy.

On-Resin Macrocyclization of Peptides Using Vinyl Sulfonamides as a Thiol-Michael "Click" Acceptor.

Macrocyclization of linear peptides imparts improved stability to enzymatic degradation and increases potency of function. Many successful macrocyclization of peptides both in solution and on-resin have been achieved but are limited in scope as they lack selectivity, require long reaction times, or necessitate heat. To overcome these drawbacks a robust and facile strategy was developed employing thiol-Michael click chemistry via an N-methyl vinyl sulfonamide. We demonstrate its balance of reactivity and high stability through FTIR model kinetic studies, reaching 88% conversion over 30 min, and NMR stability studies, revealing no apparent degradation over an 8 day period in basic conditions. Using a commercially available reagent, 2-chloroethane sulfonyl chloride, the cell adhesion peptide, RGDS, was functionalized and macrocyclized on-resin with a relative efficiency of over 95%. The simplistic nature of this process demonstrates the effectiveness of vinyl sulfonamides as a thiol-Michael click acceptor and its applicability to many other bioconjugation applications.

Blue-light activated rapid polymerization for defect-free bulk Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) crosslinked networks.

A visible-light (470 nm wavelength) sensitive Type II photoinitiator system is developed for bulk Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions in crosslinked networks. The accelerated photopolymerization eliminates UV-mediated azide decomposition allowing for the formation of defect-free glassy networks which exhibit a narrow glass transition temperature.

Dynamic Bonds in Covalently Crosslinked Polymer Networks for Photoactivated Strengthening and Healing.

A photoactivated-strengthening polymer network is reported. This approach incorporates dynamic bonds into the network architecture, which enables a secondary polymerization triggered by UV light. Three attributes of this material are demonstrated, including: i) there is simultaneous photoinduced strengthening and healing after the material is severed, ii) bulk property changes are spatially confined via photopatterning, and iii) there is permanent shape change post-irradiation.

Gold(I)-promoted heterocyclization of internal alkynes: a comparative study of direct metallate 5-endo-dig cyclization versus a stepwise cyclization.

With cationic gold catalysts, internal alkynes bearing both propargylic acyloxy groups and tosylamide pronucleophiles were found to cyclize to give either five- or six-membered ring nitrogen heterocycles. A wide variety of gold catalysts, counterions, and solvents were examined to elucidate their effect on product distribution. In most cases, the direct 5-endo-dig cyclization was found to be the major pathway leading to good yields of dehydropyrrolidine products. Alkyne substrates bearing additional normal alkyl substituents at the propargylic position gave dehydropiperidines as the major product. This pathway is thought to proceed by way of a 1,2- Rautenstrauch rearrangement to produce a vinyl gold(I) carbene, which undergoes conjugate addition by the nitrogen pronucleophile. Structural and electronic factors were studied in the nitrogen pronucleophile and in the migrating acyloxy group. Each was found to have a minor effect on the product ratio.

Removal of ruthenium using a silica gel supported reagent.

A solid-supported isocyanide ligand was developed to destroy active metathesis catalysts and to remove ruthenium byproducts from metathesis reactions. This method was able to significantly reduce the concentration of residual ruthenium from the organic products of several alkene and ene-yne metathesis reactions, under a variety of different conditions.

Probing a 2-aminobenzimidazole library for binding to RNA internal loops via two-dimensional combinatorial screening.

There are many potential RNA drug targets in bacterial, viral, and human transcriptomes. However, there are few small molecules that modulate RNA function. This is due, in part, to a lack of fundamental understanding about RNA-ligand interactions including the types of small molecules that bind to RNA structural elements and the RNA structural elements that bind to small molecules. In an effort to better understand RNA-ligand interactions, we diversified the 2-aminobenzimidazole core (2AB) and probed the resulting library for binding to a library of RNA internal loops. We chose the 2AB core for these studies because it is a privileged scaffold for binding RNA based on previous reports. These studies identified that N-methyl pyrrolidine, imidazole, and propylamine diversity elements at the R1 position increase binding to internal loops; variability at the R2 position is well tolerated. The preferred RNA loop space was also determined for five ligands using a statistical approach and identified trends that lead to selective recognition.

Geminal alkene-alkyne cross metathesis using a relay strategy.

A relay strategy was employed to achieve an intermolecular ene-yne metathesis between 1,1-disubstituted alkenes and alkynes. The relay serves to activate an unreactive alkene which will not participate in ene-yne metathesis. The new relay cross ene-yne metathesis gives rise to 1,1,3-trisubstituted-1,3-dienes previously inaccessible by direct ene-yne metathesis methods.

Alkene metathesis approach to ß-unsubstituted anti-allylic alcohols and their use in ene-yne metathesis.

The synthesis of ß-unsubstituted, anti-allylic alcohols using a catalytic Evans aldol reaction conjoined with a relay-type ring-closing alkene metathesis is reported. The metathesis step serves to remove a ß-alkenyl group, which facilitated the aldol step. The ß-substituted enals serve as acrolein surrogates. The products were employed in ene-yne cross metathesis.

Influencing uptake and localization of aminoglycoside-functionalized peptoids.

The development of small-molecule therapeutics that target RNA remains a promising field but one hampered with considerable challenges that include programming high affinity, specificity, cell permeability, and favorable pharmacokinetic profiles. Previously, we employed the use of peptoids to modularly display RNA-binding modules to enhance binding affinity and specificity by altering valency and the distance between ligand modules. Herein, factors that affect uptake, localization, and toxicity of peptoids that display a kanamycin derivative into a variety of mammalian cells lines are reported. A series of peptoids that display various spacing modules was synthesized to determine if the spacing module affects permeability and localization. The spacing module does affect cellular permeability into C2C12, A549, HeLa, and MCF7 cell lines but not into Jurkat cells. Moreover, the modularly assembled peptoids carrying the kanamycin cargo localize in the cytoplasm and perinuclear region of C2C12 and A549 cells and throughout HeLa cells, including the nucleus. These studies could contribute to the development of general strategies to afford cell permeable, modularly assembled small molecules that specifically target RNAs present in a variety of cell types.

Controlling the specificity of modularly assembled small molecules for RNA via ligand module spacing: targeting the RNAs that cause myotonic muscular dystrophy.

Myotonic muscular dystrophy types 1 and 2 (DM1 and DM2, respectively) are caused by expansions of repeating nucleotides in noncoding regions of RNA. In DM1, the expansion is an rCUG triplet repeat, whereas the DM2 expansion is an rCCUG quadruplet repeat. Both RNAs fold into hairpin structures with periodically repeating internal loops separated by two 5'GC/3'CG base pairs. The sizes of the loops, however, are different: the DM1 repeat forms 1 x 1 nucleotide UU loops while the DM2 repeat forms 2 x 2 nucleotide 5'CU/3'UC loops. DM is caused when the expanded repeats bind the RNA splicing regulator Muscleblind-like 1 protein (MBNL1), thus compromising its function. Therefore, one potential therapeutic strategy for these diseases is to prevent MBNL1 from binding the toxic RNA repeats. Previously, we designed nanomolar inhibitors of the DM2-MBNL1 interaction by modularly assembling 6'-N-5-hexyonate kanamycin A (K) onto a peptoid backbone. The K ligand binds the 2 x 2 pyrimidine-rich internal loops found in the DM2 RNA with high affinity. The best compound identified from that study contains three K modules separated by four propylamine spacing modules and is 20-fold selective for the DM2 RNA over the DM1 RNA. Because the modularly assembled K-containing compounds also bound the DM1 RNA, albeit with lower affinity, and because the loop size is different, we hypothesized that the optimal DM1 RNA binder may display K modules separated by a shorter distance. Indeed, here the ideal DM1 RNA binder has only two propylamine spacing modules separating the K ligands. Peptoids displaying three and four K modules on a peptoid scaffold bind the DM1 RNA with K(d)'s of 20 nM (3-fold selective for DM1 over DM2) and 4 nM (6-fold selective) and inhibit the RNA-protein interaction with IC(50)'s of 40 and 7 nM, respectively. Importantly, by coupling the two studies together, we have determined that appropriate spacing can affect binding selectivity by 60-fold (20- x 3-fold). The trimer and tetramer also bind approximately 13- and approximately 63-fold more tightly to DM1 RNAs than does MBNL1. The modularly assembled compounds are cell permeable and nontoxic as determined by flow cytometry. The results establish that for these two systems: (i) a programmable modular assembly approach can provide synthetic ligands for RNA with affinities and specificities that exceed those of natural proteins; and, (ii) the spacing of ligand modules can be used to tune specificity for one RNA target over another.

Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3.

Herein, we describe the design of high affinity ligands that bind expanded rCUG and rCAG repeat RNAs expressed in myotonic dystrophy type 1 (DM1) and spinocerebellar ataxia type 3. These ligands also inhibit, with nanomolar IC(50) values, the formation of RNA-protein complexes that are implicated in both disorders. The expanded rCUG and rCAG repeats form stable RNA hairpins with regularly repeating internal loops in the stem and have deleterious effects on cell function. The ligands that bind the repeats display a derivative of the bisbenzimidazole Hoechst 33258, which was identified by searching known RNA-ligand interactions for ligands that bind the internal loop displayed in these hairpins. A series of 13 modularly assembled ligands with defined valencies and distances between ligand modules was synthesized to target multiple motifs in these RNAs simultaneously. The most avid binder, a pentamer, binds the rCUG repeat hairpin with a K(d) of 13 nM. When compared to a series of related RNAs, the pentamer binds to rCUG repeats with 4.4- to >200-fold specificity. Furthermore, the affinity of binding to rCUG repeats shows incremental gains with increasing valency, while the background binding to genomic DNA is correspondingly reduced. Then, it was determined whether the modularly assembled ligands inhibit the recognition of RNA repeats by Muscleblind-like 1 (MBNL1) protein, the expanded-rCUG binding protein whose sequestration leads to splicing defects in DM1. Among several compounds with nanomolar IC(50) values, the most potent inhibitor is the pentamer, which also inhibits the formation of rCAG repeat-MBNL1 complexes. Comparison of the binding data for the designed synthetic ligands and MBNL1 to repeating RNAs shows that the synthetic ligand is 23-fold higher affinity and more specific to DM1 RNAs than MBNL1. Further studies show that the designed ligands are cell permeable to mouse myoblasts. Thus, cell permeable ligands that bind repetitive RNAs have been designed that exhibit higher affinity and specificity for binding RNA than natural proteins. These studies suggest a general approach to targeting RNA, including those that cause RNA dominant disease.