Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effect of macrocyclization and tetramethylrhodamine labeling on chemokine binding peptides.

Receptor-derived peptides have played an important role in elucidating chemokine-receptor interactions. For the inflammatory chemokine CXC-class chemokine ligand 8 (CXCL8), a site II-mimetic peptide has been derived from parts of extracellular loops 2 and 3 and adjacent transmembrane helices of its receptor CXC-class chemokine receptor 1 (Helmer et al., RSC Adv., 2015, 5, 25657). The peptide sequence with a C-terminal glutamine did not bind to CXCL8, whereas one with a C-terminal glutamate did but with low micromolar affinity. We sought to improve the affinity and protease stability of the latter peptide through cyclization while also cyclizing the former for control purposes. To identify a cyclization strategy that permits a receptor-like interaction, we conducted a molecular dynamics simulation of CXCL8 in complex with full-length CXC-class chemokine receptor 1. We introduced a linker to provide an appropriate spacing between the termini and used an on-resin side-chain-to-tail cyclization strategy. Upon chemokine binding, the fluorescence intensity of the tetramethylrhodamine (TAMRA)-labeled cyclic peptides increased whereas the fluorescence anisotropy decreased. Additional molecular dynamics simulations indicated that the fluorophore interacts with the peptide macrocycle so that chemokine binding leads to its displacement and observed changes in fluorescence. Macrocyclization of both 18-amino acid-long peptides led to the same low micromolar affinity for CXCL8. Likewise, both TAMRA-labeled linear peptides interacted with CXCL8 with similar affinities. Interestingly, the linear TAMRA-labeled peptides were more resistant to tryptic digestion than the unlabeled counterparts, whereas the cyclized peptides were not degraded at all. We conclude that the TAMRA fluorophore tends to interact with peptides altering their protease stability and behavior in fluorescence-based assays.

Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions.

The activation process of G protein-coupled receptors (GPCRs) has been extensively studied, both experimentally and computationally. In particular, Molecular Dynamics (MD) simulations have proven useful in exploring GPCR conformational space. The typical behaviour of class A GPCRs, when subjected to unbiased MD simulations from their crystallized inactive state, is to fluctuate between inactive and intermediate(s) conformations, even with bound agonist. Fully active conformation(s) are rarely stabilized unless a G protein is also bound. Despite several crystal structures of the adenosine A2a receptor (A2aR) having been resolved in complex with co-crystallized agonists and Gs protein, its agonist-mediated activation process is still not completely understood. In order to thoroughly examine the conformational landscape of A2aR activation, we performed unbiased microsecond-length MD simulations in quadruplicate, starting from the inactive conformation either in apo or with bound agonists: endogenous adenosine or synthetic NECA, embedded in two homogeneous phospholipid membranes: 1,2-dioleoyl-sn-glycerol-3-phosphoglycerol (DOPG) or 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC). In DOPC with bound adenosine or NECA, we observe transition to an intermediate receptor conformation consistent with the known adenosine-bound crystal state. In apo state in DOPG, two different intermediate conformations are obtained. One is similar to that observed with bound adenosine in DOPC, while the other is closer to the active state but not yet fully active. Exclusively, in DOPG with bound adenosine or NECA, we reproducibly identify receptor conformations with fully active features, which are able to dock Gs protein. These different receptor conformations can be attributed to the action/absence of agonist and phospholipid-mediated allosteric effects on the intracellular side of the receptor.

Structural Assessment of Agonist Efficacy in the µ-Opioid Receptor: Morphine and Fentanyl Elicit Different Activation Patterns.

Over the past two decades, the opioid epidemic in the United States and Canada has evidenced the need for a better understanding of the molecular mechanisms of medications used to fight pain. Morphine and fentanyl are widely used in opiate-mediated analgesia for the treatment of chronic pain. These compounds target the µ-opioid receptor (MOR), a class A G protein-coupled receptor (GPCR). In light of described higher efficacy of fentanyl with respect to morphine, we have performed independent µs-length unbiased molecular dynamics (MD) simulations of MOR complexes with each of these ligands, including the MOR antagonist naltrexone as a negative control. Consequently, MD simulations totaling 58 µs have been conducted to elucidate at the atomic level ligand-specific receptor activity and signal transmission in the MOR. In particular, we have identified stable binding poses of morphine and fentanyl, which interact differently with the MOR. Different ligand-receptor interaction landscapes directly induce sidechain conformational changes of orthosteric pocket residues: Asp1493.32, Tyr1503.33, Gln1262.60, and Lys2355.39. The induced conformations determine Asp1493.32-Tyr3287.43 sidechain-sidechain interactions and Trp2956.48-Ala2425.46 sidechain-backbone H-bond formations, as well as Met1533.36 conformational changes. In addition to differences in ligand binding, different intracellular receptor conformational changes are observed as morphine preferentially activates transmembrane (TM) helices: TM3 and TM5, while fentanyl preferentially activates TM6 and TM7. As conformational changes in TM6 and TM7 are widely described as being the most crucial aspect in GPCR activation, this may contribute to the greater efficacy of fentanyl over morphine. These computationally observed functional differences between fentanyl and morphine may provide new avenues for the design of safer but not weaker opioid drugs because it is desirable to increase the safety of medicines without sacrificing their efficacy.

Physiological involvement of presynaptic L-type voltage-dependent calcium channels in GABA release of cerebellar molecular layer interneurons.

While high threshold voltage-dependent Ca2+ channels (VDCCs) of the N and P/Q families are crucial for evoked neurotransmitter release in the mammalian CNS, it remains unclear to what extent L-type Ca2+ channels (LTCCs), which have been mainly considered as acting at postsynaptic sites, participate in the control of transmitter release. Here, we investigate the possible role of LTCCs in regulating GABA release by cerebellar molecular layer interneurons (MLIs) from rats. We found that BayK8644 (BayK) markedly increases mIPSC frequency in MLIs and Purkinje cells (PCs), suggesting that LTCCs are expressed presynaptically. Furthermore, we observed (1) a potentiation of evoked IPSCs in the presence of BayK, (2) an inhibition of evoked IPSCs in the presence of the LTCC-specific inhibitor Compound 8 (Cp8), and (3) a strong reduction of mIPSC frequency by Cp8. BayK effects are reduced by dantrolene, suggesting that ryanodine receptors act in synergy with LTCCs. Finally, BayK enhances presynaptic AP-evoked Ca2+ transients and increases the frequency of spontaneous axonal Ca2+ transients observed in TTX. Taken together, our data demonstrate that LTCCs are of primary importance in regulating GABA release by MLIs.

Bending the Curve of Global Freshwater Biodiversity Loss: An Emergency Recovery Plan.

Despite their limited spatial extent, freshwater ecosystems host remarkable biodiversity, including one-third of all vertebrate species. This biodiversity is declining dramatically: Globally, wetlands are vanishing three times faster than forests, and freshwater vertebrate populations have fallen more than twice as steeply as terrestrial or marine populations. Threats to freshwater biodiversity are well documented but coordinated action to reverse the decline is lacking. We present an Emergency Recovery Plan to bend the curve of freshwater biodiversity loss. Priority actions include accelerating implementation of environmental flows; improving water quality; protecting and restoring critical habitats; managing the exploitation of freshwater ecosystem resources, especially species and riverine aggregates; preventing and controlling nonnative species invasions; and safeguarding and restoring river connectivity. We recommend adjustments to targets and indicators for the Convention on Biological Diversity and the Sustainable Development Goals and roles for national and international state and nonstate actors.

C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.

Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

Verbatim Theater: Prompting Reflection and Discussion about Healthcare Culture as a Means of Promoting Culture Change.

Problem: The mistreatment of medical and nursing students and junior health professionals has been reported internationally in research and the media. Mistreatment can be embedded and normalized in hierarchical healthcare workplaces, limiting the effectiveness of policies and reporting tools to generate change; as a result, some of those who experience mistreatment later perpetuate it. We used a novel, creative approach, verbatim theater, to highlight the complexity of healthcare workplaces, encourage critical reflection, and support long-term culture change. Intervention: Verbatim theater is a theater-for-change documentary genre in which a playscript is devised using only the words spoken by informants. In 2017, 30 healthcare students and health professionals were recruited and interviewed about their experience of work and training by the multidisciplinary Sydney Arts and Health Collective using semi-structured interviews. Interview transcripts became the primary material from which the script for the verbatim theater play 'Grace Under Pressure' was developed. The performing arts have previously been used to develop the communication skills of health professional students; this esthetic expression of the real-life effects of healthcare workplace culture on trainees and students was implemented to stimulate consciousness of, and dialogue about, workplace mistreatment in healthcare work and training. Context: The play premiered at a major Sydney theater in October 2017, attended by the lay public and student and practicing health professionals. In November 2017, three focus groups were held with a sample of audience members comprising healthcare professionals and students. These focus groups explored the impact of the play on reflection and discussion of healthcare culture and/or promoting culture change in the health workplace. We analyzed the focus group data using theoretical thematic analysis, informed by Turner's theory of the relation between 'social' and 'esthetic' drama to understand the impact of the play on its audience. Impact: Focus group members recognized aspects of their personal experience of professionalism, training, and workplace culture in the play, Grace Under Pressure. They reported that the play's use of real-life stories and authentic language facilitated their critical reflection. Participants constructed some learning as 'revelation,' in which the play enabled them to gain significant new insight into the culture of health care and opened up discussions with colleagues. As a result, participants suggested possible remedies for unhealthy aspects of the culture, including systemic issues of bullying and harassment. A small number of participants critiqued aspects of the play they believed did not adequately reflect their experience, with some believing that the play over-emphasized workplace mistreatment. Lessons Learned: Verbatim theater is a potent method for making personal experiences of healthcare workplace and training culture more visible to lay and health professional audiences. In line with Turner's theory, the play's use of real-life stories and authentic language enabled recognition of systemic challenges in healthcare workplaces by training and practicing health professionals in the audience. Verbatim theater provides a means to promote awareness and discussion of difficult social issues and potential means of addressing them.

Cholinergic modulation of striatal nitric oxide-producing interneurons.

Striatal GABAergic interneurons that express nitric oxide synthase-so-called low-threshold spike interneurons (LTSIs)-play several key roles in the striatum. But what drives the activity of these interneurons is less well defined. To fill this gap, a combination of monosynaptic rabies virus mapping (msRVm), electrophysiological and optogenetic approaches were used in transgenic mice in which LTSIs expressed either Cre recombinase or a fluorescent reporter. The rabies virus studies revealed a striking similarity in the afferent connectomes of LTSIs and neighboring cholinergic interneurons, particularly regarding connections arising from the parafascicular nucleus of the thalamus and cingulate cortex. While optogenetic stimulation of cingulate inputs excited both cholinergic interneurons and LTSIs, thalamic stimulation excited cholinergic interneurons, but inhibited LTSIs. This inhibition was dependent on cholinergic interneurons and had two components: a previously described GABAergic element and one that was mediated by M4 muscarinic acetylcholine receptors. In addition to this phasic signal, cholinergic interneurons tonically excited LTSIs through a distinct, M1 muscarinic acetylcholine receptor pathway. This coordinated cholinergic modulation of LTSIs predisposed them to rhythmically burst in response to phasic thalamic activity, potentially reconfiguring striatal circuitry in response to salient environmental stimuli.

Structure and evolution of double minutes in diagnosis and relapse brain tumors.

Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.

Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization.

Dopamine D2 receptors (D2R) are known to form transient homodimer complexes, of which the increased formation has already been associated with development of schizophrenia. Pharmacological targeting and modulation of the equilibrium of these receptor homodimers might lead to a better understanding of the critical role played by these complexes in physiological and pathological conditions. Whereas agonist addition has shown to prolong the D2R dimer lifetime and increase the level of dimer formation, the possible influence of D2R antagonists on dimerization has remained rather unexplored. Here, using a live-cell reporter assay based on the functional complementation of a split Nanoluciferase, a panel of six D2R antagonists were screened for their ability to modulate the level of D2LR dimer formation. Incubation with the D2R antagonist spiperone decreased the level of D2LR dimer formation significantly by 40-60% in real-time and after long-term (≥16 h) incubations. The fact that dimer formation of the well-studied A2a-D2LR dimer was not altered following incubation with spiperone supports the specificity of this observation. Other D2R antagonists, such as clozapine, risperidone, and droperidol did not significantly evoke this dissociation event. Furthermore, molecular modeling reveals that spiperone presents specific Tyr1995.48 and Phe3906.52 conformations, compared to clozapine, which may determine D2R homodimerization.

Striatal cholinergic interneurons and Parkinson's disease.

Giant, aspiny cholinergic interneurons (ChIs) have long been known to be key nodes in the striatal circuitry controlling goal-directed actions and habits. In recent years, new experimental approaches, like optogenetics and monosynaptic rabies virus mapping, have expanded our understanding of how ChIs contribute to the striatal activity underlying action selection and the interplay of dopaminergic and cholinergic signaling. These approaches also have begun to reveal how ChI function is distorted in disease states affecting the basal ganglia, like Parkinson's disease (PD). This review gives a brief overview of our current understanding of the functional role played by ChIs in striatal physiology and how this changes in PD. The translational implications of these discoveries, as well as the gaps that remain to be bridged, are discussed as well.

CONSERTING: integrating copy-number analysis with structural-variation detection.

We developed Copy Number Segmentation by Regression Tree in Next Generation Sequencing (CONSERTING), an algorithm for detecting somatic copy-number alteration (CNA) using whole-genome sequencing (WGS) data. CONSERTING performs iterative analysis of segmentation on the basis of changes in read depth and the detection of localized structural variations, with high accuracy and sensitivity. Analysis of 43 cancer genomes from both pediatric and adult patients revealed novel oncogenic CNAs, complex rearrangements and subclonal CNAs missed by alternative approaches.

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

Pharmacologic activation of estrogen receptor ß increases mitochondrial function, energy expenditure, and brown adipose tissue.

Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor ß (ER-ß) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-ß and its ligands. Estrogen receptor ß (ER-ß) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-ß-selective ligand increased markers of tricarboxylic acid-dependent and -independent energy biogenesis and oxygen consumption in mice without a concomitant increase in physical activity or food consumption, all culminating in significantly reduced weight gain and adiposity. The antiobesity effects of ER-ß ligand were not observed in ER-ß-knockout mice. Serum metabolite profiles of adult lean and juvenile mice were comparable, while that of adult obese mice was distinct, indicating a possible impact of obesity on age-dependent metabolism. This phenotype was partially reversed by ER-ß-selective ligand. These data highlight a new role for ER-ß in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.-Ponnusamy, S., Tran, Q. T., Harvey, I., Smallwood, H. S., Thiyagarajan, T., Banerjee, S., Johnson, D. L., Dalton, J. T., Sullivan, R. D., Miller, D. D., Bridges, D., Narayanan, R. Pharmacologic activation of estrogen receptor ß increases mitochondrial function, energy expenditure, and brown adipose tissue.

The long and winding road for selective androgen receptor modulators.

Numerous selective androgen receptor modulators (SARMs) with differing chemical structures and nearly ideal pharmacological and pharmacokinetic properties have been developed that are well tolerated and selectively increase lean body mass in humans. However, definitive demonstration of the linkage between lean body mass and physical function in a relevant, large patient population has remained elusive for a SARM. The clinical endpoints serving as their basis of approval have shifted with time and clinical indication and are likely to continue to do so as the field matures with additional safety and efficacy data pertaining to the relationship between lean body mass and physical function, regulatory decisions with SARMs and other agents, and yet unexplored clinical indications.

YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation.

Medulloblastoma is the most common solid malignancy of childhood, with treatment side effects reducing survivors' quality of life and lethality being associated with tumor recurrence. Activation of the Sonic hedgehog (Shh) signaling pathway is implicated in human medulloblastomas. Cerebellar granule neuron precursors (CGNPs) depend on signaling by the morphogen Shh for expansion during development, and have been suggested as a cell of origin for certain medulloblastomas. Mechanisms contributing to Shh pathway-mediated proliferation and transformation remain poorly understood. We investigated interactions between Shh signaling and the recently described tumor-suppressive Hippo pathway in the developing brain and medulloblastomas. We report up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human medulloblastomas with aberrant Shh signaling. Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs. Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation. Furthermore, YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly growing tumor cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.

Do surgical helmet systems affect intraoperative wound contamination? A randomised controlled trial.

BACKGROUND: Deep infection following arthroplasty remains a devastating complication. Some registry data suggests that modern positive-pressure surgical helmet systems (SHS) are associated with a paradoxical increase in infection rates, and as such their role in arthroplasty remains unclear. The aim of this study was to investigate whether SHS increase wound contamination in total knee arthroplasty (TKA) and if this contamination can be reduced by placing tape around the gown/glove interface. METHODS: Seventy-five patients were randomised into three groups: scrubbed theatre staff wore standard surgical gowns (SG), SHS without tape at the gown/glove interface, or SHS with tape. All TKA operations were carried out by the same surgeon. Wound contamination was assessed using a wound culture technique. Blinded laboratory analysis was performed. RESULTS: There were 5/50 culture positive cases when a SHS was used compared to 0/25 when a SG was used; but this difference was not statistically significant (p = 0.16). There were 4/24 culture positive cases when SHS with tape was used compared to 1/26 when SHS without tape was used; but this difference was not statistical significant p = 0.18. CONCLUSION: We found no difference in wound contamination between SG and SHS. Addition of tape at the gown/glove interface did not alter the contamination rate. The choice of surgical gown should take into account cost, comfort and personal protection; as this study found no evidence that wound contamination rates will be altered.