sp3 -Rich Heterocycle Synthesis on DNA: Application to DNA-Encoded Library Production.

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2 -rich molecules. Herein, we show that sp3 -rich mono- and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space.

Progressive loss of hearing and balance in superficial siderosis due to occult spinal dural defects.

PURPOSE: Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension. METHODS: Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur. RESULTS: The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve. CONCLUSIONS: In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect.

Partner, Neighbor, Housekeeper and Dimension: 3D versus 2D Glomerular Co-Cultures Reveal Drawbacks of Currently Used Cell Culture Models.

Signaling-pathway analyses and the investigation of gene responses to different stimuli are usually performed in 2D monocultures. However, within the glomerulus, cells grow in 3D and are involved in direct and paracrine interactions with different glomerular cell types. Thus, the results from 2D monoculture experiments must be taken with caution. We cultured glomerular endothelial cells, podocytes and mesangial cells in 2D/3D monocultures and 2D/3D co-cultures and analyzed cell survival, self-assembly, gene expression, cell-cell interaction, and gene pathways using live/dead assay, time-lapse analysis, bulk-RNA sequencing, qPCR, and immunofluorescence staining. Without any need for scaffolds, 3D glomerular co-cultures self-organized into spheroids. Podocyte- and glomerular endothelial cell-specific markers and the extracellular matrix were increased in 3D co-cultures compared to 2D co-cultures. Housekeeping genes must be chosen wisely, as many genes used for the normalization of gene expression were themselves affected in 3D culture conditions. The transport of podocyte-derived VEGFA to glomerular endothelial cells confirmed intercellular crosstalk in the 3D co-culture models. The enhanced expression of genes important for glomerular function in 3D, compared to 2D, questions the reliability of currently used 2D monocultures. Hence, glomerular 3D co-cultures might be more suitable in the study of intercellular communication, disease modelling and drug screening ex vivo.

Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis.

BACKGROUND: Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies. METHODS: Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB. RESULTS: Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner. CONCLUSIONS: Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.

Management of open elbow fractures: experiences and outcomes from a UK major trauma center.

HYPOTHESIS AND BACKGROUND: Open fractures about the elbow are an infrequent but complex injury with limited existing literature. The aims of the study were to review the treatment strategies of open elbows fractures, functional outcome and complication rates associated with the injury, and correlate the outcome with the topography of the fracture. METHODS: Patients (n = 21) with open elbow fractures injuries over a 2-year period were analyzed. They were assessed regarding the orthoplastic characteristics of their injury as well any other associated injuries. Outcomes were assessed objectively (achievement of bony union, range of movement, infection status, need for further procedures) and subjectively (Oxford Elbow Score, EQ-5D, EQ-VAS). RESULTS: The commonest grade of open injury was grade 3 (43%). Associated orthopedic injuries were present in 62% and associated system injuries in 57%. Almost half of the patients were noted to have had a significantly increased presenting mortality risk as per Injury Severity Score assessment. Mean time to first wound débridement was 31 hours. There were no cases of deep or chronic infection. Complete bony union was noted in 85% of patients, and 48% of patients required removal of metalwork. Subgroup analysis of the cohort by fracture topography (single unipolar elbow bone injury vs. multiple elbow bony injuries) demonstrated no significant difference (P > .05) regarding rate of complication or final Oxford Elbow Score, EQ-5D or EQ-VAS. Patients with injuries that involved the distal humerus had the highest rate for further procedures (P < .05). The average Oxford Elbow Score, EQ-5D, and EQ-VAS scores for the whole cohort at final follow-up were 37.4, 0.54, and 62.18, respectively. DISCUSSION: Open elbow injuries are usually from high-energy trauma and often combined with other significant injuries. As a result, the timelines to elbow surgery were often delayed. However, this did not impact the local infection rates nor did it necessitate further surgery, but made achieving all British Orthopaedic Association Standards for Trauma targets difficult. Chronic infection was not an issue in this cohort. Subgroup analysis indicates open distal humerus fractures carry the highest risk for further procedures. This is most commonly in the form of removal of metalwork and fibrinolysis. End outcomes for patients with open elbow fractures can be positive, despite the notable presenting Injury Severity Score. A subspecialist elbow and orthoplastic approach whenever possible is advocated.

Self-assembled uracil complexes containing tautomeric uracils: an IRMPD spectroscopic and computation study of the structures of gaseous uracilnCa2+ (n = 4, 5, or 6) complexes.

The structures of doubly-charged uracil (U) complexes with Ca2+, UnCa2+ (n = 4, 5, 6), were studied by infrared multiple photon dissociation (IRMPD) spectroscopy and computational methods. The ions were produced by electrospray ionization (ESI) and were isolated in the gas phase in a Fourier-transform ion cyclotron resonance mass spectrometer (FT-ICR-MS). The recorded IRMPD spectra in both the fingerprint and the C-H/N-H/O-H stretching regions, combined with computed vibrational spectra, reveal that the structures present in the greatest abundance consist of both canonical uracil as well as the lactam (or colloquially "enol") tautomer of uracil. U4Ca2+ consists of two hydrogen-bonded dimers of uracil, one canonical and one tautomer, with each uracil interacting with Ca2+ through a carbonyl oxygen. The structures most consistent with the vibrational spectrum of U6Ca2+ consist of two hydrogen-bonded uracil trimers, each composed of two canonical and one enolic uracil, with each uracil also interacting with Ca2+ through carbonyl oxygen. U5Ca2+ consists of one of the aforementioned trimers and dimers, each containing one enol tautomerized uracil. The computed structures whose vibrational spectra best agree with the experimental vibrational spectra are also the lowest-energy structures for all three complexes. This study clearly shows that some uracils adopt the normally very high energy enol tautomer in the lowest energy gas phase complexes of uracil with a doubly-charged ion like Ca2+.

Stack, PAP and Bury: Technical refinements from a case series of 56 profunda artery perforator flaps for breast reconstruction.

AIMS: To share experiences and learning curve of the introduction of profunda artery perforator (PAP) flaps in breast reconstruction. The secondary aim was to share techniques to improve outcomes. METHODS: Case series reviewing outcomes of 56 consecutive PAP flaps performed by a single surgeon across five institutions between March 2021 and May 2023 were reported. The senior author's preference is to routinely stack and bury the flaps to optimise cosmetic outcomes. RESULTS: Fifty-six PAP flaps were performed in 30 patients. The majority of the PAPs were stacked (n = 43, 77%). The mean age at surgery was 46 years (SD 8.44 years) and mean body mass index was 23.86 (SD 3.59). The mean flap weight was 198.83 g (SD 82.86 g) and the mean combined weight for stacked flaps was 369.57 g (SD 98.65 g). Mean ischaemia time was 56.59 min (SD 17.83 min). There was one flap loss (2%). Of the immediate flaps, 90% were buried and monitored using flow couplers. CONCLUSION: The routine use of PAPs, in particular stacked PAPs, allows for adequate volume and height for breast reconstruction in patients who may have otherwise been deemed unsuitable for autologous breast reconstruction. The PAP flap has replaced the transverse upper gracilis and superior gluteal artery perforator flaps as the second line flap choice in our practice.

Buried Autologous Breast Reconstruction: Outcomes and Technical Considerations.

The purpose of this study is to compare outcomes in patients undergoing buried and non-buried free flaps for breast reconstruction, in addition to evaluating the safety and reliability of venous flow couplers. A retrospective review was performed of all patients undergoing free flap breast reconstruction between 2013 and 2023. The primary outcomes were free flap failure, complications and the number of procedures required to complete the reconstructive journey. A total of 322 flaps were performed in 254 consecutive patients, with 47.5% (n = 153) being buried and 52.0% (n = 169) being non-buried reconstructions. The most common flap of choice being deep inferior epigastric artery perforator flaps (81.9%) followed by profunda artery perforator flaps (14.3%). There was no significant difference between the two groups in complications, including flap failure (buried 2.0% vs. non-buried 1.8% p = 0.902). There was a significant reduction in the number of procedures required to complete the reconstructive journey, with 52.2% (n = 59) of patients undergoing single-stage breast reconstruction in the buried group compared with only 25.5% (n = 36) in the non-buried group (p < 0.001). Two (0.6%) patients experienced a false negative in which the signal of the flow coupler was lost but the flap was perfused during re-exploration. No flap losses occurred without being identified in advance by a loss of audible venous flow signal. Buried free flap breast reconstruction is safe and requires fewer operations to complete patients' reconstructive journey. Flow couplers are a safe and effective method of monitoring buried free flaps in breast reconstruction.

One-stop autologous breast reconstruction: A safe and effective cost-saving pathway.

INTRODUCTION: Patients undergoing autologous breast reconstruction usually require further operations as part of their reconstructive journey. This involves contralateral breast symmetrization and nipple-areola complex (NAC) reconstruction. Restrained access to elective operating space led us to implement a one-stop breast reconstruction pathway. METHODS: Patients undergoing contemporaneous contralateral breast symmetrization and immediate NAC reconstruction with free nipple grafts between July 2020 and June 2021 were identified. A retrospective review of our prospectively maintained database was conducted, to retrieve surgical notes, postoperative complications, and length of inpatient stay. A cost analysis was performed considering savings from contralateral symmetrization. RESULTS: A total of 50 eligible cases were identified, which had unilateral one-stop breast reconstructions. Complication rates and length of stay were not affected by this approach, with only one free flap being lost for this cohort. This approach resulted in £181,000 being saved for our service over a calendar year. DISCUSSION: A one-stop breast reconstruction pathway has proven to be safe and effective in our unit. During these uncertain times, it has streamlined the management of eligible patients, while releasing capacity for other elective operations. Patients avoid having to wait for secondary procedures, finishing their reconstructive pathway earlier. We plan to continue providing this service which has shown to be beneficial clinically and financially.

Generation of Patient-Derived Podocytes from Skin Biopsies.

Podocytes are epithelial cells sitting on the urinary site of the glomerular filtration barrier that contribute to the selective filter function of the glomerulus. Mutations in podocyte-specific genes can cause focal segmental glomerulosclerosis (FSGS), and podocytes are also affected in many other primary and secondary nephropathies. Due to their differentiated nature, primary cell culture models are limited for podocytes. Therefore, commonly conditionally immortalized cells are used. However, these conditionally immortalized podocytes (ciPodocytes) have several limitations: the cells can dedifferentiate in culture, especially when they reach confluency, and several podocyte-specific markers are either only slightly or not expressed at all. This brings the use of ciPodocytes and their applicability for physiological, pathophysiological, and clinical reach into question. Here, we describe a protocol for the generation of human podocytes-including patient-specific podocytes-from a skin punch biopsy by episomal reprogramming of dermal fibroblasts into hiPSCs and subsequent differentiation into podocytes. These podocytes resemble in vivo podocytes much better in terms of morphological characteristics, like the development of foot processes and the expression of the podocyte-specific marker. Finally, yet importantly, these cells maintain patients' mutations, resulting in an improved ex vivo model to study podocyte diseases and potential therapeutic substances in an individualized approach.

Exposure of plastic surgery and urology registrars in the United Kingdom to gender affirming care of transgender patients: A cross-sectional survey of training programme directors.

OBJECTIVES: To assess the expected duration of exposure of United Kingdom urology and plastic surgery trainees to the provision of gender affirming healthcare to transgender patients. This observational, cross-sectional survey asked UK training programme directors (TPDs) to report the volume of training in gender affirming care of transgender patients that urology and plastic surgery trainees are expected to receive. METHODS: A Google Form online questionnaire was distributed to each regional TPD in the UK both for plastic surgery and urology. RESULTS: Eleven of 14 TPDs in plastic surgery and 13 of 19 urology TPDs completed the survey with responses representing 487 trainees. The total estimated exposure of UK trainees to any aspect of gender affirming healthcare was a median of one hour of training per trainee per year (clinical or didactic). Thirteen deaneries reported that trainees received some (didactic or clinical) training in transgender care each year. Only eight of these deaneries reported provision of direct clinical training. The remaining eleven deaneries reported that trainees received no training in gender affirming care. No training was expected to take place for any trainee of either speciality within multi-disciplinary team meetings or in masculinising genital surgery. CONCLUSION: The above evidence demonstrates the low exposure of plastic surgery and urology registrar trainees to gender affirming care during their training years in the UK.

Characterizing Intraindividual Podocyte Morphology In Vitro with Different Innovative Microscopic and Spectroscopic Techniques.

Podocytes are critical components of the glomerular filtration barrier, sitting on the outside of the glomerular basement membrane. Primary and secondary foot processes are characteristic for podocytes, but cell processes that develop in culture were not studied much in the past. Moreover, protocols for diverse visualization methods mostly can only be used for one technique, due to differences in fixation, drying and handling. However, we detected by single-cell RNA sequencing (scRNAseq) analysis that cells reveal high variability in genes involved in cell type-specific morphology, even within one cell culture dish, highlighting the need for a compatible protocol that allows measuring the same cell with different methods. Here, we developed a new serial and correlative approach by using a combination of a wide variety of microscopic and spectroscopic techniques in the same cell for a better understanding of podocyte morphology. In detail, the protocol allowed for the sequential analysis of identical cells with light microscopy (LM), Raman spectroscopy, scanning electron microscopy (SEM) and atomic force microscopy (AFM). Skipping the fixation and drying process, the protocol was also compatible with scanning ion-conductance microscopy (SICM), allowing the determination of podocyte surface topography of nanometer-range in living cells. With the help of nanoGPS Oxyo®, tracking concordant regions of interest of untreated podocytes and podocytes stressed with TGF-ß were analyzed with LM, SEM, Raman spectroscopy, AFM and SICM, and revealed significant morphological alterations, including retraction of podocyte process, changes in cell surface morphology and loss of cell-cell contacts, as well as variations in lipid and protein content in TGF-ß treated cells. The combination of these consecutive techniques on the same cells provides a comprehensive understanding of podocyte morphology. Additionally, the results can also be used to train automated intelligence networks to predict various outcomes related to podocyte injury in the future.

Fournier's gangrene reconstruction: A 10-year retrospective analysis of practice at Guys and St Thomas's NHS Foundation Trust.

Fournier's gangrene is a rare and potentially fatal condition that affects the external genitalia and perineum as a necrotizing soft-tissue infection. It is equally prevalent in men and women and although there are many ways to manage the condition, it must be done so effectively because there is a chance that life-threatening complications could develop. This retrospective study set out to fill any knowledge gaps, compare reconstructive options to those described in the literature, and promote reflection on current management. Between January 2010 and January 2020, all perineal debridement operation notes were examined. The primary conclusions were that a large majority of defects could be repaired using split skin grafts to reduce surgical time and donor site morbidity. To avoid secondary contracture and the need for revision surgery, full-thickness skin grafts should be used whenever possible to treat penile defects.

A Novel Semi-automated Proofreading and Mesh Error Detection Pipeline for Neuron Extension.

The immense scale and complexity of neuronal electron microscopy (EM) datasets pose significant challenges in data processing, validation, and interpretation, necessitating the development of efficient, automated, and scalable error-detection methodologies. This paper proposes a novel approach that employs mesh processing techniques to identify potential error locations near neuronal tips. Error detection at tips is a particularly important challenge since these errors usually indicate that many synapses are falsely split from their parent neuron, injuring the integrity of the connectomic reconstruction. Additionally, we draw implications and results from an implementation of this error detection in a semi-automated proofreading pipeline. Manual proofreading is a laborious, costly, and currently necessary method for identifying the errors in the machine learning based segmentation of neural tissue. This approach streamlines the process of proofreading by systematically highlighting areas likely to contain inaccuracies and guiding proofreaders towards potential continuations, accelerating the rate at which errors are corrected.

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

NEURD: automated proofreading and feature extraction for connectomics.

We are now in the era of millimeter-scale electron microscopy (EM) volumes collected at nanometer resolution (Shapson-Coe et al., 2021; Consortium et al., 2021). Dense reconstruction of cellular compartments in these EM volumes has been enabled by recent advances in Machine Learning (ML) (Lee et al., 2017; Wu et al., 2021; Lu et al., 2021; Macrina et al., 2021). Automated segmentation methods can now yield exceptionally accurate reconstructions of cells, but despite this accuracy, laborious post-hoc proofreading is still required to generate large connectomes free of merge and split errors. The elaborate 3-D meshes of neurons produced by these segmentations contain detailed morphological information, from the diameter, shape, and branching patterns of axons and dendrites, down to the fine-scale structure of dendritic spines. However, extracting information about these features can require substantial effort to piece together existing tools into custom workflows. Building on existing open-source software for mesh manipulation, here we present "NEURD", a software package that decomposes each meshed neuron into a compact and extensively-annotated graph representation. With these feature-rich graphs, we implement workflows for state of the art automated post-hoc proofreading of merge errors, cell classification, spine detection, axon-dendritic proximities, and other features that can enable many downstream analyses of neural morphology and connectivity. NEURD can make these new massive and complex datasets more accessible to neuroscience researchers focused on a variety of scientific questions.

Single-stage buried autologous breast reconstruction (BABR).

BACKGROUND: Breast reconstructive standards are increasingly high oncologically, aesthetically, and practically. Autologous breast reconstruction remains the gold standard which, buried, after nipple-sparing mastectomy (where oncologically safe) or wise pattern reduction for large or ptotic patients, with contralateral symmetrisation where required, enables single-stage reconstruction. However, previous series report prohibitively high revision rates. This series prospectively compares a series of buried and non-buried free flaps for breast reconstruction. METHODS: All breast reconstructions with free autologous tissue transfer, buried or with a cutaneous paddle, conducted over 8 years by a single surgeon were included. Demographic, oncologic and reconstructive details, immediate complications and revision surgeries were recorded and compared between the two groups. RESULTS: A total of 182 free flaps were performed on 156 patients, 69 buried and 113 with cutaneous paddles. There were no significant demographic or complication differences between the two groups. Of the buried group, 51% did not require further surgery compared to 29% of the paddle group. CONCLUSIONS: Buried autologous breast reconstruction is a safe and aesthetic option for breast reconstruction, and potentially single stage. This is particularly true where it is combined with nipple-sparing mastectomy (where oncologically safe) or breast reduction mastectomy, and contralateral symmetrisation, where required. Further research could include patient reported outcome measures and cost analysis.

Dual pedicle epiphyseal transfer for paediatric bony sarcoma reconstruction: Technique and review of outcomes.

Skeletal reconstruction after tumour resection in paediatric patients is challenging. The resultant reconstruction needs to meet the demands of graft incorporation as well as the potential for growth. The vascularised fibular epiphyseal transfer (VFET) offers the potential for both. We retrospectively reviewed eight paediatric patients treated with VFET after bony tumour resection. All patients underwent a dual pedicle transfer with the peroneal artery for the diaphyseal blood supply and the recurrent branch of the anterior tibial artery for the physis. This is the largest series in literature for dual pedicle transfers for bony reconstruction. We present our surgical technique and outcomes in terms of functional limb salvage and growth.

Trainee and trainer experiences and recommendations for plastic surgery training: A qualitative pilot study.

BACKGROUND: The COVID-19 pandemic has compounded existing training issues for plastic surgeons. The issues that exist result from a complex interplay of system, generational and individual factors, and can be hard to tease out by quantitative means. This pilot study aimed to investigate the perceptions of trainees and trainers of plastic surgical training in the UK. METHODS: Ten semi-structured interviews were performed using purposive sampling in a central London plastic surgical unit. These were coded into and discussed in four themes: Medical directives and service demands; Sociocultural norms within plastic surgical training; Equity and access; and Plastic surgery training methods. RESULTS: This study showed that current plastic surgery training is not optimised for learning or well-being, and that inequities are fostered, to the detriment of the specialty. Investment and planning are required to support our trainers and protect the diversity of our trainee group, with efficient and monitored learning essential to maintain our breadth and competence of practice. CONCLUSION: Expanding this work through a broader study could provide valuable information to contribute to the development of future training schemes and curricula within British plastic surgery.

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.