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RNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA three-dimensional structure prediction. With agreement from structural biologists, RNA structures are predicted by modeling groups before publication of the experimental structures. We report a large-scale set of predictions by 18 groups for 23 RNA-Puzzles: 4 RNA elements, 2 Aptamers, 4 Viral elements, 5 Ribozymes and 8 Riboswitches. We describe automatic assessment protocols for comparisons between prediction and experiment. Our analyses reveal some critical steps to be overcome to achieve good accuracy in modeling RNA structures: identification of helix-forming pairs and of non-Watson-Crick modules, correct coaxial stacking between helices and avoidance of entanglements. Three of the top four modeling groups in this round also ranked among the top four in the CASP15 contest.

Musician-teacher identity is a "work-in-progress" spanning a career lifetime, yet little research appears to explore how this culminative development occurs, particularly from an individualized musician-teacher viewpoint. Using a qualitative epistemology, the author examines autoethnographic vignettes of life experience to highlight how changes of aging, work environments, and personal circumstances guide such a musician-teacher's journey. A "rivers of experience" approach, combined with several frames of reference, uncovers epiphanic moments showing how local and international contexts shape musician-teacher identity. Given the enormous changes in education over the past 40 years, and the changing, challenging world of COVID-19, this article is a timely and needed catalyst for others to reflect on their own experiences as they look to their futures.

Category: Ankle Arthritis; Ankle Introduction/Purpose: The Infinity (Wright Medical Group) Total Ankle Replacement (TAR) has been implanted in patients since 2014 and is now the most common primary ankle used in the National Joint Registry of England and Wales. We report a prospective series of 106 Infinity TARs, with 8-year survivorship data from two, non-designer centres in the UK. The primary aims were to assess survivorship and complications of the Infinity TAR. The secondary aims were to assess patient reported and radiological outcomes. Methods: Prospectively collected data between March 2014 to December 2016 was assessed from two specialist centres in the United Kingdom. All operations were performed, or supervised, by one of 5 surgeons with a minimum experience of 10 TAR per year. Inclusion criteria were any patient with end-stage tibiotalar arthritis, considered by the operating surgeon to be suitable for primary TAR. Revision TAR, or conversion from arthrodesis, were not included in this study. Implant survivorship, complications, patient reported outcome scores (PROMS) and radiological data were collected for each patient. PROMS data comprised the Manchester Oxford Foot Questionnaire (MOX-FQ) and the EuroQol-5 Dimension (EQ5D-5L) score. Pre-operatively, weight bearing radiographs were assessed for the degree of sagittal and coronal deformity. Post-operatively, weight bearing radiographs at 6 weeks were assessed for the degree of deformity correction. Cystic radiolucencies on the most recent follow up radiograph was assessed by using an established scoring system. Results: 102 patients, comprising 106 TARs, were included. Mean age at implantation was 68 years (range 42 to 89 years). Mean follow up time was 98 months (range 83 to 113 months). 12 patients received further surgeries: 8 revision TARs, 3 debridement and grafting of talar cysts, and 1 capsular release. The reasons for revision surgery were unexplained pain (5 patients), proven deep infection (1 patient), tibial subsidence (1 patient) and instability (1 patient). Mean time to revision surgery was 43 months (range 15 to 82 months). Current survivorship of the cohort is 91%. Cystic radiolucencies were present in 35% of patients but the majority were small and asymptomatic. MOXFQ and EQ5D-5L PROMS showed significant and sustained post-operative improvements (p < 0.01). Conclusion: This series of 106 modern fixed bearing TAR shows an 8-year survivorship of 91%. 3 cases of talar cysts were grafted. The most common reason for revision surgery was unexplained pain and the deep infection rate was 1%. The fixed bearing Infinity TAR appears to be a safe, effective intervention in the treatment of end stage ankle osteoarthritis and gives significant improvement in disease specific and general health status outcomes.

Category: Bunion; Other Introduction/Purpose: Minimally invasive surgery for hallux valgus deformity is gaining popularity over the traditional Open scarf osteotomy. Emerging evidences are showing similar clinical outcomes but further studies are needed to ascertain this. The aim of this study was to assess the feasibility of conducting a randomised controlled trial to compare the patient recorded and clinical outcomes for the surgical management of Hallux Valgus between open scarf osteotomy (OS) and minimally invasive chevron osteotomy (MICA). Methods: Patients suitable for surgical correction were invited to participate. Post op rehabilitation was standardised for both groups. Patients completed a validated questionnaire (Manchester Oxford Foot questionnaire and EQ-5D) preoperatively and post operatively at 6 months and 1 year. Radiological parameters and range of motion were measure pre and post operatively. A total of 41 patients were eligible for the study, 31 were successfully recruited and operated between Dec 2017 and June 2022. Results: 17 patients were randomised to MIS (15 female, mean age 51 years) and 14 to OS (13 female, mean age 51 years). Both groups have a significant improvement in the MOXFQ parameters (walking, pain and social) at 6m and 12m, as well as radiological parameters. VAS improved for OS at 6m (p=0.048) and 12m (p=0.025) but only improvement at 6m was seen for MICA (p=0.059 and p=0.054 at 12m). There was no improvement in EQ-5D in either group at 12 months and no difference in surgical time (p=0.53).There was a higher number of complication in the MICA group with 5 removal of metalwork (29.4%) and 2 superficial infections (11.8%) vs none in the OS group. Conclusion: Both surgical options show similar clinical results but higher complication rate was seen with MICA. A larger study is needed to evaluate further.

Category: Ankle Arthritis; Ankle Introduction/Purpose: Large bone defects such as those encountered after failed total ankle replacement have previously been a relative contraindication to revision ankle replacement due to inadequate bone stock. We describe our early experience and patient reported outcomes with a modular ankle replacement system with tibial and talar augments. Methods: This is a retrospective case series analysis of patients who underwent a total ankle replacement using the INVISION system across two centres between 2016 and 2022. Local approvals were granted. Patients completed f the Manchester-Oxford Foot Questionnaire (MOXFQ), Ankle Osteoarthritis Scale (AOS) and EQ-5D pre-operatively and then post-operatively at 6 months, 1 year, 2 years, 3 years and 5 years. Medical records were reviewed for complications and re-operations. X-rays were reviewed for cysts or lucencies and alignment. Results: 17 patients were included in the study; 14 men and 3 women with an average age at the time of surgery of 67.9 years (range 56 years to 80 years). The average follow-up post operatively was 40.5 months (range 7 to 78). The indication for surgery was revision of failed TAR in 16 and revision of failed ankle fusion in 1. An augmented tibia was used in 13, augmented talus in 13, and both augmented tibia and talus in 9 cases. There were no early surgical complications. One patient required debridement and implant retention for late deep infection. No implants have been revised. The average MOXFQ score improved by 19.3 points at most recent follow up. The average AOS score improved by 25.2 points. Conclusion: The early results of a modular augmented ankle arthroplasty system have shown satisfactory patient outcomes with a low complication and re-operation rate, however, this study is confined to two centres, has a small patient number and relatively short follow up period. Further research with longer follow up periods will be beneficial in the future to support revision ankle replacement systems as another option for patients with larger bone defects.

The motivations for consumption of Image and Performance Enhancement Drugs (IPEDs) have been widely explored in recent years, particularly due to the identification of wide-ranging associated public health concerns. The majority demographic of those consuming these substances are men, primarily utilising these substances in pursuit of physical appearance and/or performance goals. Historically, consumers of IPEDs were understood to be those predominantly intent on athletic pursuits, for sporting performance or bodybuilding. More recently, though, there has been greater diffusion of these substances, with growing non-sporting populations consuming them in pursuit of increased muscularity or other body image goals. A novel mixed-methodologies approach consisting of two studies was utilised, consisting of a netnography investigating posts across four major online fitness forums, and a cross-sectional survey investigation, involving an in-depth qualitative analysis utilising images and original data. Results suggest that societal contemporary ideals of the masculine body, particularly as they are presented online and, in the media, are increasingly sexualised. This objectification then fosters the internalisation of body image concerns, ultimately influencing the motivation for the consumption of IPEDs. Hence, it becomes imperative to recognise masculinities as a pivotal focal point for the facilitation of efficient harm reduction strategies and the development of educational resources pertaining to IPEDs.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Abstract Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Criollo cattle, the descendants of animals brought by Iberian colonists to the Americas, have been the subject of natural and human-mediated selection in novel tropical agroecological zones for centuries. Consequently, these breeds have evolved distinct characteristics such as resistance to diseases and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.

Abstract Background and Aim High autoimmune hepatitis (AIH) and overlap syndrome (OS) prevalence have been previously documented among Alaska Native people. The purpose of this project is to report changes in AIH/OS prevalence over time, clinical characteristics, and factors associated with biochemical remission. Methods We reviewed medical records for Alaska Native/American Indian (AN/AI) patients diagnosed with AIH/OS between 1984 and 2021. Point prevalence was calculated based on AIH/OS patients alive at the end of 2021 and at 5‐year intervals from July 1, 2000, to July 1, 2020. Results We identified 189 AN/AI persons diagnosed with AIH or OS (157 AIH, 32 OS). Of these 189, 137 were alive at the end of 2021 for a point prevalence of 91.2 per 100 000 (95% confidence interval [CI]: 77.2–107.8)—75.9 (95% CI: 63.2–91.2) for AIH and 15.3 (95% CI: 10.2–23.0) for OS. Prevalence for both AIH and OS has risen steadily since 2000. Eighty‐nine consented participants (62.7%) achieved biochemical remission with a median time from diagnosis to start of remission of 1.9 years (IQR 0.5–5.0 years). Consented patients with fatty liver were less likely to achieve remission, but their time to remission was shorter than for patients without fatty liver. Conclusion The AN/AI population in Alaska continues to have the highest reported prevalence of AIH/OS in the world, with prevalence rising steadily since 2000. High reported AIH/OS prevalence is likely due in part to strong referral networks for liver disease. Detection and treatment can lead to biochemical remission and improved health outcomes.