The Virtual Child.

SUMMARY: We are building the world's first Virtual Child-a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will "develop cancer" that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.

A Quantitative Examination of Illness Models Among People With Opioid Use Disorder Receiving Methadone Treatment.

BACKGROUND: Few studies have examined illness models among people with addiction. We investigated illness models and their associations with demographics and treatment beliefs among patients receiving methadone treatment for opioid use disorder. METHODS: From January 2019 to February 2020, patients receiving methadone treatment at outpatient opioid treatment programs provided demographics and rated using 1 to 7 Likert-type scales agreement with addiction illness models (brain disease model, chronic medical condition model [CMCM], and no explanation [NEM]) and treatment beliefs. Pairwise comparisons and multivariate regressions were used to examine associations between illness models, demographics, and treatment beliefs. Statistical significance was set at P < 0.05. RESULTS: A total of 450 patients participated in the study. Forty percent self-identified as female, 13% as Hispanic, and 78% as White; mean age was 38.5 years. Brain disease model was the most frequently endorsed illness model (46.2%), followed by CMCM (41.7%) and NEM (21.9%). In multivariate analyses, agreement with brain disease model was significantly positively associated with beliefs that methadone treatment would be effective, counseling is important, and methadone is lifesaving, whereas agreement with CMCM was significantly positively associated with beliefs that methadone treatment would be effective, counseling is important, 12-step is the best treatment, taking methadone daily is important, and methadone is lifesaving. In multivariate analyses, agreement with NEM was negatively significantly associated with beliefs that methadone would be effective, counseling is important, taking methadone daily is important, and methadone is lifesaving. DISCUSSION: Many patients in methadone treatment endorsed medicalized addiction models. Agreement with addiction illness models appear to be related to treatment beliefs.

Perceptions of Community Corrections and Treatment Experience: A Qualitative Study Among People With Incarceration Histories Receiving Outpatient Methadone Treatment.

BACKGROUND: Community correctional experiences among individuals receiving methadone treatment (MT) for opioid use disorder (OUD) are poorly understood. We qualitatively investigated perceptions of community corrections and treatment experiences among individuals with criminal-legal system experience currently receiving outpatient MT. METHODS: From January to December 2017, we recruited 42 individuals with history of criminal-legal system involvement enrolled in outpatient MT at a low-barrier nonprofit organization operating multiple clinics in Connecticut. An experienced qualitative research team conducted one-to-one, in-person, semistructured interviews about incarceration and treatment experiences with individuals receiving MT. Participants completed a demographics survey. The interviews were audiorecorded, transcribed, de-identified, and independently coded using NVivo. RESULTS: Participants described the community corrections system as restrictive and abstinence-focused. Most participants described positive perceptions of and experiences with community corrections officers (CCOs), yet described negative perceptions of and experiences with the community corrections system overall. Participants perceived CCOs to have limited knowledge of OUD and MT. Participants described a range of CCO judgment toward their OUD, with some appearing understanding and nonjudgmental while others were perceived to have stigma and prejudice. Few participants noted assistance from CCOs with seeking MT or community-based substance use disorder care. Some participants desired improved treatment facilitation, but viewed forced or coercive treatment negatively. CONCLUSION: To our knowledge, this is the first qualitative study to examine community corrections experience among people receiving outpatient medication for OUD. While individuals receiving MT have negative experiences with the community corrections system, they perceive individual CCOs positively. Interventions addressing gaps in CCOs knowledge of OUD and MT are needed to optimize support for individuals on probation or parole with OUD. Provision of OUD treatment facilitation appears desirable to some individuals in community supervision.

Interleukin-3 production by basal-like breast cancer cells is associated with poor prognosis.

Breast cancer represents a collection of pathologies with different molecular subtypes, histopathology, risk factors, clinical behavior, and responses to treatment. "Basal-like" breast cancers predominantly lack the receptors for estrogen and progesterone (ER/PR), lack amplification of human epidermal growth factor receptor 2 (HER2) but account for 10-15% of all breast cancers, are largely insensitive to targeted treatment and represent a disproportionate number of metastatic cases and deaths. Analysis of interleukin (IL)-3 and the IL-3 receptor subunits (IL-3RA + CSF2RB) reveals elevated expression in predominantly the basal-like group. Further analysis suggests that IL-3 itself, but not the IL-3 receptor subunits, associates with poor patient outcome. Histology on patient-derived xenografts supports the notion that breast cancer cells are a significant source of IL-3 that may promote disease progression. Taken together, these observations suggest that IL-3 may be a useful marker in solid tumors, particularly triple negative breast cancer, and warrants further investigation into its contribution to disease pathogenesis.

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as keystone of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies reveal pore "turret arch" bonding as a KCNQ structural novelty and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7.

Chimeric antigen receptor (CAR)-T cell immunotherapy is a novel treatment that genetically modifies the patients' own T cells to target and kill malignant cells. However, identification of tumour-specific antigens expressed on multiple solid cancer types, remains a major challenge. P2X purinoceptor 7 (P2X7) is a cell surface expressed ATP gated cation channel, and a dysfunctional version of P2X7, named nfP2X7, has been identified on cancer cells from multiple tissues, while being undetectable on healthy cells. We present a prototype -human CAR-T construct targeting nfP2X7 showing potential antigen-specific cytotoxicity against twelve solid cancer types (breast, prostate, lung, colorectal, brain and skin). In xenograft mouse models of breast and prostate cancer, CAR-T cells targeting nfP2X7 exhibit robust anti-tumour efficacy. These data indicate that nfP2X7 is a suitable immunotherapy target because of its broad expression on human tumours. CAR-T cells targeting nfP2X7 have potential as a wide-spectrum cancer immunotherapy for solid tumours in humans.

Concealing, Tolerating, and Adjusting to Emotions in Obsessive-Compulsive and Anxiety Disorders: A Cross-Sectional Study.

BACKGROUND: Although research has shown that mood and anxiety disorders manifest disturbed emotion regulation, it is unclear whether anxiety disorders differ between each other in terms of their emotion regulation strategies. In the present study, we investigated whether patients with anxiety disorders present different affective styles. METHODS: We assessed affective styles of 32 obsessive-compulsive disorder (OCD) patients, 29 social anxiety disorder (SAD) patients, 29 panic disorder (PD) patients, and 20 healthy controls through the Affective Style Questionnaire (ASQ). A multivariate analysis of covariance (MANCOVA) was performed to compare the affective styles across groups (OCD, SAD, PD and control), while controlling for depression, anxiety symptoms and age. RESULTS: The MANCOVA revealed a significant, small-medium, main effect of diagnostic group on affective styles. The planned contrasts revealed that OCD and SAD patients reported significantly lower scores for "tolerance" (ASQ-T) compared to healthy controls group. There were no differences between PD group and healthy controls. CONCLUSIONS: Our findings provide evidence that OCD and SAD have difficulty tolerating strong emotions existing in the present moment in an open and non-defensive way.

Menstrual Suppression in the Myelosuppressed: A Retrospective Cohort Study.

PURPOSE: Adolescent and young adult female patients receiving myelosuppressive cancer treatments are at risk of abnormal uterine bleeding (AUB). The frequency with which patients with cancer receive menstrual suppression and the agents used have not previously been well-characterized. We studied the rate of menstrual suppression, the effect of suppression on bleeding and blood product utilization, and if there were practice pattern differences between adult and pediatric oncologists. METHODS: We established a retrospective cohort of 90 females with a diagnosis of Hodgkin or non-Hodgkin lymphoma (n = 25), AML (n = 46), or sarcoma (n = 19) and treated with chemotherapy between 2008 and 2019 at our institutions (University of Alabama at Birmingham [UAB] adult oncology: UAB hospital; UAB pediatric oncology: Children's of Alabama). Data were abstracted from the medical record including sociodemographics, primary oncologist specialty (pediatric v adult), cancer details (diagnosis and treatment) and gynecologic course (documented gynecologic history, menstrual suppression agents used, reported AUB outcomes, and treatments). RESULTS: The majority of patients (77.8%) received menstrual suppression. Compared with nonsuppressed patients, suppressed patients had similar rates of packed red blood cell transfusions but higher number of platelet transfusions. Adult oncologists were more likely to document a gynecologic history, consult gynecology, and list AUB as a problem. Among suppressed patients, there was heterogeneity in the agents used for menstrual suppression, with a predilection toward progesterone-only agents; a low rate of thrombotic events was observed. CONCLUSION: Menstrual suppression was common in our cohort with variability in agents used. Pediatric and adult oncologists demonstrated different practice patterns.

The dinitrobenzamide mustard prodrugs, PR-104A and SN27686, for use in a novel MNDEPT cancer prodrug therapy approach.

Directed enzyme prodrug therapy is a highly promising anti-cancer strategy. However, the current technology is limited by inefficient prodrug activation and the dose-limiting toxicity associated with the prodrugs being tested; to overcome these limitations, the dinitrobenzamide mustard prodrugs, PR-104A and SN27686, have been developed. The present study will assess both of these prodrugs for their potential uses in a novel magnetic-nanoparticle directed enzyme prodrug therapy strategy by determining their kinetic parameters, assessing the products formed during enzymatic reduction using HPLC and finally their ability to cause cell death in the ovarian cancer cell line, SK-OV-3. It was shown for the first time that the dinitrobenzamide mustard prodrugs are able to be reduced by the genetically modified nitroreductases, NfnB-cys and YfkO-cys, and that these enzyme/prodrug combinations can induce a significant cell death in the SK-OV-3 cell line, highlighting the potential for both enzyme/prodrug combinations for use in magnetic-nanoparticle directed enzyme prodrug therapy.

Kinetics of Guest-Induced Structural Transitions in Metal-Organic-Framework MIL-53(Al)-NH2 Probed by High-Pressure Nuclear Magnetic Resonance.

A nuclear magnetic resonance (NMR) study of a pore opening in amino-functionalized metal-organic framework (MOF) MIL-53(Al) in response to methane pressure variation is presented. Variations of both NMR signal intensities and transversal relaxation rates for methane are found to reveal hysteretic structural transitions in the MOF material, which are smeared out over broad pressure ranges. Experiments with pressure reversals upon an incomplete adsorption/desorption gave deeper insight into the microscopic transition mechanisms. These experiments have unequivocally proven that the non-stepwise pore opening/closing transitions observed in the experiments are governed by a distribution of the opening/closing pressures over different MOF crystallites, for example, due to a distribution of the crystal sizes or shapes. The slow kinetics of the structural transitions measured in the hysteresis regime revealed a complex free energy landscape for the phase transition process.

"Just fighting for my life to stay alive": a qualitative investigation of barriers and facilitators to community re-entry among people with opioid use disorder and incarceration histories.

BACKGROUND: During the period of community re-entry immediately following release from jail or prison, individuals with opioid use disorder (OUD) face structural barriers to successful re-entry and high risk of overdose. Few published studies investigate experiences in the immediate period (i.e., first 24 h) of re-entry among people with OUD. AIM: To understand the barriers and facilitators to treatment and reintegration of people with OUD during the initial transition from carceral settings back into the community. METHODS: From January-December 2017, we conducted 42 semi-structured qualitative interviews with patients with a history of incarceration who were receiving methadone at a not-for-profit, low-barrier opioid treatment program. Interviews probed participants' community re-entry experiences immediately following incarceration. Interviews were transcribed and analyzed using a Thematic Analysis approach. RESULTS: The main themes described the experiences during the 24 h following release, reacclimating and navigating re-entry barriers, and re-entry preparedness and planning. Participants noted the initial 24 h to be a period of risk for returning to substance use or an opportunity to engage with OUD treatment as well as a tenuous period where many lacked basic resources such as shelter or money. When discussing the subsequent re-entry period, participants noted social challenges and persistent barriers to stable housing and employment. Participants overall described feeling unprepared for release and suggested improvements including formal transition programs, improved education, and support to combat the risk of overdose and return to substance use after incarceration. CONCLUSIONS: In this study that qualitatively examines the experiences of people with incarceration histories and OUD enrolled in methadone treatment, we found that participants faced many barriers to community re-entry, particularly surrounding basic resources and treatment engagement. Participants reported feeling unprepared for release but made concrete suggestions for interventions that might improve the barriers they encountered. Future work should examine the incorporation of these perspectives of people with lived experience into the development of transition programs or re-entry classes.

A functional genomics pipeline to identify high-value asthma and allergy CpGs in the human methylome.

BACKGROUND: DNA methylation of cytosines at cytosine-phosphate-guanine (CpG) dinucleotides (CpGs) is a widespread epigenetic mark, but genome-wide variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput arrays. OBJECTIVES: To explore this hidden portion of the epigenome, this study combined whole-genome bisulfite sequencing with in silico evidence of gene regulatory regions to design a custom array of high-value CpGs. This study focused on airway epithelial cells from children with and without allergic asthma because these cells mediate the effects of inhaled microbes, pollution, and allergens on asthma and allergic disease risk. METHODS: This study identified differentially methylated regions from whole-genome bisulfite sequencing in nasal epithelial cell DNA from a total of 39 children with and without allergic asthma of both European and African ancestries. This study selected CpGs from differentially methylated regions, previous allergy or asthma epigenome-wide association studies (EWAS), or genome-wide association study loci, and overlapped them with functional annotations for inclusion on a custom Asthma&Allergy array. This study used both the custom and EPIC arrays to perform EWAS of allergic sensitization (AS) in nasal epithelial cell DNA from children in the URECA (Urban Environment and Childhood Asthma) birth cohort and using the custom array in the INSPIRE [Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure] birth cohort. Each CpG on the arrays was assigned to its nearest gene and its promotor capture Hi-C interacting gene and performed expression quantitative trait methylation (eQTM) studies for both sets of genes. RESULTS: Custom array CpGs were enriched for intermediate methylation levels compared to EPIC CpGs. Intermediate methylation CpGs were further enriched among those associated with AS and for eQTMs on both arrays. CONCLUSIONS: This study revealed signature features of high-value CpGs and evidence for epigenetic regulation of genes at AS EWAS loci that are robust to race/ethnicity, ascertainment, age, and geography.

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Is action understanding an automatic process? Both cognitive and perceptual processing are required for the identification of actions and intentions.

The ability to identify others' actions and intentions, "action understanding," is crucial for successful social interaction. Under direct accounts, action understanding takes place without the involvement of inferential processes, a claim that has yet to be tested using behavioural measures. Using a dual-task paradigm, the present study aimed to establish whether the identification of others' actions and intentions depends on automatic or inferential processing, by manipulating working memory load during performance of a task designed to target the identification of actions and intentions. Experiment 1 tested a novel action understanding task targeting action identification and intention identification. This task was then combined with two working memory manipulations (cognitive: Experiment 2; perceptual: Experiment 3) to determine whether action identification and intention identification are disrupted by concurrent cognitive or perceptual load. Both action identification and intention identification were impaired by concurrent cognitive and perceptual processing, indicating that action understanding requires additional perceptual and cognitive resources. These findings contradict a direct account of action understanding.

Desmoglein-2 is important for islet function and ß-cell survival.

Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic ß-cells. Although ß-cell targeted autoimmune processes and ß-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions that support pancreatic function is still lacking. To characterize the pancreatic endocrine compartment, we studied pancreata from healthy adult donors and investigated a single cell surface adhesion molecule, desmoglein-2 (DSG2). Genetically-modified mice lacking Dsg2 were examined for islet cell mass, insulin production, responses to glucose, susceptibility to a streptozotocin-induced mouse model of hyperglycaemia, and ability to cure diabetes in a syngeneic transplantation model. Herein, we have identified DSG2 as a previously unrecognized adhesion molecule that supports ß-cells. Furthermore, we reveal that DSG2 is within the top 10 percent of all genes expressed by human pancreatic islets and is expressed by the insulin-producing ß-cells but not the somatostatin-producing δ-cells. In a Dsg2 loss-of-function mice (Dsg2lo/lo), we observed a significant reduction in the number of pancreatic islets and islet size, and consequently, there was less total insulin content per islet cluster. Dsg2lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocin-induced diabetes, and islets isolated from Dsg2lo/lo mice were more susceptible to cytokine-induced ß-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2lo/lo mice were less effective than their wildtype counterparts at curing diabetes. In vitro assays using the Beta-TC-6 murine ß-cell line suggest that DSG2 supports the actin cytoskeleton as well as the release of cytokines and chemokines. Taken together, our study suggests that DSG2 is an under-appreciated regulator of ß-cell function in pancreatic islets and that a better understanding of this adhesion molecule may provide new opportunities to combat type 1 diabetes.

Internalized HIV-Related Stigma and Neurocognitive Functioning Among Women Living with HIV.

The prevalence of HIV-associated neurocognitive impairment persists despite highly effective antiretroviral therapy (ART). In this study we explore the role of internalized stigma, acceptance of negative societal characterizations, and perceptions about people living with HIV (PLWH) on neurocognitive functioning (executive function, learning, memory, attention/working memory, psychomotor speed, fluency, motor skills) in a national cohort of women living with HIV (WLWH) in the United States. We utilized observational data from a multicenter study of WLWH who are mostly African American living in low-resource settings. Neurocognitive function was measured using an eight-test battery. A multiple linear regression model was constructed to investigate the relationship between internalized stigma and overall neurocognitive functioning (mean of all neurocognitive domain standardized T-scores), adjusting for age, education, race, previous neuropsychological battery scores, illicit drug use, viral load, and years on ART. Our analysis revealed that internalized HIV-related stigma is significantly associated with worse performance on individual domain tests and overall neurocognitive performance (B = 0.27, t = 2.50, p = 0.01). This suggests HIV-related internalized stigma may be negatively associated with neurocognitive functioning for WLWH. This finding highlights a specific psychosocial factor associated with poor neurocognitive function that may be targeted to better promote the health of PLWH. Future research on the longitudinal relationship between these variables and the effects of other stigma dimensions on poor neurocognitive function would provide further insights into the pathways explaining the relationship between internalized stigma and neurocognition.

Mirror neuron brain regions contribute to identifying actions, but not intentions.

Previous studies have struggled to determine the relationship between mirror neuron brain regions and two distinct "action understanding" processes: identifying actions and identifying the intentions underlying those actions. This may be because the identification of intentions from others' actions requires an initial action identification process. Disruptive transcranial magnetic stimulation was administered to left inferior frontal gyrus (lIFG) during a novel cognitive task to determine which of these "action understanding" processes is subserved by mirror neuron brain regions. Participants identified either the actions performed by observed hand actions or the intentions underlying those actions. The extent to which intention identification was disrupted by lIFG (vs. control site) stimulation was dependent on the level of disruption to action identification. We subsequently performed functional magnetic resonance imaging during the same task. During action identification, responses were widespread within mirror neuron areas including lIFG and inferior parietal lobule. However, no independent responses were found in mirror neuron brain regions during intention identification. Instead, responses occurred in brain regions associated with two distinct mentalizing localizer tasks. This supports an account in which mirror neuron brain regions are involved in an initial action identification process, but the subsequent identification of intentions requires additional processing in mentalizing brain regions.

Insights to the Structural Basis for the Stereospecificity of the Escherichia coli Phytase, AppA.

AppA, the Escherichia coli periplasmic phytase of clade 2 of the histidine phosphatase (HP2) family, has been well-characterized and successfully engineered for use as an animal feed supplement. AppA is a 1D-6-phytase and highly stereospecific but transiently accumulates 1D-myo-Ins(2,3,4,5)P4 and other lower phosphorylated intermediates. If this bottleneck in liberation of orthophosphate is to be obviated through protein engineering, an explanation of its rather rigid preference for the initial site and subsequent cleavage of phytic acid is required. To help explain this behaviour, the role of the catalytic proton donor residue in determining AppA stereospecificity was investigated. Four variants were generated by site-directed mutagenesis of the active site HDT amino acid sequence motif containing the catalytic proton donor, D304. The identity and position of the prospective proton donor residue was found to strongly influence stereospecificity. While the wild-type enzyme has a strong preference for 1D-6-phytase activity, a marked reduction in stereospecificity was observed for a D304E variant, while a proton donor-less mutant (D304A) displayed exclusive 1D-1/3-phytase activity. High-resolution X-ray crystal structures of complexes of the mutants with a non-hydrolysable substrate analogue inhibitor point to a crucial role played by D304 in stereospecificity by influencing the size and polarity of specificity pockets A and B. Taken together, these results provide the first evidence for the involvement of the proton donor residue in determining the stereospecificity of HP2 phytases and prepares the ground for structure-informed engineering studies targeting the production of animal feed enzymes capable of the efficient and complete dephosphorylation of dietary phytic acid.

The price of love: an investigation into the relationship between romantic love and the expression of obsessive-compulsive disorder.

BACKGROUND: The present study explored the influence of romantic love on the expression of several obsessive-compulsive disorder (OCD) characteristics, including symptom severity, symptom dimensions, age at onset, sensory phenomena (SP), and developmental course, as well as other related comorbid disorders. It was hypothesized that love-precipitated OCD would be associated with a set of distinct characteristics and exhibit greater rates of comorbid disorders. METHODS: The analyses were performed using a large sample (n = 981) of clinical patients with a primary diagnosis of OCD (Females = 67.3%, M age = 35.31). RESULTS: Love-precipitated OCD was associated with greater severity of SP and later age at onset of obsessions. However, symptom severity, symptom dimension, developmental course, and psychiatric comorbidities were not associated with love-precipitated OCD. CONCLUSION: It was concluded that romantic love does shape the expression of OCD, especially with regard to SP and onset age. These findings encourage further exploration to determine its clinical significance as a phenotype.

The future of orthopaedic surgical education: Where do we go now?

INTRODUCTION: COVID-19 will undoubtedly change the future landscape of medical and surgical education. The economic and environmental advantages of virtual learning are clear, while access to a wider range of resources and subject specialists makes the adoption of virtual learning within surgical education an attractive prospect. AIMS: This literature review aims to evaluate evidence on the effectiveness of virtual education in orthopaedics and how we might implement positive changes to educational practice in the future, as a result of lessons learned during the COVID-19 pandemic. METHODOLOGY: We performed a review of the literature reporting on efficacy of learning outcomes achieved as a result of virtual education within orthopaedic surgery. Electronic searches were performed using NICE healthcare databases from the date of inception to March 2021. Relevant studies were identified, data extracted, and qualitative synthesis performed. RESULTS: 14 manuscripts with a total of 1548 participants (orthopaedic trainees or medical students) were included for analysis. Nine studies (n = 1109) selected compared e-learning to conventional learning material (control group). All nine studies reported significantly higher outcome scores for e-learning participants compared to control participants (p < 0.001 to p < 0.05). The remaining studies compared blended e-learning approaches or evaluated pre/post intervention improvements in learning outcomes. All studies demonstrated a significant improvement in learning outcomes (p < 0.0001 to p < 0.01). The majority of studies (64%) used a blended approach. No studies were identified reporting efficacy of webinars or videoconferencing within orthopaedic education. CONCLUSION: A blended approach, combining virtual teaching, face-to-face instruction and distance learning tools, based on the evidence we have provided, would improve the quality of knowledge reception and retention, and learner satisfaction. However, in order to be successful, it is vital that these educational programmes are designed with the needs of the learner in mind, and an awareness of best practice for virtual teaching and learning.