Understanding cancer patient cohorts in virtual reality environment for better clinical decisions: a usability study.

BACKGROUND: Visualising patient genomic data in a cohort with embedding data analytics models can provide relevant and sensible patient comparisons to assist a clinician with treatment decisions. As immersive technology is actively used around the medical world, there is a rising demand for an efficient environment that can effectively display genomic data visualisations on immersive devices such as a Virtual Reality (VR) environment. The VR technology will allow clinicians, biologists, and computer scientists to explore a cohort of individual patients within the 3D environment. However, demonstrating the feasibility of the VR prototype needs domain users' feedback for future user-centred design and a better cognitive model of human-computer interactions. There is limited research work for collecting and integrating domain knowledge into the prototype design. OBJECTIVE: A usability study for the VR prototype--Virtual Reality to Observe Oncology data Models (VROOM) was implemented. VROOM was designed based on a preliminary study among medical users. The goals of this usability study included establishing a baseline of user experience, validating user performance measures, and identifying potential design improvements that are to be addressed to improve efficiency, functionality, and end-user satisfaction. METHODS: The study was conducted with a group of domain users (10 males, 10 females) with portable VR devices and camera equipment. These domain users included medical users such as clinicians and genetic scientists and computing domain users such as bioinformatics and data analysts. Users were asked to complete routine tasks based on a clinical scenario. Sessions were recorded and analysed to identify potential areas for improvement to the data visual analytics projects in the VR environment. The one-hour usability study included learning VR interaction gestures, running visual analytics tool, and collecting before and after feedback. The feedback was analysed with different methods to measure effectiveness. The statistical method Mann-Whitney U test was used to analyse various task performances among the different participant groups, and multiple data visualisations were created to find insights from questionnaire answers. RESULTS: The usability study investigated the feasibility of using VR for genomic data analysis in domain users' daily work. From the feedback, 65% of the participants, especially clinicians (75% of them), indicated that the VR prototype is potentially helpful for domain users' daily work but needed more flexibility, such as allowing them to define their features for machine learning part, adding new patient data, and importing their datasets in a better way. We calculated the engaged time for each task and compared them among different user groups. Computing domain users spent 50% more time exploring the algorithms and datasets than medical domain users. Additionally, the medical domain users engaged in the data visual analytics parts (approximately 20%) longer than the computing domain users.

The role of radiation therapy in the management of primary retroperitoneal sarcoma: A systematic review and clinical practice guidelines from the Australia and New Zealand Sarcoma Association.

While surgery is the mainstay of treatment for localised retroperitoneal sarcoma, the use of radiotherapy (RT) remains controversial. This systematic review aimed to evaluate the role of RT for retroperitoneal sarcoma. A systematic review using the population, intervention, comparison, and outcome model from 1990 to 2022 identified 66 studies (a mixture of preoperative and postoperative RT); one randomised controlled trial (RCT) with two publications, 18 registry studies, and 46 retrospective studies. In the RCT of preoperative RT, there was no difference in local/abdominal recurrence. The pooled analysis of this RCT and a retrospective study showed a significant abdominal recurrence free survival benefit with preoperative RT in low grade liposarcoma. The RCT and the majority of retrospective series found RT did not improve recurrence free survival (11 of 16 no difference in combined local and distant RFS, 11 of 13 no difference in distant metastasis free survival), disease specific survival (9 of 12 studies) or overall survival (33 of 49 studies). The majority of studies found no association between RT and perioperative morbidity. In summary, preoperative RT may improve local control for low grade (well-differentiated or grades 1-2 dedifferentiated) liposarcoma, but not other histological subtypes. There is no strong evidence that perioperative RT provides an overall survival benefit. Patients with low grade retroperitoneal liposarcoma can be considered for preoperative RT to improve abdominal recurrence free survival. The rationale and level of evidence in this scenario should be carefully discussed by the multidisciplinary team with patients. RT should not be routinely recommended for other histological subtypes.

Stabilisation of the RirA [4Fe-4S] cluster results in loss of iron-sensing function.

RirA is a global iron regulator in diverse Alphaproteobacteria that belongs to the Rrf2 superfamily of transcriptional regulators, which can contain an iron-sulfur (Fe-S) cluster. Under iron-replete conditions, RirA contains a [4Fe-4S] cluster, enabling high-affinity binding to RirA-regulated operator sequences, thereby causing the repression of cellular iron uptake. Under iron deficiency, one of the cluster irons dissociates, generating an unstable [3Fe-4S] form that subsequently degrades to a [2Fe-2S] form and then to apo RirA, resulting in loss of high-affinity DNA-binding. The cluster is coordinated by three conserved cysteine residues and an unknown fourth ligand. Considering the lability of one of the irons and the resulting cluster fragility, we hypothesized that the fourth ligand may not be an amino acid residue. To investigate this, we considered that the introduction of an amino acid residue that could coordinate the cluster might stabilize it. A structural model of RirA, based on the Rrf2 family nitrosative stress response regulator NsrR, highlighted residue 8, an Asn in the RirA sequence, as being appropriately positioned to coordinate the cluster. Substitution of Asn8 with Asp, the equivalent, cluster-coordinating residue of NsrR, or with Cys, resulted in proteins that contained a [4Fe-4S] cluster, with N8D RirA exhibiting spectroscopic properties very similar to NsrR. The variant proteins retained the ability to bind RirA-regulated DNA, and could still act as repressors of RirA-regulated genes in vivo. However, they were significantly more stable than wild-type RirA when exposed to O2 and/or low iron. Importantly, they exhibited reduced capacity to respond to cellular iron levels, even abolished in the case of the N8D version, and thus were no longer iron sensing. This work demonstrates the importance of cluster fragility for the iron-sensing function of RirA, and more broadly, how a single residue substitution can alter cluster coordination and functional properties in the Rrf2 superfamily of regulators.

Surgery at specialised sarcoma centres improves patient outcomes - A systematic review by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

BACKGROUND: Optimal management of sarcoma requires multidisciplinary team input throughout the process of diagnosis, treatment and follow up. This systematic review aimed to evaluate the impact of surgery performed at specialised sarcoma centres on outcomes. METHODS: A systematic review was conducted using the population, intervention, comparison and outcome (PICO) model. Medline, Embase, Cochrane Central databases were queried for publications that evaluated the local control, limb salvage rate, 30-day and 90-day surgical mortality, and overall survival in patients undergoing surgery in a specialist sarcoma centre compared with non-specialist centre. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Sixty-six studies were identified. The majority of studies were Level III-3 as assessed by the NHMRC Evidence Hierarchy, whilst just over half of the studies were of good quality. Definitive surgery performed at specialised sarcoma centres was associated with improved local control as defined by lower rate of local relapse, higher rate of negative surgical margins, improved local recurrence free survival and higher limb conservation rate. Available evidences show a favourable pattern of lower 30-day and 90-day mortality rates, and greater overall survival when surgery was performed in specialist sarcoma centres compared with non-specialised centres. CONCLUSIONS: Evidences support better oncological outcomes when surgery is performed at specialised sarcoma centre. Patients with suspected sarcoma should be referred early to a specialised sarcoma centre for multidisciplinary management, which includes planned biopsy and definitive surgery.

Epigenetic liquid biopsies for minimal residual disease, what's around the corner?

Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy.

Relapsed mantle cell lymphoma presenting with lactic acidosis and hypoglycemia: A case report.

Lactic acidosis and hypoglycemia are rare presentations of malignancy with a poor prognosis. We present the case of a mantle cell lymphoma patient who relapsed with lactic acidosis and hypoglycemia. Although blood glucose, pH, and lactate normalized following chemotherapy and intensive care support, the patient died from ventilator-associated pneumonia.

High-Rate and Selective CO2 Electrolysis to Ethylene via Metal-Organic-Framework-Augmented CO2 Availability.

High-rate conversion of carbon dioxide (CO2 ) to ethylene (C2 H4 ) in the CO2 reduction reaction (CO2 RR) requires fine control over the phase boundary of the gas diffusion electrode (GDE) to overcome the limit of CO2 solubility in aqueous electrolytes. Here, a metal-organic framework (MOF)-functionalized GDE design is presented, based on a catalysts:MOFs:hydrophobic substrate materials layered architecture, that leads to high-rate and selective C2 H4 production in flow cells and membrane electrode assembly (MEA) electrolyzers. It is found that using electroanalysis and operando X-ray absorption spectroscopy (XAS), MOF-induced organic layers in GDEs augment the local CO2 concentration near the active sites of the Cu catalysts. MOFs with different CO2 adsorption abilities are used, and the stacking ordering of MOFs in the GDE is varied. While sputtering Cu on poly(tetrafluoroethylene) (PTFE) (Cu/PTFE) exhibits 43% C2 H4 Faradaic efficiency (FE) at a current density of 200 mA cm- 2 in a flow cell, 49% C2 H4 FE at 1 A cm- 2 is achieved on MOF-augmented GDEs in CO2 RR. MOF-augmented GDEs are further evaluated in an MEA electrolyzer, achieving a C2 H4 partial current density of 220 mA cm-2 for CO2 RR and 121 mA cm-2 for the carbon monoxide reduction reaction (CORR), representing 2.7-fold and 15-fold improvement in C2 H4 production rate, compared to those obtained on bare Cu/PTFE.

Virtual reality for the observation of oncology models (VROOM): immersive analytics for oncology patient cohorts.

The significant advancement of inexpensive and portable virtual reality (VR) and augmented reality devices has re-energised the research in the immersive analytics field. The immersive environment is different from a traditional 2D display used to analyse 3D data as it provides a unified environment that supports immersion in a 3D scene, gestural interaction, haptic feedback and spatial audio. Genomic data analysis has been used in oncology to understand better the relationship between genetic profile, cancer type, and treatment option. This paper proposes a novel immersive analytics tool for cancer patient cohorts in a virtual reality environment, virtual reality to observe oncology data models. We utilise immersive technologies to analyse the gene expression and clinical data of a cohort of cancer patients. Various machine learning algorithms and visualisation methods have also been deployed in VR to enhance the data interrogation process. This is supported with established 2D visual analytics and graphical methods in bioinformatics, such as scatter plots, descriptive statistical information, linear regression, box plot and heatmap into our visualisation. Our approach allows the clinician to interrogate the information that is familiar and meaningful to them while providing them immersive analytics capabilities to make new discoveries toward personalised medicine.

Pediatric Orbital Roof Fractures: A Ratio of Orbital Dimensions Correlated to Prevalence of Fracture.

Objective Orbital roof fractures are more likely to occur in younger children, specifically younger than 7 years. Cranium to face ratio decreases with age; however, there is no definition for measurement of the neurocranium or face. We propose using the length of the orbital roof as a measurement of the neurocranium and length of the orbital floor as a tool to estimate midface size. The purpose of this study is to test this measurement as a correlation rate of orbital roof fractures within the pediatric population. Design This is a retrospective study. Setting This study was done at the LeBonheur Children's Hospital. Participants Sixty-six patients with orbital roof fractures were identified and stratified by gender and age, specifically younger than 7 years and 7 years or older. Main Outcome Measures The main outcome measures were orbital roof length, floor length, and ratio thereof. Results Mean orbital roof length was 43.4 ± 3.06 and 45.1 ± 3.94 mm for patients <7 and ≥7 years, respectively ( p = 0.02). Mean orbital floor length was 41.3 ± 2.99 and 47.7 ± 4.19 for patients <7 and ≥7 years, respectively ( p < 0.00001). The mean roof to floor ratio (RTFR) for patients <7 years was 1.051 ± 0.039 and for patients ≥ 7 years was 0.947 ± 0.031 ( p < 0.00001). Conclusion As children age, the relative length of the orbital roof decreases when compared with the orbital floor. The RTFR was more than 1.0 in children younger than 7 years. These differences were statistically significant when compared with children 7 years and older. This measurement shift follows the differences noted in orbital fracture patterns during childhood.

Osteointegration of hydroxyapatite-coated collars in cemented massive endoprostheses following revision surgery.

AIMS: Hydroxyapatite (HA)-coated collars have been shown to reduce aseptic loosening of massive endoprostheses following primary surgery. Limited information exists about their effectiveness in revision surgery. The aim of this study was to radiologically assess osteointegration to HA-coated collars of cemented massive endoprostheses following revision surgery. METHODS: Retrospective review of osseointegration frequency, pattern, and timing to a specific HA-coated collar on massive endoprostheses used in revision surgery at our tertiary referral centre between 2010 to 2017 was undertaken. Osseointegration was radiologically classified on cases with a minimum follow-up of six months. RESULTS: In all, 39 patients underwent radiological review at mean 43.5 months; 22/39 (56.4%) showed no osseointegration to the collar. Revision endoprostheses for aseptic loosening were less likely to show osseointegration compared with other indications for revision. Oncological cases with previous or current infection were more likely to show osseointegration to ≥ 1 collar side than those without evidence of prior infection. CONCLUSION: This seven-year review identified osseointegration of HA-coated collars after revision surgery is less likely (43.6%, 17/39) than after primary surgery. Young patients who undergo revision surgery following initial oncological indication may benefit the most from this collar design. Use in revision oncological cases with a history of infection may be beneficial. HA-coated collars showed limited benefit for patients undergoing revision for failed arthroplasty with history of infection. Cite this article: Bone Jt Open 2021;2(6):371-379.

Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization.

Prurigo nodularis (PN) is an understudied, chronic inflammatory skin disease that disproportionately affects African Americans and presents with intensely pruritic nodules of unknown etiology. To better characterize the immune dysregulation in PN, PBMCs and skin biopsies were obtained from patients with PN and healthy subjects (majority African American) matched by age, race, and sex. Flow cytometric analysis of functional T-cell response comparing patients with PN with healthy subjects identified increased γδT cells (CD3+CD4-CD8-γδTCR+) and Vδ2+ γδT enrichment. Activated T cells demonstrated uniquely increased IL-22 cytokine expression in patients with PN compared with healthy controls. CD4+ and CD8+ T cells were identified as the source of increased circulating IL-22. Consistent with these findings, RNA sequencing of lesional PN skin compared with nonlesional PN skin and biopsy site‒matched control skin demonstrated robust upregulation of T helper (Th) 22‒related genes and signaling networks implicated in impaired epidermal differentiation. Th22‒related cytokine upregulation remained significant, with stratifications by race and biopsy site. Importantly, the expression of the IL-22 receptors IL22RA1 and IL22RA2 was significantly elevated in lesional PN skin. These results indicate that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22/IL-22 profile. PN may benefit from immunomodulatory therapies directed at Th22‒mediated inflammation.

The abrupt pancreatic duct cutoff sign on MDCT and MRI.

PURPOSE: To evaluate the pancreatic duct cutoff sign in detecting pancreatic adenocarcinoma using CT and MRI. METHODS: A retrospective analysis of patients with a pancreatic duct (PD) cutoff sign on CT or MRI from 2000 to 2019 was performed. The primary outcome measured was the presence or absence of a malignant pancreatic tumor. Variables evaluated included imaging characteristics of patients with a malignant versus non-malignant cause of duct cutoff and included PD size and PD-to-parenchyma ratio, contour abnormality, abnormal enhancement, diffusion abnormality, and upstream parenchymal atrophy. RESULTS: Seventy-two patients (44:28 M:F, mean age 64 years) were identified with a PD cutoff sign. Fifty-eight percent (42/72) of these patients were diagnosed with malignancy, 62% (26/42) of whom were diagnosed with pancreatic ductal adenocarcinoma. In patients diagnosed with a non-malignant cause of duct cutoff, 37% (11/30) were diagnosed with chronic pancreatitis. Eighty-eight percent (37/42) of patients with malignant causes and 33% (10/30) of patients with non-malignant causes were noted to have an associated mass on imaging. The presence of contour abnormality, diffusion abnormality, or abnormal enhancement at the level of the pancreatic cutoff was significantly higher in patients with malignancy (p < 0.05). There was no difference between groups in location of the pancreatic duct cutoff, degree of pancreatic duct dilatation, PD-to-parenchyma ratio, or presence of upstream atrophy. CONCLUSION: Abrupt cutoff of the pancreatic duct was associated with an increased likelihood of detecting malignancy. All patients who demonstrate this sign should undergo expedited workup with dedicated MRI and EUS with biopsy.

Abernethy Malformations: Evaluation and Management of Congenital Portosystemic Shunts.

PURPOSE: To assess the utility of preoperative venography in evaluating and managing patients with congenital portosystemic shunts (CPSSs). MATERIALS AND METHODS: A retrospective study was performed of 42 patients (62% female; median age, 4.1 years) diagnosed with a CPSS from 2005 to 2018. Preoperative venography (n = 39) and balloon occlusive pressure measurements (n = 33) within the mesenteric venous system guided treatment. Primary outcome was serum ammonia levels at 1 month after shunt closure. Management strategies included single (n = 12) or staged (n = 18) operative ligation, endovascular occlusion (n = 8), combined surgical and endovascular closure (n = 2), and observation (n = 2). RESULTS: At 1 month, serum ammonia levels decreased from 82.5 ± 10.3 µmol/L to 38.4 ± 4.6 µmol/L (P < .001). No difference was observed in the decrease between patients treated surgically or endovascularly (P = .91). Mean occluded to non-occluded pressure gradients were significantly lower for endovascular closure (5.3 ± 1.8 mmHg) than for surgical closure (12.3 ± 3.3 mmHg, P = .02). Shunts were classified as extrahepatic in 29 patients and as intrahepatic in 13 patients; all shunts demonstrated filling of the portal system with occlusive venography. Broad and short shunts were closed surgically; narrow and long shunts were closed endovascularly. Shunts were closed in a single session (n = 20) if the pressure gradient was less than 10 mmHg and the occluded mesenteric pressure was less than 25 mmHg. CONCLUSIONS: Preoperative venography delineates shunt morphology, and balloon occlusion simulates closure hemodynamics. This information is necessary to determine whether definitive closure should be performed through endovascular or surgical methods and whether closure should be performed in a single or staged setting.

Outcomes of conservatively managed complex acetabular fractures in the frail and elderly one year post injury.

BACKGROUND: Acetabular fractures in the elderly are associated with high levels of morbidity and mortality. Despite advances in operative techniques, there remains a cohort of elderly, extremely frail patients with comminuted fractures who are considered unfit for surgery and are treated conservatively. We aim to assess mortality, mobility and radiological outcomes one-year post injury in this challenging cohort. METHODS: We performed a review of the regional Fracture Outcome and Research Database for patients over 65 with associated type acetabular fractures which were treated conservatively. We collected data on demographics, fracture classification, pre-injury mobility and habitation, and length of acute hospital stay. Mobility status, habitation, radiographic result and mortality were also recorded at one-year post injury. RESULTS: There were 49 patients with a mean age of 80 years. The mean estimated American Society of Anaesthesiologist (ASA) score was 3.1. 92% sustained a low energy injury, and the most common fracture pattern was anterior posterior hemi-transverse (84%). Mean acute hospital stay was 20 days and mortality was 24% at one year. 56% of patients maintained habitation in their own home and 35% returned to their premorbid level of mobility. Of the surviving patients, 30% had an 'excellent/good' reduction on x-ray at one year, 70% had a 'fair/poor' reduction. There was no correlation between fracture reduction and either one year mobility status or maintenance of mobility. CONCLUSIONS: The data confirms that conservatively managed complex acetabular fractures in the elderly, frail patient are associated with a significant reduction in mobility and living independence, a high level of mortality and poor radiological outcomes. IMPLICATIONS: Conservative management of this cohort is associated with poor outcomes and current operative solutions are unsuitable for this frail cohort of patients. Future developments should focus on minimising surgical insult and allowing weight bearing mobilisation to maximise the rehabilitation potential in this frail cohort.

Primary Blast Lung Injury: The UK Military Experience.

INTRODUCTION: Primary blast lung injury occurs when an explosive shock wave passes through the thorax and transits through tissues of varying densities. It requires close proximity to an explosion and presents quick with respiratory distress in survivors. MATERIALS AND METHODS: The Joint Theatre Trauma Registry and the Defence Statistics (Health) Database were interrogated for casualties injured as a result of an explosion during the conflict in Afghanistan. The case notes and imaging of casualties meeting the criteria for diagnosis were reviewed. Demographic and clinical data on casualties with primary blast lung injury were analyzed. RESULTS: 848 blast-exposed casualties survived to discharge from intensive care, and 238 blast-exposed casualties were killed in action. Following exclusions, 111 case notes and all postmortem reports were reviewed in detail. About, 25 casualties had isolated primary blast lung injury (2.9% of casualties surviving to discharge from intensive care) and 31 nonsurvivors (13% of nonsurvivors) had the disease documented at postmortem. Severe cases of primary blast lung injury required an estimated average of 4.5 days of conventional mechanical ventilation. CONCLUSIONS: 8.1% of blast exposed casualties suffered primary blast lung injury. It was a less severe disease than other nontraumatic forms of acute lung injury and did not cause deaths once a casualty had reached a combat support hospital. It was well managed with a relatively brief period of conventional mechanical ventilation.

Mechanisms of iron- and O2-sensing by the [4Fe-4S] cluster of the global iron regulator RirA.

RirA is a global regulator of iron homeostasis in Rhizobium and related α-proteobacteria. In its [4Fe-4S] cluster-bound form it represses iron uptake by binding to IRO Box sequences upstream of RirA-regulated genes. Under low iron and/or aerobic conditions, [4Fe-4S] RirA undergoes cluster conversion/degradation to apo-RirA, which can no longer bind IRO Box sequences. Here, we apply time-resolved mass spectrometry and electron paramagnetic resonance spectroscopy to determine how the RirA cluster senses iron and O2. The data indicate that the key iron-sensing step is the O2-independent, reversible dissociation of Fe2+ from [4Fe-4S]2+ to form [3Fe-4S]0. The dissociation constant for this process was determined as Kd = ~3 µM, which is consistent with the sensing of 'free' iron in the cytoplasm. O2-sensing occurs through enhanced cluster degradation under aerobic conditions, via O2-mediated oxidation of the [3Fe-4S]0 intermediate to form [3Fe-4S]1+. This work provides a detailed mechanistic/functional view of an iron-responsive regulator.

Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding.

Functional variants in the genome are usually identified by their association with local gene expression, DNA methylation or chromatin states. DNA sequence motif analysis and chromatin immunoprecipitation studies have provided indirect support for the hypothesis that functional variants alter transcription factor binding to exert their effects. In this study, we provide direct evidence that functional variants can alter transcription factor binding. We identify a multifunctional variant within the TBC1D4 gene encoding a canonical NFκB binding site, and edited it using CRISPR-Cas9 to remove this site. We show that this editing reduces TBC1D4 expression, local chromatin accessibility and binding of the p65 component of NFκB. We then used CRISPR without genomic editing to guide p65 back to the edited locus, demonstrating that this re-targeting, occurring ~182 kb from the gene promoter, is enough to restore the function of the locus, supporting the central role of transcription factors mediating the effects of functional variants.

High-efficiency genomic editing in Epstein-Barr virus-transformed lymphoblastoid B cells using a single-stranded donor oligonucleotide strategy.

While human lymphoblastoid cell lines represent a valuable resource for population genetic studies, they have usually been regarded as difficult for CRISPR-mediated genomic editing because of very inefficient DNA transfection and retroviral or lentiviral transduction in these cells, which becomes a substantial problem when multiple constructs need to be co-expressed. Here we describe a protocol using a single-stranded donor oligonucleotide strategy for 'scarless' editing in lymphoblastoid cells, yielding 12/60 (20%) of clones with homology-directed recombination, when rates of <5-10% are frequently typical for many other cell types. The protocol does not require the use of lentiviruses or stable transfection, permitting lymphoblastoid cell lines to be used for CRISPR-mediated genomic targeting and screening in population genetic studies.