The gene expression profile and cell of origin of canine peripheral T-cell lymphoma.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-not otherwise specified (PTCL-NOS), leading to interest in this canine disease as a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. METHODS: Bulk RNA-sequencing was performed on tumor samples from 33 dogs with either CD4+ (26/33), CD8+ (4/33), or CD4-CD8- (3/33) PTCL as diagnosed by flow cytometry, and sorted CD4+ and CD8+ lymphocytes from healthy control dogs. Following normalization of RNA-seq data, we performed differential gene expression and unsupervised clustering methods. Gene set enrichment analysis was performed to determine the enrichment of canine CD4+ PTCL for human PTCL-NOS, oncogenic pathways, and various stages of T-cell development gene signatures. We utilized gene set variation analysis to evaluate individual canine CD4+ PTCLs for various human and murine T-cell and thymocyte gene signatures. Cultured canine PTCL cells were treated with a pan-PI3K inhibitor, and cell survival and proliferation were compared to DMSO-treated controls. Expression of GATA3 and phosphorylated AKT was validated by immunohistochemistry. RESULTS: While the canine CD4+ PTCL phenotype exhibited a consistent gene expression profile, the expression profiles of CD8+ and CD4-CD8- canine PTCLs were more heterogeneous. Canine CD4+ PTCL had increased expression of GATA3, upregulation of its target genes, enrichment for PI3K/AKT/mTOR signaling, and downregulation of PTEN, features consistent with the more aggressive GATA3-PTCL subtype of human PTCL-NOS. In vitro assays validated the reliance of canine CD4+ PTCL cells on PI3K/AKT/mTOR signaling for survival and proliferation. Canine CD4+ PTCL was enriched for thymic precursor gene signatures, exhibited increased expression of markers of immaturity (CD34, KIT, DNTT, and CCR9), and downregulated genes associated with the T-cell receptor, MHC class II associated genes (DLA-DQA1, DLA-DRA, HLA-DQB1, and HLA-DQB2), and CD25. CONCLUSIONS: Canine CD4+ PTCL most closely resembled the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin.

SynLeGG: analysis and visualization of multiomics data for discovery of cancer 'Achilles Heels' and gene function relationships.

Achilles' heel relationships arise when the status of one gene exposes a cell's vulnerability to perturbation of a second gene, such as chemical inhibition, providing therapeutic opportunities for precision oncology. SynLeGG (www.overton-lab.uk/synlegg) identifies and visualizes mutually exclusive loss signatures in 'omics data to enable discovery of genetic dependency relationships (GDRs) across 783 cancer cell lines and 30 tissues. While there is significant focus on genetic approaches, transcriptome data has advantages for investigation of GDRs and remains relatively underexplored. SynLeGG depends upon the MultiSEp algorithm for unsupervised assignment of cell lines into gene expression clusters, which provide the basis for analysis of CRISPR scores and mutational status in order to propose candidate GDRs. Benchmarking against SynLethDB demonstrates favourable performance for MultiSEp against competing approaches, finding significantly higher area under the Receiver Operator Characteristic curve and between 2.8-fold to 8.5-fold greater coverage. In addition to pan-cancer analysis, SynLeGG offers investigation of tissue-specific GDRs and recovers established relationships, including synthetic lethality for SMARCA2 with SMARCA4. Proteomics, Gene Ontology, protein-protein interactions and paralogue information are provided to assist interpretation and candidate drug target prioritization. SynLeGG predictions are significantly enriched in dependencies validated by a recently published CRISPR screen.

Atypical multiple myeloma in 3 young dogs.

Three dogs under 12 months old were diagnosed with atypical multiple myeloma (MM), having an aggressive multifocal anaplastic round cell sarcoma in bone marrow, viscera, and/or peripheral blood, which were confirmed by cytology and immunohistochemistry to be of plasma cell origin. The intramedullary sarcomas caused myelophthisis, osteolysis, and hypercalcemia. Complete or free light chain monoclonal gammopathy in the serum and/or urine was demonstrated by protein electrophoresis and immunofixation. The polymerase chain reaction for antigen receptor rearrangement assay performed on 2 cases identified a clonally rearranged immunoglobulin gene. Neoplastic cells lacked expression of CD45, CD3, CD18, CD21, CD34, and MHCII by flow cytometry. Immunohistochemistry revealed MUM1 immunoreactivity of the neoplastic cells. Combining all data, the diagnosis was MM. An aggressive form of MM in young dogs should be a differential diagnosis for patients with an immunoglobulin-productive, B cell-clonal, CD45-negative, MUM1-positive discrete cell neoplasm arising from the bone marrow.

Stigma, Trust, and procedural integrity: Covid-19 testing in Malawi.

An emerging consensus in public health views testing for Covid-19 as key to managing the pandemic. It is often assumed that citizens have a strong desire to know their Covid-19 status, and will therefore take advantage of testing opportunities. This may not be the case in all contexts, however, especially those where citizens perceive stigma associated with the Covid-19, have low trust in health institutions, and doubt the procedural integrity of the testing process. This article explores willingness to receive a free Covid-19 test via a vignette experiment (conjoint design) embedded in a phone survey conducted in Malawi in May 2020. The experiment varied test provider (public clinic versus international health organization), proximity to illness, and reassurance of confidentiality. We find that Malawians expect higher uptake of testing in their community when the international health organization offered the test rather than a public clinic, an effect we attribute to higher trust in the organization and/or perceptions of greater capacity to ensure procedural integrity. The confidentiality reassurance did not substantially alter beliefs about the privacy of results, but did increase doubts about the willingness of community members to get tested in a public health clinic. Our findings suggest the importance of considering the demand side of testing in addition to well-known challenges of supply.

The ABCs of Covid-19 prevention in Malawi: Authority, benefits, and costs of compliance.

A wide array of authorities-from religious leaders to government ministers-call upon citizens to take preventative measures against Covid-19. Which authorities can most effectively gain public compliance, and which measures will the public take up? Moreover, do people comply with authorities out of respect for their legitimacy, due to their expertise, or for fear of sanctioning? Answers to these questions are important for development practitioners, who need to understand how different partnerships might affect health behavior, and for scholars interested in understanding authority, legitimacy, and compliance. We explore these questions using a conjoint experiment embedded in a telephone survey of 641 Malawians. Individuals in our sample are more likely to say that they will comply with precautionary measures when the costs are low and expected benefits are high. Respondents view both traditional authorities and hospital heads as legitimately issuing directives and having the ability to monitor and sanction non-compliance, but appear to comply more with hospital heads and to do so out of respect for their expertise. These results emphasize how who issues directives affects whether individuals comply and provides insights as to why they do so. The findings also reflect individuals' cost-benefit calculations when considering precautionary measures, highlighting the importance of steps that can reduce costs (e.g., food security or income measures) or accurately reflect risks (e.g., information signaling the prevalence of Covid-19). The study not only helps to address the Coronavirus crisis but also has important implications for broader questions of authority and compliance.

Epidermolysis Bullosa Patients' Perception of Surgical Wound and Scar Healing.

BACKGROUND: There is limited evidence to suggest patients with epidermolysis bullosa (EB) have more postoperative wound complications than the general population. Despite this, the authors have noted reluctance among some surgeons to operate on these patients. OBJECTIVE: A cross-sectional study was designed to investigate postoperative wound and scar healing outcomes in patients with EB. METHODS: Patients were asked to complete the "Surgical Wound and Scar Healing in EB" questionnaire, and data gathered were analyzed. RESULTS: Forty-six patients completed the questionnaire for a total of 94 different surgical procedures. Five patients reported blistering at the surgical wound site. All 5 had generalized forms of EB. Four patients reported wound infections, and 1 patient reported wound dehiscence. The postoperative scar healed with keloid or hypertrophic scarring after 26% of the reported surgical procedures. CONCLUSION: Blistering at the postoperative site seems to be uncommon and particularly unlikely to occur in localized forms of EB. Postoperative wound infections and dehiscence are uncommon. Patients with EB may have a propensity to develop keloid or hypertrophic scarring. With these data, the authors hope clinicians have greater confidence in referring patients with EB for surgery, and surgeons more reassured about postoperative wound healing.

Severe cutaneous eruptions following the topical use of preparations containing bufexamac: Is it time to reconsider its registration in Australia?

Despite being a well-recognised cause of allergic contact dermatitis with an embargo in many countries around the world, bufexamac is available over the counter in topical preparations in Australia. We present a series of patients who developed severe cutaneous eruptions after the topical application of bufexamac containing preparations to highlight the potential risks of this medication, as well as advocate for the reconsideration of its registration by the Therapeutic Goods Administration in Australia.

Midterm Performance of a Guided-Motion Bicruciate-Stabilized Total Knee System: Results From the International Study of Over 2000 Consecutive Primary Total Knee Arthroplasties.

BACKGROUND: The JOURNEY II Bi-Cruciate Stabilizing Total Knee System (BLINDED) is a second-generation guided-motion knee implant that has been used in over 100,000 primary total knee arthroplasties (TKAs) worldwide. However, performance information is limited. METHODS: Data for 2059 primary TKAs were abstracted at 7 US and 3 European sites. Estimates of cumulative incidence of revision were compared with registry data for cemented posterior-stabilized implants. RESULTS: Average age was 64.3 years (range, 18-91); 58.5% were females; and 12.3% TKAs were in subjects younger than 55 years. Patellae were resurfaced in 95.9%. Median time since primary TKA was 4.2 years; longest was 6.1 years; and 78.9% were 3 years or more since primary TKA. Of 67 revisions (3.2%), 20 (30%) involved femoral or tibial component removal compared to 42% in the Australian Joint Registry (Australian Orthopedic Association National Joint Replacement Registry). All-component revisions accounted for 15 of 67, femoral component only for 2 of 67, tibial component only for 3 of 67, patellar component with/without tibial insert exchange for 17 of 67, and isolated tibial insert exchange for 30 of 67. In addition, there were 18 reoperations without component exchange. Component revision indications were infection (33%), mechanical loosening (21%), fracture of bone around the joint (16%), and instability (15%). Kaplan-Meier revision estimate was 3.1 and 3.6 per 100 TKAs at 3 and 5 years, respectively, compared to Australian Orthopedic Association National Joint Replacement Registry estimates of 3.1 and 4.1 per 100 TKAs. CONCLUSION: The revision rate for the second-generation implant was similar to cemented posterior-stabilized registry controls.

Understanding the coherence of the severity effect and optimism phenomena: Lessons from attention.

Claims that optimism is a near-universal characteristic of human judgment seem to be at odds with recent results from the judgment and decision making literature suggesting that the likelihood of negative outcomes are overestimated relative to neutral outcomes. In an attempt to reconcile these seemingly contrasting phenomena, inspiration is drawn from the attention literature in which there is evidence that both positive and negative stimuli can have attentional privilege relative to neutral stimuli. This result provides a framework within which I consider three example phenomena that purport to demonstrate that people's likelihood estimates are optimistic: Wishful thinking; Unrealistic comparative optimism and Asymmetric belief updating. The framework clarifies the relationships between these phenomena and stimulates future research questions. Generally, whilst results from the first two phenomena appear reconcilable in this conceptualisation, further research is required in reconciling the third.

A Review of 52 Pedigrees with Epidermolysis Bullosa Simplex Identifying Ten Novel Mutations in KRT5 and KRT14 in Australia.

Epidermolysis bullosa simplex (EBS) is a rare heritable skin fragility disorder, most commonly caused by dominant mutations in KRT5 and KRT14. EBS shows clinical heterogeneity with localised, intermediate and generalised severe forms, which tend to correlate with the location and nature of the disease causing mutations. We therefore aimed to identify the KRT5 and KRT14 mutations in patients diagnosed with EBS in Australia, and explore in depth the genotype to the phenotype correlations in patients with novel variants. Australian patients who were diagnosed with EBS after referral to the Australian National Diagnostic Laboratory for EB were offered mutation screening in the KRT5 and KRT14 genes. From this, 32 different mutations in KRT5 and KRT14 were identified within 39 of 52 pedigrees. Ten of these mutations from 9 different pedigrees were novel, a further fatal case caused by KRT5 E477K is reported and in addition the third reported case of digenic inheritance in EBS was also observed.

The distribution of epidermolysis bullosa in Australia with a focus on rural and remote areas.

BACKGROUND/OBJECTIVES: Patients with epidermolysis bullosa (EB) require specialised medical care. In Australia this expertise is located in the major cities, with patients living in rural and remote areas having reduced access to these services. We aim to analyse the geographical distribution of patients with EB in Australia to determine the relevance of this potential geographical disadvantage for this population. METHODS: Using postal codes obtained from the Australian National Diagnostic Laboratory Database for EB and the Australasian EB Registry, living patients with EB in Australia were categorised using the Australian standard geographical classification, remoteness areas. An analysis of EB subtype, including severity was also performed. RESULTS: A total of 318 patients were categorised, of whom 221 lived in major cities, 65 in inner regional areas, 26 in outer regional areas, four in remote and two in very remote areas. Half the patients living in remote and very remote areas had severe forms of EB. CONCLUSIONS: A significant proportion of patients with EB live outside the major cities in Australia. Half of the patients living in remote and very remote areas had severe forms of EB. Targeted strategies to improve access to EB-specific medical care may be needed for patients living in rural and remote areas.

A pessimistic view of optimistic belief updating.

Received academic wisdom holds that human judgment is characterized by unrealistic optimism, the tendency to underestimate the likelihood of negative events and overestimate the likelihood of positive events. With recent questions being raised over the degree to which the majority of this research genuinely demonstrates optimism, attention to possible mechanisms generating such a bias becomes ever more important. New studies have now claimed that unrealistic optimism emerges as a result of biased belief updating with distinctive neural correlates in the brain. On a behavioral level, these studies suggest that, for negative events, desirable information is incorporated into personal risk estimates to a greater degree than undesirable information (resulting in a more optimistic outlook). However, using task analyses, simulations, and experiments we demonstrate that this pattern of results is a statistical artifact. In contrast with previous work, we examined participants' use of new information with reference to the normative, Bayesian standard. Simulations reveal the fundamental difficulties that would need to be overcome by any robust test of optimistic updating. No such test presently exists, so that the best one can presently do is perform analyses with a number of techniques, all of which have important weaknesses. Applying these analyses to five experiments shows no evidence of optimistic updating. These results clarify the difficulties involved in studying human 'bias' and cast additional doubt over the status of optimism as a fundamental characteristic of healthy cognition.

Fingermark submission decision-making within a UK fingerprint laboratory: Do experts get the marks that they need?

Within UK policing it is routinely the responsibility of fingerprint laboratory practitioners to chemically develop areas of latent fingerprint ridge detail on evidential items and to determine which areas of ridge detail are of sufficient quality to be submitted to fingerprint experts for search or comparison against persons of interest. This study assessed the effectiveness of the fingermark submission process within the Evidence Recovery Unit Fingerprint Laboratory of the Metropolitan Police Service. Laboratory practitioners were presented with known source fingermark images previously deemed identifiable or insufficient by fingerprint experts, and were asked to state which of the marks they would forward to the Fingerprint Bureau. The results indicated that practitioners forwarded a higher percentage of insufficient fingermarks than is acceptable according to current laboratory guidelines, and discarded a number of marks that were of sufficient quality for analysis. Practitioners forwarded more insufficient fingermarks when considering fingermarks thought to be related to a murder and discarded more sufficient fingermarks when considering those thought to be related to a crime of 'theft from vehicle'. The results highlight the need for fingerprint laboratories to work alongside fingerprint experts to ensure that a consistent approach to decision-making is, as far as possible, achieved, and that appropriate thresholds are adopted so as to prevent the loss of valuable evidence and improve the efficiency of the fingerprint filtering process.

Hip arthroscopy: prevalence of intra-articular pathologic findings after traumatic injury of the hip.

PURPOSE: The purpose of this study was to document and compare the incidence of intra-articular hip pathologic findings identified using arthroscopy versus conventional imaging in patients with acute trauma to the hip. METHODS: This was a blinded prospective case series study designed to review the incidence of intra-articular pathologic disorders in patients with post-traumatic injury between the ages of 18 and 65 years who were referred to a single surgeon. Injuries included hip dislocation, proximal femur fracture, pelvic ring fracture, acetabular fracture, penetrating injury (gunshot wound), and soft tissue injury. Preoperative radiographs, computed tomographic (CT) scans, or magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) scans (or a combination of these) were obtained. Findings were documented and compared with intraoperative findings. RESULTS: A total of 29 post-traumatic hips were enrolled in this study. Hip arthroscopy identified 17 of 29 hips (59%) as having loose bodies, 11 of 29 (38%) hips as having an intra-articular step deformity, 14 of 29 (49%) hips as having an osteochondral lesion, and 27 of 29 (93%) hips as having a labral tear. Plain radiographs and CT scans yielded low sensitivity when compared with arthroscopy for the identification of loose bodies and step deformities. MRI/MRA comparison with arthroscopic findings suggest that MRI/MRA is an accurate tool for identification of labral tears, because 91% of tears seen on arthroscopy were also identified by MRI/MRA. In 4 hips, however, MRI/MRA failed to identify osteochondral lesions that were subsequently identified by arthroscopy. CONCLUSIONS: Traumatic injuries of the hip result in substantial intra-articular pathologic findings, including loose bodies, labral tears, step deformities, and osteochondral lesions. The arthroscope is a powerful tool in identifying these injuries. Plain radiographs and CT scans appear to underestimate the true incidence of loose bodies and step deformities within the joint when compared with hip arthroscopy after a traumatic injury of the hip. LEVEL OF EVIDENCE: Level IV, diagnostic case series.

Exploring open science practices in behavioural public policy research.

In their book 'Nudge: Improving Decisions About Health, Wealth and Happiness', Thaler & Sunstein (2009) argue that choice architectures are promising public policy interventions. This research programme motivated the creation of 'nudge units', government agencies which aim to apply insights from behavioural science to improve public policy. We closely examine a meta-analysis of the evidence gathered by two of the largest and most influential nudge units (DellaVigna & Linos (2022 Econometrica 90, 81-116 (doi:10.3982/ECTA18709))) and use statistical techniques to detect reporting biases. Our analysis shows evidence suggestive of selective reporting. We additionally evaluate the public pre-analysis plans from one of the two nudge units (Office of Evaluation Sciences). We identify several instances of excellent practice; however, we also find that the analysis plans and reporting often lack sufficient detail to evaluate (unintentional) reporting biases. We highlight several improvements that would enhance the effectiveness of the pre-analysis plans and reports as a means to combat reporting biases. Our findings and suggestions can further improve the evidence base for policy decisions.

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor in a patient with von Willebrand disease: perioperative optimization for patients with coagulopathies. Illustrative case.

BACKGROUND: Essential tremor (ET) is one of the most common movement disorders worldwide. In medically refractory ET, deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus is the current standard of care. However, DBS carries an inherent 2% to 3% risk of hemorrhage, a risk that can be much higher in patients with concomitant coagulopathy. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy is a surgical alternative that is highly effective in treating ET, with no reports of intracranial hemorrhage to date. OBSERVATIONS: This is the first documented case of successful MRgFUS thalamotomy in a patient with von Willebrand disease (VWD). A 60-year-old left-handed male had medically refractory ET, VWD type 2B, and a family history of clinically significant hemorrhage after DBS. He underwent right-sided MRgFUS thalamotomy and received a perioperative course of VONVENDI (recombinant von Willebrand factor) to ensure appropriate hemostasis. Postprocedure imaging confirmed a focal lesion in the right thalamus without evidence of hemorrhage. The patient reported 90% improvement of his left-hand tremor and significant improvement in his quality of life without obvious side effects. LESSONS: MRgFUS thalamotomy with peri- and postoperative hematological management is a promising alternative to DBS for patients with underlying coagulopathies.

Severity influences categorical likelihood communications: A case study with Southeast Asian weather forecasters.

Risk assessments are common in multiple domains, from finance to medicine. They require evaluating an event's potential severity and likelihood. We investigate the possible dependence of likelihood and severity within the domain of impact-based weather forecasting (IBF), following predictions derived from considering asymmetric loss functions. In a collaboration between UK psychologists and partners from four meteorological organisations in Southeast Asia, we conducted two studies (N = 363) eliciting weather warnings from forecasters. Forecasters provided warnings denoting higher likelihoods for high severity impacts than low severity impacts, despite these impacts being described as having the same explicit numerical likelihood of occurrence. This 'Severity effect' is pervasive, and we find it can have a continued influence even for an updated forecast. It is additionally observed when translating warnings made on a risk matrix to numerical probabilities.

Subchondral pre-solidified chitosan/blood implants elicit reproducible early osteochondral wound-repair responses including neutrophil and stromal cell chemotaxis, bone resorption and repair, enhanced repair tissue integration and delayed matrix deposition.

BACKGROUND: In this study we evaluated a novel approach to guide the bone marrow-driven articular cartilage repair response in skeletally aged rabbits. We hypothesized that dispersed chitosan particles implanted close to the bone marrow degrade in situ in a molecular mass-dependent manner, and attract more stromal cells to the site in aged rabbits compared to the blood clot in untreated controls. METHODS: Three microdrill hole defects, 1.4 mm diameter and 2 mm deep, were created in both knee trochlea of 30 month-old New Zealand White rabbits. Each of 3 isotonic chitosan solutions (150, 40, 10 kDa, 80% degree of deaceylation, with fluorescent chitosan tracer) was mixed with autologous rabbit whole blood, clotted with tissue factor to form cylindrical implants, and press-fit in drill holes in the left knee while contralateral holes received tissue factor or no treatment. At day 1 or day 21 post-operative, defects were analyzed by micro-computed tomography, histomorphometry and stereology for bone and soft tissue repair. RESULTS: All 3 implants filled the top of defects at day 1 and were partly degraded in situ at 21 days post-operative. All implants attracted neutrophils, osteoclasts and abundant bone marrow-derived stromal cells, stimulated bone resorption followed by new woven bone repair (bone remodeling) and promoted repair tissue-bone integration. 150 kDa chitosan implant was less degraded, and elicited more apoptotic neutrophils and bone resorption than 10 kDa chitosan implant. Drilled controls elicited a poorly integrated fibrous or fibrocartilaginous tissue. CONCLUSIONS: Pre-solidified implants elicit stromal cells and vigorous bone plate remodeling through a phase involving neutrophil chemotaxis. Pre-solidified chitosan implants are tunable by molecular mass, and could be beneficial for augmented marrow stimulation therapy if the recruited stromal cells can progress to bone and cartilage repair.