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Abstract Although placebo-controlled trials are considered the gold standard for evaluating the efficacy of healthcare interventions, they can be perceived to be controversial and challenging to conduct for surgical treatments. The SUcceSS trial is the first placebo-controlled trial of lumbar decompression surgery for symptomatic lumbar canal stenosis. The SUcceSS trial has experienced common issues affecting the implementation of randomised placebo-controlled surgery trials, accentuated by the COVID-19 pandemic. Using the SUcceSS trial as an example, we discuss key challenges and mitigation strategies specific to the conduct of a randomised placebo-controlled surgical trial. Overall, the key lessons learned were (i) involving key stakeholders early and throughout the trial design phase may increase clinician and patient willingness to participate in a placebo-controlled trial of surgical interventions, (ii) additional resources (e.g. budget, staff time) are likely required to successfully operationalise trials of this nature, (iii) the level of placebo fidelity, timing of randomisation relative to intervention delivery, and nuances of the surgical procedure under investigation should be considered carefully. Findings are based on one example of a placebo-controlled surgical trial; however, researchers may benefit from employing or building from the strategies described and lessons learned when designing or implementing future trials of this nature.

AbstractBackground Infections are rare and poorly studied complications of unicompartmental knee arthroplasty (UKA) surgery. They are significantly less common compared to infections after total knee arthroplasties (TKAs). Optimal management of periprosthetic joint infections (PJIs) after a UKA is not clearly defined in the literature. This article presents the results of the largest multicentre clinical study of UKA PJIs treated with Debridement, Antibiotics and Implant Retention (DAIR).Materials and Methods In this retrospective case series, patients presenting between January 2016 and December 2019 with early UKA infection were identified at three specialist centres using the Musculoskeletal Infection Society (MSIS) criteria. All patients underwent a standardized treatment protocol consisting of the DAIR procedure and antibiotic therapy comprising two weeks of intravenous (IV) antibiotics followed by six weeks of oral therapy. The main outcome measure was overall survivorship free from reoperation for infection.Results A total of 3225 UKAs (2793 (86.2%) medial and 432 (13.8%) lateral UKAs) were performed between January 2016 and December 2019. Nineteen patients had early infections necessitating DAIR. The mean follow-up period was 32.5 months. DAIR showed an overall survivorship free from septic reoperation of 84.2%, with overall survivorship free from all-cause reoperation of 78.95%.The most common bacteria were Coagulase-negative Staphylococci, Staphylococcus aureus and Group B Streptococci. Three patients required a second DAIR procedure but remained free from re-infection at follow-up obviating the need for more demanding, staged revision surgery.Conclusions In infected UKAs, the DAIR procedure produces a high rate of success, with a high survivorship of the implant.Key messagesDebridement, Antibiotics and Implant Retention (DAIR) is a successful and minimally invasive surgical option for the management of periprosthetic joint infections (PJIs) after UKA.The surface area available for bacteria to colonise is much smaller in UKAs compared to total knee arthroplasties (TKAs), and this may account for the higher success rates of the DAIR procedure in infected UKAs versus infected TKAs.A second DAIR procedure can be considered in the management of the early recurrence of PJIs with a well-fixed UKA.

Abstract Aim The aim of the study was to assess the suitability of an online education package to prepare health professionals to use a new paediatric early warning system. Design Quasi‐experimental mixed methods using co‐production. Methods Participants completed the Package and participated in up to four clinical scenarios. Data were collected using self‐report surveys, and during clinical scenarios; escalation of care, documentation, family involvement, communication handovers were assessed, and recorded debriefings were thematically analysed. Data were integrated using tabulated joint displays. Results Eleven nurses and three doctors were recruited from three mixed adult and paediatric hospitals. Following completion of the Package and clinical scenarios 13/14 (93%) participants agreed preparedness and confidence to use the ESCALATION System had increased. For 53% handovers, the communication framework was followed, for 79% charts, documentation was complete. Participants engaged with the parent (actor) for 97% scenario interactions. The Package was effective and participation in clinical scenarios appeared to enhance learning. Patient or public contribution Consumers participated in the steering group overseeing the study and in the expert panel who reviewed the education package and clinical scenarios.

The purpose of this study is to provide an overview of patients’ experiences using a precision medicine (PM) clinic that conducts pharmacogenomics-based (PGx) testing for adverse drug reactions. The study aimed to identify the features of the clinic valued most by patients and areas for improvement. A paper survey was used to collect data. Survey questions focused on patients’ perceptions of the PM testing and the overall clinic experience. Sixty-seven patients completed the survey. Quantitative data were analyzed using SPSS and frequencies were reported. Open-ended responses were coded and organized thematically. Patients reported that the clinic services increased confidence in their medication usage. Feeling respected by staff, receiving education, and quick appointments were highly valued by patients. Suggested areas for improvement included better communication from the clinic to patients, expansion of clinic services, and education for other healthcare providers. The findings demonstrate that patient experience goes beyond the clinical care provided. Current and potential future providers of PM should invest the time and energy to configure their care delivery system to enhance the patient experience.

The anterior part (third space) of the knee appears important in the soft tissue functional outcome following knee replacement surgery. Native patellofemoral kinematics are complex and variable, and further understanding has led to prosthetic redesign. Attention to soft tissue tension anteriorly (balancing the third space) during knee replacement may maximise post-operative function and avoid issues with understuffing and overstuffing. Patellofemoral compression forces may now be measured dynamically during knee replacement, allowing an objective approach to balancing the third space.

Abstract Background Chimeric antigen receptor (CAR)-T cell therapies for the treatment of hematological malignancies experienced tremendous progress in the last decade. However, essential limitations need to be addressed to further improve efficacy and reduce toxicity to assure CAR-T cell persistence, trafficking to the tumor site, resistance to an hostile tumor microenvironment (TME), and containment of toxicity restricting production of powerful but potentially toxic bioproducts to the TME; the last could be achieved through contextual release upon tumor antigen encounter of factors capable of converting an immune suppressive TME into one conducive to immune rejection. Methods We created an HER2-targeting CAR-T (RB-312) using a clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) system, which induces the expression of the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. This circuit includes two lentiviral constructs. The first one (HER2-TEV) expresses an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3z co-stimulatory domains linked to the tobacco etch virus (TEV) protease and two single guide RNAs (sgRNA) targeting the interleukin (IL)-12A and IL12B transcription start site (TSS), respectively. The second construct (LdCV) encodes linker for activation of T cells (LAT) fused to nuclease-deactivated Streptococcus Pyogenes Cas9 (dCas9)-VP64-p65-Rta (VPR) via a TEV-cleavable sequence (TCS). Activation of the CAR brings HER2-TEV in close proximity to LdCV releasing dCas9 for nuclear localization. This conditional circuit leads to conditional and reversible induction of the IL-12/p70 heterodimer. RB-312 was compared in vitro to controls (cRB-312), lacking the IL-12 sgRNAs and conventional HER2 CAR (convCAR). Results The inducible CRISPRa system activated endogenous IL-12 expression resulting in enhanced secondary interferon (FN)-γ production, cytotoxicity, and CAR-T proliferation in vitro, prolonged in vivo persistence and greater suppression of HER2+ FaDu oropharyngeal cancer cell growth compared to the conventional CAR-T cell product. No systemic IL-12 was detected in the peripheral circulation. Moreover, the combination with programmed death ligand (PD-L1) blockade demonstrated robust synergistic effects. Conclusions RB-312, the first clinically relevant product incorporating a CRISPRa system with non-gene editing and reversible upregulation of endogenous gene expression that promotes CAR-T cells persistence and effectiveness against HER2-expressing tumors. The autocrine effects of reversible, nanoscale IL-12 production limits the risk of off-tumor leakage and systemic toxicity.

The solid tumor microenvironment (TME) suppresses immune responses. Three alterations in the TME converge on a pathway triggered by elevated cyclic AMP (cAMP) that suppresses T cell receptor (TCR) signaling. We developed a phenotypic assay to screen for small molecules that interfere with this pathway using TALL-104 human leukemic cytotoxic T lymphocytes pretreated with prostaglandin E2 to elevate cAMP. Beads coated with anti-CD3 antibodies stimulate lytic granule exocytosis, which is detected via binding of an antibody against lysosome associated membrane protein 1 (LAMP-1) measured with flow cytometry. Confirming that the assay can find compounds with desired activity, treating cells with a phorbol ester restores exocytosis. The assay behaves well in 96-well format and we screened a collection of compounds expected to have effects on epigenetic regulatory proteins. Compounds in this collection affected lytic granule exocytosis after 24-hour treatment, but none prevented cAMP from suppressing lytic granule exocytosis. We used a fully automated 384-well version of the assay to screen the Prestwick Compound Library but obtained no confirmed hits. Analyzing this assay's performance reveals two points of interest. First, cytometry offers multiple ways to quantify signals. Z’ was higher using percent positive cells than mean fluorescence because the relationship between the two measures saturates, but using percent positive could make it harder to find hits in some assays. Second, variance was higher in positive controls than in negative controls in this assay, which degrades assay performance less than if variance was higher in negative controls.

Abstract Background Instability is one of the most common reasons for revision after a total knee replacement. It accounts for 17.4% of all single-stage revision procedures performed in the UK National Joint Registry. Through a careful patient evaluation, physical assessment and review of investigations one can identify the likely type of instability. Aims To critically examine the different types of instability, their presentation and evidence-based management options. Method A comprehensive literature search was conducted to identify articles relevant to the aetiology and management of instability in total knee replacements. Results Instability should be categorised as isolated or global and then, as flexion, mid-flexion, extension or recurvatum types. By identifying the aetiology of instability one can correctly restore balance and stability. Conclusion With careful judgement and meticulous surgical planning, instability can be addressed and revision surgery can provide patients with successful outcomes.

Abstract Pharmacogenomics (PGx)‐based personalized medicine (PM) is increasingly utilized to guide treatment decisions for many drug‐disease combinations. Notably, London Health Sciences Centre (LHSC) has pioneered a PGx program that has become a staple for London‐based specialists. Although implementational studies have been conducted in other jurisdictions, the Canadian healthcare system is understudied. Herein, the multistakeholder perspectives on implementational drivers and barriers are elucidated. Using a mixed‐method qualitative model, key stakeholders, and patients from LHSC’s PGx‐based PM clinic were interviewed and surveyed, respectively. Interview transcripts were thematically analyzed in a stepwise process of customer profiling, value mapping, and business model canvasing. Value for LHSC located specialist users of PGx was driven by the quick turnaround time, independence of the PGx clinic, and the quality of information. Engagement of external specialists was only limited by access and awareness, whereas other healthcare nonusers were limited by education and applicability. The major determinant of successful adoption at novel sites were institutional champions. Patients valued and approved of the service, expressed a general willingness to pay, but often traveled far to receive genotyping. This paper discusses the critical pillars of education, awareness, advocacy, and efficiency required to address implementation barriers to healthcare service innovation in Canada. Further adoption of PGx practices into Canadian hospitals is an important factor for advancing system‐level changes in care delivery, patient experiences, and outcomes. The findings in this paper can help inform efforts to advance clinical PGx practices, but also the potential adoption and implementation of other innovative healthcare service solutions.

The rapid expansion of the gene therapy pipeline in recent years offers significant potential to treat diseases with great unmet medical need. However, the unique nature of these therapies poses challenges to regulating them within traditional frameworks, even when developing in a single country. Various factors exacerbate the issues in commercializing products across regions, including the lack of established regulatory frameworks for developing gene therapy products in many jurisdictions. While some countries have established separate regulatory frameworks for advanced therapies/regenerative medicine products, differences exist between them. Recommended solutions to overcome these hurdles include fostering convergence among countries with separate regulatory frameworks for these products and utilizing reliance and recognition for countries without such frameworks. Additionally, regulators who choose to establish new dedicated frameworks for regulating gene therapies should consider the inclusion of key elements such as expedited regulatory pathways that offer early engagement with regulators, innovative clinical trial design, and adequate post-market confirmatory studies. Increasing the alignment of regulatory pathways across countries will be crucial to facilitating the development of, and access to, gene therapies on a global scale.

The business model canvas is a popular tool used to develop value-driven business models. Specific emphasis is placed on understanding what customers value and providing users with steps on how to design and deliver value for their customers. In health care, creating and delivering value for patients is an often-discussed topic, with the provision of patient-centered care becoming a standard for many health care organizations. While patients play a key role in determining value, providers are the key to delivering value. Therefore, effective health care management relies on integrating multiple perspectives from key stakeholders. This process requires consideration of the key needs that must be addressed, the resources and capabilities necessary to meet these needs, and the interests and values specific to each set of stakeholders. The business model canvas lends itself well to health care service planning as it incorporates the factors described above into the business model’s conceptualization and subsequent realization. This article outlines how the business model canvas was applied to assess the needs of physician stakeholders to help guide the expansion of a pharmacogenomic-based precision medicine clinic that conducts genetic testing for patients at risk of experiencing adverse drug reactions. The article provides a detailed description of how the business model canvas was used and adapted to understand physician’s responsibilities and challenges related to drug prescription and dosing, and how the clinic could address physician needs and create value by mapping clinic services onto physician needs and wants. Interviews were conducted with physicians and the data were analyzed following the recommendations of the developers of the business model canvas. The article examines the strengths and limitations of the business model canvas and discusses its applicability to a health care setting.

Understanding the genetics of fur characteristics and skin size is important for developing effective breeding programs in the mink industry. Therefore, the objectives of this study were to estimate the genetic and phenotypic parameters for pelt quality traits including live grading overall quality (LQU), live grading nap size (LNAP), dried pelt size (DPS), dried pelt nap size (DNAP) and overall quality of dried pelt (DQU), and body length and weight traits, including November body weight (Nov_BW), November body length (Nov_BL), harvest weight (HW) and harvest length (HL) in American mink. Dried pelt quality traits on 1195 mink and pelt quality traits on live animals on 1680 were collected from mink raised at two farms, in Nova Scotia and Ontario. A series of univariate analyses were implemented in ASReml 4.1 software to identify the significance (p < 0.05) of random effects (maternal genetic effects, and common litter effects) and fixed effects (farm, sex, color type, year, and age) for each trait. Subsequently, bivariate models were used to estimate the genetic and phenotypic parameters using ASReml 4.1. Heritability (±SE) estimates were 0.41 ± 0.06 for DPS, 0.23 ± 0.10 for DNAP, 0.12 ± 0.04 for DQU, 0.28 ± 0.06 for LQU, 0.44 ± 0.07 for LNAP, 0.29 ± 0.10 for Nov_BW, 0.28 ± 0.09 for Nov_BL, 0.41 ± 0.07 for HW and 0.31 ± 0.06 for HL. DPS had high positive genetic correlations (±SE) with Nov_BW (0.89 ± 0.10), Nov_BL (0.81 ± 0.07), HW (0.85 ± 0.05) and HL (0.85 ± 0.06). These results suggested that body weight and length measured on live animals in November of the first year were reliable indicators of dried pelt size. DQU had favorable genetic correlations with Nov_BL (0.55 ± 0.24) and HL (0.46 ± 0.20), and nonsignificant genetic correlations with DNAP (0.13 ± 0.25), Nov_BW (0.25 ± 0.25) and HW (0.06 ± 0.20), which made body length traits an appealing trait for selection for increased pelt size. High positive genetic correlation (±SE) was observed between LNAP and DNAP (0.82 ± 0.22), which revealed that nap size measurement on live animals is a reliable indicator trait for dried pelt nap size. However, nonsignificant (p > 0.05) low genetic correlation (±SE) was obtained between LQU and DQU (0.08 ± 0.45), showing that indirect selection based on live grading might not lead to the satisfactory improvement of dried pelt overall quality. The estimated genetic parameters for live grading, dried pelt quality, and body weight and body length traits may be incorporated into breeding programs to improve fur characteristics in Canadian mink populations.

Functional dissatisfaction following total knee replacement (TKR) is recorded as high as 20%. The majority of these patients report anterior knee pain (AKP) as the main source of dissatisfaction. Elevated patellofemoral compression forces and soft tissue extensor hood strain have been implicated in the generation of significant AKP. A novel method of assessing and measuring patellofemoral compression forces dynamically in the native and resurfaced patella for TKR in four different quadrants of the patella is described. Results are reported from an in vitro model and cadaveric studies in the native and resurfaced knee. Patellofemoral compression forces are shown to be characteristic and consistent over repeated assessments in the native knee. Placement of a TKR significantly alters this pattern. Furthermore, over-stuffing or under-stuffing the resurfaced patella also significantly alters the nature and magnitude of patellofemoral compression forces. These studies may lead to an improved understanding of the nature of AKP following TKR, and using this assessment tool presents an opportunity to more effectively balance the third space, reproduce the native patellofemoral forces, and subsequently reduce AKP following TKR.

Even though informatics is a term used commonly in healthcare, it can be a confusing and disengaging one. Many definitions exist in the literature, and attempts have been made to develop a clear taxonomy. Despite this, informatics is still a term that lacks clarity in both its scope and the classification of sub-terms that it encompasses.This paper reviews the importance of an agreed taxonomy and explores the challenges of establishing exactly what is meant by health informatics (HI). It reviews what a taxonomy should do, summarises previous attempts at categorising and organising HI and suggests the elements to consider when seeking to develop a system of classification.The paper does not provide all the answers, but it does clarify the questions. By plotting a path towards a taxonomy of HI, it will be possible to enhance understanding and optimise the benefits of embracing technology in clinical practice.

Computerised decision support software (CDSS) for anticoagulation management has become established practice in the UK, offering significant advantages for patients and clinicians over traditional methods of dose calculation. The New GMS Contract has been partly responsible for this shift of management from secondary to primary care, in which INRstar has been the market leader for many years. In September 2004, INRstar received the John Perry Prize, awarded by the PHCSG for excellence and innovation in medical applications of information technology.