Proceedings of the United Kingdom Periprosthetic Joint Infection Meeting 2022: Fracture-Related Infection Session.

Implant-related infections represent a relatively common and significant challenge in the surgical management of musculoskeletal trauma patients. The third United Kingdom Periprosthetic Joint Infection (UK PJI) Meeting convened in Glasgow on 1 April 2022, and brought together over 180 delegates, representing orthopaedics, infectious diseases, microbiology, plastic surgery, anaesthetics, and allied health professions, including pharmacy and specialist nurses. The meeting comprised a plenary session for all delegates, and separate breakout sessions for fracture-related infection (FRI) and arthroplasty. The UK PJI working group prepared consensus statements in advance of each session, based upon topics that were discussed at previous meetings, and delegates engaged in an anonymous electronic voting process. This article presents the findings of the FRI session, and examines each consensus topic within the context of the contemporary literature.

Survivorship of the Stryker Ascend Flex uncemented metaphyseal bearing stem at a minimum 2- and 5-year follow-up.

Introduction: The Ascend Flex short stem implant has been reported to have good early clinical outcomes and low revision rates. This retrospective study aimed to evaluate the early to mid-term radiographic and clinical outcomes of patients who underwent primary shoulder arthroplasty with this implant. Methods: All consecutive patients who underwent primary shoulder arthroplasty with short uncemented Ascend Flex stems with a minimum of 24-month follow-up were included. The primary outcomes were revision and reoperation rate. The secondary outcomes included stress shielding and Oxford Shoulder Score (OSS). Results: Totally, 151 shoulders were eligible for inclusion. Out of which 73 were anatomic total shoulder arthroplasty, 77 were reverse geometry, and 1 was a hemiarthroplasty. Mean follow-up duration was 52 ± 17.2 months. The revision and reoperation rates were 0.6% and 2.6%, respectively. 1.3% anatomic total shoulder arthroplasty (aTSA) cases and 6.5% RSA cases demonstrated stress shielding. OSS improved from 16.1 ± 8.5 to 34.1 ± 12.3 in aTSA cases (Z = -3.98, p < 0.001) and from 15.6 ± 8.4 to 30.0 ± 13.5 in RSA cases (Z = -3.41, p < 0.001). Conclusion: These findings demonstrate reassuring outcomes for this implant at a mean of 52 months. Further reports are required to document the long-term outcomes for this component.

Mid to Long-Term Outcomes of Grade III-B Open Tibial Fractures Definitively Managed With a Circular Frame: A 13-Year Prospective Database Study at a Major Trauma Center.

OBJECTIVES: The aim of this study was to report experience of a major trauma center utilizing circular frames as definitive fixation in patients sustaining Gustilo-Anderson 3B open tibial fractures. DESIGN: A prospectively maintained database was retrospectively interrogated. SETTING: Single major trauma center in the United Kingdom. PATIENT SELECTION CRITERIA: All patients over the age of 16 sustaining an open tibial fracture with initial debridement performed at the study center. All patients also received orthoplastic care for a soft tissue defect (via skeletal deformation or a soft tissue cover procedure) and subsequent definitive management using an Ilizarov ring fixator. Patients who received primary debridement at another center, had preexisting infection, sustained a periarticular fracture, or those who did not afford a minimum of 12-month follow-up were excluded. Case notes and radiographs were reviewed to collate patient demographics and injury factors. OUTCOME MEASURES AND COMPARISONS: The primary outcome of interest was deep infection rate with secondary outcomes including time to union and secondary interventions. RESULTS: Two hundred twenty-five patients met inclusion criteria. Mean age was 43.2 year old, with 72% males, 34% smokers, and 3% diabetics. Total duration of frame management averaged 6.4 months (SD 7.7). Eight (3.5%) patients developed a deep infection and 41 (20%) exhibited signs of a pin site infection. Seventy-nine (35.1%) patients had a secondary intervention, of which 8 comprised debridement of deep infection, 29 bony procedures, 8 soft tissue operations, 30 frame adjustments, and 4 patients requiring a combination of soft tissue and bony procedures. Bony union was achieved in 221 cases (98.2%), 195 (86.7%) achieved union in a single frame without the need for secondary intervention, 26 required frame adjustments to achieve union. Autologous bone grafts were used in 10 cases. CONCLUSIONS: Orthoplastic care including circular frame fixation for Gustilo-Anderson-3B fractures of the tibia resulted in a low rate of deep infection (3.5%) and achieved excellent union rates (98.2%). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Clinical outcome of wedged glenoid reconstruction in anatomic total shoulder arthroplasty for osteoarthritic retroverted glenoid: a minimum 2-year follow-up.

Background: Glenoid retroversion and humeral head subluxation is a progressive disorder due to abnormal force coupling and increased contact force. In situ placement of anatomic total shoulder arthroplasty (TSA) components in this scenario results in edge loading, progressive subluxation, and early failure. Wedged glenoid components have been demonstrated to improve glenohumeral alignment, but have not been correlated with mid-term clinical outcomes. Methods: Patients undergoing TSA using a wedged all-polyethylene glenoid component for retroverted glenoid deformity were identified from a prospectively maintained database. Preoperative planning computed tomography was routinely performed and compared to postoperative correction on radiographic evaluation. Evidence of loosening was correlated to prospectively collect clinical outcome using patient-reported outcome measures. A matched group of neutrally aligned glenohumeral joints undergoing anatomic TSA was used to compare improvement in clinical outcomes. Results: Over a 5-year period, 17 patients with mean age 60 (range 43-81, standard deviation 10.5) were identified with a mean preoperative neoglenoid retroversion of 16.7° (standard deviation 4.5). At a mean follow-up of 43.8 months (range 27-60), no revision surgeries were undertaken. Improvement in the Oxford Shoulder Score was 18 points (P < .0001). The mean improvement was compared to a matched control group demonstrating a comparable magnitude of improvement of 20.4 points. Conclusion: Wedged polyethylene components for Walch B2-type glenoids in TSA yield acceptable correction of the joint line, excellent clinical outcomes, and survivorship is maintained in the short term. The clinical and radiological outcome demonstrated similar improvement to that seen in A type deformities.

Proceedings of the United Kingdom Periprosthetic Joint Infection Meeting 2022: Combined and Arthroplasty Sessions.

Considerable variation in practice exists in the prevention, diagnosis, and treatment of periprosthetic joint infection (PJI), which is a devastating complication for patients and surgeons. The consensus principle has been increasingly embraced by the orthopaedic community to help guide practice, especially where high-level evidence remains unavailable. The third United Kingdom Periprosthetic Joint Infection (UK PJI) Meeting was held in Glasgow on April 1, 2022, with more than 180 delegates in attendance, representing orthopaedics, microbiology, infectious diseases, plastic surgery, anesthetics, and allied health professions, including pharmacy and arthroplasty nurses. The meeting comprised a combined session for all delegates, and separate breakout sessions for arthroplasty and fracture-related infection. Consensus questions for each session were prepared in advance by the UK PJI working group, based upon topics that were proposed at previous UK PJI Meetings, and delegates participated in an anonymized electronic voting process. We present the findings of the combined and arthroplasty sessions of the meeting in this article, and each consensus topic is discussed in relation to the contemporary literature.

Guanine-containing ssDNA and RNA induce dimeric and tetrameric structural forms of SAMHD1.

The dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNA and telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish in cryo-EM and biochemical studies that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with ∼20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.

Guanine-containing ssDNA and RNA induce dimeric and tetrameric SAMHD1 in cryo-EM and binding studies.

The dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNA, and telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with ~20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.

Clinical and radiologic outcomes of Lima ProMade custom 3D-printed glenoid components in primary and revision reverse total shoulder arthroplasty with severe glenoid bone loss: a minimum 2-year follow-up.

BACKGROUND: The purpose of this study is to report the clinical and radiologic outcomes of patients undergoing primary or revision reverse total shoulder arthroplasty using custom 3D-printed components to manage severe glenoid bone loss with a minimum of 2-year follow-up. METHODS: Following ethical approval, patients were identified and invited to participate. Inclusion criteria were (1) severe glenoid bone loss necessitating the need for custom implants and (2) patients with definitive glenoid and humeral components implanted more than 2 years prior. Included patients underwent clinical assessment using the Oxford Shoulder Score (OSS), Constant-Murley score, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), and the quick Disabilities of the Arm, Shoulder, and Hand questionnaire (QuickDASH). Radiographic assessment included anteroposterior and axial projections. Patients were invited to attend a computed tomography (CT) scan to confirm osseointegration. Statistical analysis used descriptive statistics (mean and standard deviation [SD]) and paired t test for parametric data. RESULTS: Eleven patients declined to participate. Five patients were deceased prior to study commencement, leaving 42 remaining patients in this analysis. Three patients had revision surgery before the 2-year follow-up; of these, 2 retained their custom glenoid components. Mean follow-up was 31.6 months from surgery (range 24-52 months). All 4 scores improved: OSS from a mean 15 (SD 8.4) to 36 (SD 12) (P < .001), Constant-Murley score from a mean 15 (SD 11.2) to 52 (SD 20.1) (P < .001), QuickDASH from a mean 70 (SD 21) to 31 (SD 24.8) (P = .004), and the ASES score from a mean 22 (SD 17.8) to 71 (SD 23.3) (P = .007). Radiologic evaluation demonstrated good osseointegration in all but 1 included patient. CONCLUSION: The utility of custom 3D-printed components for managing severe glenoid bone loss in primary and revision reverse total shoulder arthroplasty yields significant clinical improvements in this complex cohort. Large complex glenoid bone defects can be managed successfully with custom 3D-printed glenoid components.

Pin-site Infection: A Systematic Review of Prevention Strategies.

Introduction: Circular frame fixation remains a key tool in the armamentarium of the limb reconstruction surgeon. One of the key drawbacks is the onset of pin-site infection (PSI). As a result of limited evidence and consensus of PSI prevention, a wide variation in practice remains. Aim: The principal aim of this review is to synthesise primary research concerning all aspects of treatment regarded as relevant to PSI in frame constructs. Materials and methods: Comparative studies until week 26, 2021, were included in the trial. Studies were included that concerned patients undergoing management of a musculoskeletal condition in which pin-site care is necessary for over 4 weeks. Results: Eighteen studies over a 13-year period were captured using the search strategy. Sulphadiazine and hydrogen peroxide cleansing was found to reduce PSI, with the use of low-energy fine wires and hydroxyapatite (HA)-coated pins also associated with lower infection rate. The remainder of studies found no significant improvement across interventions. Conclusion: There is no superiority between weekly and daily care. Low-energy pin-insertion technique had lower rates of infection. Sulphadiazine has positive results as a pin-care solution, but more research is necessary to determine the most effective care regime. Current literature is limited by absence of established definitions and by a lack of studies addressing all aspects of care relevant to PSI. How to cite this article: Shields DW, Iliadis AD, Kelly E, et al. Pin-site Infection: A Systematic Review of Prevention Strategies. Strategies Trauma Limb Reconstr 2022;17(2):93-104.

Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation and ssDNA binding kinetics.

SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator and dNTP activators/substrates. In addition, the inactive monomeric and dimeric forms of the enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated by CDK1 and CDK2 at its C-terminal threonine 592 (pSAMHD1), localizing the enzyme to stalled replication forks (RFs) to promote their restart. Although phosphorylation has only a small effect on the dNTPase activity and ssDNA binding affinity of SAMHD1, perturbation of the native T592 by phosphorylation decreased the thermal stability of tetrameric SAMHD1 and accelerated tetramer dissociation in the absence and presence of ssDNA (∼15-fold). In addition, we found that ssDNA binds competitively with GTP to the A1 site. A full-length SAMHD1 cryo-EM structure revealed substantial dynamics in the C-terminal domain (which contains T592), which could be modulated by phosphorylation. We propose that T592 phosphorylation increases tetramer dynamics and allows invasion of ssDNA into the A1 site and the previously characterized DNA binding surface at the dimer-dimer interface. These features are consistent with rapid and regiospecific inactivation of pSAMHD1 dNTPase at RFs or other sites of free ssDNA in cells.

Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours.

BACKGROUND: Childhood cancer is still a leading cause of death around the world. To improve outcomes, there is an urgent need for tailored treatment. The systematic evaluation of existing preclinical data can provide an overview of what is known and identify gaps in the current knowledge. Here, we applied the target actionability review (TAR) methodology to assess the strength and weaknesses of available scientific literature on CDK4/6 as a therapeutic target in paediatric solid and brain tumours by structured critical appraisal. METHODS: Using relevant search terms in PubMed, a list of original publications investigating CDK4/6 in paediatric solid tumour types was identified based on relevancy criteria. Each publication was annotated for the tumour type and categorised into separate proof-of-concept (PoC) data modules. Based on rubrics, quality and experimental outcomes were scored independently by two reviewers. A third reviewer evaluated and adjudicated score discrepancies. Scores for each PoC module were averaged for each tumour type and visualised in a heatmap matrix in the publicly available R2 data portal. RESULTS AND CONCLUSIONS: This CDK4/6 TAR, generated by analysis of 151 data entries from 71 publications, showed frequent genomic aberrations of CDK4/6 in rhabdomyosarcoma, osteosarcoma, high-grade glioma, medulloblastoma, and neuroblastoma. However, a clear correlation between CDK4/6 aberrations and compound efficacy is not coming forth from the literature. Our analysis indicates that several paediatric indications would need (further) preclinical evaluation to allow for better recommendations, especially regarding the dependence of tumours on CDK4/6, predictive biomarkers, resistance mechanisms, and combination strategies. Nevertheless, our TAR heatmap provides support for the relevance of CDK4/6 inhibition in Ewing sarcoma, medulloblastoma, malignant peripheral nerve sheath tumour and to a lesser extent neuroblastoma, rhabdomyosarcoma, rhabdoid tumour and high-grade glioma. The interactive heatmap is accessible through R2 [r2platform.com/TAR/CDK4_6].

Autologous versus synthetic bone grafts for the surgical management of tibial plateau fractures: a systematic review and meta-analysis of randomized controlled trials.

AIMS: Our objective was to conduct a systematic review and meta-analysis, to establish whether differences arise in clinical outcomes between autologous and synthetic bone grafts in the operative management of tibial plateau fractures. METHODS: A structured search of MEDLINE, EMBASE, the online archives of Bone & Joint Publishing, and CENTRAL databases from inception until 28 July 2021 was performed. Randomized, controlled, clinical trials that compared autologous and synthetic bone grafts in tibial plateau fractures were included. Preclinical studies, clinical studies in paediatric patients, pathological fractures, fracture nonunion, or chondral defects were excluded. Outcome data were assessed using the Risk of Bias 2 (ROB2) framework and synthesized in random-effect meta-analysis. The Preferred Reported Items for Systematic Review and Meta-Analyses guidance was followed throughout. RESULTS: Six studies involving 353 fractures were identified from 3,078 records. Following ROB2 assessment, five studies (representing 338 fractures) were appropriate for meta-analysis. Primary outcomes showed non-significant reductions in articular depression at immediate postoperative (mean difference -0.45 mm, p = 0.25, 95%confidence interval (CI) -1.21 to 0.31, I2 = 0%) and long-term (> six months, standard mean difference -0.56, p = 0.09, 95% CI -1.20 to 0.08, I2 = 73%) follow-up in synthetic bone grafts. Secondary outcomes included mechanical alignment, limb functionality, and defect site pain at long-term follow-up, perioperative blood loss, duration of surgery, occurrence of surgical site infections, and secondary surgery. Mean blood loss was lower (90.08 ml, p < 0.001, 95% CI 41.49 to 138.67) and surgery was shorter (16.17 minutes, p = 0.04, 95% CI 0.39 to 31.94) in synthetic treatment groups. All other secondary measures were statistically comparable. CONCLUSION: All studies reported similar methodologies and patient populations; however, imprecision may have arisen through performance variation. These findings supersede previous literature and indicate that, despite perceived biological advantages, autologous bone grafting does not demonstrate superiority to synthetic grafts. When selecting a void filler, surgeons should consider patient comorbidity, environmental and societal factors in provision, and perioperative and postoperative care provision. Cite this article: Bone Jt Open 2022;3(3):218-228.

GARDE: a standards-based clinical decision support platform for identifying population health management cohorts.

Population health management (PHM) is an important approach to promote wellness and deliver health care to targeted individuals who meet criteria for preventive measures or treatment. A critical component for any PHM program is a data analytics platform that can target those eligible individuals. OBJECTIVE: The aim of this study was to design and implement a scalable standards-based clinical decision support (CDS) approach to identify patient cohorts for PHM and maximize opportunities for multi-site dissemination. MATERIALS AND METHODS: An architecture was established to support bidirectional data exchanges between heterogeneous electronic health record (EHR) data sources, PHM systems, and CDS components. HL7 Fast Healthcare Interoperability Resources and CDS Hooks were used to facilitate interoperability and dissemination. The approach was validated by deploying the platform at multiple sites to identify patients who meet the criteria for genetic evaluation of familial cancer. RESULTS: The Genetic Cancer Risk Detector (GARDE) platform was created and is comprised of four components: (1) an open-source CDS Hooks server for computing patient eligibility for PHM cohorts, (2) an open-source Population Coordinator that processes GARDE requests and communicates results to a PHM system, (3) an EHR Patient Data Repository, and (4) EHR PHM Tools to manage patients and perform outreach functions. Site-specific deployments were performed on onsite virtual machines and cloud-based Amazon Web Services. DISCUSSION: GARDE's component architecture establishes generalizable standards-based methods for computing PHM cohorts. Replicating deployments using one of the established deployment methods requires minimal local customization. Most of the deployment effort was related to obtaining site-specific information technology governance approvals.

A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas.

Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose-regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD. Results: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9-67.2). Conclusions: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met. Trial Registration: Pfizer Inc (NCT02501902). Significance: In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.

A Systematic Review of the Utility of Intraoperative Navigation During Total Shoulder Arthroplasty.

Total shoulder arthroplasty (TSA) has been demonstrated to successfully recover function to shoulders impaired by arthrosis and rotator cuff insufficiency. Long-term survival depends on the correct positioning of glenoid components and secure bone fixation. Computed tomography (CT)-based intraoperative navigation has proven to be an effective technique for successful TSA procedures. This paper presents a review of CT-based intraoperative navigation considering its advantages and disadvantages. The crucial factors that contribute to the success of this technique are glenoid component positioning, operative duration, and screw selection, which are detailed in this review.

Closed incision negative pressure wound therapy versus conventional dressings following soft-tissue sarcoma excision: a prospective, randomized controlled trial.

AIMS: The primary objective of this study was to compare the postoperative infection rate between negative pressure wound therapy (NPWT) and conventional dressings for closed incisions following soft-tissue sarcoma (STS) surgery. Secondary objectives were to compare rates of adverse wound events and functional scores. METHODS: In this prospective, single-centre, randomized controlled trial (RCT), patients were randomized to either NPWT or conventional sterile occlusive dressings. A total of 17 patients, with a mean age of 54 years (21 to 81), were successfully recruited and none were lost to follow-up. Wound reviews were undertaken to identify any surgical site infection (SSI) or adverse wound events within 30 days. The Toronto Extremity Salvage Score (TESS) and Musculoskeletal Tumor Society (MSTS) score were recorded as patient-reported outcome measures (PROMs). RESULTS: There were two out of seven patients in the control group (28.6%), and two out of ten patients in the intervention group (20%) who were diagnosed with a SSI (p > 0.999), while one additional adverse wound event was identified in the control group (p = 0.593). No significant differences in PROMs were identified between the groups at either 30 days (TESS, p = 0.987; MSTS, p = 0.951) or six-month (TESS, p = 0.400) follow-up. However, neoadjuvant radiotherapy was significantly associated with a SSI within 30 days of surgery, across all patients (p = 0.029). The mean preoperative modified Glasgow Prognostic Score (mGPS) was also significantly higher among patients who developed a postoperative adverse wound event (p = 0.028), including a SSI (p = 0.008), across both groups. CONCLUSION: This is the first RCT comparing NPWT with conventional dressings following musculoskeletal tumour surgery. Postoperative wound complications are common in this group of patients and we observed an overall SSI rate of 23.5%. We propose proceeding to a multicentre trial, which will help more clearly define the role of closed incision NPWT in STS surgery. Cite this article: Bone Jt Open 2021;2(12):1049-1056.

Establishing a multidisciplinary initiative for interoperable electronic health record innovations at an academic medical center.

OBJECTIVE: To establish an enterprise initiative for improving health and health care through interoperable electronic health record (EHR) innovations. MATERIALS AND METHODS: We developed a unifying mission and vision, established multidisciplinary governance, and formulated a strategic plan. Key elements of our strategy include establishing a world-class team; creating shared infrastructure to support individual innovations; developing and implementing innovations with high anticipated impact and a clear path to adoption; incorporating best practices such as the use of Fast Healthcare Interoperability Resources (FHIR) and related interoperability standards; and maximizing synergies across research and operations and with partner organizations. RESULTS: University of Utah Health launched the ReImagine EHR initiative in 2016. Supportive infrastructure developed by the initiative include various FHIR-related tooling and a systematic evaluation framework. More than 10 EHR-integrated digital innovations have been implemented to support preventive care, shared decision-making, chronic disease management, and acute clinical care. Initial evaluations of these innovations have demonstrated positive impact on user satisfaction, provider efficiency, and compliance with evidence-based guidelines. Return on investment has included improvements in care; over $35 million in external grant funding; commercial opportunities; and increased ability to adapt to a changing healthcare landscape. DISCUSSION: Key lessons learned include the value of investing in digital innovation initiatives leveraging FHIR; the importance of supportive infrastructure for accelerating innovation; and the critical role of user-centered design, implementation science, and evaluation. CONCLUSION: EHR-integrated digital innovation initiatives can be key assets for enhancing the EHR user experience, improving patient care, and reducing provider burnout.

International Consensus on Minimum Preclinical Testing Requirements for the Development of Innovative Therapies For Children and Adolescents with Cancer.

Cancer remains the leading cause of disease-related death in children. For the many children who experience relapses of their malignant solid tumors, usually after very intensive first-line therapy, curative treatment options are scarce. Preclinical drug testing to identify promising treatment elements that match the molecular make-up of the tumor is hampered by the fact that (i) molecular genetic data on pediatric solid tumors from relapsed patients and thus our understanding of tumor evolution and therapy resistance are very limited to date and (ii) for many of the high-risk entities, no appropriate and molecularly well-characterized patient-derived models and/or genetic mouse models are currently available. However, recent regulatory changes enacted by the European Medicines Agency (class waiver changes) and the maturation of the RACE for Children act with the FDA, will require a significant increase in preclinical pediatric cancer research and clinical development must occur. We detail the outcome of a pediatric cancer international multistakeholder meeting whose output aims at defining an international consensus on minimum preclinical testing requirements for the development of innovative therapies for children and adolescents with cancer. Recommendations based on the experience of the NCI funded PPTP/C (www.ncipptc.org) and the EU funded ITCC-P4 public private partnership (www.itccp4.eu) are provided for the use of cell-based and mouse models for pediatric solid malignancies, as well as guidance on the scope and content of preclinical proof-of-concept data packages to inform clinical development dependent on clinical urgency. These recommendations can serve as a minimal guidance necessary to jumpstart preclinical pediatric research globally.

Leveraging Artificial Intelligence to Improve Chronic Disease Care: Methods and Application to Pharmacotherapy Decision Support for Type-2 Diabetes Mellitus.

OBJECTIVES: Artificial intelligence (AI), including predictive analytics, has great potential to improve the care of common chronic conditions with high morbidity and mortality. However, there are still many challenges to achieving this vision. The goal of this project was to develop and apply methods for enhancing chronic disease care using AI. METHODS: Using a dataset of 27,904 patients with diabetes, an analytical method was developed and validated for generating a treatment pathway graph which consists of models that predict the likelihood of alternate treatment strategies achieving care goals. An AI-driven clinical decision support system (CDSS) integrated with the electronic health record (EHR) was developed by encapsulating the prediction models in an OpenCDS Web service module and delivering the model outputs through a SMART on FHIR (Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources) web-based dashboard. This CDSS enables clinicians and patients to review relevant patient parameters, select treatment goals, and review alternate treatment strategies based on prediction results. RESULTS: The proposed analytical method outperformed previous machine-learning algorithms on prediction accuracy. The CDSS was successfully integrated with the Epic EHR at the University of Utah. CONCLUSION: A predictive analytics-based CDSS was developed and successfully integrated with the EHR through standards-based interoperability frameworks. The approach used could potentially be applied to many other chronic conditions to bring AI-driven CDSS to the point of care.