Discussions With End Users to Inform the Vision for a Shared Care Record in Ontario: Qualitative Interview Study.

BACKGROUND: Improving the health outcomes of populations of individuals through population health management requires the use of electronic health records that can exchange real-time digital information using an accurate and complete shared care record that is accessible to health care providers, services, and patients. OBJECTIVE: The aims of this study were to understand end users' (health care providers) experiences, attitudes, and insights using current electronic health records; their expectations of what is required to establish a shared care record; and how they anticipate adapting to the use of a shared care record in daily practice. This work is the result of a quality improvement initiative deemed not to require ethics approval according to the Western research ethics board checklist. METHODS: Clinicians were contacted using voluntary response sampling and interviewed via Zoom (Zoom Video Communications) between June 2022 and July 2022. The participants were from various health care sectors and at various stages of career development. RESULTS: Overall, adaptation to the use of a shared care record was viewed positively by health care providers, highlighting the benefits of a centralized, shared, and accessible location for real-time data, promoting patient continuity of care. The main concerns included the privacy, confidentiality, and security of the record along with patients' ability to interpret their own medical information found in a patient portal. The resources requested by end users included multifaceted ongoing training on the use of a shared care record. CONCLUSIONS: This study provides practical findings that will help emphasize factors that facilitate clinicians' practical use and process of adaptation to the use of a shared care record.

Sterile surgical supply waste identification using asynchronous analysis: Pediatric surgery QI pilot.

Background: The operating room (OR) is a major cost and revenue center for a hospital. One of the few modifiable costs in the OR is single-use, sterile surgical supplies (SUSSS). If SUSSS are opened on the scrub table and not used, then they are wasted. High-fidelity SUSSS usage data is important to strategically implement solutions to reduce waste of SUSSS in the OR. OR waste reduction may decrease health systems' carbon footprints and reduce spending. Methods: A convenience sample of general pediatric surgical cases was observed in summer 2021. HIPAA-free images of the surgical scrub table were acquired every 2 s with minimal impact on pediatric OR workflow. These images were asynchronously analyzed to obtain SUSSS usage data for each case. Results: Image data from three pediatric surgeons performing 41 pediatric surgeries was reviewed. The median cost of unused SUSSS was $13.10 (IQR = $2.73-$47.97) with a range of $0.07 to $489.08 wasted in a single surgery. The mean number of items wasted was 9.3 ± 6.4. The most frequently wasted items were sutures, syringes, towels, paper rulers, and specimen cups. The most expensive sources of waste were laparoscopic trocars, sutures, insufflation needles, drapes, and guidewires. Conclusions: SUSSS that were discarded without being used were successfully identified through the asynchronous analysis of HIPAA-free OR scrub table image data. This may be an opportunity to identify SUSSS waste efficiently without an observer in the OR.

Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.

Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.

Clinical implications of preoperative echocardiographic findings on cardiovascular outcomes following vascular surgery: An observational trial.

INTRODUCTION: Peripheral artery disease and cardiac disease are often comorbid conditions. Echocardiography is a diagnostic tool that can be performed preoperatively to risk stratify patients by a functional cardiac test. We hypothesized that ventricular dysfunction and valvular lesions were associated with an increased incidence of expanded major adverse cardiac events (Expanded MACE). METHODS AND MATERIALS: Retrospective cohort study from 2011 to 2020 including all patients from a major academic center who had vascular surgery and an echocardiographic study within two years of the index procedure. RESULTS: 813 patients were included in the study; a majority had a history of smoking (86%), an ASA score of 3 (65%), and were male (68%). Carotid endarterectomy was the most common surgery (24%) and the least common surgery was open abdominal aortic aneurysm repair (5%). We found no significant association between the echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction, or valvular lesions and the postoperative development of Expanded MACE. CONCLUSIONS: The preoperative echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction and moderate to severe valvular lesions were not predictive of an increased incidence of postoperative Expanded MACE. We identified a significant association between RV dysfunction and post-operative dialysis that should be interpreted carefully due to the small number of outcomes. The transition from open to endovascular surgery and advances in perioperative management may have led to improved cardiovascular outcomes. TRIAL REGISTRATION: Trial Registration: NCT04836702 (clinicaltrials.gov). https://www.google.com/search?client=firefox-b-d&q=NCT04836702.

CRISPR screening identifies T cell-intrinsic regulators of CD3-bispecific antibody responses.

CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased in vitro CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation. These analyses revealed that CD8+ T cells are dependent on CD4+ T cell-derived signaling factors in order to achieve sustained killing in vitro. Moreover, the mammalian target of rapamycin (mTOR) pathway and several other candidate genes were identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation, highlighting promising approaches to enhancing the utility of these potent therapeutics.

Surgeons' perspectives on operating room waste: Multicenter survey.

BACKGROUND: Waste is endemic in the U.S. health care system. Operating rooms are a source of significant solid waste. Surgeons are integral to many decisions in the operating room. METHOD: Online survey of surgeons at 2 major academic centers in the United States assessing perspectives on intraoperative waste and willingness to work to actively reduce intraoperative waste. RESULTS: We received responses from 219 surgeons: 90% agreed or strongly agreed that waste of sterile surgical items is an issue, and 95% agreed or strongly agreed to a willingness to change the operating room workflow to reduce waste. Surgeons estimated 26% of single-use, sterile supplies opened for surgery were unused at the end of the case. The barriers to waste reduction cited most frequently were: (1) lack of awareness of waste, (2) lack of concern for waste, and (3) lack of time to address the waste. CONCLUSION: Surgeons understand there is significant waste in the operating room and are willing to change their workflow to reduce waste. Changes in operating room practices that reduce waste will be beneficial to health systems' finances and their efforts to improve population health through a reduction in consumption and pollution. Efforts should be directed toward reducing operating room waste with an initial focus on the elimination of unnecessary waste of sterile surgical supplies. Further work is needed to determine the precise sources of perioperative waste and what initiatives can be implemented to reduce this burden while maintaining high-value patient care.

Self-perception and self-representation preference between 2-dimensional and 3-dimensional facial reconstructions among dentists, dental students, and laypersons.

STATEMENT OF PROBLEM: Computer-aided design (CAD) software can merge the intraoral digital scan with patient photographs or 3-dimensional (3D) facial reconstructions for treatment planning purposes. However, whether an individual perceives a 3D facial reconstruction as a better self-representation compared with a 2-dimensional (2D) photograph is unclear. PURPOSE: The purpose of this observational study was to compare self-perception ratings and self-representation preference of the 2D and 3D facial reconstructions among laypersons, dental students, and dentists. MATERIAL AND METHODS: Three populations participated in the study: laypersons, dental students, and dentists (n=20, N=60). Facial and intraoral features were digitized by using facial and intraoral scanners, and a complete-face smile photograph was obtained. Two simulations were performed for each participant: 2D (2D group) and 3D (3D group) reconstructions. In the 2D group, a maxillary digital veneer waxing from the left to the right second premolars was produced without altering the shape, position, or length of the involved teeth. A software program (Dental Systems; 3Shape A/S) was used to merge the maxillary digital waxing with the full-face smile photograph. One image was obtained for each participant. In the 3D group, a dental software program (Matera 2.4; exocad GmbH) was used to merge the intraoral and facial scans. Subsequently, 1 video of a 180-degree rotation of each 3D superimposition was obtained. Participants evaluated both superimpositions on a scale from 1 (least esthetically pleasing) to 6 (most esthetically pleasing). Finally, participants were asked which superimposition they preferred for a potential treatment outcome representation. RESULTS: All the ratings were esthetically pleasing (median group rating 5 or 6). When analyzed solely for differences across occupation groups, ratings for the 2D representation varied significantly across populations (Kruskal-Wallis chi-squared=13.241, df=2, P=.001), but the ratings for the 3D representation did not exhibit statistically significant differences (Kruskal-Wallis chi-squared=4.3756, df=2, P=.112). Ordinal logistic regression revealed no significant main effects but a significant effect of the population×image-type interaction on the esthetic rating. All participants felt well-represented in both the 2D and 3D representations. Also, 40% of dentists, 55% of dental students, and 50% of laypersons preferred the 3D reconstructions. Sex and occupation in general had no effect on the ratings. However, students tended to give higher ratings to the 3D representations of themselves. CONCLUSIONS: There is no evidence based on the current study that 2D and 3D representations were perceived differently, but representation preferences may depend on a person's occupation. When individuals rated 3D visualization higher than 2D visualization, they strongly preferred the 3D visualization for representing the treatment outcome.

Confronting complexity and supporting transformation through health systems mapping: a case study.

INTRODUCTION: Health systems are a complex web of interacting and interconnected parts; introducing an intervention, or the allocation of resources, in one sector can have effects across other sectors and impact the entire system. A prerequisite for effective health system reorganisation or transformation is a broad and common understanding of the current system amongst stakeholders and innovators. Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are common chronic diseases with high health care costs that require an integrated health system to effectively treat. STUDY DESCRIPTION: This case study documents the first phase of system transformation at a regional level in Ontario, Canada. In this first phase, visual representations of the health system in its current state were developed using a collaborative co-creation approach, and a focus on COPD and HF. Multiple methods were used including focus groups, open-ended questionnaires, and document review, to develop a series of graphical and visual representations; a health care ecosystem map. RESULTS: The ecosystem map identified key sectoral components, inter-component interactions, and care requirements for patients with COPD and HF and inventoried current programs and services available to deliver this care. Main findings identified that independent system-wide navigation for this vulnerable patient group is limited, primary care is central to the accessibility of nearly half of the identified care elements, and resources are not equitably distributed. The health care ecosystem mapping helped to identify care gaps and illustrates the need to resource the primary care provider and the patient with system navigation resources and interdisciplinary team care. CONCLUSION: The co-created health care ecosystem map brought a collective understanding of the health care system as it applies to COPD and HF. The map provides a blueprint that can be adapted to other disease states and health systems. Future transformation will build on this foundational work, continuing the robust interdisciplinary co-creation strategies, exploring predictive health system modelling and identifying areas for integration.

Variation in Patient-Reported Advance Care Preferences in the Preoperative Setting.

BACKGROUND: High-quality shared decision-making for patients undergoing elective surgical procedures includes eliciting patient goals and treatment preferences. This is particularly important, should complications occur and life-sustaining therapies be considered. Our objective was to determine the preoperative care preferences of older higher-risk patients undergoing elective procedures and to determine any factors associated with a preference for limitations to life-sustaining treatments. METHODS: Cross-sectional survey conducted between May and December 2018. Patients ≥55 years of age presenting for a preprocedural evaluation in a high-risk anesthesia clinic were queried on their desire for life-sustaining treatments (cardiopulmonary resuscitation, mechanical ventilation, dialysis, and artificial nutrition) as well as tolerance for declines in health states (physical disability, cognitive disability, and daily severe pain). RESULTS: One hundred patients completed the survey. The median patient age was 68. Most patients were Caucasian (87%) and had an American Society of Anesthesiologists (ASA) score of III (88%). The majority of patients (89%) desired cardiopulmonary resuscitation. However, most patients would not accept mechanical ventilation, dialysis, or artificial nutrition for an indefinite period of time. Similarly, most patients (67%-81%) indicated they would not desire treatments to sustain life in the event of permanent physical disability, cognitive disability, or daily severe pain. CONCLUSIONS: Among older, higher-risk patients presenting for elective procedures, most patients chose limitations to life-sustaining treatments. This work highlights the need for an in-depth goals of care discussion and establishment of advance care preferences before a procedure or operative intervention.

Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling.

PURPOSE: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development. EXPERIMENTAL DESIGN: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti-programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. RESULTS: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient-derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti-PD-1 antibody. CONCLUSIONS: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Development of Anti-CD32b Antibodies with Enhanced Fc Function for the Treatment of B and Plasma Cell Malignancies.

The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcγRIIIa on immune effector cells. The NVS32b mAbs selectively target CD32b+ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32b+ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc-binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b+ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32b+ malignant cells.

Hippocampal Volume in Psychiatric Diagnoses: Should Psychiatry Biomarker Research Account for Comorbidities?

BACKGROUND: Many research papers claim that patients with specific psychiatric disorders (major depressive disorder, posttraumatic stress disorder, borderline personality disorder, alcohol use disorder, and others) have smaller hippocampi, but most of those reports compared patients to healthy controls. We hypothesized that if psychiatrically matched controls (psychiatric control, matched for demographics and psychiatric comorbidities) were used, much of the biomarker literature in psychiatric research would not replicate. We used hippocampus and amygdala volume only as examples, as these are very commonly replicated results in psychiatry biomarker research. We propose that psychiatry biomarker research could benefit from using psychiatric controls, as the use of healthy controls results in data that are not disorder-specific. METHOD: Hippocampus/amygdala volumes were compared between major depressive disorder, sex-/age-/race-matched healthy control, and psychiatric control (N = 126/group). Similar comparisons were performed for posttraumatic stress disorder (N = 67), borderline personality disorder (N = 111), and alcohol use disorder (N = 136). RESULTS: Major depressive disorder patients had smaller left (p = 8.79 × 10-3) and right (p = 3.13 × 10-3) hippocampal volumes than healthy control. Posttraumatic stress disorder had smaller left (p = 0.018) and right (p = 8.64 × 10-4) hippocampi than healthy control. Borderline personality disorder had smaller right hippocampus (p = 7.90 × 10-3) and amygdala (p = 1.49 × 10-3) than healthy control. Alcohol use disorder had smaller right hippocampus (p = 0.034) and amygdala (p = .024) than healthy control. No differences were found between any of the four diagnostic groups and psychiatric control. CONCLUSION: When psychiatric controls were used, there was no difference in hippocampal or amygdalar volume between any of the diagnoses studied and controls. This strategy (keeping all possible relevant variables matched between experimental groups) has been used to advance science for hundreds of years, and we propose should also be used in biomarker psychiatry research.

Layperson and Dental Professional Perception When Evaluating Their Own Virtually 2D or 3D Simulated Esthetic Discrepancies.

PURPOSE: To analyze the perceptions of laypersons, dental students, and dentists regarding disparities of the maxillary dental midline and the occlusal plane (OP) when analyzing their own 2D or 3D clinical simulation. MATERIAL AND METHODS: 20 participants per group volunteered (N = 60). Intraoral and facial scans, and a photograph were obtained from each participant. Two simulation groups were created: 2D and 3D groups, which were subdivided into two subgroups. In the first subgroup, the OP was modified by 1-degree increments without changing the maxillary midline. In the second subgroup, the OP was modified by the same increments, but the maxillary midline was altered to match the OP inclination. Participants were asked to rate the simulations on a 1-to-6 scale and a question survey. Ordinal logistic regression (OR) was used to analyze the ratings. RESULTS: Tilt of the OP had the strongest negative effect on the ratings which was further amplified by the dental midline inclination (OR = 0.122). Midline modification alone did not affect the ratings (OR = 0.744). 3D simulations had a stronger positive effect on the ratings compared to 2D simulations. For dental students, the positive rating effect of 3D simulations was similar to dentists. For laypersons, the positive rating effect of 3D simulations compared to the 2D simulations decreased relative to dentists. The survey revealed that 45% of the dentists, 80% of the students, and 50% of the laypersons preferred the 3D simulation. CONCLUSIONS: The type of dimensional representation affected the esthetic perception of all participants. 3D simulations obtained higher esthetic ratings for the same esthetic discrepancy than 2D simulations. However, all participants' ratings decreased with increased tilt of the OP and were further decreased with the inclination of the dental midline.

Additive manufacturing technologies for processing zirconia in dental applications.

OBJECTIVE: The objective of this narrative review was to summarize the current status and future perspectives of additive manufacturing (AM) technologies with a particular emphasis on manufacturing zirconia-based materials. AM technologies include vat photopolymerization, material jetting, material extrusion, selective laser sintering (SLS), and selective laser melting (SLM) technologies based on either powder bed fusion (PBF) technologies or direct energy deposition, or sheet lamination based on binder jetting technologies. MATERIALS AND METHODS: A comprehensive literature review was performed, specifically evaluating AM technologies assigned for processing zirconia. An electronic database search was performed using keywords and MeSH terms. The search was confined to full-text articles written in English and published in peer-reviewed journals between 1999 and 2018. RESULTS: A total of 62 articles were included in this review, of which 56 described the AM processes and 6 reported on AM applications in the field of dentistry. A broad diversity of literature exists regarding AM technologies for ceramic materials, which complicates the establishment of a classification system for the current AM technologies for zirconia. The variations in the composition of zirconia slurries or mixtures across different technologies often made it difficult to identify the proper nature of such information. Mechanical properties of printed zirconia materials utilizing different technologies were investigated through a wide range of tests. Overall, the review indicates that manufacturing zirconia using AM technologies could be achieved without issues, but mechanical properties appear to be poor compared with conventional manufacturing procedures. CONCLUSIONS: The results of this review indicate the necessity for further potential improvement in AM technologies for manufacturing zirconia reconstructions along with advances in material composition before zirconia could be considered as a material for standard care.

Intention to Return to Work after Stroke Following Rehabilitation in Ontario.

BACKGROUND.: Returning to work is important for many people following stroke. An estimate of the prevalence of people intending to return to work post-stroke would be helpful in planning services supporting work reintegration. PURPOSE.: This study examined the prevalence of intention to return to work after discharge among stroke rehabilitation inpatients. METHODS.: We performed secondary analysis of National Rehabilitation Reporting System data for all stroke rehabilitation inpatients across Ontario (2012-2017). Intention to return to work was examined by gender, age, and level of disability. FINDINGS.: Among 25,691 stroke rehabilitation inpatients, 4,668 (18.2%) were employed pre-stroke and 2,039 (43.7%) of them intended to return to work. Intention to return to work was somewhat higher among younger and middle-aged stroke survivors and those with mild disability. IMPLICATIONS.: Providers and planners should be aware that almost half of previously employed stroke-rehabilitation inpatients may be seeking services to assist with return to work.