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Tumour immune evasion presents a significant challenge to the effectiveness of cancer immunotherapies. Recent advances in high-throughput screening techniques have uncovered that loss of antigen presentation and cytokine signalling pathways are central mechanisms by which tumours evade T cell immunity. To uncover additional vulnerabilities in tumour cells beyond the well-recognized antigen presentation pathway, we conducted a genome-wide CRISPR/Cas9 screen to identify genes that mediate resistance to chimeric-antigen receptor (CAR)-T cells, which function independently of classical antigen presentation. Our study revealed that loss of core-binding factor subunit beta (CBFß) enhances tumour cell resistance to T cell killing, mediated through T cell-derived TNF. Mechanistically, RNA-sequencing and elemental analyses revealed that deletion of CBFß disrupts numerous pathways including those involved in zinc homoeostasis. Moreover, we demonstrated that modulation of cellular zinc, achieved by supplementation or chelation, significantly altered tumour cell susceptibility to TNF by regulating the levels of inhibitor of apoptosis proteins. Consistent with this, treatment of tumour cells with a membrane-permeable zinc chelator had no impact on tumour cell viability alone, but significantly increased tumour cell lysis by CD8+ T cells in a TNF-dependent but perforin-independent manner. These results underscore the crucial role of intracellular zinc in regulating tumour cell susceptibility to T cell-mediated killing, revealing a novel vulnerability in tumour cells that might be exploited for the development of future cancer immunotherapeutics.

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Virtually every professional society globally now endorses a plant-forward diet that is lower in fat and processed foods as key components of disease prevention and health promotion. It is characterized by whole grain foods, and predominantly made of fresh foods. With healthcare expenditures at record levels across the globe, implementing a treatment plan that has larger magnitude health improvements than nearly any known medicine, that is extremely inexpensive, and has the power to not only improve human health but also planetary health is critical. That plan is Food is Medicine (FIM) which will be explored in this manuscript.

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BACKGROUND: In Canada, primary care reforms led to the implementation of various team-based care models to improve access and provide more comprehensive care for patients. Despite these advances, ongoing challenges remain. The aim of this scoping review is to explore current understanding of the functioning of these care models as well as the contexts in which they have emerged and their impact on the population, providers and healthcare costs. METHODS: The Medline and CINAHL databases were consulted. To be included, team-based care models had to be co-located, involve a family physician, specify the other professionals included, and provide information about their organization, their relevance and their impact within a primary care context. Models based on inter-professional intervention programs were excluded. The organization and coordination of services, the emerging contexts and the impact on the population, providers and healthcare costs were analysed. RESULTS: A total of 5952 studies were screened after removing duplicates; 15 articles were selected for final analysis. There was considerable variation in the information available as well as the terms used to describe the models. They are operationalized in various ways, generally consistent with the Patient's Medical Home vision. Except for nurses, the inclusion of other types of professionals is variable and tends to be associated with the specific nature of the services offered. The models primarily focus on individuals with mental health conditions and chronic diseases. They appear to generally satisfy the expectations of the overarching framework of a high-performing team-based primary care model at patient and provider levels. However, economic factors are seldom integrated in their evaluations. CONCLUSIONS: The studies rarely provide an overarching view that permits an understanding of the specific contexts, service organization, their impacts, and the broader context of implementation, making it difficult to establish universal guidelines for the operationalization of effective models. Negotiating the inherent complexity associated with implementing models requires a collaborative approach between various stakeholders, including patients, to tailor the models to the specific needs and characteristics of populations in given areas, and reflection about the professionals to be included in delivering these services.

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BACKGROUND: The use of targeted advertisements on social media platforms (eg, Facebook and Instagram) has become increasingly popular for recruiting participants for online survey research. Many of these surveys offer monetary incentives for survey completion in the form of gift cards; however, little is known about whether the incentive amount impacts the cost, speed, and quality of data collection. OBJECTIVE: This experiment addresses this gap in the literature by examining how different incentives in paid advertising campaigns on Instagram for completing a 10-minute online survey influence the response rate, recruitment advertising cost, data quality, and length of data collection. METHODS: This experiment tested three incentive conditions using three Instagram campaigns that were each allocated a US $1400 budget to spend over a maximum of 4 days; ads targeted users aged 15-24 years in three nonadjacent designated market areas of similar size to avoid overlapping audiences. Four ad creatives were designed for each campaign; all ads featured the same images and text, but the incentive amount varied: no incentive, US $5 gift card, and US $15 gift card. All ads had a clickable link that directed users to an eligibility screener and a 10-minute online survey, if eligible. Each campaign ran for either the full allotted time (4 days) or until there were 150 total survey completes, prior to data quality checks for fraud. RESULTS: The US $15 incentive condition resulted in the quickest and cheapest data collection, requiring 17 hours and ad spending of US $338.64 to achieve 142 survey completes. The US $5 condition took more than twice as long (39 hours) and cost US $864.33 in ad spending to achieve 148 survey completes. The no-incentive condition ran for 60 hours, spending nearly the full budget (US $1398.23), and achieved only 24 survey completes. The US $15 and US $5 incentive conditions had similar levels of fraudulent respondents, whereas the no-incentive condition had no fraudulent respondents. The completion rate for the US $15 and US $5 incentive conditions were 93.4% (155/166) and 89.8% (149/166), respectively, while the completion rate for the no-incentive condition was 43.6% (24/55). CONCLUSIONS: Overall, we found that a higher incentive resulted in quicker data collection, less money spent on ads, and higher response rates, despite some fraudulent cases that had to be dropped from the sample. However, when considering the total incentive amounts in addition to the ad spending, a US $5 incentive appeared to be the most cost-effective data collection option. Other costs associated with running a campaign for a longer period should also be considered. A longer experiment is warranted to determine whether fraud varies over time across conditions.

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Despite numerous advances in basic understanding of cardiovascular disease pathophysiology, pharmacology, therapeutic procedures, and systems improvement, there hasn't been much decline in heart disease related mortality in the US since 2010. Hypertension and diet induced risk continue to be the leading causes of cardiovascular morbidity. Even with the excessive mortality associated with the COVID-19 pandemic, in 2020, heart disease remained the leading cause of death. Given the degree of disease burden, morbidity, and mortality, there is an urgent need to redirect medical professionals' focus towards prevention through simple and cost effective lifestyle strategies. However, current practice paradigm and financial compensation systems are mainly centered disease management and not health promotion. For example, the financial value placed on 3-10 min smoking cessation counseling (.24RVUs) is 47-fold lower than an elective PCI (11.21 RVUs). The medical community seems to be enamored with the latest and greatest technology, new devices, and surgical procedures. What if the greatest technology of all was simply the way we live every day? Perhaps when this notion is known by enough, we will switch to this lifestyle medicine technology to prevent disease in the first place.

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The burden of noncommunicable chronic diseases has relevant and negative consequences to persons, health care systems, and economies worldwide. Chronic diseases are the leading cause of disability and mortality and are responsible for 90% of health care expenditure. The most common chronic diseases are diabetes mellitus (DM), cardiovascular disease, and cerebrovascular disease (stroke and vascular cognitive impairment). Modifiable risk factors (MRFs) for these conditions include hypertension, hyperlipidemia, smoking, poor diet, and low-physical activity; with hypertension being the most prevalent MRF. Most MRFs can be successfully targeted through lifestyle medicine (LSM), which is a medical specialty that addresses the root causes of chronic diseases through its primary, secondary, and tertiary preventative approaches. Lifestyle medicine comprises 6 pillars (nutrition, physical activity, sleep health, stress reduction, social connections, and substance use) which through various behavioral approaches, focus on regular physical activity, healthy eating, good quality and quantity sleep, and meaningful social connections coupled with the reduction of stress and substance use. This paper will briefly review the evidence and promise of individual LSM pillars in addressing the underlying MRFs of DM, cardiovascular and cerebrovascular disease (specifically stroke and vascular cognitive impairment). Lifestyle medicine holds a great promise for comprehensive and much improved population health. However, the adoption of LSM at the societal scale requires a multifaceted approach and widespread integration would galvanize a paradigm shift to prevent, treat or reverse chronic diseases from the root causes and achieve health equity.

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Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long-lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination, there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study, we have examined the anti-Onchocerca activity of a range of existing FDA-approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against O. gutturosa adult male parasites using a concentration of 1.25 × 10-5 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50-99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate and rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti-Onchocerca drug candidates worthy of further investigation.

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OBJECTIVES: To assess the utility and performance of the large language model ChatGPT 4.0 regarding accuracy, completeness, and its potential as a time-saving tool for pathologists and laboratory directors. METHODS: A deidentified database of questions previously sent to pathology residents from health care providers was used as a source of general knowledge-type pathology questions. These questions were submitted to the large language model and the responses graded by subject matter experts in different pathology subspecialties. The grading criteria assessed accuracy, completeness, and the potential time savings for helping the pathologist craft the response. RESULTS: Overall, respondents thought that most of the answers would take less than 5 minutes of additional work to be used (85%). Accuracy and completeness for the 61 questions was high, with 98% of responses being at least "completely or mostly accurate" and 82% of responses "containing all relevant information." Of the respondents, 97% stated that the response would have "zero or near-zero potential for medical harm," and all thought the tool had potential to save time in constructing answers to health care providers' queries. Performance was similar in both Anatomic Pathology (AP) and Clinical Pathology (CP), with the only exception being some relevant information was excluded in 46% of AP answers vs only 10% in CP (P < .01). CONCLUSIONS: ChatGPT version 4.0 gave responses that were predominantly accurate and complete for general knowledge-type pathology questions. With further research and when reviewed by a pathologist or laboratorian, this could facilitate its use as a pathologist's aid in answering questions from health care providers.

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INTRODUCTION: Cardiac rehabilitation (CR) has proven to be beneficial for patients with heart failure (HF), potentially reducing morbidity and mortality while improving fitness and psychological outcomes. Intensive cardiac rehabilitation (ICR) represents an emerging form of CR that has demonstrated advantages for patients with various cardiovascular diseases. Nevertheless, the specific outcomes of ICR in patients with HF remain unknown. OBJECTIVES: The purpose of this study is to assess the effectiveness of ICR in patients with HF. METHODS: This retrospective study involved 12,950 patients who participated in ICR at 46 centers from January 2016 to December 2020. Patients were categorized into two groups: the HF group, comprising 1400 patients (11%), and the non-HF group, consisting of 11,550 patients (89%). The primary endpoints included the ICR completion rate, changes in body mass index (BMI), exercise minutes per week (EMW), and depression scores (CESD). A t-test was employed to compare variables between the two groups. RESULTS: The HF group comprises older patients, with 37% being females (compared to 44% in the non-HF group). The ICR completion rate was higher in the non-HF group. After ICR completion, adjusted analyses revealed that patients without HF demonstrated a greater improvement in BMI. There were no differences in fitness, as measured via EMW, or in depression scores, as measured via CESD, between the two groups. CONCLUSIONS: Despite the lower baseline functional status and psychosocial scores of HF patients compared to non-HF patients, patients with HF were able to attain similar or even better functional and psychosocial outcomes after ICR.

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Scholarly practice (SP) is considered a key competency of occupational therapy and physiotherapy. To date, the three sectors-education/research, practice, and policy/regulation-that support SP have been working relatively independently. The goals of this project were to (a) understand how representatives of the three sectors conceptualize SP; (b) define each sector's individual and collective roles in supporting SP; (c) identify factors influencing the enactment of SP and the specific needs of how best to support SP; and (d) co-develop goals and strategies to support SP across all sectors. We used interpretive description methodology. Consistent with an integrated knowledge translation approach, partners representing the three sectors across Canada recruited individuals from each sector, developed the content and questions for three focus groups, and collected and analyzed the data. Inspired by the Consolidated Framework for Implementation Research, we developed the questions for the second focus group. We analyzed the data using an inductive thematic analysis method. Thirty-nine participants from the three sectors participated. Themes related to participants' conceptualization of SP included (a) ongoing process, (b) reflective process, (c) broad concept, and (d) collective effort. Themes describing factors influencing and supporting SP were (a) recognition, (b) appropriate conceptualization, (c) social network, (d) accessibility to resources, and (e) forces outside of practitioners' effort. Goals to support SP included (a) further recognizing SP, (b) sustaining SP competency, and (c) ensuring access to information. SP requires collaborative and integrated intersectoral support and further recognition of its importance through the collaboration of multiple stakeholders.

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PURPOSE: The null hypothesis is that there would be no difference in medial gapping under valgus load between the intact MCL and the ruptured MCL with an internal brace in place. METHODS: Eight pairs of cadaver knees were used (16 knees). Alternating sides, one knee from each pair was used for one of two "internal brace" constructs. The constructs involved different methods of fixation for securing FiberTape (Arthrex, Naples, FL) to both the femur and tibia in an effort to brace the MCL. The knees were then subjected to valgus stress by applying 10 N m of torque with the knee at 20 degrees of flexion. The amount of medial joint space opening was measured on radiographs. The stress testing was conducted with three MCL states: intact, grade 2 tear, and grade 3 tear. RESULTS: In the Construct I specimens, gapping increased from 0.7 mm with the MCL intact to 1.1 mm with grade 2 tearing (p < 0.01), and to 1.3 mm with grade 3 tearing (p < 0.01). In the Construct II specimens, gapping increased from 0.7 mm with the MCL intact to 1.0 mm with grade 2 tearing (p < 0.01), and to 1.1 mm with grade 3 tearing (n.s.). Construct I specimens failed primarily at the femoral attachment. All Construct II specimens survived the valgus stress testing. CONCLUSION: Construct I did not maintain tension. Construct II did maintain tension during application of valgus load, but did not restore valgus opening to the intact state. It is important for clinicians who are considering using this commercially available technique to be aware of how the construct performs under valgus stress testing compared to the intact MCL.

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INTRODUCTION: One family medicine group (FMG) in Quebec has commenced a 5-year pilot project, which is herein referred to as the Archimède model, to implement a patient-centred model based on interprofessional care and the optimal use of healthcare providers' practice scopes. A research project will be conducted to: (1) assess this model's effect on the FMG's operational performance, and its users' resource utilisation at the public health system level; (2) investigate its optimisation with respect to professional roles, interprofessional teamwork and patient-centredness and (3) document users' experience with the model. The aim of this article is to describe the protocol that will be used for this research. METHODS AND ANALYSIS: A hybrid implementation approach (type 2 model) will be used. We will collect both quantitative and qualitative data. Regarding the quantitative dimension, and because this is a single-unit intervention study, we will use either or both synthetic control methods and one-sample generalised linear models for analyses at the FMG level. To evaluate the broader impact of Archimède on the public health system, we will use mixed-effects models and propensity score matching methods. Regarding the qualitative research dimension, using an interpretative descriptive approach, we will document users' experience and identify the factors that optimise professional scopes of practice, collaborative practices and patient-centredness. We will conduct individual in-depth semistructured interviews with healthcare providers, administrative staff, stakeholders involved in the Archimède model implementation and patients. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of the Sectoral Research in Population Health and Primary Care of the Centre intégré universitaire de santé et de services sociaux de la Capitale-Nationale (#2019-1503). The results of the investigation will be presented to the stakeholders involved in the advisory committees and at several scientific conferences. Manuscripts will be submitted to peer-reviewed journals.

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OBJECTIVE: The authors used a machine-learning approach to model clinician decision making regarding psychiatric hospitalization of children and youths in crisis and to identify factors associated with the decision to hospitalize. METHODS: Data consisted of 4,786 mobile crisis response team assessments of children and youths, ages 4.0-19.5 years (mean±SD=14.0±2.7 years, 56% female), in Nevada. The sample assessments were split into training and testing data sets. A random-forest machine-learning algorithm was used to identify variables related to the decision to hospitalize a child or youth after the crisis assessment. Results from the training sample were externally validated in the testing sample. RESULTS: The random-forest model had good performance (area under the curve training sample=0.91, testing sample=0.92). Variables found to be important in the decision to hospitalize a child or youth were acute suicidality, followed by poor judgment or decision making, danger to others, impulsivity, runaway behavior, other risky behaviors, nonsuicidal self-injury, psychotic or depressive symptoms, sleep problems, oppositional behavior, poor functioning at home or with peers, depressive or schizophrenia spectrum disorders, and age. CONCLUSIONS: In crisis settings, clinicians were found to mostly focus on acute factors that increased risk for danger to self or others (e.g., suicidality, poor judgment), current psychiatric symptoms (e.g., psychotic symptoms), and functioning (e.g., poor home functioning, problems with peer relationships) when deciding whether to hospitalize or stabilize a child or youth. To reduce psychiatric hospitalization, community-based services should target interventions to address these important factors associated with the need for a higher level of care among youths in psychiatric crisis.

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OBJECTIVES: This study benchmarks quality of life (QoL) of youth with bipolar disorder (BD) against healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. The relative impacts of depressive, (hypo)manic, mixed, and externalizing symptoms on QoL are tested for youth with BD. METHOD: In total, 657 youth completed the Schedule for Affective Disorders and Schizophrenia for Children (KSADS), the KSADS depression and mania scales, the Parent General Behavior Inventory (PGBI), and the Child Behavior Checklist (CBCL). Youth-reported QoL was determined by the Revised Children Quality of Life Questionnaire (KINDL) and was compared to healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. RESULTS: Youth with BD reported poorer QoL overall and on most subscales compared to healthy youth, youth with chronic medical conditions, youth with behavior disorders, and youth with other non-behavior/non-mood disorders. QoL in youth with BD did not differ significantly from QoL in youth with unipolar depression. Parent-report and interview-rated depressive symptoms were associated with decreases in Total QoL and all QoL subscales except Family. Externalizing symptoms were associated with decreases in Family QoL and increases in Friend QoL, and (hypo)manic symptoms were associated with increases in Emotional Well-Being QoL. CONCLUSIONS: Depressive symptoms may drive the decline in QoL causing youth with BD to rate their QoL worse than healthy youth, youth with chronic medical conditions, and youth with behavior disorders, but not worse than youth with unipolar depression.

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Traditional cardiac rehabilitation (CR) programs historically have had considerable gender gaps in CR outcomes. Intensive-Cardiac-Rehabilitation (ICR) has nonexercise components such as stress management, peer support and diet modification, in addition to exercise, which may reduce barriers to CR completion. However, there is a paucity of data in ICR outcomes based on gender. We conducted a nationwide retrospective cohort study of 15,613 patients enrolled in 46 Ornish-ICR programs across the United States from January 2016 to December 2020 and compared ICR physical and psychological outcomes in women vs men. Primary endpoints were depression scores (CESD), health status (SF-36 physical and mental composite-scores) and exercise minutes per week. Of 15,613 ICR participants who participated in the program, 6788 (44%) were women. ICR completion rates were 64.7% overall and nearly equal between men and women (63.3% women vs 65.9% men). There were a few small differences in outcomes after ICR completion: women had slightly more improvement in depression scores (women: -6.10 ± 8.79, 49.6% reduction vs men: -4.92 ± 7.80, 46.4% reduction; P < 0.01) and SF-36 physical (women: 5.95 ± 6.86 vs men: 5.28 ± 6.71, P < 0.01) and SF-36 mental (women: 5.76 ± 8.11 vs men: 4.60 ± 7.33, P < 0.01) composite scores than men. There was no significant difference in exercise-minutes per week between the 2 groups. ICR attenuates the gender gap in CR completion. Further, of the completers, women achieved slightly higher depression and quality-of-life improvements compared to men. As such, ICR can be a good option to reduce gender-based differences in CR participation.

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Gender identity is a core component of human experience, critical to account for in broad health, development, psychosocial research, and clinical practice. Yet, the psychometric characterization of gender has been impeded due to challenges in modeling the myriad gender self-descriptors, statistical power limitations related to multigroup analyses, and equity-related concerns regarding the accessibility of complex gender terminology. Therefore, this initiative employed an iterative multi-community-driven process to develop the Gender Self-Report (GSR), a multidimensional gender characterization tool, accessible to youth and adults, nonautistic and autistic people, and gender-diverse and cisgender individuals. In Study 1, the GSR was administered to 1,654 individuals, sampled through seven diversified recruitments to be representative across age (10-77 years), gender and sexuality diversity (∼33% each gender diverse, cisgender sexual minority, cisgender heterosexual), and autism status (> 33% autistic). A random half-split subsample was subjected to exploratory factor analytics, followed by confirmatory analytics in the full sample. Two stable factors emerged: Nonbinary Gender Diversity and Female-Male Continuum (FMC). FMC was transformed to Binary Gender Diversity based on designated sex at birth to reduce collinearity with designated sex at birth. Differential item functioning by age and autism status was employed to reduce item-response bias. Factors were internally reliable. Study 2 demonstrated the construct, convergent, and ecological validity of GSR factors. Of the 30 hypothesized validation comparisons, 26 were confirmed. The GSR provides a community-developed gender advocacy tool with 30 self-report items that avoid complex gender-related "insider" language and characterize diverse populations across continuous multidimensional binary and nonbinary gender traits. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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BACKGROUND: Bone autograft options may be limited in revision spinal fusion cases. Reconstruction of the iliac bone graft (IBG) donor site with cancellous bone allograft allows for reharvest for patients who subsequently have another fusion. This study examined viability of the reconstructed IBG (RIBG) donor sites. Secondarily, we assessed the feasibility of whether the RIBG sites could be reharvested for obtaining a successful arthrodesis for a secondary fusion. METHODS: Prospectively collected data of 154 consecutive lumbar revision fusions were reviewed, of which 17 cases had their IBG donor site backfilled with allograft bone at the time of their primary fusion and subsequently had secondary surgery for a pseudarthrosis repair or fusion extension. Biopsies of the RIBG and computed tomography (CT) images were obtained at the time of secondary fusion. Histology analyzed the ratio of filled to unfilled lacunae and marrow cellularity. Histology controls were from normal iliac crest. Clinically, postoperative CT and >2-year outcomes (visual analog scale [VAS] and Oswestry Disability Index [ODI]) evaluated the feasibility of the secondary fusion surgery using RIBG. The RIBG fusion rate and outcomes were compared with clinical control revision groups that had IBG and/or bone morphogenetic protein (BMP) used for their revision fusion. RESULTS: CT images prior to RIBG harvest found bony healing of the original graft donor site in all except 1 case. RIBG bone marrow histology found lower cellularity vs controls, but this characteristic did not appear to compromise bone viability with filled lacunae in 83% ± 14% in the RIBG group, vs 88% ± 8% for iliac controls. After revision fusion, often combined with bone growth stimulator or BMP, repeat CT demonstrated solid spinal fusions in 16 of 17 patients, whereas control revision group fusion rates were approximately 80%. Clinical improvement was significant (VAS decrease = 3.8, ODI decrease = 16.5) and comparable with the IBG revision controls. CONCLUSION: RIBG using allograft remodels into viable predominately cancellous bone and is clinically feasible for revision fusion if IBG or BMP is unavailable. CLINICAL RELEVANCE: Reconstructed iliac bone graft is viable and may be used as a bone graft option.