Optimizing energy utilization in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter-2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of oral empagliflozin 25 mg/day in 40 normotensive, normoalbuminuric young adults with T1D. A consecutive two-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and post-treatment visit. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways – aminoacyl-tRNA, valine, leucine and isoleucine, arginine, as well as phenylalanine, tyrosine, and tryptophan. Under acute hyperglycemia, empagliflozin significantly attenuated the increases to aminoacyl-tRNA biosynthesis and valine, leucine and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism.
The immunogenicity of transplanted allogeneic cells and tissues is a major hurdle to the advancement of cell therapies. Here we show that the overexpression of eight immunomodulatory transgenes ( Pdl1 , Cd200 , Cd47 , H2-M3 , Fasl , Serpinb9 , Ccl21 and Mfge8 ) in mouse embryonic stem cells (mESCs) is sufficient to immunologically ‘cloak’ the cells as well as tissues derived from them, allowing their survival for months in outbred and allogeneic inbred recipients. Overexpression of the human orthologues of these genes in human ESCs abolished the activation of allogeneic human peripheral blood mononuclear cells and their inflammatory responses. Moreover, by using the previously reported FailSafe transgene system, which transcriptionally links a gene essential for cell division with an inducible and cell-proliferation-dependent kill switch, we generated cloaked tissues from mESCs that served as immune-privileged subcutaneous sites that protected uncloaked allogeneic and xenogeneic cells from rejection in immune-competent hosts. The combination of cloaking and FailSafe technologies may allow for the generation of safe and allogeneically accepted cell lines and off-the-shelf cell products.
Considerable advancements in next generation sequencing (NGS) techniques have sparked the use of comprehensive genomic profiling (CGP) as a guiding tool for precision-centered oncological treatments. The past two decades have seen the completion of the human genome project, and the consequential invention of NGS. High-throughput sequencing technologies support the discovery and commonplace use of individualized cancer treatments, specifically immune-centered checkpoint inhibitor therapies, and oncogene and tumor suppressor gene targeted therapies. Nevertheless, CGP is not commonly used in all clinical settings. This review investigates the clinically relevant applications of CGP. Studies published between the years 2000–2023 have shown substantial evidence of the benefits of integrating CGP into routine care practice, while also making important comparisons to current-standard oncological treatment strategies. Findings of a comprehensive genomic profile includes predictive, prognostic, and diagnostic biomarkers, together with somatic mutation identification which can indicate the efficacy of immunotherapies and molecularly guided therapies. This review highlights the importance of CGP in identifying driver mutations in tumors that subsequently can be effectively targeted with molecular therapeutics and lead to drug discovery, allowing for increased precision in treating tumors selectively based on their specific genetic mutations, thereby improving patient outcomes.
Background Given current health system trends, clinicians increasingly care for patients with complex care needs. There is a recognized lack of evidence to support clinician decision-making in these situations, as complex or multimorbid patients have been historically excluded from the types of research that inform clinical practice guidelines. However, expert clinicians at sites of excellence (e.g., Stroke Distinction sites) provide measurably excellent care. We sought to review profession-specific competency frameworks to locate information that may be supporting the development of clinician expertise when managing the care of patients with complex care needs. Methods We conducted a review of the professional competency frameworks for core members of the inpatient stroke rehabilitation team, to determine the degree of guidance and/or preparation for the management of patients with complex care needs. We developed and applied an assessment rubric to locate references to patient complexity, multimorbidity and complexity theory. Results Across the professional competency frameworks, there are some references to complexity at patient- and team-levels; there are fewer references to system-level complexity. We noted a lack of clear guidance for clinicians regarding the management of patients with complex care needs. Conclusion Further research is needed to explore how clinicians develop expertise in the management of patients with complex care needs, as we noted minimal guidance in the professional competency frameworks. However, we suggest that integrating complexity-related language into professional competency frameworks could better prime novice clinicians for new learning in the workplace and ease their transition into working in a complex context.
Importance The association between COVID-19 social disruption and young children’s development is largely unknown. Objective To examine associations of pandemic exposure with neurocognitive and socioemotional development at 24 and 54 months of age. Design, Setting, and Participants This cross-sectional study evaluated associations between pandemic exposure vs nonexposure and developmental outcomes with covariate adjustment using data from the Ontario Birth Study collected between February 2018 and June 2022. Eligible participants were children aged 24 and 54 months. Data were analyzed from June to November 2022. Exposure COVID-19 pandemic exposure defined as assessment after March 11, 2020. Main Outcome and Measures Neurodevelopmental assessment using the ASQ-3 (Ages and Stages Questionnaire, Third Edition) and MCHAT-R (Modified Checklist for Autism in Toddlers, Revised) at 24 months of age, and neurocognitive and socioemotional assessment using the National Institutes of Health Toolbox at 54 months of age. Results A total of 718 children at age 24 months (mean [SD] age, 25.6 [1.7] months; 342 female [47.6%]; 461 White [64.2%]) and 703 at age 54 months (mean [SD] age, 55.4 [2.6] months; 331 female [47.1%]; 487 White [69.3%]) were included. At 24 months of age, 460 participants (232 female [50.4%]) were assessed during the pandemic (March 17, 2020, to May 17, 2022) and 258 (110 female [42.6%]) were assessed prepandemic (April 17, 2018, to March 10, 2020). At 54 months of age, 286 participants (129 female [45.1%]) were assessed from March 14, 2020, to June 6, 2022, and 417 (202 female [48.4%]) were assessed from February 8, 2018, to March 10, 2020. At 24 months of age, pandemic-exposed children had reduced risk of problem-solving difficulties using cutoff scores (odds ratio [OR], 0.33; 95% CI, 0.18-0.62; P = .005) and higher problem-solving ( B , 3.93; 95% CI, 2.48 to 5.38; P < .001) compared with nonexposed children. In contrast, pandemic-exposed children had greater risk for personal-social difficulties using cutoff scores (OR, 1.67; 95% CI, 1.09-2.56; P = .02) and continuous scores ( B , −1.70; 95% CI, −3.21 to −0.20; P = .02) compared with nonexposed children. At 54 months of age, pandemic-exposed children had higher receptive vocabulary ( B , 3.16; 95% CI, 0.13 to 6.19; P = .04), visual memory ( B , 5.95; 95% CI, 1.11 to 10.79; P = .02), and overall cognitive performance ( B , 3.89; 95% CI, 0.73 to 7.04; P = .02) compared with nonexposed children, with no differences in socioemotional development. Conclusions and Relevance This cross-sectional study found both positive and negative associations between pandemic exposure and preschool children’s cognitive and emotional well-being within a relatively socioeconomically advantaged sample.
Integrated early childhood development (ECD) programs boost child health and developmental outcomes. However, the factors contributing to the successful implementation of such programs in informal urban settlements are not well researched. We conducted 14 focus group discussions and 13 key informant interviews with 125 caregivers of children under the age of 5 years and stakeholders, exploring their views on enablers and barriers to implementing an integrated ECD program in an informal settlement in Kenya. Strategic engagement, capacity building, transparency, fair compensation of ECD workforce, communication skills, and the need to tailor ECD programs to local realities were discussed. An equity-focused implementation approach for integrated ECD programs is timely.
Genetic studies in mice and human cancers established BCL11B as a haploinsufficient tumor suppressor gene. Paradoxically, BCL11B is overexpressed in some human cancers where its knockdown is synthetic lethal. We identified the BCL11B protein in a proximity-dependent biotinylation screen performed with the DNA glycosylase NTHL1. In vitro DNA repair assays demonstrated that both BCL11B and a small recombinant BCL11B213-560 protein lacking transcription regulation potential can stimulate the enzymatic activities of two base excision repair (BER) enzymes: NTHL1 and Pol β. In cells, BCL11B is rapidly recruited to sites of DNA damage caused by laser microirradiation. BCL11B knockdown delays, whereas ectopic expression of BCL11B213-560 accelerates, the repair of oxidative DNA damage. Inactivation of one BCL11B allele in TK6 lymphoblastoid cells causes an increase in spontaneous and radiation-induced mutation rates. In turn, ectopic expression of BCL11B213-560 cooperates with the RAS oncogene in cell transformation by reducing DNA damage and cellular senescence. These findings indicate that BCL11B functions as a BER accessory factor, safeguarding normal cells from acquiring mutations. Paradoxically, it also enables the survival of cancer cells that would otherwise undergo senescence or apoptosis due to oxidative DNA damage resulting from the elevated production of reactive oxygen species.
Driver mutations in IDH1 and IDH2 characterize a substantial proportion of diffuse gliomas. These tumors are typically of lower grade at diagnosis, but many eventually transform to more aggressive disease. Furthermore, there is a lack of effective curative treatments. Mutated IDH molecules acquire neomorphic enzymatic activity, favoring the synthesis of D-2-hydroxyglutarate (D-2-HG). Accumulation of this metabolite perturbs many cellular functions and drives gliomagenesis through incompletely understood mechanisms. IDH mutations are early events in gliomagenesis, but the identity of the initiating cell type has been debated. Here, using genetically engineered mice, we found that combining Idh1R132H and Trp53 loss in oligodendrocyte progenitors leads to fully penetrant development of diffuse gliomas. The tumors recapitulate the cardinal features of the corresponding human disease. While heterogeneous, the mouse Idh1R132H and Idh1WT tumors show distinct patterns of transcriptional alterations and oncogenic copy number variants. Mutant IDH itself is an attractive drug target, as it is clonally expressed and usually retained during tumor evolution, even though its relevance for disease progression has been questioned. Nevertheless, recent clinical trials have demonstrated clear, but variable, anti-tumor effects of mutant IDH inhibitors in patients. To better understand the mechanistic basis for heterogeneous responses to mutant IDH inhibition, we performed CRISPR/Cas9 functional genomic screens in cell lines derived from the mouse Idh1R132H;Trp53MUT tumors. These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.
The atomic‐resolution structural information that X‐ray crystallography can provide on the binding interface between a Fab and its cognate antigen is highly valuable for understanding the mechanism of interaction. However, many Fab:antigen complexes are recalcitrant to crystallization, making the endeavor a considerable effort with no guarantee of success. Consequently, there have been significant steps taken to increase the likelihood of Fab:antigen complex crystallization by altering the Fab framework. In this investigation, we applied the surface entropy reduction strategy coupled with phage‐display technology to identify a set of surface substitutions that improve the propensity of a human Fab framework to crystallize. In addition, we showed that combining these surface substitutions with previously reported Crystal Kappa and elbow substitutions results in an extraordinary improvement in Fab and Fab:antigen complex crystallisability, revealing a strong synergistic relationship between these sets of substitutions. Through comprehensive Fab and Fab:antigen complex crystallization screenings followed by structure determination and analysis, we defined the roles that each of these substitutions play in facilitating crystallization and how they complement each other in the process. This article is protected by copyright. All rights reserved.
Background Perinatal depression affects an estimated 1 in 5 women in North America during the perinatal period, with annualized lifetime costs estimated at $20.6 billion CAD in Canada and over $45.9 billion USD in the US. Access to psychological treatments remains limited for most perinatal women suffering from depression and anxiety. Some barriers to effective care can be addressed through task-sharing to non-specialist providers and through telemedicine platforms. The cost-effectiveness of these strategies compared to traditional specialist and in-person models remains unknown. This protocol describes an economic evaluation of non-specialist providers and telemedicine, in comparison to specialist providers and in-person sessions within the ongoing Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) trial. Methods The economic evaluation will be undertaken alongside the SUMMIT trial. SUMMIT is a pragmatic, randomized, non-inferiority trial across five North American study sites (N = 1,226) of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a behavioural activation treatment for perinatal depressive and anxiety symptoms. The primary economic evaluation will be a cost-utility analysis. The outcome will be the incremental cost-effectiveness ratio, which will be expressed as the additional cost required to achieve an additional quality-adjusted life-year, as assessed by the EuroQol 5-Dimension 5-Level instrument. A secondary cost-effectiveness analysis will use participants’ depressive symptom scores. A micro-costing analysis will be conducted to estimate the resources/costs required to implement and sustain the interventions; healthcare resource utilization will be captured via self-report. Data will be pooled and analysed using uniform price and utility weights to determine cost-utility across all trial sites. Secondary country-specific cost-utility and cost-effectiveness analyses will also be completed. Sensitivity analyses will be conducted, and cost-effectiveness acceptability-curves will be generated, in all instances. Discussion Results of this study are expected to inform key decisions related to dissemination and scale up of evidence-based psychological interventions in Canada, the US, and possibly worldwide. There is potential impact on real-world practice by informing decision makers of the long-term savings to the larger healthcare setting in services to support perinatal women with common mental health conditions.
Background Immunologically impaired individuals respond poorly to vaccines, highlighting the need for additional strategies to protect these vulnerable populations from COVID-19. While monoclonal antibodies (mAbs) have emerged as promising tools to manage infectious diseases, the transient lifespan of neutralizing mAbs in patients limits their ability to confer lasting, passive prophylaxis from SARS-CoV-2. Here, we attempted to solve this problem by combining cell and mAb engineering in a way that provides durable immune protection against viral infection using safe and universal cell therapy. Methods Mouse embryonic stem cells equipped with our FailSafe™ and induced allogeneic cell tolerance technologies were engineered to express factors that potently neutralize SARS-CoV-2, which we call ‘neutralizing biologics’ (nBios). We subcutaneously transplanted the transgenic cells into mice and longitudinally assessed the ability of the cells to deliver nBios into circulation. To do so, we quantified plasma nBio concentrations and SARS-CoV-2 neutralizing activity over time in transplant recipients. Finally, using similar cell engineering strategies, we genetically modified FailSafe™ human-induced pluripotent stem cells to express SARS-CoV-2 nBios. Results Transgenic mouse embryonic stem cells engineered for safety and allogeneic-acceptance can secrete functional and potent SARS-CoV-2 nBios. As a dormant, subcutaneous tissue, the transgenic cells and their differentiated derivatives long-term deliver a supply of protective nBio titers in vivo. Moving toward clinical relevance, we also show that human-induced pluripotent stem cells, similarly engineered for safety, can secrete highly potent nBios. Conclusions Together, these findings show the promise and potential of using ‘off-the-shelf’ cell products that secrete neutralizing antibodies for sustained protective immunity against current and future viral pathogens of public health significance.
Background Given the increasing integration of digital health technologies in team-based primary care, this review aimed at understanding the impact of eHealth on patient-provider and provider-provider relationships. Methods A review of reviews was conducted on three databases to identify papers published in English from 2008 onwards. The impact of different types of eHealth on relationships and trust and the factors influencing the impact were thematically analyzed. Results A total of 79 reviews were included. Patient-provider relationships were discussed more frequently as compared to provider-provider relationships. Communication systems like telemedicine were the most discussed type of technology. eHealth was found to have both positive and negative impacts on relationships and/or trust. This impact was influenced by a range of patient-related, provider-related, technology-related, and organizational factors, such as patient sociodemographics, provider communication skills, technology design, and organizational technology implementation, respectively. Conclusions Recommendations are provided for effective and equitable technology selection, application, and training to optimize the impact of eHealth on relationships and trust. The review findings can inform providers’ and policymakers’ decision-making around the use of eHealth in primary care delivery to facilitate relationship-building.
Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as TP53 , FAT1 , and APC . Tobacco-driven SGMs in lung cancer correlate with smoking history and highlight a preventable determinant of these harmful mutations. APOBEC-driven SGMs are enriched in YTCA motifs and associate with APOBEC3A expression. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes directly contribute to protein loss of function, oncogenesis, and tumor heterogeneity.
Background The pan‐Canadian Maternal–Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. Objectives The MIREC‐Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. Population MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research ( n = 1459) were invited to participate in MIREC–CD PLUS which combines data collected from an online Maternal Self‐Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in‐person visits. Preliminary Results Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children‐2, Behaviour Rating Inventory of Executive Function, MacArthur‐Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development‐III are available on close to 900 children. There were 610 singleton children who completed in‐person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence‐III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC–ENDO). Conclusions Data collection for the MIREC–CD PLUS study is complete and analysis of the data continues. We are now extending the follow‐up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC–ENDO). MIREC–CD PLUS is limited by loss to follow‐up and the fact that mothers are predominately of higher socioeconomic status and ‘White’ ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.
Background The generalizability of treatments examined in rehabilitation randomized controls trials (RCTs) partly depend on the similarity between trial subjects and a stroke rehabilitation inpatient population. The aim of this study was to determine the proportion of stroke rehabilitation inpatients that would have been eligible or ineligible to participate in published stroke RCTs. Methods This was a secondary analysis of chart review data collected as part of an independent quality improvement initiative. Data pertaining to the characteristics of stroke rehabilitation inpatients (e.g. age, cognitive impairment, previous stroke, comorbidities) were extracted from the medical charts of patients consecutively admitted to an inpatient stroke rehabilitation unit at a large urban rehabilitation hospital in Canada. Using the exclusion criteria categories of stroke RCTs identified from a systematic scoping review of 428 RCTs, we identified how many stroke rehabilitation inpatients would have been eligible or ineligible to participate in stroke RCTs based on their age, cognitive impairment, previous stroke and presence of comorbidities. Results In total, 110 stroke rehabilitation inpatients were included. Twenty-four percent of patients were 80 years of age or older, 84.5% had queries or concerns regarding patient cognitive abilities, 28.0% had a previous stroke, and 31.8% had a severe stroke. Stroke rehabilitation inpatients had six comorbidities on average. Based on these factors, most stroke rehabilitation inpatients could have been excluded from stroke RCTs, with cognitive impairment the most common RCT exclusion criteria. Conclusions Changes to the design of RCTs would support the development of clinical practice guidelines that reflect stroke rehabilitation inpatient characteristics, enhancing equity, diversity, and inclusion within samples and the generalizability of results.
The person-centered care movement has influenced hospitals to make patient and family engagement (PE) an explicit commitment in their strategic plans. This is often reflected in mission, vision, and value (MVV) statements, which are organizational artifacts intended to influence the attitudes, beliefs, and actions of hospital teams and employees because of their saliency in organizational documents and communications. Previous research has found that organizational goals for PE, like those articulated in MVV statements, can lead to effective and meaningful PE. However, a deeper understanding of how and under which circumstances MVV statements encourage and promote PE practices is needed. A scoping review was conducted to understand the connection between hospital PE goals (such as MVV statements) and PE processes and practices. The research question was: what is known about how hospital MVV statements relate to PE processes and activities? Following Arksey and O’Malley’s scoping review approach, 27 articles were identified as relevant to the research question. These articles revealed five strategies that help realize hospital PE goals: communicating organizational goals; aligning documents that convey organizational goals; aligning organizational processes to support PE; providing employees with resources and support; and motivating and empowering employees to integrate PE into their work. We discuss the implications of misalignment between hospital goals and practices, which reduce team and individual motivation toward hospital PE goals.
Background Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk‐prediction model (called SPLC‐RAT) was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking. The predictive performance of SPLC‐RAT was evaluated in a hospital‐based cohort of lung cancer survivors. Methods The authors analyzed data from 8448 ever‐smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997–2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC‐RAT and further explored the potential of improving SPLC detection through risk model‐based surveillance using SPLC‐RA T versus existing clinical surveillance guidelines. Results Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person‐years. The application of SPLC‐RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10‐year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC‐RAT development cohort), the observed SPLC incidence was significantly elevated in the high‐risk versus low‐risk subgroup (13.1% vs. 1.1%, p < 1 × 10 –6 ). The risk‐based surveillance through SPLC‐RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow‐ups needed to detect one SPLC (162 vs. 202). Conclusion In a large, hospital‐based cohort, the authors validated the predictive performance of SPLC‐RAT in identifying high‐risk survivors of SPLC and showed its potential to improve SPLC detection through risk‐based surveillance. Plain Language Summary Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence‐based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk‐prediction model was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking. Using a large, real‐world cohort of lung cancer survivors, we showed the high predictive accuracy and risk‐stratification ability of the SPLC risk‐prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model‐based surveillance strategies compared to the existing consensus‐based clinical guidelines, including the National Comprehensive Cancer Network.
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