'We're taught green is good': Perspectives on time in range and time in tight range from youth with type 1 diabetes, and parents of youth with type 1 diabetes.

AIMS: Continuous glucose monitoring (CGM) systems are standard of care for youth with type 1 diabetes with the goal of spending >70% time in range (TIR; 70-180 mg/dL, 3.9-10 mmol/L). We aimed to understand paediatric CGM user experiences with TIR metrics considering recent discussion of shifting to time in tight range (TITR; >50% time between 70 and 140 mg/dL, 3.9 and 7.8 mmol/L). METHODS: Semi-structured interviews and focus groups with adolescents with type 1 diabetes and parents of youth with type 1 diabetes focused on experiences with TIR goals and reactions to TITR. Groups and interviews were audio-recorded, transcribed and analysed using content analysis. RESULTS: Thirty participants (N = 19 parents: age 43.6 ± 5.3 years, 79% female, 47% non-Hispanic White, 20 ± 5 months since child's diagnosis; N = 11 adolescents: age 15.3 ± 2 years, 55% female, 55% non-Hispanic White, 16 ± 3 months since diagnosis) attended. Participants had varying levels of understanding of TIR. Some developed personally preferred glucose ranges. Parents often aimed to surpass 70% TIR. Many described feelings of stress and disappointment when they did not meet a TIR goal. Concerns about TITR included increased stress and burden; risk of hypoglycaemia; and family conflict. Some participants said TITR would not change their daily lives; others said it would improve their diabetes management. Families requested care team support and a clear scientific rationale for TITR. CONCLUSIONS: The wealth of CGM data creates frequent opportunities for assessing diabetes management and carries implications for management burden. Input from people with type 1 diabetes and their families will be critical in considering a shift in glycaemic goals and targets.

Intravenous Cetirizine Premedication to Mitigate Infusion-Related Reactions.

Infusion-related reactions (IRRs) are a recognized concern for chemotherapy, biologic agents, and newer immunotherapies. Antihistamines are frequently recommended to prevent or manage these reactions. For over 60 years, diphenhydramine has been the only H1 antihistamine for intravenous (IV) administration. It has been considered the standard of care as part of premedication regimens to prevent IRRs associated with these therapies despite the lack of a US Food and Drug Administration (FDA)-approved indication and no evidence of efficacy data. Intravenous cetirizine was approved in 2019 for acute urticaria treatment, making it the only second-generation H1 antihistamine that can be administered intravenously. Compared with diphenhydramine, cetirizine has an improved safety profile with less sedation, fewer contraindications, lower incidence of anticholinergic side effects, and minimal risk of adverse events in elderly patients. A head-to-head study demonstrated that IV cetirizine is as effective as IV diphenhydramine in reducing IRRs and may decrease chair time, treatment center visits, and the need for rescue medication. Over the past 3 decades, the FDA has addressed the issue of IRRs by mandating language regarding the requirement or recommendation for premedication in the label of over 50 FDA-approved infusion products. As more therapeutics have premedication required or recommended, IV cetirizine should be considered an antihistamine for preventing and treating IRRs. In this article, we describe a patient whose IRR was successfully managed with IV cetirizine and discuss first- vs. second-generation H1 antihistamines and their use in treating and preventing IRRs.

Injectable shear-thinning hydrogels promote oligodendrocyte progenitor cell survival and remyelination in the central nervous system.

Cell therapy for the treatment of demyelinating diseases such as multiple sclerosis is hampered by poor survival of donor oligodendrocyte cell preparations, resulting in limited therapeutic outcomes. Excessive cell death leads to the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft to eventual rejection. Here, we engineered innovative cell-instructive shear-thinning hydrogels (STHs) with tunable viscoelasticity and bioactivity for minimally invasive delivery of primary human oligodendrocyte progenitor cells (hOPCs) to the brain of a shiverer/rag2 mouse, a model of congenital hypomyelinating disease. The STHs enabled immobilization of prosurvival signals, including a recombinantly designed bidomain peptide and platelet-derived growth factor. Notably, STHs reduced the death rate of hOPCs significantly, promoted the production of myelinating oligodendrocytes, and enhanced myelination of the mouse brain 12 weeks post-implantation. Our results demonstrate the potential of STHs loaded with biological cues to improve cell therapies for the treatment of devastating myelopathies.

Modeling Radiologists' Assessments to Explore Pairing Strategies for Optimized Double Reading of Screening Mammograms.

PURPOSE: To develop a model that simulates radiologist assessments and use it to explore whether pairing readers based on their individual performance characteristics could optimize screening performance. METHODS: Logistic regression models were designed and used to model individual radiologist assessments. For model evaluation, model-predicted individual performance metrics and paired disagreement rates were compared against the observed data using Pearson correlation coefficients. The logistic regression models were subsequently used to simulate different screening programs with reader pairing based on individual true-positive rates (TPR) and/or false-positive rates (FPR). For this, retrospective results from breast cancer screening programs employing double reading in Sweden, England, and Norway were used. Outcomes of random pairing were compared against those composed of readers with similar and opposite TPRs/FPRs, with positive assessments defined by either reader flagging an examination as abnormal. RESULTS: The analysis data sets consisted of 936,621 (Sweden), 435,281 (England), and 1,820,053 (Norway) examinations. There was good agreement between the model-predicted and observed radiologists' TPR and FPR (r ≥ 0.969). Model-predicted negative-case disagreement rates showed high correlations (r ≥ 0.709), whereas positive-case disagreement rates had lower correlation levels due to sparse data (r ≥ 0.532). Pairing radiologists with similar FPR characteristics (Sweden: 4.50% [95% confidence interval: 4.46%-4.54%], England: 5.51% [5.47%-5.56%], Norway: 8.03% [7.99%-8.07%]) resulted in significantly lower FPR than with random pairing (Sweden: 4.74% [4.70%-4.78%], England: 5.76% [5.71%-5.80%], Norway: 8.30% [8.26%-8.34%]), reducing examinations sent to consensus/arbitration while the TPR did not change significantly. Other pairing strategies resulted in equal or worse performance than random pairing. CONCLUSIONS: Logistic regression models accurately predicted screening mammography assessments and helped explore different radiologist pairing strategies. Pairing readers with similar modeled FPR characteristics reduced the number of examinations unnecessarily sent to consensus/arbitration without significantly compromising the TPR. HIGHLIGHTS: A logistic-regression model can be derived that accurately predicts individual and paired reader performance during mammography screening reading.Pairing screening mammography radiologists with similar false-positive characteristics reduced false-positive rates with no significant loss in true positives and may reduce the number of examinations unnecessarily sent to consensus/arbitration.

Modelling Salmonella Typhi in high-density urban Blantyre neighbourhood, Malawi, using point pattern methods.

Salmonella Typhi is a human-restricted pathogen that is transmitted by the faecal-oral route and causative organism of typhoid fever. Using health facility data from 2016 to 2020, this study focuses on modelling the spatial variation in typhoid risk in Ndirande township in Blantyre. To pursue this objective, we developed a marked inhomogeneous Poisson process model that allows us to incorporate both individual-level and environmental risk factors. The results from our analysis indicate that typhoid cases are spatially clustered, with the incidence decreasing by 54% for a unit increase in the water, sanitation, and hygiene (WASH) score. Typhoid intensity was also higher in children aged below 18 years than in adults. However, our results did not show evidence of a strong temporal variation in typhoid incidence. We also discuss the inferential benefits of using point pattern models to characterise the spatial variation in typhoid risk and outline possible extensions of the proposed modelling framework.

UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension.

Background: Angiotensin (Ang)-II impairs the function of the antihypertensive enzyme ACE2 by promoting its internalization, ubiquitination and degradation thus contributing to hypertension. However, few ACE2 ubiquitination partners have been identified and their role in hypertension remains unknown. Methods: Proteomics and bioinformatic analysis were used to identify ACE2 ubiquitination partners in the brain, heart, and kidney from Ang-II-infused C57BL6/J mice from both sexes and validated the interaction between UBR1 and ACE2 in cells. Central and peripheral UBR1 knockdown was then performed in male mice to investigate its role in the maintenance of hypertension. Results: Proteomics analysis from hypothalamus identified UBR1 as a potential E3 ligase promoting ACE2 ubiquitination. Enhanced UBR1 expression, associated with ACE2 reduction, was confirmed in various tissues from hypertensive male mice and human samples. Treatment of endothelial and smooth muscle cells with testosterone, but not 17ß-estradiol, confirmed a sex-specific regulation of UBR1. In vivo silencing of UBR1 using chronic administration of small interference RNA resulted in the restoration of ACE2 levels in hypertensive males. A transient decrease in blood pressure following intracerebroventricular, but not systemic, infusion was also observed. Interestingly, UBR1 knockdown increased the brain activation of Nedd4-2, an E3 ligase promoting ACE2 ubiquitination and reduced expression of SGK1, the kinase inactivating Nedd4-2. Conclusions: These data demonstrate that UBR1 is a novel ubiquitin ligase targeting ACE2 in hypertension. UBR1 and Nedd4-2 E3 ligases appear to work synergistically to ubiquitinate ACE2. Targeting of these ubiquitin ligases may represent a novel strategy to restore ACE2 compensatory activity in hypertension.

Evolutionary ecology of masting: mechanisms, models, and climate change.

Many perennial plants show mast seeding, characterized by synchronous and highly variable reproduction across years. We propose a general model of masting, integrating proximate factors (environmental variation, weather cues, and resource budgets) with ultimate drivers (predator satiation and pollination efficiency). This general model shows how the relationships between masting and weather shape the diverse responses of species to climate warming, ranging from no change to lower interannual variation or reproductive failure. The role of environmental prediction as a masting driver is being reassessed; future studies need to estimate prediction accuracy and the benefits acquired. Since reproduction is central to plant adaptation to climate change, understanding how masting adapts to shifting environmental conditions is now a central question.

Uncovering strain- and age-dependent innate immune responses to SARS-CoV-2 infection in air-liquid-interface cultured nasal epithelia.

Continuous assessment of the impact of SARS-CoV-2 on the host at the cell-type level is crucial for understanding key mechanisms involved in host defense responses to viral infection. We investigated host response to ancestral-strain and Alpha-variant SARS-CoV-2 infections within air-liquid-interface human nasal epithelial cells from younger adults (26-32 Y) and older children (12-14 Y) using single-cell RNA-sequencing. Ciliated and secretory-ciliated cells formed the majority of highly infected cell-types, with the latter derived from ciliated lineages. Strong innate immune responses were observed across lowly infected and uninfected bystander cells and heightened in Alpha-infection. Alpha highly infected cells showed increased expression of protein-refolding genes compared with ancestral-strain-infected cells in children. Furthermore, oxidative phosphorylation-related genes were down-regulated in bystander cells versus infected and mock-control cells, underscoring the importance of these biological functions for viral replication. Overall, this study highlights the complexity of cell-type-, age- and viral strain-dependent host epithelial responses to SARS-CoV-2.

Widespread breakdown in masting in European beech due to rising summer temperatures.

Climate change effects on tree reproduction are poorly understood, even though the resilience of populations relies on sufficient regeneration to balance increasing rates of mortality. Forest-forming tree species often mast, i.e. reproduce through synchronised year-to-year variation in seed production, which improves pollination and reduces seed predation. Recent observations in European beech show, however, that current climate change can dampen interannual variation and synchrony of seed production and that this masting breakdown drastically reduces the viability of seed crops. Importantly, it is unclear under which conditions masting breakdown occurs and how widespread breakdown is in this pan-European species. Here, we analysed 50 long-term datasets of population-level seed production, sampled across the distribution of European beech, and identified increasing summer temperatures as the general driver of masting breakdown. Specifically, increases in site-specific mean maximum temperatures during June and July were observed across most of the species range, while the interannual variability of population-level seed production (CVp) decreased. The declines in CVp were greatest, where temperatures increased most rapidly. Additionally, the occurrence of crop failures and low seed years has decreased during the last four decades, signalling altered starvation effects of masting on seed predators. Notably, CVp did not vary among sites according to site mean summer temperature. Instead, masting breakdown occurs in response to warming local temperatures (i.e. increasing relative temperatures), such that the risk is not restricted to populations growing in warm average conditions. As lowered CVp can reduce viable seed production despite the overall increase in seed count, our results warn that a covert mechanism is underway that may hinder the regeneration potential of European beech under climate change, with great potential to alter forest functioning and community dynamics.

Dysregulated Cholinergic Signaling Inhibits Oligodendrocyte Maturation Following Demyelination.

Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS.

A single-center experience of COVID-19 infection in patients with primary immunodeficiency.

Background: Reported outcomes in patients with primary immunodeficiency (PID) infected by coronavirus disease 2019 (COVID-19) have been variable owing to a combination of viral strain heterogeneity, differences in patient populations and health systems, and local availability of vaccination and specific COVID-19 therapies. There are few reports on the experience of Australian patients with PID during the pandemic. Objectives: In this retrospective study, we describe the baseline characteristics and short-term outcomes of patients with PID who were infected by COVID-19 and known to the Royal Melbourne Hospital, a major tertiary center in Victoria, Australia. Methods: Between April 2021 and April 2022, a total of 31 of 138 patients with PID were affected by COVID-19. More than half of them had 3 vaccine doses at the time of infection (which at the time was considered being fully vaccinated) and received COVID-19-targeted treatment. Results: All of the infected patients had ambulatory disease, with no cases of morbidity or mortality. In line with the current literature, the PID subtypes described did not appear to independently predict worse outcomes. Conclusions: Some protective factors include this cohort's relatively younger average age and its high uptake of vaccination and COVID-19 therapies.

Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.

ABSTRACT: Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)-based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes, with a limit of detection of 0.2%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In conclusion, mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression and may help upfront TKI selection.

The associations between invasive group A streptococcal disease and infection with influenza, varicella, or hepatitis C viruses: A data linkage study, Victoria, Australia.

OBJECTIVES: To quantify the associations between invasive group A streptococcal disease (iGAS) incidence and influenza, varicella, and chronic hepatitis C virus (HCV). METHODS: We used individual-level linked data of iGAS cases from Victoria, Australia (2007-2017) to assess associations between these viral infections and iGAS. A self-controlled case series method was used to estimate the relative incidence of iGAS following an influenza or varicella infection, while the relative incidence of iGAS among HCV cases, and HCV cases who inject drugs, was estimated using population-level data and a negative binomial regression model. RESULTS: Of the 1949 individuals with at least one iGAS diagnosis, 82 were diagnosed with influenza at least once, 30 with varicella, and 118 with HCV during the study period. The relative incidence of iGAS increased substantially following infection with influenza (incidence rate ratio [IRR]: 34.5, 95% confidence interval [CI]: 21.3-55.8) or varicella (IRR: 22.4, 95% CI: 10.3-48.8). iGAS incidence was higher among HCV cases (IRR: 5.7, 95% CI: 4.4-7.3) compared to individuals without HCV. iGAS incidence was also higher among HCV cases who inject drugs (IRR: 17.9, 95% CI: 13.0-24.4) compared to individuals without HCV who did not inject drugs. CONCLUSIONS: We found a significantly higher risk of iGAS following an influenza or varicella infection and for chronic HCV cases, particularly those who inject drugs. These findings are relevant to public health practice and support the timely identification of iGAS cases.

Satisfaction with diabetes involvement: Exploring parent and adolescent perspectives.

AIMS: Both parent and adolescent involvement in type 1 diabetes management are critical during adolescence. The current study sought to understand the factors associated with parent and adolescent satisfaction with their own and one another's involvement in diabetes management. METHODS: Cross-sectional baseline data from 157 parent-adolescent dyads enrolled in an RCT were used. Adolescent ages ranged from 12 to 19 (Mage = 14.7, SD = 1.89) and were balanced by gender (50.3% male). Paired t-tests examined concordance between parent and adolescent satisfaction, bivariate correlations identified correlates, and regressions examined unique associations. RESULTS: Roughly, 43% of adolescents and 29% of parents were very satisfied with adolescent involvement in diabetes management, whereas 71% of adolescents and 26.1% of parents were very satisfied with parent involvement. Indicators of better glycaemic health (via higher percent time-in-range and lower HbA1c and percent time in hyperglycaemia) and psychosocial functioning (less diabetes distress and depression) were correlated with higher satisfaction. Parent satisfaction with adolescent involvement was higher among older adolescents (R = 0.198, p = 0.013). Non-Hispanic white youth were more satisfied with their own involvement than youth of colour (t(149) = -2.783, p = 0.003). Both percent time-in-range and one's own diabetes distress uniquely related to parent and adolescent satisfaction with adolescent involvement. Conversely, parent satisfaction with their own involvement was only uniquely associated with parent diabetes distress. CONCLUSION: Both adolescent and parents' satisfaction with adolescents' involvement in self-management are indicators of both glycaemic control and psychosocial well-being, whereas parents' self-evaluations are more closely tied to diabetes-specific distress.

Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review.

BACKGROUND: The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care. METHODS: Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years). RESULTS: We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact. CONCLUSIONS: Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes.

In the last decade, there have been significant advances in how technology is used in the treatment of people living with type 1 diabetes. These technologies primarily aim to help manage blood sugar levels. Here, we reviewed research published over the last decade to evaluate the impact of such technologies on type 1 diabetes treatment. We find that various types of novel technologies, such as devices to monitor blood sugar levels continuously or deliver insulin, improve important diabetes-related measures and can reduce the risk of having low blood sugar levels. Importantly, several studies showed a positive impact of technologies on quality of life in people living with diabetes. Our findings highlight the benefits of novel technologies in the treatment of type 1 diabetes and identify areas for further research to optimize and personalize diabetes care.

Optimizing the Pairs of Radiologists That Double Read Screening Mammograms.

Background Despite variation in performance characteristics among radiologists, the pairing of radiologists for the double reading of screening mammograms is performed randomly. It is unknown how to optimize pairing to improve screening performance. Purpose To investigate whether radiologist performance characteristics can be used to determine the optimal set of pairs of radiologists to double read screening mammograms for improved accuracy. Materials and Methods This retrospective study was performed with reading outcomes from breast cancer screening programs in Sweden (2008-2015), England (2012-2014), and Norway (2004-2018). Cancer detection rates (CDRs) and abnormal interpretation rates (AIRs) were calculated, with AIR defined as either reader flagging an examination as abnormal. Individual readers were divided into performance categories based on their high and low CDR and AIR. The performance of individuals determined the classification of pairs. Random pair performance, for which any type of pair was equally represented, was compared with the performance of specific pairing strategies, which consisted of pairs of readers who were either opposite or similar in AIR and/or CDR. Results Based on a minimum number of examinations per reader and per pair, the final study sample consisted of 3 592 414 examinations (Sweden, n = 965 263; England, n = 837 048; Norway, n = 1 790 103). The overall AIRs and CDRs for all specific pairing strategies (Sweden AIR range, 45.5-56.9 per 1000 examinations and CDR range, 3.1-3.6 per 1000; England AIR range, 68.2-70.5 per 1000 and CDR range, 8.9-9.4 per 1000; Norway AIR range, 81.6-88.1 per 1000 and CDR range, 6.1-6.8 per 1000) were not significantly different from the random pairing strategy (Sweden AIR, 54.1 per 1000 examinations and CDR, 3.3 per 1000; England AIR, 69.3 per 1000 and CDR, 9.1 per 1000; Norway AIR, 84.1 per 1000 and CDR, 6.3 per 1000). Conclusion Pairing a set of readers based on different pairing strategies did not show a significant difference in screening performance when compared with random pairing. © RSNA, 2023.

Fibromyalgia in Patients With Hidradenitis Suppurativa.

This case-control study compares the prevalence of fibromyalgia between adults with hidradenitis suppurativa and adults with non­pain-related conditions.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

The Influence of Lipid Microdomain Heterogeneity on Protein-Protein Interactions: Proteomic Analysis of Co-Immunoprecipitated Binding Partners of P450 1A2 and P450 3A in Rat Liver Microsomes.

Liver cytochrome P450s (CYPs) of the endoplasmic reticulum (ER) are involved in the metabolism of exogenous and endogenous chemicals. The ER is not uniform, but possesses ordered lipid microdomains containing higher levels of saturated fatty acids, sphingomyelin, and cholesterol and disordered regions containing higher levels of polyunsaturated fatty acid chains. The various forms of drug-metabolizing P450s partition to either the ordered or disordered lipid microdomains with different degrees of specificity. P450s readily form complexes with ER-resident proteins, including other forms of P450. This study aims to ascertain whether lipid microdomain localization influences protein-P450 interactions in rat liver microsomes. Thus, liver microsomes were co-immunoprecipitated with CYP1A2-specific and CYP3A-specific antibodies, and the co-immunoprecipitating proteins were identified by liquid chromatography mass spectrometry proteomic analysis. These two P450s preferentially partition to ordered and disordered microdomains, respectively. More than 100 proteins were co-immunoprecipitated with each P450. Segregation of proteins into different microdomains did not preclude their interaction. However, CYP3A interacted broadly with proteins from ordered microdomains, whereas CYP1A2 reacted with a limited subset of these proteins. This is consistent with the concept of lipid raft heterogeneity and may indicate that CYP1A2 is targeted to a specific type of lipid raft. Although many of the interacting proteins for both P450s were other-drug metabolizing enzymes, other interactions were also evident. The consistent CYP3A binding partners were predominantly involved in phase I/II drug metabolism; however, CYP1A2 interacted not only with xenobiotic metabolizing enzymes, but also with enzymes involved in diverse cellular responses such as ER stress and protein folding. SIGNIFICANCE STATEMENT: This work describes the protein interactomes in rat liver microsomes of two important cytochromes P450s (CYP1A2 and CYP3A) in drug metabolism and describes the relationship of the interacting proteins to lipid microdomain distribution.

Quantifying and Visualizing Uncertainty for Source Localization in Electrocardiographic Imaging.

Electrocardiographic imaging (ECGI) presents a clinical opportunity to noninvasively understand the sources of arrhythmias for individual patients. To help increase the effectiveness of ECGI, we provide new ways to visualize associated measurement and modeling errors. In this paper, we study source localization uncertainty in two steps: First, we perform Monte Carlo simulations of a simple inverse ECGI source localization model with error sampling to understand the variations in ECGI solutions. Second, we present multiple visualization techniques, including confidence maps, level-sets, and topology-based visualizations, to better understand uncertainty in source localization. Our approach offers a new way to study uncertainty in the ECGI pipeline.