The role of structural racism and geographical inequity in diabetes outcomes.

Diabetes is pervasive, exponentially growing in prevalence, and outpacing most diseases globally. In this Series paper, we use new theoretical frameworks and a narrative review of existing literature to show how structural inequity (structural racism and geographical inequity) has accelerated rates of diabetes disease, morbidity, and mortality globally. We discuss how structural inequity leads to large, fixed differences in key, upstream social determinants of health, which influence downstream social determinants of health and resultant diabetes outcomes in a cascade of widening inequity. We review categories of social determinants of health with known effects on diabetes outcomes, including public awareness and policy, economic development, access to high-quality care, innovations in diabetes management, and sociocultural norms. We also provide regional perspectives, grounded in our theoretical framework, to highlight prominent, real-world challenges.

Interventions to address global inequity in diabetes: international progress.

Diabetes is a serious chronic disease with high associated burden and disproportionate costs to communities based on socioeconomic, gender, racial, and ethnic status. Addressing the complex challenges of global inequity in diabetes will require intentional efforts to focus on broader social contexts and systems that supersede individual-level interventions. We codify and highlight best practice approaches to achieve equity in diabetes care and outcomes on a global scale. We outline action plans to target diabetes equity on the basis of the recommendations established by The Lancet Commission on Diabetes, organising interventions by their effect on changing the ecosystem, building capacity, or improving the clinical practice environment. We present international examples of how to address diabetes inequity in the real world to show that approaches addressing the individual within a larger social context, in addition to addressing structural inequity, hold the greatest promise for creating sustainable and equitable change that curbs the global diabetes crisis.

A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.

Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson's disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.

Increasing Continuous Glucose Monitoring Use for Non-Hispanic Black and Hispanic People With Type 1 Diabetes: Results From the T1D Exchange Quality Improvement Collaborative Equity Study.

Despite the benefits of continuous glucose monitoring (CGM), there is lower use of this technology among non-Hispanic Black and Hispanic people with type 1 diabetes compared with their non-Hispanic White counterparts. The T1D Exchange Quality Improvement Collaborative recruited five endocrinology centers to pilot an equity-focused quality improvement (QI) study to reduce racial inequities in CGM use. The centers used rapid QI cycles to test and expand interventions such as provider bias training, translation of CGM materials, provision of CGM education in multiple languages, screening for social determinants of health, and shared decision-making. After implementation of these interventions, median CGM use increased by 7% in non-Hispanic White, 12% in non-Hispanic Black, and 15% in Hispanic people with type 1 diabetes. The gap between non-Hispanic White and non-Hispanic Black patients decreased by 5%, and the gap between non-Hispanic White and Hispanic patients decreased by 8%.

The Use of Diabetes Technology to Address Inequity in Health Outcomes: Limitations and Opportunities.

PURPOSE OF REVIEW: The management of diabetes has been revolutionized by the introduction of novel technological treatments and modalities of care, such as continuous glucose monitoring, insulin pump therapy, and telehealth. While these technologies have demonstrated improvement in health outcomes, it remains unclear whether they have reduced inequities from racial/ethnic minority or socioeconomic status. We review the current literature to discuss evidence of benefit, current limitations, and future opportunities of diabetes technologies. FINDINGS: While there is ample evidence of the health and psychological benefit of diabetes technologies in large populations of people with type 1 and type 2 diabetes, there remain wide disparities in the use of diabetes technologies, which may be perpetuating or widening inequities. Multilevel barriers include inequitable prescribing practices, lack of support for social determinants of health, mismatch of patient preferences and care models, and cost. We provide a review of disparities in diabetes technology use, possible root causes of continued inequity in outcomes, and insight into ways to overcome remaining gaps.

Achieving Equity in Diabetes Research: Borrowing From the Field of Quality Improvement Using a Practical Framework and Improvement Tools.

There are limited tools to address equity in diabetes research and clinical trials. The T1D Exchange has established a 10-step equity framework to advance equity in diabetes research. Herein, the authors outline this approach and expand on its practical application.

Factors Associated With Improved A1C Among Adults With Type 1 Diabetes in the United States.

Many adults with diabetes do not reach optimal glycemic targets, and, despite advances in diabetes management, diabetes technology use remains significantly lower in racial/ethnic minority groups. This study aimed to identify factors associated with achieving the recommended A1C target of <7% using data on 12,035 adults with type 1 diabetes from 15 centers participating in the T1D Exchange Quality Improvement Collaborative. Individuals attaining the target A1C were more likely to be older, White, have private health insurance, and use diabetes technology and less likely to report depressive symptoms or episodes of severe hypoglycemia or diabetic ketoacidosis than those with higher A1C levels. These findings highlight the importance of overcoming inequities in diabetes care.

Effect of lacosamide on neuroinflammation-mediated seizures comorbid with depression in C57BL/6 mice- Role of kynurenine pathway.

Comorbid conditions in persons with epilepsy (PWE) are very common with depression being highly prevalent. Lacosamide (LCM) is used to treat patients with seizures, but the underlying pathways associating the seizures and comorbid depression are still unknown. Kynurenine pathway (KP) has a major role in seizures, inflammation as well as depression, considering which we evaluated the effect of LCM on kynurenine levels in murine model of neuroinflammation-mediated seizures. We then evaluated the effects on the depressive symptoms associated with seizures. Lipopolysaccharide (LPS) primed pilocarpine (PILO) is an established model for neuro-inflammation-mediated seizures. The anti-seizure and anti-depressive effects of 21 days of LCM administration were studied in this model. After 24 h of seizure termination, behavioral parameters viz. forced swimming test and sucrose preference test were performed to study its antidepressant effect. Biochemical estimations of levels of kynurenine, inflammatory cytokines, and oxidative markers were also evaluated. Lacosamide significantly reduced hippocampal kynurenine levels in LPS and LPS + PILO groups but did not show significant reduction in the PILO alone group. Levels of inflammatory cytokines and oxidative stress markers were also reduced significantly. Lacosamide has shown positive effects against neuroinflammation-mediated model of seizures comorbid with depression by reducing hippocampal kynurenine levels. No reduction in the PILO group is suggestive of the principal contribution of its anti-inflammatory and antioxidant activity in its anti-seizure potential in this model via KP.

Identifying and Reducing Disparities in Young Adults With Diabetes.

This article outlines how social and health care determinants can affect young adults with diabetes. The authors provide a detailed description of each determinant's influence on diabetes self-management and offer solutions to help mitigate these harmful effects.

Disparities in Care Delivery and Outcomes in Young Adults With Diabetes.

PURPOSE OF REVIEW: This review summarizes the literature on care and outcome disparities in young adults (YA) with type 1 and type 2 diabetes, and outlines remaining needs and suggestions to reduce disparities and improve care. RECENT FINDINGS: Despite well-documented disparities and data from large national and international diabetes populations, the role that social determinants of health play in disease management is largely unstudied. Further, mechanisms of how these risk factors interact with the unique developmental needs of racial-ethnic minority and economically vulnerable young adults with diabetes remain unknown. Little intervention research has focused on improving outcomes in this vulnerable population. More research needs to focus on identifying and addressing risk factors in racial-ethnic minority and economically vulnerable young adults with diabetes. Interventions need to be adapted and developed to meet the unique needs of this high-risk population. Clinicians and healthcare systems must recognize the inequity in care and outcomes for this group and structure clinical programs and policies to promote their optimal care.

Support Vector Algorithms for Optimizing the Partial Area under the ROC Curve.

The area under the ROC curve (AUC) is a widely used performance measure in machine learning. Increasingly, however, in several applications, ranging from ranking to biometric screening to medicine, performance is measured not in terms of the full area under the ROC curve but in terms of the partial area under the ROC curve between two false-positive rates. In this letter, we develop support vector algorithms for directly optimizing the partial AUC between any two false-positive rates. Our methods are based on minimizing a suitable proxy or surrogate objective for the partial AUC error. In the case of the full AUC, one can readily construct and optimize convex surrogates by expressing the performance measure as a summation of pairwise terms. The partial AUC, on the other hand, does not admit such a simple decomposable structure, making it more challenging to design and optimize (tight) convex surrogates for this measure. Our approach builds on the structural SVM framework of Joachims ( 2005 ) to design convex surrogates for partial AUC and solves the resulting optimization problem using a cutting plane solver. Unlike the full AUC, where the combinatorial optimization needed in each iteration of the cutting plane solver can be decomposed and solved efficiently, the corresponding problem for the partial AUC is harder to decompose. One of our main contributions is a polynomial time algorithm for solving the combinatorial optimization problem associated with partial AUC. We also develop an approach for optimizing a tighter nonconvex hinge loss-based surrogate for the partial AUC using difference-of-convex programming. Our experiments on a variety of real-world and benchmark tasks confirm the efficacy of the proposed methods.

Perspectives on care for young adults with type 1 diabetes transitioning from pediatric to adult health systems: A national survey of pediatric endocrinologists.

BACKGROUND: Healthcare transition from pediatric to adult care for young adults (YA) with type 1 diabetes (T1D) is associated with risk of adverse outcomes. Consensus recommendations exist from US professional societies on transition care for YA with T1D, but it is not known whether they have been widely adopted. We describe experiences, barriers, and provider characteristics associated with transition care in a national sample of pediatric endocrinologists. METHODS: US pediatric endocrinologists identified through the American Medical Association Physician Masterfile were sent an electronic survey. RESULTS: Response rate was 16% (164/1020) representing 32 states. The majority of pediatric endocrinologists (age 44 ± 10; years in practice 12 ± 11) were female (67%) and worked in academic centers (75%). Main reasons for transfer were age (49%) and glycemic control (18%). Barriers to transition included ending long-therapeutic relationships with patients (74%), lack of transition protocols (46%), and perceived deficiencies in adult care (42%). The majority of pediatric endocrinologists reported lack of transition training (68%); those who received training were less likely to have difficulty ending patient relationships [odds ratio (OR) = 0.39, P = .03], more likely to perform patient record transfer to adult systems (OR=1.27, P = .006), and less likely to report patient returns to pediatric care after transfer (OR=0.49, P = .01), independent of endocrinologist gender, years in practice, or practice type. CONCLUSIONS: There is wide variation in transition care for YA with T1D among US pediatric endocrinologists despite consensus recommendations. Dissemination of educational programming on transition care and provision of actionable solutions to overcome local health system and perceived barriers is needed.

Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain.

Vibrio cholerae O1 El Tor strains have been responsible for pandemic cholera since 1961. These strains have evolved over time, spreading globally in three separate waves. Wave 3 is caused by altered El Tor (AET) variant strains, which include the strain with the signature ctxB7 allele that was introduced in 2010 into Haiti, where it caused a devastating epidemic. In this study, we used phenotypic analysis to compare an early isolate from the Haiti epidemic to wave 1 El Tor isolates commonly used for research. It is demonstrated that the Haiti isolate has increased production of cholera toxin (CT) and hemolysin, increased motility, and a reduced ability to form biofilms. This strain also outcompetes common wave 1 El Tor isolates for colonization of infant mice, indicating that it has increased virulence. Monitoring of CT production and motility in additional wave 3 isolates revealed that this phenotypic variation likely evolved over time rather than in a single genetic event. Analysis of available whole-genome sequences and phylogenetic analyses suggested that increased virulence arose from positive selection for mutations found in known and putative regulatory genes, including hns and vieA, diguanylate cyclase genes, and genes belonging to the lysR and gntR regulatory families. Overall, the studies presented here revealed that V. cholerae virulence potential can evolve and that the currently prevalent wave 3 AET strains are both phenotypically distinct from and more virulent than many El Tor isolates.

The Streptococcus pyogenes orphan protein tyrosine phosphatase, SP-PTP, possesses dual specificity and essential virulence regulatory functions.

Group A Streptococcus (GAS) is a human pathogen that causes high morbidity and mortality. GAS lacks a gene encoding tyrosine kinase but contains one encoding tyrosine phosphatase (SP-PTP). Thus, GAS is thought to lack tyrosine phosphorylation, and the physiological significance of SP-PTP is, therefore, questionable. Here, we demonstrate that SP-PTP possesses dual phosphatase specificity for Tyr- and Ser/Thr-phosphorylated GAS proteins, such as Ser/Thr kinase (SP-STK) and the SP-STK-phosphorylated CovR and WalR proteins. Phenotypic analysis of GAS mutants lacking SP-PTP revealed that the phosphatase activity per se positively regulates growth, cell division and the ability to adhere to and invade host cells. Furthermore, A549 human lung cells infected with GAS mutants lacking SP-PTP displayed increased Ser-/Thr-/Tyr-phosphorylation. SP-PTP also differentially regulates the expression of ∼50% of the total GAS genes, including several virulence genes potentially through the two-component regulators, CovR, WalR and PTS/HPr regulation of Mga. Although these mutants exhibit attenuated virulence, a GAS mutant overexpressing SP-PTP is hypervirulent. Our study provides the first definitive evidence for the presence and importance of Tyr-phosphorylation in GAS and the relevance of SP-PTP as an important therapeutic target.

Vibrio cholerae MARTX toxin heterologous translocation of beta-lactamase and roles of individual effector domains on cytoskeleton dynamics.

The Vibrio cholerae MARTXVc toxin delivers three effector domains to eukaryotic cells. To study toxin delivery and function of individual domains, the rtxA gene was modified to encode toxin with an in-frame beta-lactamase (Bla) fusion. The hybrid RtxA::Bla toxin was Type I secreted from bacteria; and then Bla was translocated into eukaryotic cells and delivered by autoprocessing, demonstrating that the MARTXVc toxin is capable of heterologous protein transfer. Strains that produce hybrid RtxA::Bla toxins that carry one effector domain in addition to Bla were found to more efficiently translocate Bla. In cell biological assays, the actin cross-linking domain (ACD) and Rho-inactivation domain (RID) are found to cross-link actin and inactivate RhoA, respectively, when other effector domains are absent, with toxin autoprocessing required for high efficiency. The previously unstudied alpha-beta hydrolase domain (ABH) is shown here to activate CDC42, although the effect is ameliorated when RID is also present. Despite all effector domains acting on cytoskeleton assembly, the ACD was sufficient to rapidly inhibit macrophage phagocytosis. Both the ACD and RID independently disrupted polarized epithelial tight junction integrity. The sufficiency of ACD but strong selection for retention of RID and ABH suggests these two domains may primarily function by modulating cell signaling.

Induced autoprocessing of the cytopathic Makes caterpillars floppy-like effector domain of the Vibrio vulnificus†MARTX toxin.

The multifunctional-autoprocessing repeats-in-toxin (MARTX(Vv)) toxin that harbours a varied repertoire of effector domains is the primary virulence factor of Vibrio vulnificus. Although ubiquitously present among Biotype I toxin variants, the 'Makes caterpillars floppy-like' effector domain (MCF(Vv)) is previously unstudied. Using transient expression and protein delivery, MCF(Vv) and MCF(Ah) from the Aeromonas hydrophila MARTX(Ah)) toxin are shown for the first time to induce cell rounding. Alanine mutagenesis across the C-terminal subdomain of MCF(Vv) identified an Arg-Cys-Asp (RCD) tripeptide motif shown to comprise a cysteine protease catalytic site essential for autoprocessing of MCF(Vv). The autoprocessing could be recapitulated in vitro by the addition of host cell lysate to recombinant MCF(Vv), indicating induced autoprocessing by cellular factors. The RCD motif is also essential for cytopathicity, suggesting autoprocessing is essential first to activate the toxin and then to process a cellular target protein resulting in cell rounding. Sequence homology places MCF(Vv) within the C58 cysteine protease family that includes the type III secretion effectors YopT from Yersinia spp. and AvrPphB from Pseudomonas syringae. However, the catalytic site RCD motif is unique compared with other C58 peptidases and is here proposed to represent a new subgroup of autopeptidase found within a number of putative large bacterial toxins.