Bringing an end to diabetes stigma and discrimination: an international consensus statement on evidence and recommendations.

People with diabetes often encounter stigma (ie, negative social judgments, stereotypes, prejudice), which can adversely affect emotional, mental, and physical health; self-care, access to optimal health care; and social and professional opportunities. To accelerate an end to diabetes stigma and discrimination, an international multidisciplinary expert panel (n=51 members, from 18 countries) conducted rapid reviews and participated in a three-round Delphi survey process. We achieved consensus on 25 statements of evidence and 24 statements of recommendations.

L-Methylfolate in Diabetic Peripheral Neuropathy: A Narrative Review.

Objective: One of the most frequently occurring complications of diabetes mellitus is peripheral neuropathy. Despite the painful symptoms associated with diabetic peripheral neuropathy (DPN), the current treatment landscape focuses on managing symptoms without addressing the underlying causes of DPN. This narrative review describes the mechanistic effects and clinical trial data supporting the use of L-methylfolate calcium (LMF), the bioactive form of folate, which is available in the United States as a prescription medical food that also contains other B vitamins for the dietary management of DPN.

Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice.

SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death.

Limitations of mouse models for sickle cell disease conferred by their human globin transgene configurations.

We characterized the human β-like globin transgenes in two mouse models of sickle cell disease (SCD) and tested a genome-editing strategy to induce red blood cell fetal hemoglobin (HbF; α2γ2). Berkeley SCD mice contain four to 22 randomly arranged, fragmented copies of three human transgenes (HBA1, HBG2-HBG1-HBD-HBBS and a mini-locus control region) integrated into a single site of mouse chromosome 1. Cas9 disruption of the BCL11A repressor binding motif in the γ-globin gene (HBG1 and HBG2; HBG) promoters of Berkeley mouse hematopoietic stem cells (HSCs) caused extensive death from multiple double-strand DNA breaks.

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia.

Unlabelled: The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases.

Canagliflozin for the Treatment of Diabetic Kidney Disease and Implications for Clinical Practice: A Narrative Review.

Type 2 diabetes mellitus (T2DM) affects millions of people worldwide, elevating their risk of developing a range of complications, including chronic kidney disease (CKD). People with T2DM and CKD (i.e.

The Most Important Thing We Give to People Is Hope: Overcoming Stigma in Diabetes and Obesity.

This article is adapted from the address Ms. Valentine delivered as the recipient of the American Diabetes Association's (ADA's) Outstanding Educator in Diabetes Award for 2019. She delivered the address in June 2019 at the Association's 79th Scientific Sessions in San Francisco, CA.

Human Factors Usability and Validation Studies of a Glucagon Autoinjector in a Simulated Severe Hypoglycemia Rescue Situation.

A room-temperature stable, soluble liquid glucagon formulation loaded into a prefilled, single-use, two-step autoinjector is under development for severe hypoglycemia rescue. We report a human factors validation program evaluating the glucagon autoinjector (GAI) (Gvoke HypoPen™; Xeris Pharmaceuticals, Inc., Chicago, IL) versus marketed glucagon emergency kits (GEKs) for managing severe hypoglycemia.

Adjunct Therapy in Type 1 Diabetes: A Survey to Uncover Unmet Needs and Patient Preferences Beyond HbA1c Measures.

Adjunct therapy can help patients with type 1 diabetes achieve glycemic goals while potentially mitigating some of the side effects of insulin. In this study, we used a patient survey to identify the unmet needs in type 1 diabetes therapy, patient views of treatment benefit-risk trade-offs, and patient preferences for the use of an adjunct therapy. A quantitative survey was sent to 2084 adults with type 1 diabetes in November 2017.

Genomic subtyping and therapeutic targeting of acute erythroleukemia.

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival.

Optimizing Fixed-Ratio Combination Therapy in Type 2 Diabetes.

The progressive nature of type 2 diabetes (T2D) means that many patients will require basal insulin therapy at some point in the course of the disease due to β-cell failure. As basal insulin primarily targets fasting plasma glucose, patients may still experience considerable postprandial glucose excursions and therefore require an additional agent to achieve good glycemic control. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide an alternative to prandial insulin, with the benefits of fewer daily injections, and a lower risk of hypoglycemia and weight gain.

How Similar Are Biosimilars? What Do Clinicians Need to Know About Biosimilar and Follow-On Insulins?

As more patents on biological medicines expire, increased numbers of biologic copies, referred to as "biosimilars," will likely become available in the United States in the coming years. With greater availability and the drive for health care savings, the use of biosimilars and of "follow-on" biological products is likely to increase in routine clinical practice. Health care practitioners need to be fully aware of these products and accompanying considerations if they are to make informed decisions together with their patients.

ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer.

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras). We show that partial or total ATM deficiency cooperates with Kras to promote highly metastatic pancreatic cancer.

Rationale for, Initiation and Titration of the Basal Insulin/GLP-1RA Fixed-Ratio Combination Products, IDegLira and IGlarLixi, for the Management of Type 2 Diabetes.

Type 2 diabetes (T2D) is a progressive disease affecting glucose regulation and a major cause of morbidity and mortality globally. Many patients are not escalated up the treatment ladder appropriately despite failing to achieve glycemic control, with barriers such as fear of hypoglycemia, weight gain, and treatment burden recognized as factors. Exogenous basal insulin is titrated to address control of fasting plasma glucose and may preserve residual β-cell function, thus promoting a greater endogenous prandial insulin response.

INSULIN TIMING: A PATIENT-CENTERED APPROACH TO IMPROVE CONTROL IN TYPE 1 DIABETES.

Objective: The goal of insulin therapy in type 1 diabetes (T1D) is to reduce hemoglobin A1C (A1C) to ≤7.0% (53 mmol/mol) with minimal hypoglycemia. We investigated the possibility that "insulin timing" would improve A1C without incurring severe hypoglycemia in volunteers with T1D over a 6-month observation period.

Modeling of the human alveolar rhabdomyosarcoma Pax3-Foxo1 chromosome translocation in mouse myoblasts using CRISPR-Cas9 nuclease.

Many recurrent chromosome translocations in cancer result in the generation of fusion genes that are directly implicated in the tumorigenic process. Precise modeling of the effects of cancer fusion genes in mice has been inaccurate, as constructs of fusion genes often completely or partially lack the correct regulatory sequences. The reciprocal t(2;13)(q36.

Clinical implications of canagliflozin treatment in patients with type 2 diabetes.

IN BRIEF Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antihyperglycemic agents that lower blood glucose levels in patients with type 2 diabetes. SGLT2 inhibitors have an insulin-independent mechanism of action, acting to inhibit the reabsorption of glucose in the kidney, which leads to increases in urinary glucose excretion in individuals with elevated blood glucose levels. This article provides an overview of the role of the kidney in type 2 diabetes, describes the rationale for renal SGLT2 as a new target for glycemic control, and focuses on the clinical implications of incorporating the SGLT2 inhibitor canagliflozin into type 2 diabetes treatment regimens based on data from phase 3 studies.

Is the masked continuous glucose monitoring system clinically useful for predicting hemoglobin A1C in type 1 diabetes?

Background: The masked continuous glucose monitoring system (Masked-CGMS) differs from standard CGMSs in three ways: (1) there is no feedback to the user so that no immediate regimen changes can be made; (2) it can only be worn for up to 5 days; and (3) there are no alarms to warn of hyperglycemia or hypoglycemia. Since 2008 masked-CGMS has become popular for identifying reasons that a patient's hemoglobin A1C does not correlate closely with his or her capillary blood glucose measurements. To date only one study addressing the clinical utility of Masked-CGMS for improving A1C in diabetes has been published.

Simultaneous gene editing by injection of mRNAs encoding transcription activator-like effector nucleases into mouse zygotes.

Injection of transcription activator-like effector nucleases (TALEN) mRNAs into mouse zygotes transferred into foster mothers efficiently generated founder mice with heritable mutations in targeted genes. Immunofluorescence visualization of phosphorylated histone 2A (γH2AX) combined with fluorescence in situ hybridization revealed that TALEN pairs targeting the Agouti locus induced site-directed DNA breaks in zygotes within 6 h of injection, an activity that continued at reduced efficiency in two-cell embryos. TALEN-Agouti mRNAs injected into zygotes of brown FvB × C57BL/6 hybrid mice generated completely black pups, confirming that mutations were induced prior to, and/or early after, cell division.

Targeting oxidative stress in embryonal rhabdomyosarcoma.

Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors.

Practice tips and tools for the successful use of U-500 regular human insulin: the diabetes educator is key.

This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin.

Cross-species genomic and epigenomic landscape of retinoblastoma.

Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma.