Rationale of Basic and Cellular Mechanisms Considered in Updating the Staging System for Diabetic Retinal Disease.

Purpose: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness. Design: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system. Participants: Not applicable. Methods: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these. Main Outcome Measures: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD. Results: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome. Conclusion: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Discovery of PSMA in the prostate of the common marmoset (Callithrix jacchus).

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a biomarker and therapeutic target of high relevance in prostate cancer. Although upregulated PSMA expression is a well-documented feature of prostatic neoplasia in both humans and canids, to date humans are the only species known to express PSMA basally in the prostate. Thus, traditional laboratory animal species have limited utility for studying PSMA biology in the prostate or for predicting efficacy or toxicity of PSMA-targeted agents. METHODS: PSMA expression in human, macaque, and marmoset prostates was determined by immunohistochemistry, employing an antibody with validated cross-species reactivity in a PSMA-positive control tissue; kidney. RESULTS: We newly discover that the common marmoset endogenously expresses PSMA in non-diseased prostate, similar to humans, and thus may be a valuable preclinical model for researchers studying PSMA.

Malglycemia in the critical care setting. Part III: Temporal patterns, relative potencies, and hospital mortality.

INTRODUCTION: The relationship between critical care mortality and combined impact of malglycemia remains undefined. METHODS: We assessed the risk-adjusted relationship (n = 4790) between hospital mortality with malglycemia, defined as hypergycemia (hours Glycemic Ratio ≥ 1.1, where GR is quotient of mean ICU blood glucose (BG) and estimated average BG), absolute hypoglycemia (hours BG < 70 mg/dL) and relative hypoglycemia (excursions GR < 0.7 in those with HbA1c ≥ 8%). RESULTS: Each malglycemia was independently associated with mortality - hyperglycemia (OR 1.0020/h, 95%CI 1.0009-1.0031, p = 0.0004), absolute hypoglycemia (OR 1.0616/h, 95%CI 1.0190-1.1061, p = 0.0043), and relative hypoglycemia (OR 1.2813/excursion, 95%CI 1.0704-1.5338, p = 0.0069). Absolute (7.4%) and relative hypoglycemia (6.7%) exposure dominated the first 24 h, decreasing thereafter. While hyperglycemia had lower risk association with mortality, it was persistently present across the length-of-stay (68-76% incidence daily), making it the dominant form of malglycemia. Relative contributions in the first five days from hyperglycemia, absolute hypoglycemia and relative hypoglycemia were 60%, 21% and 19% respectively. CONCLUSIONS: Absolute and relative hypoglycemia occurred largely in the first 24 h. Relative to all hypoglycemia, the associated mortality from the seemingly less potent but consistently more prevalent hyperglycemia steadily accumulated with increasing length-of-stay. This has important implications for interpretation of study results.

Malglycemia in the critical care setting. Part II: Relative and absolute hypoglycemia.

INTRODUCTION: The relationship between critical care mortality and hypoglycemia, both relative (>30% below average preadmission glycemia) and absolute (blood glucose (BG) <70 mg/dL (<10 mmol/L)) requires further definition. METHODS: We assessed the risk-adjusted relationship between hospital mortality with relative hypoglycemia using the Glycemic Ratio (GR), and with absolute hypoglycemia using BG in a retrospective cohort investigation (n = 4790). RESULTS: Relative hypoglycemia excursions below GR 0.7 with a of 24-h non-exposure period between excursions in those with HbA1c ≥ 8% were independently associated with mortality (n = 373, OR 2.49, 95% CI 1.54-4.04, p = 0.0002) but not those with HbA1c < 8% (n = 4417, OR 0.98 95% CI 0.89-1.08, p = 0.70). Hours below GR 0.7 (1.0037, 0.9995-1.0080, 0.0846) or minimum GR (0.0896, 0.0030-2.6600, 0.1632) were not independently associated with outcome. Absolute hypoglycemia occurred across the HbA1c spectrum in a U-shaped pattern. There was no difference in mortality associated with exposure to BG < 70 mg/dL for HbA1c ≥ 6.5% vs <6.5% (29.7% vs 24.3%, p = 0.77). Hours below 70 mg/dL demonstrated strongest association with outcome, while minimum BG, and excursions below 70 mg/dL were also independently associated. CONCLUSIONS: Relative hypoglycemia represented by excursions below GR 0.7 in those with HbA1c ≥ 8% occurred commonly and was independently associated with mortality. Absolute hypoglycemia had similar association with mortality regardless of HbA1c.