Reduction In Hemoglobin Research Articles

Abstract 1374: The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models

Abstract Current clinical poly (ADP-ribose) polymerase (PARP) inhibitors target both PARP1 and PARP2 and they all cause clinical cytopenias with varying severity. Understanding the mechanism underlying the hematological toxicity of these agents is key for the rational design of a best-in-class molecule with greater therapeutic potential, both as monotherapy and in combination with chemotherapy. We validated the rat as a physiologically competent translational model to investigate PARP inhibitor-driven hematological toxicity. Here we demonstrate that in comparison with a representative PARP1/2 inhibitor, olaparib, the novel highly potent PARP1-selective inhibitor and trapper, AZD5305, does not cause hematological toxicity as a monotherapy in pre-clinical rat models at predicted clinically efficacious exposures. Thus, monotherapy toxicity of PARP1/2 inhibitors likely depends on PARP2 inhibition. Next, we proceeded to investigate whether PARP1-selective inhibition would be better tolerated in chemotherapy combinations than PARP1/2 inhibition. We performed a rat in vivo study comparing daily olaparib or daily AZD5305 at matched exposures in combination with one cycle of intravenous carboplatin for 14 days. We show that olaparib and PARP1-selective AZD5305 cause comparable exacerbation of carboplatin-induced peripheral blood effects implicating PARP1 inhibition in combination-driven hematological toxicity. Importantly however, AZD5305+carboplatin showed improved hematological tolerability over olaparib+carboplatin because peripheral reticulocytes and bone marrow erythroid precursor cells recover in the presence of continuous AZD5305 but not in the presence of continuous olaparib. Importantly, this differentiation was maintained in a subsequent rat in vivo study, where daily olaparib or daily AZD5305 were combined with two three-weekly cycles of a higher dose of carboplatin to more closely mimic clinical protocol. AZD5305+carboplatin was associated with a more rapid recovery of reticulocytes, red blood cells and hemoglobin following both cycles of carboplatin. In contrast, olaparib+carboplatin was associated with a slower recovery resulting in a more sustained reduction in red cells and hemoglobin during both the first and second cycle of carboplatin. Thus, in rodents the novel potent PARP1-selective inhibitor AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors, both as a monotherapy and in carboplatin combinations. Citation Format: Sonja J. Gill, Ruth Macdonald, Carmen Pin, Rob Collins, Emilyanne Leonard, Gareth Maglennon, Andy Pike, Peter Cotton, Glen Hawthorne, Jordan Pugh, Rebecca Sargeant, Daniel Sutton, James Atkinson, Stewart Jones, Sarah Chinery, Mark Anderton. The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1374.

IMPACT India

India has the second largest population with diabetes mellitus in the world. Long-term, uncontrolled diabetes is associated with increased microvascular and macrovascular (commonly cardiovascular) complications and death. The large burden of uncontrolled diabetes in India could be because of lack of treatment adherence, limited access to laboratory testing, lack of physical activity, and poor dietary habits. This creates a compelling need for a greater involvement of healthcare professionals (HCPs) in improving societal awareness and regular monitoring of glycemic control, which is limited in patient outreach programs. IMPACT India, launched in November 2018, is a diabetes control program with a three-pronged approach aimed at creating an impact at the level of HCPs, society, and individuals living with diabetes. The India Diabetes Care Index (iDCI®), a quarterly aggregate index of glycated hemoglobin, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG), forms the backbone of IMPACT India. The program uses iDCI® to evaluate glycemic control at periodic intervals, sensitize HCPs about the glycemic control status, and optimize diabetes care by escalating pharmacotherapy including insulin whenever required. Societal awareness will be created by social media to achieve actionable awareness based on the iDCI® reports. At baseline (January 2018 to June 2018), the database (2.39 million) revealed an average glycated hemoglobin of 8.56%, FPG of 172 mg/dL, and PPG of 253 mg/dL. Also, 74% of the patients had HbA1c >7% and FPG >130 mg/dL and >83% of the patients had PPG >160 mg/dL. The IMPACT India program aims to positively impact diabetes care in India by achieving at least 1% glycated hemoglobin reduction in 1000 days.

Glycated haemoglobin reduction and fixed ratio combinations of analogue basal insulin and glucagon-like peptide-1 receptor agonists: A systematic review

Glycated haemoglobin reduction and fixed ratio combinations of analogue basal insulin and glucagon-like peptide-1 receptor agonists: A systematic review

Quantifying the Pathophysiology of Beta-Thalassemia Using a Novel in-Silico Model of Red Blood Cell Production and Lifespan

Background: From a qualitative perspective the pathophysiology of beta-thalassemia (BT) is generally well understood. Reduction in hemoglobin (Hb) beta-chain synthesis relative to the normal rate of alpha-chain synthesis causes a free alpha-chain excess (ACE) that is toxic to the RBC and its precursors. Circulating RBCs are hemolyzed in the spleen, shortening their lifespan from the normal value of 120 days. RBC precursors in the bone marrow undergo early apoptosis leading to reduced RBC production relative to other anemic states (so called “ineffective erythropoiesis”). Together with low MCH levels these mechanisms lead to Hb levels ranging from 10 - 12 g/dL in BT trait, 7 - 10 g/dL in non-transfusion dependent (NTD) BT, below 7 g/dL in transfusion-dependent (TD) BT at baseline and above 9 - 10.5 g/dL in TD patients receiving regular transfusions administered every 2 to 5 weeks. To quantify the mechanisms responsible for the different BT phenotypes and the response to transfusion in TD patients, we have developed an in-silico model of RBC production and lifespan.Methods: The theoretical amount of ACE per cell was estimated by assuming that the alpha-chain level corresponds to an MCH of 30 pg and the non-alpha chain level (beta, gamma and delta chains) corresponds to the MCH of the BT phenotype, which varies from ~12 to 20 pg in TD BT to ~16 to 23 pg in NTD BT and ~18 to 24 pg in BT trait. The in-silico model consists of a bone marrow module - representing the production and aging of reticulocytes, Hb synthesis and entry to the bloodstream (equivalent to the RBC production rate, PRBC); a circulation module - representing the total blood volume (TBV), conversion of reticulocytes to mature RBCs, attainment of the final MCH, normal aging of RBCs, and a hemolytic process in BT (with rate constant kH that depends on the ACE level); and a transfusion module - representing the volume of transfused blood (VTF) with hematocrit H, a normal RBC age-distribution, and a separate hemolytic process (with rate constant kH_Tf). Reticulocyte lifespans in the bone marrow and circulation were set to ~3 days and ~1 day, respectively, but can vary oppositely at high PRBC (stress erythropoiesis). A key assumption of the model is that PRBC is down-regulated by the Hb level according to a sigmoidal Hill function, which was calibrated using PRBC data from normal subjects and patients with sickle cell disease, and was assumed to have a maximum value 10-fold the normal PRBC rate. In BT the PRBC function is also modulated by a factor FBT, dependent on the ACE level. Additional data from BT patients were used to derive the kH and FBT values. The model was expressed in ordinary differential equations using the Berkeley Madonna platform (Version 8.3.18).Results: To simulate the spectrum of BT phenotypes, MCH levels were varied from 15 pg to the normal value of 30 pg and the ACE levels, kH and FBT values were computed from the model. The simulated steady-state dependences of Hb vs. MCH (Figure 1A) and Reticulocyte count vs. Hb level (Figure 1B) are in good agreement with published literature data. For virtual patients (VPs) with MCH levels of 23, 21 and 18 pg, typical of BT trait, NTD and TD phenotypes, respectively, the estimated ACE levels were 0.22, 0.28 and 0.38 fmole/cell; kH values were 0.01, 0.019 and 0.037 day-1 and values of FBT were 0.65, 0.6 and 0.55. The effective RBC lifespans for these VPs were 68, 47 and 23 days, respectively. Regular transfusions (VTF = 15 mL/kg; H = 0.6) were simulated over 24 weeks for a TD VP (MCH = 18 pg; baseline Hb = 6.61 g/dL) to maintain the Hb level above 9 g/dL. In Figure 2A, where kH_Tf = 0 (no hemolysis of transfused blood), the transfusion interval stabilizes at 3.71 weeks. In Figure 2B, where kH_Tf = 0.0165 day-1(an effective RBC lifespan of 50.7 days), the transfusion interval stabilizes at 2 weeks. Reticulocyte counts decrease markedly in both cases. To achieve a ~3 g/dL increment in the Hb level, TBV must equal 100 mL/kg (~40% greater than normal).Conclusions: Our in-silico model explains the phenotypic variation of Hb levels and reticulocyte counts in BT in terms of the effects of ACE on the hemolysis rate constant (kH) and the fractional reduction in RBC production (FBT). The 2-week transfusion interval required in some patients to maintain Hb above 9 g/dL is explained by a shortened lifespan of the transfused blood. More clinical data would be helpful to confirm and refine these observations to better understand the key drivers of disease pathology in BT. [Display omitted] DisclosuresMazer:Roche: Employment, Equity Ownership. Hermosilla:Roche: Employment. Koerner:Roche: Employment.

Clinical Risk Factors Associated with Recurrent Venous Thromboembolism and Major Bleeding in Gastrointestinal Cancer Patients Receiving Doacs for Secondary Thromboprophylaxis

IntroductionCancer associated venous thromboembolism (VTE) is associated with a significant morbidity and mortality burden in cancer care, and anticoagulation offers a survival benefit. Recurrent VTE and major bleeding complications due to secondary prophylaxis remain a salient issue in treating patients with cancer associated-VTE, regardless of validated risk assessment models. Gastrointestinal (GI) cancers confer an increased risk for recurrent VTE and bleeding. We evaluated our current institutional utilization of Direct Oral Anticoagulants (DOACs) in patients with active GI malignancies addressing both efficacy and safety profiles with these agents. We estimated the association strength between each risk factor and the outcomes to further contribute in future risk assessment tools.MethodsThis is a retrospective chart review of patients receiving DOACs with histologically proven GI malignancy and a symptomatic or incidental VTE treated at the University of Arizona Cancer Center from November 2013 to February 2017. Patients were excluded if DOACs were prescribed for any other reason not related to VTE: VTE was determined to be in the context of a non-GI malignancy or when anticoagulation was contraindicated. The primary efficacy outcome was defined as documented recurrent deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), or fatal PE before and after 6 months of DOAC therapy. The secondary safety outcome was defined as documented major bleeding (hemoglobin reduction of ≥2 g/dL, requirement of transfusion of ≥2 units of Packed Red Blood Cells, bleeding in a critical site, or bleeding contributing to death) before and after 6 months of therapy. Descriptive statistical analyses were utilized. The t- test was performed to compare continuous variables. Fisher exact test is used for testing the difference in categorical variables. Odds ratios were used to compare the relative odds of the occurrence of the outcome given exposure to the risk factor. The 95% confidence interval (CI) was used to estimate the precision of the OR. Results were determined to be ‘statistically significant’ when this value was less than or equal to 0.05.ResultsOur review included 62 patients with balanced baseline characteristics whom were prescribed apixaban (n=28) and rivaroxaban (n=34) [Table 1]. Primary outcome events at 6 months were 4.8% in total (2 DVT & 1 PE); 7.4% (2 DVT) for patients on apixaban and 2.9% (1 PE) for those taking rivaroxaban. Beyond 6 months on DOACs therapy, 6.4% of patients experienced recurrent VTE (1 DVT event in the apixiban subgroup). Secondary outcome events at 6 months were 11.2% total (7 major bleeds), 7.1% (n=2) and 14.7% (n=5) for apixaban and rivaroxaban respectively. There were 2 bleeds contributing to death (hemopericardium and upper GI bleed) and 2 other bleed in critical sites (subarachnoid hemorrhage and retroperitoneal) in the rivaroxaban group, with all other adverse outcomes being upper or lower GI bleeds. Including those events beyond 6 months, 17.7% of patients had recorded bleeding events (2 additional major bleeds for each therapy). Significant predictors of a primary or secondary outcome were pancreatic cancer (OR, 9.6, 95% CI, 1.48 to 62.16, p =0.017), stage IV disease (OR, 15, 95% CI, 7.55 to 297.63, p = 0.0075) and high Khorana Score [≥3] (OR, 7.5, 95% CI, 1.3 to 43.92, p= 0.0238). Those who suffered a primary or secondary outcome were 67 times more likely to die within a month period, compared to those who completed their therapy (CI, 5.33 to 854.82, p = 0.0011).ConclusionsCancer associated VTE remains a challenging clinical scenario with a lack of data for utilization of DOACs in the setting of secondary prophylaxis. The utilization of DOACs in cancer patients provides another therapy for VTE secondary prophylaxis treatment, which must be weighed, based on safety profiles in our study population. The utilization of rivaroxaban led to a higher bleeding rate in patients, with both apixaban and rivaroxaban showing similar efficacy for prophylaxis. This study warrants further exploration of DOACs in the setting of VTE treatment for patients on active chemotherapy who are at high risk of recurrent VTE. In addition, further evaluation of clinical predictors that may influence the risk of VTE recurrence and major bleeding is warranted. Wide confidence intervals reflect of our sample size and future studies may benefit from multi-center participation to maximize sample size. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematological Profiles of Patients Referred to Intensive Care Unit Due to COVID-19 in Southern Saudi Arabia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic infection that emerged in December 2019 leading to an outbreak worldwide. We aimed to investigate the hematological parameters and coagulation profiles specifically for the referral of coronavirus disease 2019 (COVID-19) patients to intensive care unit (ICU) due to the severity of illness to determine a pathognomonic association of infection severity and the hematological markers. The pathognomonic markers could assist physicians in better management of the infection to reduce mortality and morbidity. Thirty patients infected with COVID-19 who were receiving treatment during November and October 2020, in the ICU at Asir Central Hospital, Asir Region, Saudi Arabia, were recruited. The age of patients ranged between 30 and 90 years old. COVID-19 patients in the ICU displayed a statistical reduction in red blood cells (RBCs), hemoglobin (HBG), and hematocrit (HCT). Leukocytosis, neutrophilia, thrombocytopenia, and lymphocytopenia were significant in ICU COVID-19 patients.�Hematological parameters and coagulation profiles may be used as signs to predict the severity of the coronavirus infection. COVID-19 cases in the ICU showed a dramatic change in hematological parameters and coagulation profiles, indicating that the virus may interfere with hemoglobin, platelet, and immune cell functions through either inhibition or stimulation, leading to severe complications.

Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

Objective:The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.Summary Background Data:This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.Methods:In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.Results:There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44–2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8–39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group.Conclusions:The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions.Trial Registration:ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Novel 4-Hydroxybenzyl Adducts in Human Hemoglobin: Structures and Mechanisms of Formation.

Humans are exposed to large numbers of electrophiles from their diet, the environment, and endogenous physiological processes. Adducts formed at the N-terminal valine of hemoglobin are often used as biomarkers of human exposure to electrophilic compounds. We previously reported the formation of hemoglobin N-terminal valine adducts (added mass, 106.042 Da) in the blood of human smokers and nonsmokers and identified their structure as 4-hydroxybenzyl-Val. In the present work, mass spectrometry-based proteomics was utilized to identify additional sites for 4-hydroxybenzyl adduct formation at internal nucleophilic amino acid side chains within hemoglobin. Hemoglobin isolated from human blood was treated with para-quinone methide (para-QM) followed by global nanoLC-MS/MS and targeted nanoLC-MS/MS to identify amino acid residues containing the 4-hydroxybenzyl modification. Our experiments revealed the formation of 4-hydroxybenzyl adducts at the αHis20, αTyr24, αTyr42, αHis45, βSer72, βThr84, βThr87, βSer89, βHis92, βCys93, βCys112, βThr123, and βHis143 residues (in addition to N-terminal valine) through characteristic MS/MS spectra. These amino acid side chains had variable reactivity toward para-QM with αHis45, αTyr42, βCys93, βHis92, and βSer72 forming the largest numbers of adducts upon exposure to para-QM. Two additional mechanisms for formation of 4-hydroxybenzyl adducts in humans were investigated: exposure to 4-hydroxybenzaldehyde (4-HBA) followed by reduction and UV-mediated reactions of hemoglobin with tyrosine. Exposure of hemoglobin to a 5-fold molar excess of 4-HBA followed by reduction with sodium cyanoborohydride produced 4-hydroxybenzyl adducts at several amino acid side chains of which αHis20, αTyr24, αTyr42, αHis45, βSer44, βThr84, and βHis92 were verified in targeted mass spectrometry experiments. Similarly, exposure of human blood to ultraviolet radiation produced 4-hydroxybenzyl adducts at αHis20, αTyr24, αTyr42, αHis45, βSer44, βThr84, and βSer89. Overall, our results reveal that 4-hydroxybenzyl adducts form at multiple nucleophilic sites of hemoglobin and that para-QM is the most likely source of these adducts in humans.

Alleviating Effects of Vitamins C and E Supplementation on Oxidative Stress, Hematobiochemical, and Histopathological Alterations Caused by Copper Toxicity in Broiler Chickens.

Simple SummaryExcessive copper in diets is associated with numerous disadvantageous impacts on poultry. The current study evaluated the efficacy of vitamin C and vitamin E in mitigating oxidative stress, hematobiochemical, and histopathological changes in the kidney induced by copper sulfate (CuSO4) toxicity in broiler chickens. The birds were assigned to five experimental groups: 1st group—basal diet with no additives (control group), 2nd group—basal diet complemented with CuSO4 (300 mg/kg diet), 3rd group—basal diet with CuSO4 (300 mg/kg diet) + vitamin C (250 mg/kg diet), 4th group—basal diet with CuSO4 (300 mg/kg diet) + vitamin E (250 mg/kg diet), and 5th group—basal diet with CuSO4 (300 mg/kg diet) + vitamin C (250 mg/kg diet) + vitamin E (250 mg/kg diet). The current study’s findings showed the possible preventive impacts of dietary antioxidants on hematobiochemical alterations, oxidative stress, and kidney damage induced by CuSO4 toxicity.The current investigation evaluated the alleviating effects of vitamin C and vitamin E on oxidative stress, hematobiochemical, and histopathological changes in the kidney induced by copper sulfate (CuSO4) toxicity in chickens. Two hundred and fifty-one-day-old male broiler chicks were randomly allotted into five experimental groups (five replicates/group, ten chicks/replicate): 1st group—basal diet with no additives (control group), 2nd group—basal diet complemented with CuSO4 (300 mg/kg diet), 3rd group—basal diet with CuSO4 (300 mg/kg diet) + vitamin C (250 mg/kg diet), 4th group—basal diet with CuSO4 (300 mg/kg diet) + vitamin E (250 mg/kg diet), and 5th group—basal diet with CuSO4 (300 mg/kg diet) + vitamin C (250 mg/kg diet) + vitamin E (250 mg/kg diet) for a 42 day feeding period. The results showed a significant reduction in red blood cells (RBCs), hemoglobin (Hb) concentration, and hematocrit values as well as total leukocyte counts (WBCs), lymphocyte, heterophil, and monocyte counts in the CuSO4-intoxicated birds (2.42 × 106/µL, 9.54 g/dL, 26.02%, 15.80 × 103/µL, 7.86 × 103/µL, 5.26 × 103/µL, and 1.18 × 103/µL, respectively, at the 6th week) compared to (2.79 × 106/µL, 10.98 g/dL, 28.46%, 21.07 × 103/µL, 10.84 × 103/µL, 7.12 × 103/µL, and 1.60 × 103/µL, respectively) in the control group. Moreover, CuSO4-intoxicated birds showed hypoglycemia with a rise in serum uric acid and creatinine levels (122.68, 5.18, and 0.78 mg/dL at the 6th week) compared to (159.46, 4.41, and 0.61 mg/dL) in the control group. The CuSO4 toxicity in birds induced oxidative stress, indicated by a high serum malondialdehyde level (MDA) and diminished activity of the antioxidant enzymes (glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD)) (2.01 nmol/mL, 37.66 U/mL, and 2.91 U/mL, respectively, at the 6th week) compared to (1.34 nmol/mL, 57.00 U/mL, 4.99 U/mL, respectively) in the control group. High doses of Cu exposure caused severe microscopic alterations in kidney architecture. The addition of vitamins C and E, singularly or in combination, displayed a beneficial effect in alleviating these harmful effects of Cu toxicity. These findings showed the possible mitigating impacts of dietary antioxidants on the hematobiochemical alterations, oxidative stress, and kidney damage induced by CuSO4 toxicity.

Efficacy and Cardiovascular Safety of Alpha Glucosidase Inhibitors.

Alpha Glucosidase Inhibitors (AGIs) are a group of drugs which act on the gastrointestinal tract and help in reducing fasting and postprandial hyperglycemia by reducing the absorption of carbohydrates. This group comprises Acarbose, Miglitol and Voglibose. They are available on the market for almost three decades now. When used as monotherapy, Glycated Haemoglobin (HbA1c) reduction can be as high as 0.77%, which is predominantly noted in the Eastern Asian population and those on a high carbohydrate diet. There is a more pronounced reduction in HbA1c in those who present with higher baseline values. Despite not showing a significant cardiovascular benefit with regards to mortality and morbidity, they have proven to be a safe class of drugs which can be used in patients not tolerating various other anti-diabetic agents due to their local site of action and poor systemic absorption. Though they are available worldwide, AGIs are used more often in the Far East and South Asia. They have shown benefits in reducing the development of diabetes when used in those with impaired glucose tolerance or pre-diabetes. They have been shown to improve postprandial hyperglycemia, which in itself is an independent risk factor for cardiovascular morbidity. These have proven their safety from both cardiovascular and non-cardiovascular perspectives and can be combined with any class of anti-diabetic agents. They are not favoured in most of the current Western Guidelines due to their modest HbA1c reduction, neutrality with cardiovascular benefit as well as their significant gastrointestinal side effect profile.

Effect of a proton-pump inhibitor on intestinal microbiota in patients taking low-dose aspirin.

Low-dose aspirin (LDA) administration prevents cerebral infarction and myocardial infarction, but many studies found an association with mucosal injury. Proton-pump inhibitors (PPIs) can prevent gastric and duodenal mucosal damage, but they may exacerbate small-intestinal mucosal injury by altering the microbiota. We aimed to assess the effect of PPIs on the intestinal flora of LDA users. Thirty-two recruited patients, who received LDA (100mg/day) but did not take PPIs, were divided into 15 patients additionally receiving esomeprazole (20mg/day) and 17 patients additionally receiving vonoprazan (10mg/day). On days 0, 30, 90, and 180, the microbiota of each patient was examined by terminal restriction fragment length polymorphism analysis, and the serum gastrin, hemoglobin, and hematocrit levels were measured. Additional PPI administration increased the proportion of Lactobacillales in the microbiota of LDA users. This trend was more prevalent in the vonoprazan group (p < 0.0001) than in the esomeprazole group (p = 0.0024). The Lactobacillales proportion was positively correlated with the gastrin level (r = 0.5354). No significant hemoglobin or hematocrit level reduction was observed in subjects receiving LDA with additional PPI. Additional PPI administration increased the Lactobacillales proportion in the microbiota of LDA users. The positive correlation between the gastrin level and the proportion of Lactobacillales suggested that the change in the intestinal flora was associated with the degree of suppression of gastric acid secretion. Additional oral PPI did not significantly promote anemia, but the risk of causing PPI-induced small-intestinal mucosal injury in LDA users should be considered.

Association of Real-time Continuous Glucose Monitoring With Glycemic Control and Acute Metabolic Events Among Patients With Insulin-Treated Diabetes

Continuous glucose monitoring (CGM) is recommended for patients with type 1 diabetes; observational evidence for CGM in patients with insulin-treated type 2 diabetes is lacking. To estimate clinical outcomes of real-time CGM initiation. Exploratory retrospective cohort study of changes in outcomes associated with real-time CGM initiation, estimated using a difference-in-differences analysis. A total of 41 753 participants with insulin-treated diabetes (5673 type 1; 36 080 type 2) receiving care from a Northern California integrated health care delivery system (2014-2019), being treated with insulin, self-monitoring their blood glucose levels, and having no prior CGM use were included. Initiation vs noninitiation of real-time CGM (reference group). Ten end points measured during the 12 months before and 12 months after baseline: hemoglobin A1c (HbA1c); hypoglycemia (emergency department or hospital utilization); hyperglycemia (emergency department or hospital utilization); HbA1c levels lower than 7%, lower than 8%, and higher than 9%; 1 emergency department encounter or more for any reason; 1 hospitalization or more for any reason; and number of outpatient visits and telephone visits. The real-time CGM initiators included 3806 patients (mean age, 42.4 years [SD, 19.9 years]; 51% female; 91% type 1, 9% type 2); the noninitiators included 37 947 patients (mean age, 63.4 years [SD, 13.4 years]; 49% female; 6% type 1, 94% type 2). The prebaseline mean HbA1c was lower among real-time CGM initiators than among noninitiators, but real-time CGM initiators had higher prebaseline rates of hypoglycemia and hyperglycemia. Mean HbA1c declined among real-time CGM initiators from 8.17% to 7.76% and from 8.28% to 8.19% among noninitiators (adjusted difference-in-differences estimate, -0.40%; 95% CI, -0.48% to -0.32%; P < .001). Hypoglycemia rates declined among real-time CGM initiators from 5.1% to 3.0% and increased among noninitiators from 1.9% to 2.3% (difference-in-differences estimate, -2.7%; 95% CI, -4.4% to -1.1%; P = .001). There were also statistically significant differences in the adjusted net changes in the proportion of patients with HbA1c lower than 7% (adjusted difference-in-differences estimate, 9.6%; 95% CI, 7.1% to 12.2%; P < .001), lower than 8% (adjusted difference-in-differences estimate, 13.1%; 95% CI, 10.2% to 16.1%; P < .001), and higher than 9% (adjusted difference-in-differences estimate, -7.1%; 95% CI, -9.5% to -4.6%; P < .001) and in the number of outpatient visits (adjusted difference-in-differences estimate, -0.4; 95% CI, -0.6 to -0.2; P < .001) and telephone visits (adjusted difference-in-differences estimate, 1.1; 95% CI, 0.8 to 1.4; P < .001). Initiation of real-time CGM was not associated with statistically significant changes in rates of hyperglycemia, emergency department visits for any reason, or hospitalizations for any reason. In this retrospective cohort study, insulin-treated patients with diabetes selected by physicians for real-time continuous glucose monitoring compared with noninitiators had significant improvements in hemoglobin A1c and reductions in emergency department visits and hospitalizations for hypoglycemia, but no significant change in emergency department visits or hospitalizations for hyperglycemia or for any reason. Because of the observational study design, findings may have been susceptible to selection bias.

FC 058THE IMPORTANCE OF ADDRESSING MULTIPLE RISK MARKERS IN TYPE 2 DIABETES: RESULTS FROM THE LEADER AND SUSTAIN 6 TRIALS

Abstract Background and Aims The extent to which improvements in multiple risk markers affect outcomes in type 2 diabetes is unclear. Our aim was to investigate whether clinically relevant improvement in multiple risk markers confers lower risk of micro- and macrovascular disease in a contemporary type 2 diabetes population with cardiovascular disease or high risk for cardiovascular disease, independent of specific treatments. Method Exploratory post-hoc analysis of the two cardiovascular outcome trials in patients with type 2 diabetes LEADER (NCT01179048; n=8638 with baseline and year 1 assessment of at least one of the parameters of interest; patients randomised to the glucagon like peptide-1 receptor agonist [GLP-1 RA] liraglutide or placebo [1:1]; median observation time: 3.8 years) and SUSTAIN 6 (NCT01720446; n=3040 with baseline and year 1 assessment of at least one of the parameters of interest; patients randomised to the GLP-1 RA semaglutide or placebo [1:1]; median observation time: 2.1 years). We pooled all participants, including the active (liraglutide/semaglutide) and placebo-treated groups. We categorised patients according to number of risk markers with a clinically relevant change 1 year after randomisation and investigated subsequent risk of major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction and nonfatal stroke), expanded MACE (MACE plus coronary revascularisation and hospitalisation for heart failure or unstable angina pectoris), cardiovascular death or nephropathy (new onset of macroalbuminuria or doubling of the serum creatinine level and an estimated glomerular filtration rate [eGFR] ≤45 ml/min/1.73 m2, or the need for continuous renal-replacement therapy, or death from renal disease). We defined clinically relevant change as: body weight loss ≥5%, glycated haemoglobin reduction ≥1%, systolic blood pressure reduction ≥5 mmHg, low-density lipoprotein cholesterol reduction ≥0.5 mmol/L, eGFR reduction ≥0 ml/min/1.73m2 and urinary albumin-to-creatinine ratio reduction ≥30% of baseline value. Numbers of risk markers with change were classified as: none (group G0), 1 (G1), 2 (G2), 3 (G3) and ≥4 (G4). Cox regression analysed risk of each outcome and tested for trends; models were adjusted for continuous baseline levels of the risk markers and treatment group (liraglutide/semaglutide and placebo) and stratified by trial. Results The Table contains baseline characteristics of patients in each risk marker group. Compared to patients with no risk-marker improvement, patients with 2, 3 or ≥4 improved risk markers had reduced risk of expanded MACE [hazard ratio (95% CI): 0.80 (0.67-0.96); 0.80 (0.66-0.97); 0.82 (0.66-1.02)], cardiovascular death [0.66 (0.45-0.96); 0.67 (0.45-0.99); 0.60 (0.38-0.94)] and nephropathy [(0.71 (0.52-0.97); 0.48 (0.34-0.68); 0.43 (0.29-0.65)] (Figure). One improved risk marker conferred no risk reduction. The trend of decreased risk for each additional risk marker improvement was significant for expanded MACE (p=0.004), cardiovascular death (p=0.005) and nephropathy (p&amp;lt;0.0001). We observed a stepwise higher number of patients on GLP-1 RA treatment in the groups with 0, 1, 2, 3 or ≥4 risk marker improvements as follows: 30.5% in G0, 38.0% in G1, 48.8% in G2, 61.6% in G3 and 75.3% in G4. We observed similar results in separate analyses of the LEADER and SUSTAIN 6 trials. Conclusion In patients with type 2 diabetes, improvements in two or more risk markers confer reduced risk of cardiovascular disease and nephropathy as compared with none or one improved risk marker, most notably for nephropathy. Our findings stress the importance of multifactorial intervention and underscore the benefit of pleiotropic antidiabetic treatments.

Effects of extensive bleeding in pigs on laboratory biomarkers.

BackgroundDuring hemorrhage and resuscitation, clinical and laboratory monitoring is useful to guide further management. However, acute changes in the biochemistry due to blood loss and subsequent crystalloid fluid resuscitation have not been fully studied.Materials and methodsTwelve anesthetized, juvenile pigs were used. Atraumatic exsanguination, corresponding to a total blood loss of 40%, was performed through a catheter and completed 2 h after initiation of the experiment. Arterial samples were analyzed by point-of-care testing and venous samples were analyzed. Oxygen delivery was calculated.ResultsShortly after 40% hemorrhage and concomitant fluid supplementation, there were significant reductions in arterial hemoglobin and hematocrit (approximately 25%, respectively). Oxygen delivery was less than half of the baseline value. Lactate in arterial blood was more than doubled after 40% exsanguination. On average, no other clinically significant changes in any of the analytes were observed, but interindividual dispersion was pronounced.ConclusionsAcute exsanguination was associated with decreased hemoglobin and hematocrit levels and increased lactate levels but limited effects on the other biomarkers that were studied. Increased levels of biomarkers in severely bleeding patients could indicate tissue damage and the source should be further investigated.

The oxygen dissociation curve of blood in COVID-19.

COVID-19 hinders oxygen transport to the consuming tissues by at least two mechanisms: In the injured lung, saturation of hemoglobin is compromised, and in the tissues, an associated anemia reduces the volume of delivered oxygen. For the first problem, increased hemoglobin oxygen affinity [left shift of the oxygen dissociation curve (ODC)] is of advantage, for the second, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-bisphosphoglycerate (2,3-BPG) concentration. In three investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin (MetHb), which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. However, this “useful effect” is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19, even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional “in vivo” left shift possibly results from various factors, e.g., concentration changes of Cl−, 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interstitial fluid and is useful for O2 uptake in the lungs. Under discussion for therapy are the affinity-increasing 5-hydroxymethyl-2-furfural (5-HMF), erythropoiesis-stimulating substances like erythropoietin, and methylene blue against MetHb formation.

Complete blood counts with red blood cell determinants associate with reduced beta-cell function in seroconverted Swedish TEDDY children.

ObjectivesTo investigate whether changes in complete blood count (CBC) in islet autoantibody positive children with increased genetic risk for type 1 diabetes are associated with oral glucose tolerance tests (OGTT) and HbA1c over time.MethodsThe Environmental Determinants of Diabetes in the Young (TEDDY) study follows children with increased risk for type 1 diabetes in the United States, Germany, Sweden and Finland. In the current study, 89 Swedish TEDDY children (median age 8.8 years) positive for one or multiple islet autoantibodies were followed up to 5 (median 2.3) years for CBC, OGTT and HbA1c. A statistical mixed effect model was used to investigate the association between CBC and OGTT or HbA1c.ResultsHbA1c over time increased by the number of autoantibodies (p < .001). Reduction in mean corpuscular haemoglobin (MCH) and mean cell volume (MCV) was both associated with an increase in HbA1c (p < .001). A reduction in red blood cell (RBC) counts (p = .003), haemoglobin (p = .002) and haematocrit (p = .006) levels was associated with increased fasting glucose. Increased red blood cells, haemoglobin, haematocrit and MCH but decreased levels of red blood cell distribution widths (RDW) were all associated with increased fasting insulin.ConclusionsThe decrease in RBC indices with increasing HbA1c and the decrease in RBC and its parameters with increasing fasting glucose in seroconverted children may reflect an insidious deterioration in glucose metabolism associated with islet beta‐cell autoimmunity.

The development and validation of a multivariable model to predict the bleeding risk score for patients with non-valvular atrial fibrillation using direct oral anticoagulants in the Arab population.

BackgroundFrequently used models, such as the HAS-BLED, ATRIA, ORBIT, and GARFIELD-AF evaluate the risk of bleeding when using an anticoagulant, for example warfarin, in patients with non-valvular atrial fibrillation. Limited studies are available reporting a model with a good discriminative ability to predict the bleeding risk score when using direct oral anticoagulants.MethodsPatient data were collected from King Abdulaziz Medical City, King Fahad Cardiac Center, and Prince Sultan Cardiac Center in Riyadh, from outpatients, inpatients, or primary care clinics. In total, 1722 patients with a prescription for a new oral anticoagulant, Dabigatran, Rivaroxaban, or Apixaban, were enrolled. A resampling approach for variable selection was used and a five-fold cross-validation to assess the model fit and misclassification probabilities. The analysis used the receiver operating characteristics curve (ROC) and the concordance (c) statistic to assess the validation models’ discriminative power. The final penalized likelihood parameters were used for the development of the risk prediction tool. The accuracy of a classification and the prediction are reported with the sensitivity, specificity, and Brier score.ResultsBleeding occurred in 11.15% of cases, of which 23.08% required a blood transfusion and 51.65% had a reduction in haemoglobin of more than 2 gm. The variable selection model identified 15 predictors associated with major bleeding. The discriminative ability of the model was good (c-statistic 0.75, p = 0.035). The Brier score of the model was 0.095. With a fixed cut-off probability value of 0.12 for the logistic regression equation, the sensitivity was 72.7%, and the specificity 66.3%.ConclusionThis model demonstrated a good performance in predicting the bleeding risk in Arab patients treated with novel oral anticoagulants. This easy to use bleeding risk score will allow the clinician to quickly classify patients according to their risk category, supporting close monitoring and follow-up for high-risk patients, without laboratory and radiological monitoring.

The Cardiovascular Events in Metabolic Surgery Compared to the New Classes of Glucose-Lowering Agents in Patients With Type 2 Diabetes Mellitus: A Systematic Review With Narrative Synthesis

Abstract Globally, Type 2 Diabetes Mellitus has an immense healthcare burden and associated with increased morbidity and mortality due to macrovascular and microvascular complications. Cardiovascular disease including coronary artery disease and stroke are far more common in T2DM patients. Thus, any intervention that reduces the cardiovascular events in patients with diabetes will have positive impact on the patients and the society. Therefore, this systematic review aimed to evaluate the cardiovascular events after metabolic surgery in comparison with the new classes of glucose lowering agents in patients with T2DM. This review included 11 randomised controlled trials that used GLP-1 RA or SGLT-2 I in comparison to usual standard of care. Seven metabolic surgery studies were included, of which two were randomised controlled trials and the other five were observational studies. These were the most relevant studies to the research question. The results suggest that cardiovascular events are lower in metabolic surgery studies when compared to medication trials. It also suggests that glycated haemoglobin reduction is more in the metabolic surgery group compared to the medication group, although it was not proved to be significant difference between the groups after adjusting the duration. The remission of diabetes was very high in the metabolic surgery group while none of medication trials accomplished diabetes recovery. Additionally, weight loss in metabolic surgery group was significantly higher than medication group after adjusting the duration. However, both medication and surgery groups had adverse events. In conclusion, the review suggests that younger adult obese patients with cardiovascular diseases should undergo metabolic surgery. Whereas, older patients with established cardiovascular disease should be advised to take one of the medications that has been proved to reduce cardiovascular events. Future studies that compare metabolic surgery and the new classes of the glucose lowering agents is recommended to confirm the findings in this review.

Painful diabetic neuropathy is associated with increased nerve regeneration in patients with type2 diabetes undergoing intensive glycemic control.

Aims/IntroductionPainful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control.Materials and MethodsThis exploratory substudy of an open‐label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal–bolus insulin at baseline and 1‐year follow up, and 18 controls at baseline only.ResultsParticipants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain.ConclusionsThis study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy.

Temporary Ligation of the Bilateral Uterine Arteries During Laparoscopy Combined with Hysteroscopy in the Treatment of Caesarean Scar Pregnancy: Experience at a Chinese Teaching Hospital.

PurposeThis study aimed to investigate the clinical efficacy of temporary ligation of the bilateral uterine arteries during laparoscopy combined with hysteroscopy in the treatment of caesarean scar pregnancy (CSP).Patients and MethodsThis study was a retrospective analysis of 83 patients who had initially undergone laparoscopy combined with hysteroscopy for CSP between 2012 and 2018 at Xiamen Women and Children’s Hospital. Patients were assigned to the ligation group or the no ligation group according to whether they underwent temporary ligation of the bilateral uterine arteries. Factors extracted from the database included general preoperative information, surgical indicators (intraoperative blood loss, operation time, and blood transfusion), postoperative recovery indicators (β-hCG on day 3 after surgery, time to β-hCG normalization), and postoperative complications (decrease in menstrual bleeding, alteration in the menstrual cycle) and were compared between the two groups.ResultsThe intraoperative blood loss of patients in the ligation group was significantly less than that of patients in the no ligation group (P=0.027), especially in patients with higher serum β-hCG level (P=0.030). No significant differences in the operation time, blood transfusion, decline ratio of hCG on day 3 after surgery, reduction in haemoglobin and haematocrit value, decrease in menstrual bleeding, or alteration in the menstrual cycle were observed between the two groups (P>0.05).ConclusionFor CSP patients, temporary ligation of the bilateral uterine arteries during laparoscopy combined with hysteroscopy achieved better clinical outcomes than laparoscopy combined with hysteroscopy without ligation with respect to intraoperative blood loss. This approach offers effective and safe surgical management for CSP in clinical practice.