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Purpose Although pharmacist-provided diabetes services have been shown to be effective, the effectiveness of telepharmacy (TP) in diabetes management has not been clearly established. This systematic review and meta-analysis aims to evaluate the effectiveness of diabetes TP services. Methods PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched (from inception through September 2021) to identify published studies that evaluated the effect of TP services in patients with diabetes mellitus and reported either glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG) outcomes. Mean difference (MD), weighted mean difference (WMD), relative risk (RR), and 95% confidence intervals were calculated using the DerSimonian and Laird random-effects model. Results 36 studies involving 13,773 patients were included in the systematic review, and 23 studies were included in the meta-analysis. TP was associated with a statistically significant decrease in HbA1c (MD, –1.26%; 95% CI, –1.69 to –0.84) from baseline. FBG was not significantly affected (MD, –25.32 mg/dL; 95% CI, –57.62 to 6.98). Compared to non-TP service, TP was associated with a lower risk of hypoglycemia (RR, 0.48; 95% CI, 0.30-0.76). In a subset of studies that compared TP to face-to-face (FTF) pharmacy services, no significant difference in HbA1c lowering was seen between the 2 groups (WMD, –0.09%; 95% CI, –1.07 to 0.90). Conclusion Use of TP was associated with reduction of HbA1c and the risk of hypoglycemia in patients with diabetes mellitus. High-quality randomized controlled trials are needed to validate the effectiveness of diabetes TP services relative to FTF services. [ABSTRACT FROM AUTHOR]

Introduction: The effectiveness of probiotics in patients with abnormal glucose metabolism has not been clearly demonstrated. It is also unclear if outcomes are consistent across different probiotic formulations. Methods: A literature search was conducted using PubMed, EMBASE, and Cochrane CENTRAL database from inception through May 2020. Randomized controlled trials that evaluated the effect of probiotics on fasting blood glucose (FBG) or hemoglobin A1c (HbA1c) in patients with prediabetes, type 2 diabetes mellitus, or gestational diabetes were included. Outcomes of interest included FBG, HbA1c, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), homeostatic model assessment of β-cell function (HOMA-B), and quantitative insulin sensitivity check index (QUICKI). Weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated using the DerSimonian and Laird random-effects model. Results: 31 studies involving 1,948 participants were included in this analysis. Compared to control, probiotics had a significant favorable effect on FBG (WMD −5.77 mg/dL, 95% CI −8.48 to −3.06), HbA1c (WMD −0.32%, 95% CI −0.47 to −0.18), fasting insulin (WMD −2.95 µIU/mL, 95% CI −3.76 to −2.14), HOMA-IR (WMD −0.82, 95% CI −1.05 to −0.59), HOMA-B (WMD −14.86, 95% CI −24.57 to −5.16), and QUICKI (WMD 0.015, 95% CI 0.011–0.019). Further, probiotics were associated with favorable outcomes on all parameters at doses between 1 and 10 × 109 colony-forming unit per day (p < 0.004 for all) and formulations containing 2–4 strains (p < 0.05 for all). Discussion/Conclusion: Probiotics appear to have a modest effect on glycemic parameters in patients with abnormal glucose metabolism. Due to the limited number of trials conducted in patients with prediabetes, more studies are warranted in this population. [ABSTRACT FROM AUTHOR]

Simple Summary: In order to grow, tumors need nutrients and oxygen, which are supplied by new blood vessels that are often abnormal and leaky. The development of these blood vessels is driven by proteins called growth factors, which bind to receptor proteins on other cells. We show for the first time that an antibody against a vascular growth factor called VEGF-B, when used to treat mice with tumors, reduces the amount of abnormal tumor blood vessels, and inhibits tumor growth, as well as improving the response to chemotherapy. These results suggest that targeting VEGF-B could be a potential approach for anti-cancer therapy, particularly in combination with chemotherapy. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key regulators of blood vessel formation, including in tumors, where their deregulated function can promote the production of aberrant, leaky blood vessels, supporting tumor development. Here we investigated the VEGFR1 ligand VEGF-B, which we demonstrate to be expressed in tumor cells and in tumor stroma and vasculature across a range of tumor types. We examined the anti-VEGF-B-specific monoclonal antibody 2H10 in preclinical xenograft models of breast and colorectal cancer, in comparison with the anti-VEGF-A antibody bevacizumab. Similar to bevacizumab, 2H10 therapy was associated with changes in tumor blood vessels and intra-tumoral diffusion consistent with normalization of the tumor vasculature. Accordingly, treatment resulted in partial inhibition of tumor growth, and significantly improved the response to chemotherapy. Our studies indicate the importance of VEGF-B in tumor growth, and the potential of specific anti-VEGF-B treatment to inhibit tumor development, alone or in combination with established chemotherapies. [ABSTRACT FROM AUTHOR]

Introduction Energy drinks are an increasingly utilized beverage and are gaining popularity in recent years. The U.S. Air Force (USAF) represents a unique population where energy drink consumption may be higher than the general population. To better understand the safety and health impact of energy drinks, this large-scale comprehensive survey was conducted to study energy drink consumption patterns and its associated adverse effects. Materials and Methods A survey was conducted across 12 USAF installations to assess self-reported energy drink consumption and adverse effects in the military population. This study was approved by the David Grant USAF Medical Center Institutional Review Board. Results A total of 9,655 participants participated in the survey. Energy drink consumption was reported in 76.7% of the participants, with 12.0% consuming ≥1 energy drink per day. Male gender, younger age, and enlisted military members are more likely to be high consumers; 58.6% of participants reported having at least once tried a premixed beverage that combines alcohol, caffeine, and other stimulants. Among energy drink users, 60.0% reported experiencing ≥1 adverse effect, and 0.92% reported needing to see a physician or going to the emergency department because of adverse effects from energy drinks. Higher energy drink or premixed combination beverage consumption frequency was associated with increased likelihood of physician or emergency department visits (P  ≤ 0.002 for both). Conclusion Approximately three in four USAF members reported ever consuming an energy drink. Caution should be exercised on the amount of energy drink consumed to limit the risk of serious adverse effects. Future studies should identify populations at greatest risk for adverse effects and alternative sources of energy maintenance to attain optimal mission readiness. [ABSTRACT FROM AUTHOR]

Recent hypertension clinical trials and national guideline updates have created a debate on the most appropriate treatment goals in elderly patients with hypertension. In 2014, recommendations by the Eighth Joint National Committee allowed a more lenient goal for patients 60 years and older compared with previous guidelines. Since then, several large clinical trials and meta‐analyses have added more information regarding strict versus lenient treatment goals. Most recently, the American College of Cardiology and American Heart Association Task Force published their highly anticipated hypertension guideline developed in conjunction with nine additional interdisciplinary organizations. This review discusses the culmination of emerging data to provide more insight into the treatment of hypertension in the elderly. A literature search was conducted using PubMed, the Cumulative Index of Nursing and Allied Health, the Cochrane database, and by hand‐searching references from relevant articles. The following key terms were used: hypertension, blood pressure, systolic, and elderly. Available literature suggests that it is reasonable to target an office systolic blood pressure of less than 130 mm Hg in elderly patients with hypertension. An individualized approach is reasonable for those who are institutionalized, with high comorbidity burden, or have a short life expectancy. A diastolic blood pressure of less than 60 mm Hg should be avoided due to the potential for an increase in cardiovascular risk. The method of blood pressure measurement is extremely important to consider when determining the blood pressure goal, and proper procedures for accurate blood pressure measurement must be followed. Other factors important to consider may include the patient's comorbidities, frailty, as well as the patient's potential for adverse drug reactions. [ABSTRACT FROM AUTHOR]

Objectives: Although hyponatremia is a prognostic factor in acute heart failure (AHF), its influence on the acute clinical course of heart failure is unknown. Our objective was to evaluate the association of hyponatremia with diuretic response, renal function, and clinical outcomes in AHF. Methods: A retrospective study included 499 hospitalized AHF patients treated with intravenous loop diuretics for ≥48 h. Patients were grouped by nadir sodium concentrations (normonatremic, NN) ≥135 mEq/l, (mild hyponatremia, MHN) 130-134 mEq/l, and (moderate to severe hyponatremia, MSHN) <130 mEq/l. Association to diuretic response and clinical outcome was assessed. Results: The incidence of hyponatremia was 54% (36% MHN, 18% MSHN). Maximum diuretic dose (furosemide equivalents: NN 84 ± 132 mg/day vs. MHN 114 ± 165 mg/day vs. MSHN 249 ± 450 mg/day, p < 0.001) and incidence of diuretic regimen escalation (NN 11% vs. MHN 16% vs. MSHN 44%, p < 0.001) were significantly higher in patients experiencing hyponatremia. Hyponatremia was also associated with a higher incidence of acute increases in serum creatinine (NN 27% vs. MHN 45% vs. MSHN 63%, p < 0.001), greater increases in blood urea nitrogen, longer hospital stay, and higher mortality. Outcome disparities to NN patients were similar whether hyponatremia was acute or present upon admission. Conclusions: Acute or admission hyponatremia, especially <130 mEq/l, in AHF patients is associated with greater diuretic requirements, higher incidence of serum creatinine increases, and a poorer outcome. Alternative treatments warrant evaluation in these patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Τhis study aimed to optimize the 89Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of 89Zr-Df-bintrafusp alfa and 89Zr-Df-control radioconjugates. Methods: Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-β receptor II (TGF-βRII), avelumab (anti-PD-L1 human IgG1 control antibody), isotype control (mutated inactive anti-PD-L1 IgG1 control antibody), and trap control (mutated inactive anti-PD-L1 human IgG1 fused to active TGF-βRII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. In vivo biodistribution and imaging studies were performed with PET/CT to identify and quantitate 89Zr-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-β-positive murine breast cancer model (EMT-6). Specificity of 89Zr-Df-bintrafusp alfa was assessed via a combined biodistribution and imaging experiment in the presence of competing cold bintrafusp alfa (1 mg/kg). Results: Nanomolar affinities for PD-L1 were achieved with 89Zr-Df-bintrafusp alfa and 89Zr-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-β-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of 89Zr-Df-bintrafusp alfa and 89Zr-avelumab indicating the in vivo distribution pattern of bintrafusp alfa is driven by its PD-L1 binding arm. Competition study with 1 mg of unlabelled bintrafusp alfa or avelumab co-administered with trace dose of 89Zr-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo. Conclusion: Molecular imaging of 89Zr-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of 89Zr-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients. [ABSTRACT FROM AUTHOR]

Anti-ASCT2 antibody drug conjugate (ADC) MEDI7247 has been under development as a potential anti-cancer therapy for patients with selected relapsed/refractory hematological malignancies and advanced solid tumors by MedImmune. Although promising efficacy was observed in the clinic, pharmacokinetic (PK) analyses observed low exposure of MEDI7247 in phase I hematological patients. To investigate the biodistribution properties of MEDI7247, MEDI7247 and control antibodies were radiolabeled with zirconium-89 and in vitro and in vivo properties characterized. MEDI7247 (human anti-ASCT2 antibody conjugated with pyrrolobenzodiazepine (PBD)) and MEDI7519 (MEDI7247 without PBD drug conjugate) and an isotype control antibody drug conjugate construct were conjugated with p -isothiocyanatobenzyl-deferoxamine (Df) and radiolabeled with zirconium-89. In vitro studies included determining the radiochemical purity, protein integrity, immunoreactivity (Lindmo analysis), apparent antigen binding affinity for ASCT2-positive cells by Scatchard analysis and serum stability of the radiolabeled immunoconjugates. In vivo studies included biodistribution and PET/MRI imaging studies of the radiolabeled immunoconjugates in an ASCT2-positive tumor model, HT-29 colorectal carcinoma xenografts. Conditions for the Df-conjugation and radiolabeling of antibody constructs were determined to produce active radioimmunoconjugates. In vivo biodistribution and whole body PET/MRI imaging studies of [89Zr]Zr-Df-MEDI7519 and [89Zr]Zr-Df-MEDI7247 radioimmunoconjugates in HT-29 colon carcinoma xenografts in BALB/c nude mice demonstrated specific tumor localization. However, more rapid blood clearance and non-specific localization in liver was observed for [89Zr]Zr-Df-MEDI7247 and [89Zr]Zr-Df-MEDI7519 compared to isotype control ADC. Except for liver and bone, other normal tissues demonstrated clearance reflecting the blood clearance for all three constructs and no other abnormal tissue uptake. Preclinical biodistribution analyses of [89Zr]Zr-Df-MEDI7247 and [89Zr]Zr-Df-MEDI7519 showed the biodistribution pattern of anti-ASCT2 ADC MEDI7247 was similar to parental MEDI7519, and both antibodies showed specific tumor uptake compared to an isotype control ADC. This study highlights an important role nuclear medicine imaging techniques can play in early preclinical assessment of drug specificity as part of the drug development pipeline. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: [18F]FMISO is the most widely validated PET radiotracer for imaging hypoxic tissue. However, as a result of the pharmacokinetics of [18F]FMISO a 2h wait between tracer administration and patient scanning is required for optimal image acquisition. In order to develop hypoxia imaging agents with faster kinetics, we have synthesised and evaluated several F-18 labelled anilino sulfoxides. In this manuscript we report on the synthesis, in vitro and in vivo evaluation of a novel fluoroethyltriazolyl propargyl anilino sulfoxide. The radiolabelling of the novel tracer was achieved via 2-[18F]fluoroethyl azide click chemistry. Radiochemical yields were 23±4% based on 2-[18F]fluoroethyl azide and 7±2% based on K[18F]F. The radiotracer did not undergo metabolism or defluorination in an in vitro assay using S9 liver fractions. Imaging studies using SK-RC-52 tumors in BALB/c nude mice have indicated that the tracer may have a higher pO2 threshold than [18F]FMISO for uptake in hypoxic tumors. Although clearance from muscle was faster than [18F]FMISO, uptake in hypoxic tumors was slower. The average tumor to muscle ratio at 2h post injection in large, hypoxic tumors with a volume greater than 686mm3 was 1.7, which was similar to the observed ratio of 1.75 for [18F]FMISO. Although the new tracer showed improved pharmacokinetics when compared with the previously synthesised sulfoxides, further modifications to the chemical structure need to be made in order to offer significant in vivo imaging advantages over [18F]FMISO. [Copyright &y& Elsevier]

Abstract: The significance of imaging hypoxia with the PET ligand [18F]FMISO has been demonstrated in a variety of cancers. However, the slow kinetics of [18F]FMISO require a 2-h delay between tracer administration and patient scanning. Labelled chloroethyl sulfoxides have shown faster kinetics and higher contrast than [18F]FMISO in a rat model of ischemic stroke. However, these nitrogen mustard analogues are unsuitable for routine production and use in humans. Here we report on the synthesis and in vitro and in vivo evaluation of two novel sulfoxides which we synthesised from a single precursor molecule via either 2-[18F]fluoroethyl azide click chemistry or conventional nucleophilic displacement of a chloride leaving group. The yields of the click chemistry approach were 90±5% of [18F] based on 2-[18F]fluoroethyl azide, and the yields for the SN reaction were 15±5% of [18F] based on K[18F]F. Both radiotracers underwent metabolism in an in vitro assay using S9 liver fractions with biological half-lives of 32.39 and 43.32 min, respectively. Imaging studies using an SK-RC-52 tumor model in BALB/c nude mice have revealed that only [18F] is retained in hypoxic tumors, whereas [18F] is cleared from those tumors at a rate similar to that of muscle tissue. [18F] has emerged as a promising new lead structure for further development of sulfoxide-based hypoxia imaging agents. In particular, the mechanism of uptake needs to be elucidated and changes to the chemical structure need to be made in order to reduce metabolism and improve radiotracer kinetics. [Copyright &y& Elsevier]

The epidermal growth factor receptor (EGFR) is overexpressed or mutated in glioma. Recently, a series of missense mutations in the extracellular domain (ECD) of EGFR were reported in glioma patients. Some of these mutations clustered within a cysteine-rich region of the EGFR targeted by the therapeutic antibody mAb806. This region is only exposed when EGFR activates and appears to locally misfold during activation. We expressed two of these mutations (R324L and E330K) in NR6 mouse fibroblasts, as they do not express any EGFR-related receptors. Both mutants were autophosphorylated in the absence of ligand and enhanced cell survival and anchorage-independent and xenograft growth. The ECD truncation that produces the de2-7EGFR (or EGFRvIII), the most common EGFR mutation in glioma, generates a free cysteine in this same region. Using a technique optimized for detecting disulfide-bonded dimers, we definitively demonstrated that the de2-7EGFR is robustly dimerized and that ablation of the free cysteine prevents dimerization and activation. Modeling of the R324L mutation suggests it may cause transient breaking of disulfide bonds, leading to similar disulfide-bonded dimers as seen for the de2-7EGFR. These ECD mutations confirm that the cysteine-rich region of EGFR around the mAb806 epitope has a significant role in receptor activation. [ABSTRACT FROM AUTHOR]

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of 18F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that 18F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid1–42 fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of 18F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that 18F-THK523 fulfils ligand criteria for human imaging trials. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate—ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker. [ABSTRACT FROM AUTHOR]