Retrospective Analysis of Once-Daily Versus Twice-Daily Insulin Glargine Dosing in Noncritically Ill Individuals.

Background: Insulin is the treatment of choice for diabetes care in the hospital. There is some debate regarding the efficacy and safety of once-daily versus twice-daily insulin glargine in the hospital, particularly in the critically ill population. Objective: The purpose of this pilot study was to evaluate the efficacy and safety of insulin glargine administered as a once-daily versus twice-daily regimen in the noncritically ill population. Methods: A retrospective chart review was conducted from 1 June 2020 to 31 May 2021. Inclusion criteria were age ≥18 years and on a regimen of either once-daily or twice-daily insulin glargine for ≥72 hours during the specified time frame. The primary end point was a comparison of the number of days with all blood glucose measurements within the range of 70-180 mg/dL throughout a 24-hour period. Secondary end points included the number of hyperglycemic (>180 mg/dL) and hypoglycemic (<70 mg/dL) events that occurred in each study group. Results: Group 1 included 101 individuals who received once-daily dosing, and group 2 included 103 individuals who received twice-daily dosing. Baseline characteristics were similar between the groups except for a higher BMI at admission (P = 0.01) and a higher pre-admission A1C (P = 0.02) in group 2. No differences were found for the primary end point (P = 0.5) or for hypoglycemic (P = 0.6) or hyperglycemic (P = 0.7) events. Conclusion: There were no significant differences in efficacy or safety between once-daily and twice-daily insulin glargine in the noncritically ill population. A larger prospective study could confirm these results.

Procoagulant Activity of Umbilical Cord-Derived Mesenchymal Stromal Cells' Extracellular Vesicles (MSC-EVs).

Many cell types, including cancer cells, release tissue factor (TF)-exposing extracellular vesicles (EVs). It is unknown whether MSC-EVs pose a thromboembolism risk due to TF expression. Knowing that MSCs express TF and are procoagulant, we hypothesize that MSC-EVs also might. Here, we examined the expression of TF and the procoagulant activity of MSC-EVs and the impact of EV isolation methods and cell culture expansion on EV yield, characterization, and potential risk using a design of experiments methodology. MSC-EVs were found to express TF and have procoagulant activity. Thus, when MSC-derived EVs are employed as a therapeutic agent, one might consider TF, procoagulant activity, and thromboembolism risk and take steps to prevent them.

Effect of Pre-Processing Storage Condition of Cell Culture-Conditioned Medium on Extracellular Vesicles Derived from Human Umbilical Cord-Derived Mesenchymal Stromal Cells.

EVs can be isolated from a conditioned medium derived from mesenchymal stromal cells (MSCs), yet the effect of the pre-processing storage condition of the cell culture-conditioned medium prior to EV isolation is not well-understood. Since MSCs are already in clinical trials, the GMP-grade of the medium which is derived from their manufacturing might have the utility for preclinical testing, and perhaps, for clinical translation, so the impact of pre-processing storage condition on EV isolation is a barrier for utilization of this MSC manufacturing by-product. To address this problem, the effects of the pre-processing storage conditions on EV isolation, characterization, and function were assessed using a conditioned medium (CM) derived from human umbilical cord-derived MSCs (HUC-MSCs). Hypothesis: The comparison of three different pre-processing storage conditions of CM immediately processed for EV isolation would reveal differences in EVs, and thus, suggest an optimal pre-processing storage condition. The results showed that EVs derived from a CM stored at room temperature, 4 °C, -20 °C, and -80 °C for at least one week were not grossly different from EVs isolated from the CM immediately after collection. EVs derived from an in pre-processing -80 °C storage condition had a significantly reduced polydispersity index, and significantly enhanced dot blot staining, but their zeta potential, hydrodynamic size, morphology and size in transmission electron microscopy were not significantly different from EVs derived from the CM immediately processed for isolation. There was no impact of pre-processing storage condition on the proliferation of sarcoma cell lines exposed to EVs. These data suggest that the CM produced during GMP-manufacturing of MSCs for clinical applications might be stored at -80 °C prior to EV isolation, and this may enable production scale-up, and thus, and enable preclinical and clinical testing, and EV lot qualification.

Home Health Management of Parkinson Disease Deep Brain Stimulation: A Randomized Clinical Trial.

Importance: The travel required to receive deep brain stimulation (DBS) programming causes substantial burden on patients and limits who can access DBS therapy. Objective: To evaluate the efficacy of home health DBS postoperative management in an effort to reduce travel burden and improve access. Design, Settings, and Participants: This open-label randomized clinical trial was conducted at University of Florida Health from November 2017 to April 2020. Eligible participants had a diagnosis of Parkinson disease (PD) and were scheduled to receive DBS independently of the study. Consenting participants were randomized 1:1 to receive either standard of care or home health postoperative DBS management for 6 months after surgery. Primary caregivers, usually spouses, were also enrolled to assess caregiver strain. Interventions: The home health postoperative management was conducted by a home health nurse who chose DBS settings with the aid of the iPad-based Mobile Application for PD DBS system. Prior to the study, the home health nurse had no experience providing DBS care. Main Outcomes and Measures: The primary outcome was the number of times each patient traveled to the movement disorders clinic during the study period. Secondary outcomes included changes from baseline on the Unified Parkinson's Disease Rating Scale part III. Results: Approximately 75 patients per year were scheduled for DBS. Of the patients who met inclusion criteria over the entire study duration, 45 either declined or were excluded for various reasons. Of the 44 patients enrolled, 19 of 21 randomized patients receiving the standard of care (mean [SD] age, 64.1 [10.0] years; 11 men) and 23 of 23 randomized patients receiving home health who underwent a minimum of 1 postoperative management visit (mean [SD] age, 65.0 [10.9] years; 13 men) were included in analysis. The primary outcome revealed that patients randomized to home health had significantly fewer clinic visits than the patients in the standard of care arm (mean [SD], 0.4 [0.8] visits vs 4.8 [0.4] visits; P < .001). We found no significant differences between the groups in the secondary outcomes measuring the efficacy of DBS. No adverse events occurred in association with the study procedure or devices. Conclusions and Relevance: This study provides evidence supporting the safety and feasibility of postoperative home health DBS management. Trial Registration: ClinicalTrials.gov Identifier: NCT02474459.

Therapeutic Use of Mesenchymal Stromal Cells: The Need for Inclusive Characterization Guidelines to Accommodate All Tissue Sources and Species.

Following their discovery over 50 years ago, mesenchymal stromal cells (MSCs) have become one of the most studied cellular therapeutic products by both academia and industry due to their regenerative potential and immunomodulatory properties. The promise of MSCs as a therapeutic modality has been demonstrated by preclinical data yet has not translated to consistent, successful clinical trial results in humans. Despite the disparities across the field, MSC shareholders are unified under one common goal-to use MSCs as a therapeutic modality to improve the quality of life for those suffering from a malady in which the standard of care is suboptimal or no longer effective. Currently, there is no Food and Drug Administration (FDA)-approved MSC therapy on the market in the United States although several MSC products have been granted regulatory approval in other countries. In this review, we intend to identify hurdles that are impeding therapeutic progress and discuss strategies that may aid in accomplishing this universal goal of widespread therapeutic use.

Physical Compatibility of Medications Used in Critically Ill Patients with Balanced Fluid Solutions.

Using balanced fluids for resuscitation in patients with septic shock may lead to improved patient outcomes. However, compatibility data on co-administering balanced fluids via y-site connector with other intravenous medications is lacking. The purpose of this study was to examine the physical compatibility of frequently used intravenous medications for patients with septic shock with balanced fluids, Plasma-Lyte A, and Lactated Ringers, using a simulated y-site. Medications studied were acyclovir, amiodarone, ampicillin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, heparin, hydrocortisone, gentamicin, levofloxacin, meropenem, piperacillin-tazobactam, tobramycin, and vancomycin. All medications were assessed with Plasma-Lyte A; amiodarone, ampicillin, cefepime, hydrocortisone, and levofloxacin were also assessed for compatibility with Lactated Ringers, based on missing or conflicting compatibility data. The medications were diluted to maximum concentrations used for patient administration and mixed with the balanced fluid solution in equal volumes. Physical compatibility was determined by assessing samples visually against light and dark backgrounds and using a laboratory turbidimeter. Assessments occurred at time of mixing and at 15-minute intervals up to one hour. Amiodarone demonstrated turbidimetric incompatibility when combined with Plasma- Lyte A or Lactated Ringers and should not be co-administered with either of these fluids via y-site connector. Each remaining study drug displayed visible and turbidimetric compatibility with the assessed balanced fluid. Acyclovir, ampicillin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, heparin, hydrocortisone, levofloxacin, meropenem, piperacillin-tazobactam, tobramycin, and vancomycin exhibited physical compatibility with Plasma- Lyte A in a simulated y-site for up to one hour. Ampicillin, cefepime, hydrocortisone, and levofloxacin were also physically compatible with Lactated Ringers.

A Protocol for the Isolation, Culture, and Cryopreservation of Umbilical Cord-Derived Canine Mesenchymal Stromal Cells: Role of Cell Attachment in Long-Term Maintenance.

Mesenchymal stromal cells (MSCs) hold great promise in the field of regenerative medicine due to their ability to create a variable localized anti-inflammatory effect in injuries such as Crohn's disease and osteoarthritis or by incorporation in tissue engineered constructs. Currently, the MSC literature uses rodents for preclinical disease models. There is growing interest in using naturally occurring disease in large animals for modeling human disease. By review of the canine MSCs literature, it appears that canine MSCs can be difficult to maintain in culture for extended passages and this greatly varies between tissue sources, compared with human and rodent MSCs, and limited lifespan is an obstacle for preclinical investigation and therapeutic use. Research using canine MSCs has been focused on cells derived from bone marrow or adipose tissue, and the differences in manufacturing MSCs between laboratories are problematic due to lack of standardization. To address these issues, here, a stepwise process was used to optimize canine MSCs isolation, expansion, and cryopreservation utilizing canine umbilical cord-derived MSCs. The culture protocol utilizes coating of tissue culture surfaces that increases cellular adherence, increases colony-forming units-fibroblast efficiency, and decreases population doubling times. Canine MSCs isolated with our protocol could be maintained longer than published canine MSCs methods before senescing. Our improved cryopreservation protocols produce on average >90% viable MSCs at thaw. These methods enable master-bank and working-bank scenarios for allogeneic MSC testing in naturally occurring disease in dogs.

Clinical potential of liraglutide in cardiovascular risk reduction in patients with type 2 diabetes: evidence to date.

Metformin is the first-line therapy for the management of type 2 diabetes. After 3 months of metformin, add-on therapy can be considered if an individual's glycemic control has not been achieved for hemoglobin A1c, fasting blood glucose levels, and postprandial blood glucose levels. Liraglutide is a potential second-line option for the management of type 2 diabetes mellitus, particularly for those who are or may be at a high risk of cardiovascular disease. It can also be used an add-on therapy for those individuals with established cardiovascular disease. Liraglutide has additional benefits, such as no to minimal risk of hypoglycemia and promotion of weight loss through its mechanism of action. This particular article summarizes evidence on cardiovascular biomarkers and surrogate endpoints, along with macrovascular events, with liraglutide therapy. Overall, liraglutide has extensive cardiovascular evidence based on which it could be used as a desirable agent for glycemic control while lowering the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization from heart failure.

Using clickers to improve student engagement and performance in an introductory biochemistry class.

As part of ongoing efforts to enhance teaching practices in a large-class introductory biochemistry course, we have recently tested the effects of using a student response system (clickers) on student exam performances and engagement with the course material. We found no measurable difference in class mean composite examination score for students taught with clickers than for those taught in traditional lectures. However, there were significantly more students in the highest achievement category (91-100%) in the section that incorporated clickers than in any other section over five academic terms. Overall, students gave high approval ratings for the use of the clickers, particularly in increasing their participation and engagement in lectures. However, students who reported their performance to be in the lowest performance categories gave a lower level of approval for the use of the clickers than those who reported their performance to be in the higher performance categories. The implications for using clickers to improve teaching in biochemistry are discussed.

Cytotoxicity of 2-chlorodeoxyadenosine and arabinosylcytosine in leukaemic lymphoblasts from paediatric patients: significance of cellular nucleoside transporter content.

2-chlorodeoxyadenosine (2-CdA) and arabinosylcytosine (araC) are nucleoside drugs that are used to treat various leukaemias, although 2-CdA has not been tested extensively in children with acute lymphoblastic leukaemia (ALL). Nucleoside cytotoxicity depends on the conversion of these agents to 5'-phosphate derivatives, following drug entry into cells via nucleoside transport (NT) processes. This study compared es nucleoside transporter content, determined using a flow cytometric assay with SAENTA [5'-S-(2-aminoethyl)-N6-(4-nitrobenzyl)-5'-thioadenosine] fluorescein, and cytotoxicities of 2-CdA and araC in fresh lymphoblasts from previously untreated paediatric ALL patients and the human T-lymphoblast cell line, CCRF-CEM. Lymphoblast samples from individual patients ranged widely in sensitivity to both 2-CdA (IC50, 6 nmol/l to > 5 micromol/l; mean = 418 nmol/l; n = 8) and araC (IC50, 59 nmol/l to > 5 micromol/l; mean = 1050 nmol/l; n = 7), although IC50 values for the two drugs were correlated (r = 0.78, P = 0.032, n = 7). Cellular es nucleoside transporter content varied more than 35-fold among samples from 10 patients. The correlation between es nucleoside transporter content and drug sensitivity was statistically significant for araC (r = -0.93, P = 0.023, n = 5), but not for 2-CdA (r = -0.57, P = 0.23, n = 6). Exposure of CCRF-CEM cells to araC resulted in a substantial araC concentration-dependent increase in the relative survival of es transporter-deficient cells, whereas the increase was slight following exposure to 2-CdA. We conclude that, in ALL lymphoblasts, es nucleoside transporter content is a determinant of araC sensitivity and that a deficiency in NT may impart resistance to araC.