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Abstract Context Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. Objective To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. Methods A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. Results The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. Conclusion The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

Purpose of ReviewInpatient glucose data analysis, or glucometrics, has developed alongside the growing emphasis on glycemic control in the hospital. Shortcomings in the initial capabilities for glucometrics have pushed advancements in defining meaningful units of measurement and methods for capturing glucose data. This review addresses the growth in glucometrics and ends with its promising new state.Recent FindingsStandardization, allowing for benchmarking and purposeful comparison, has been a goal of the field. The National Quality Foundation glycemic measures and recently enacted Center for Medicare and Medicaid Services (CMS) electronic quality measures for hypo- and hyperglycemia have allowed for improved integration and consistency.SummaryPrior systems have culminated in an upcoming measure from the Center for Disease Control and Prevention’s National Healthcare Safety Network. It is poised to create a new gold standard for glucometrics by expanding and refining the CMS metrics, which should empower both local improvement and benchmarking as the program matures.

Safely improve glycemic control in the critical care units of nine hospitals. Critical care adult inpatients from nine hospitals with ≥4 point-of-care blood glucose (BG) readings over ≥2 days were targeted by collaborative improvement efforts to reduce hyper- and hypoglycemia. Balanced glucometric goals for each hospital were set targeting improvement from baseline or goals deemed desirable from Society of Hospital Medicine (SHM) benchmarking data. Collaborative interventions included standardized insulin infusion protocols, hypoglycemia prevention bundles, audit and feedback, education, and measure-vention (coupling measurement of patients \"off protocol\" with concurrent interventions to correct suboptimal care). All sites improved glycemic control. Six reached prespecified levels of improvement of the day-weighted mean BG. The day-weighted mean BG for the cohort decreased by 7.7 mg/dL (95% confidence interval [CI], 7.0 mg/dL to 8.4 mg/dL) to 151.3 mg/dL. Six of nine sites showed improvement in the percent intensive care unit (ICU) days with severe hyperglycemia (any BG >299 mg/dL). ICU severe hyperglycemic days declined from 8.6 to 7.2% for the cohort (relative risk, 0.84; 95% CI, 0.80 to 0.88). Patient days with any BG <70 mg/dL were reduced by 0.4% (95% CI, 0.06% to 0.6%), from 4.5 to 4.1%, for a small but statistically significant reduction in hypoglycemia. Seven of nine sites showed improvement. Multihospital improvements in ICU glycemic control, severe hyperglycemia, and hypoglycemia are feasible. Balanced goals for glycemic control and hypoglycemia in the ICU using SHM benchmarks and metrics enhanced successful improvement efforts with good staff acceptance and sustainability. BG = blood glucose CMI = case-mix index CY = calendar year DKA = diabetic ketoacidosis EMR = electronic medical record GBMF = Gordon and Betty Moore Foundation ICU = intensive care unit IIP = insulin infusion protocol SHM = Society of z Hospital Medicine.

Iatrogenic Inpatient Hypoglycemia: Risk Factors, Treatment, and Prevention Analysis of Current Practice at an Academic Medical Center With Implications for Improvement Efforts Gregory A. Maynard , MD, MSc , Maggie Patricia Huynh , PharmD and Marian Renvall , MSc Abstract In Brief We performed a 130-patient case-control study to examine the patient and hospital care risk factors for experiencing a hypoglycemic patient-day, comparing these factors to similar control patients who were not experiencing a hypoglycemic patient-day. We also examined adherence to our hypoglycemia management protocols, documentation of the event, and adjustments to medications and nutritional regimens that occurred in response to the hypoglycemic event. The most powerful risk factors for hypoglycemia were unexpected nutritional interruption, prior hypoglycemia during the hospital stay, and asynchrony of nutrition delivery and insulin administration. Adherence to hypoglycemia management and documentation standards was poor. Here, we outline strategies to focus improvement efforts on adherence to hypoglycemia treatment protocols and proactive management of patients with these key hypoglycemia risk factors. Footnotes Gregory A. Maynard, MD, MSc, is a clinical professor of medicine and the hospital medicine division chief at the University of California, San Diego Medical Center. Maggie Patricia Huynh, PharmD, is a resident in the University of California, San Diego Medical Center Pharmacy Practice Residency. Marian Renvall, MSc, is the senior statistician with the Division of General Internal Medicine at the University of California, San Diego. American Diabetes Association

We performed a 130-patient case-control study to examine the patient and hospital care risk factors for experiencing a hypoglycemic patient-day, comparing these factors to similar control patients who were not experiencing a hypoglycemic patient-day. We also examined adherence to our hypoglycemia management protocols, documentation of the event, and adjustments to medications and nutritional regimens that occurred in response to the hypoglycemic event. The most powerful risk factors for hypoglycemia were unexpected nutritional interruption, prior hypoglycemia during the hospital stay, and asynchrony of nutrition delivery and insulin administration. Adherence to hypoglycemia management and documentation standards was poor. Here, we outline strategies to focus improvement efforts on adherence to hypoglycemia treatment protocols and proactive management of patients with these key hypoglycemia risk factors. [PUBLICATION ABSTRACT]

Abstract Hospitalization of persons with dementia can pose specific challenges for family caregivers, with post-discharge issues in managing acute clinical care needs coupled with dementia-related care that can exacerbate caregiver fatigue and capacity. We established an academic-practice collaboration to develop an evidence-based and innovative multi-component health system-level program to support family caregivers of persons with dementia in transition from hospital to community. Using an implementation science approach aimed to decrease the gap in translation of caregiver research into practice, we co-designed the program/implementation plan as a quality improvement initiative reflecting an integration of evidence from family caregiving literature and the health system’s unique context, workflows, stakeholder perspectives, resources, and values/priorities. This paper highlights insights gained and lessons learned in establishing a successful academic-practice collaboration, including time/investment to establish a shared project vision and identify/leverage existing organizational capacity to successfully deliver a program to improve the health and wellbeing of family caregivers.

Life for many of the world’s marine fish begins at the ocean surface. Ocean conditions dictate food availability and govern survivorship, yet little is known about the habitat preferences of larval fish during this highly vulnerable life-history stage. Here we show that surface slicks, a ubiquitous coastal ocean convergence feature, are important nurseries for larval fish from many ocean habitats at ecosystem scales. Slicks had higher densities of marine phytoplankton (1.7-fold), zooplankton (larval fish prey; 3.7-fold), and larval fish (8.1-fold) than nearby ambient waters across our study region in Hawai’i. Slicks contained larger, more well-developed individuals with competent swimming abilities compared to ambient waters, suggesting a physiological benefit to increased prey resources. Slicks also disproportionately accumulated prey-size plastics, resulting in a 60-fold higher ratio of plastics to larval fish prey than nearby waters. Dissections of hundreds of larval fish found that 8.6% of individuals in slicks had ingested plastics, a 2.3-fold higher occurrence than larval fish from ambient waters. Plastics were found in 7 of 8 families dissected, including swordfish (Xiphiidae), a commercially targeted species, and flying fish (Exocoetidae), a principal prey item for tuna and seabirds. Scaling up across an ∼1,000 km² coastal ecosystem in Hawai’i revealed slicks occupied only 8.3% of ocean surface habitat but contained 42.3% of all neustonic larval fish and 91.8% of all floating plastics. The ingestion of plastics by larval fish could reduce survivorship, compounding threats to fisheries productivity posed by overfishing, climate change, and habitat loss.

Coral reef ecosystems are being fundamentally restructured by local human impacts and climate-driven marine heatwaves that trigger mass coral bleaching and mortality 1 . Reducing local impacts can increase reef resistance to and recovery from bleaching 2 . However, resource managers lack clear advice on targeted actions that best support coral reefs under climate change 3 and sector-based governance means most land- and sea-based management efforts remain siloed 4 . Here we combine surveys of reef change with a unique 20-year time series of land–sea human impacts that encompassed an unprecedented marine heatwave in Hawai‘i. Reefs with increased herbivorous fish populations and reduced land-based impacts, such as wastewater pollution and urban runoff, had positive coral cover trajectories predisturbance. These reefs also experienced a modest reduction in coral mortality following severe heat stress compared to reefs with reduced fish populations and enhanced land-based impacts. Scenario modelling indicated that simultaneously reducing land–sea human impacts results in a three- to sixfold greater probability of a reef having high reef-builder cover four years postdisturbance than if either occurred in isolation. International efforts to protect 30% of Earth’s land and ocean ecosystems by 2030 are underway 5 . Our results reveal that integrated land–sea management could help achieve coastal ocean conservation goals and provide coral reefs with the best opportunity to persist in our changing climate. Surveys of reef change are combined with a unique 20-year time series of land–sea human impacts and the results show that integrated land–sea management could help achieve coastal ocean conservation goals and provide coral reefs with the best opportunity to persist in our changing climate.

Single-cell analysis methods are valuable tools; however, current approaches do not easily enable live cell retrieval. That is a particular issue when further study of cells that were eliminated during experimentation could provide critical information. We report a clonal molecular barcoding method, called SunCatcher, that enables longitudinal tracking and live cell functional analysis. From complex cell populations, we generate single cell-derived clonal populations, infect each with a unique molecular barcode, and retain stocks of individual barcoded clones (BCs). We develop quantitative PCR-based and next-generation sequencing methods that we employ to identify and quantify BCs in vitro and in vivo. We apply SunCatcher to various breast cancer cell lines and combine respective BCs to create versions of the original cell lines. While the heterogeneous BC pools reproduce their original parental cell line proliferation and tumor progression rates, individual BCs are phenotypically and functionally diverse. Early spontaneous metastases can also be identified and quantified. SunCatcher thus provides a rapid and sensitive approach for studying live single-cell clones and clonal evolution, and performing functional analyses. DNA barcoding methods for the analysis of clonal heterogeneity in cancer have been limited in terms of throughput and practical requirements. Here, the authors develop SunCatcher, a rapid and sensitive barcoding approach for live single-cell clonal evolution analysis, and use this method to study breast cancer cell populations.

The severe acute respiratory syndrome coronavirus 2 spike protein is a critical component of coronavirus disease 2019 vaccines and diagnostics and is also a therapeutic target. However, the spike protein is difficult to produce recombinantly because it is a large trimeric class I fusion membrane protein that is metastable and heavily glycosylated. We recently developed a prefusion-stabilized spike variant, termed HexaPro for six stabilizing proline substitutions, that can be expressed with a yield of >30 mg/L in ExpiCHO cells. This protocol describes an optimized workflow for expressing and biophysically characterizing rationally engineered spike proteins in Freestyle 293 and ExpiCHO cell lines. Although we focus on HexaPro, this protocol has been used to purify over a hundred different spike variants in our laboratories. We also provide guidance on expression quality control, long-term storage, and uses in enzyme-linked immunosorbent assays. The entire protocol, from transfection to biophysical characterization, can be completed in 7 d by researchers with basic tissue cell culture and protein purification expertise. The authors present a protocol for expressing and biophysically characterizing rationally engineered SARS-CoV-2 spike proteins in Freestyle 293 and ExpiCHO cell lines.