Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines.

Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.

Frequency-Domain Low-Wavenumber Hyperspectral Stimulated Raman Scattering Microscopy.

In recent years, stimulated Raman scattering (SRS) microscopy has experienced rapid technological advancements and has found widespread applications in chemical analysis. Hyperspectral SRS (hSRS) microscopy further enhances the chemical selectivity in imaging by providing a Raman spectrum for each pixel. Time-domain hSRS techniques often require interferometry and ultrashort femtosecond laser pulses. They are especially suited to measuring low-wavenumber Raman transitions but are susceptible to scattering-induced distortions. Frequency-domain hSRS microscopy, on the other hand, offers a simpler optical configuration and demonstrates high tolerance to sample scattering but typically operates within the spectral range of 400-4000 cm-1. Conventional frequency-domain hSRS microscopy is widely employed in biological applications but falls short in detecting chemical bonds with a weaker vibrational energy. In this work, we extend the spectral coverage of picosecond spectral-focusing hSRS microscopy to below 100 cm-1. This frequency-domain low-wavenumber hSRS approach can measure the weaker vibrational energy from the sample and has a strong tolerance to sample scattering. By expanding spectral coverage to 100-4000 cm-1, this development enhances the capability of spectral-domain SRS microscopy for chemical imaging.

Strengthening Warfighter Resiliency Using Broad-Spectrum or Host-Directed Therapies within the Rapid Acquisition and Investigation of Drugs for Repurposing Program.

To maintain cadence with looming threats in a prolonged field-care environment, the broader medical countermeasure (MCM) enterprise must adopt new strategies for chemical, biological, radiological, and nuclear (CBRN)-addressing drug development. The Countering Emerging Threats - Rapid Acquisition and Investigation of Drugs for Repurposing (CET RAIDR) program within the Joint Program Manager for CBRN Medical is designed to rapidly tackle known, unknown, and emerging threats by utilizing late-stage or licensed therapeutics. The focus of the CET RAIDR effort is to bridge treatment gaps between threat identification and the implementation of licensed targeted MCMs, thereby strengthening warfighter resiliency. The repurposing approach conserves both time to market and funds by leveraging previous conventional development work as a launch point for repurposing efforts. The CET RAIDR program minimizes development and procurement costs by supplementing the military medical providers' toolbox with post-phase II therapies that demonstrate established safety and manufacturing processes, leading to a cost-sparing model for niche medicines (i.e., CBRN MCMs). SIGNIFICANCE STATEMENT: Countering Emerging Threats - Rapid Acquisition and Investigation of Drugs for Repurposing program candidates are selected based on several pillars: a proven human safety profile, the availability of tools and validated literature on the drug's mechanism of action, well defined assays, and/or animal models to demonstrate efficacy, as well as collaborations with willing and trusted industry partners. This broader repurposing approach to address the growing chemical, biological, radiological, and nuclear threat landscape will better safeguard the warfighter against well documented or unpredictable threats when a direct-acting medical countermeasure is unavailable or not yet conceived.

Patent Ductus Arteriosus and Development of Bronchopulmonary Dysplasia-associated Pulmonary Hypertension.

Rationale: Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus arteriosus (PDA) shunt may be a modifiable risk factor for BPD-PH development. Objective: To determine whether the presence and duration of ductus arteriosus patency differs between extremely preterm infants with and without BPD-PH. Methods: We conducted a retrospective case-control study among preterm infants of gestational age 22 weeks, 0 days, to 28 weeks, 6 days, who remained on respiratory support on postnatal day 28 at the University of Alabama at Birmingham from 2017 to 2020. Infants who were diagnosed with PH (cases) by echocardiography were compared with infants without PH (control subjects). Data from echocardiograms performed during the hospitalization after postnatal day 28 were included. Logistic regression adjusted for covariates that differed significantly between groups. A probit analysis related the duration of ductal patency to the development of BPD-PH. Measurements and Main Results: A total of 138 infants developed BPD alone, and 82 infants developed BPD-PH. After adjustment for differing covariates between groups, both PDA (adjusted odds ratio, 4.29; 95% confidence interval, 1.89-9.77) and moderate to large PDA (adjusted odds ratio, 4.15; 95% confidence interval, 1.78-9.64) remained significantly related to BPD-PH at discharge. By probit analysis, each additional month of PDA and hemodynamically significant PDA exposure was associated with an increased probability for the composite outcome of BPD-PH at discharge or death with coefficients of 0.40 (P < 0.001) and 0.45 (P < 0.001), respectively. Conclusions: In extremely preterm infants on respiratory support on postnatal day 28, both the presence of and a longer duration of ductus arteriosus patency were associated with the development of BPD-PH.

Sick-leave duration after elective day case surgery in ENT: Is it affected by the type of employment?

BACKGROUND: Many ENT day-case procedures are performed on otherwise healthy individuals in employment. We hypothesised patients' type of employment may affect the amount of time taken off work following such procedures. We aimed to disprove the hypothesis that there is no difference in time taken off between employees and self-employed individuals. MATERIALS AND METHODS: We prospectively collected data on working adult patients undertaking elective day-case procedures at our department. Collected information included basic patient demographics and type of employment. A telephone call was made to collect data on actual period of time taken off work, 5-6 weeks later. RESULTS: 23% of patients were self-employed, the rest were employees. 92% of self-employed patients received no pay during their time off. This compared with 10% of employed patients receiving no pay. 77% of employed patients received full pay. Although mean time taken off work was less if the patient was self-employed (9.5 days vs 10.63), this was not found to be statistically significant. DISCUSSION AND CONCLUSION: Our study demonstrates time off work following day-case ENT procedures places a higher financial burden on self-employed patients. This should inform patient counselling prior to operations. We demonstrated no statistically significant difference in time off work post-surgery between the 2 groups. There was a possible trend towards less time off in self-employed individuals and we speculate that further research with more patients may demonstrate a statistically significant difference in time off work. Perhaps most importantly is for doctors to consider how long an individual needs off after a given procedure, after taking account of their individual patient needs, rather than defaulting to a standard 2-weeks.

Global Cancer Surgery: pragmatic solutions to improve cancer surgery outcomes worldwide.

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.

Accuracy of a Risk Alert Threshold for ICU Hypoglycemia: Retrospective Analysis of Alert Performance and Association With Clinical Deterioration Events.

OBJECTIVES: To quantify the accuracy of and clinical events associated with a risk alert threshold for impending hypoglycemia during ICU admissions. DESIGN: Retrospective electronic health record review of clinical events occurring greater than or equal to 1 and less than or equal to 12 hours after the hypoglycemia risk alert threshold was met. SETTING: Adult ICU admissions from June 2020 through April 2021 at the University of Virginia Medical Center. PATIENTS: Three hundred forty-two critically ill adults that were 63.5% male with median age 60.8 years, median weight 79.1 kg, and median body mass index of 27.5 kg/m2. INTERVENTIONS: Real-world testing of our validated predictive model as a clinical decision support tool for ICU hypoglycemia. MEASUREMENTS AND MAIN RESULTS: We retrospectively reviewed 350 hypothetical alerts that met inclusion criteria for analysis. The alerts correctly predicted 48 cases of level 1 hypoglycemia that occurred greater than or equal to 1 and less than or equal to 12 hours after the alert threshold was met (positive predictive value = 13.7%). Twenty-one of these 48 cases (43.8%) involved level 2 hypoglycemia. Notably, three myocardial infarctions, one medical emergency team call, 19 deaths, and 20 arrhythmias occurred greater than or equal to 1 and less than or equal to 12 hours after an alert threshold was met. CONCLUSIONS: Alerts generated by a validated ICU hypoglycemia prediction model had a positive predictive value of 13.7% for real-world hypoglycemia events. This proof-of-concept result suggests that the predictive model offers clinical value, but further prospective testing is needed to confirm this.

Comprehensive and reliable sonographic assessment and scoring system for inflammatory lesions of the paediatric ankle.

OBJECTIVE: The clinical decision-making process in paediatric arthritis lacks an objective, reliable bedside imaging tool. The aim of this study was to develop a US scanning protocol and assess the reliability of B-mode and Doppler scoring systems for inflammatory lesions of the paediatric ankle. METHODS: As part of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) US group, 19 paediatric rheumatologists through a comprehensive literature review developed a set of standardized views and scoring systems to assess inflammatory lesions of the synovial recesses as well as tendons of the paediatric ankle. Three rounds of scoring of still images were followed by one practical exercise. Agreement among raters was assessed using two-way single score intraclass correlation coefficients (ICC). RESULTS: Of the 37 initially identified views to assess the presence of ankle synovitis and tenosynovitis, nine views were chosen for each B-mode and Doppler mode semi-quantitative evaluation. Several scoring exercises and iterative modifications resulted in a final highly reliable scoring system: anterior tibiotalar joint ICC: 0.93 (95% CI 0.92, 0.94), talonavicular joint ICC: 0.86 (95% CI 0.81, 0.90), subtalar joint ICC: 0.91 (95% CI 0.88, 0.93) and tendons ICC: 0.96 (95% CI 0.95, 0.97). CONCLUSION: A comprehensive and reliable paediatric ankle US scanning protocol and scoring system for the assessment of synovitis and tenosynovitis were successfully developed. Further validation of this scoring system may allow its use as an outcome measure for both clinical and research applications.

Reliability of the Pediatric Specific Musculoskeletal Ultrasound Scoring Systems for the Elbow, Wrist, and Finger Joints.

OBJECTIVE: Musculoskeletal ultrasound (MSUS) is increasingly being used in the evaluation of pediatric musculoskeletal diseases. In order to provide objective assessments of arthritis, reliable MSUS scoring systems are needed. Recently, joint-specific scoring systems for arthritis of the pediatric elbow, wrist, and finger joints were proposed by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) MSUS workgroup. This study aimed to assess the reliability of these scoring systems when used by sonographers with different levels of expertise. METHODS: Members of the CARRA MSUS workgroup attended training sessions for scoring the elbow, wrist, and finger. Subsequently, scoring exercises of B mode and power Doppler (PD) mode still images for each joint were performed. Interreader reliability was determined using 2-way single-score intraclass correlation coefficients (ICCs) for synovitis and Cohen [Formula: see text] for tenosynovitis. RESULTS: Seventeen pediatric rheumatologists with different levels of MSUS expertise (1-15 yrs) completed a 2-hour training session and calibration exercise for each joint. Excellent reliability (ICC > 0.75) was found after the first scoring exercise for all the finger and elbow views evaluated on B mode and PD mode, and for all of the wrist views on B mode. After a second training session and a scoring exercise, the wrist PD mode views reached excellent reliability as well. CONCLUSION: The preliminary CARRA MSUS scoring systems for assessing arthritis of the pediatric elbow, wrist, and finger joints demonstrate excellent reliability among pediatric MSUS sonographers with different levels of expertise. With further validation, this reliable joint-specific scoring system could serve as a clinical tool and scientific outcome measure.

Practical guide to coproduction in conservation science.

We considered a series of conservation-related research projects on the island of Pemba, Tanzania, to reflect on the broad significance of Beier et al.'s recommendations for linking conservation science with practical conservation outcomes. The implementation of just some of their suggestions can advance a successful coproduction of actionable science by small research teams. Key elements include, first, scientists and managers working together in the field to ensure feedback in real time; second, questions jointly identified by managers and researchers to facilitate engaged collaboration; third, conducting research at multiple sites, thereby broadening managers' abilities to reach multiple stakeholders; and fourth, establishing a multidisciplinary team because most of the concerns of local managers require input from multiple disciplines.

Consideramos una serie de proyectos de investigación relacionados con la conservación en la isla de Pemba, Tanzania, para reflexionar sobre la importancia de las recomendaciones de Beier et al. para vincular las ciencias de la conservación con sus resultados prácticos. La implementación de sólo algunas de sus sugerencias puede impulsar una coproducción exitosa de ciencia práctica hecha por pequeños equipos de investigación. Los elementos clave incluyen, primero, a los científicos y administrados trabajando juntos en el campo para asegurar respuestas en tiempo real; segundo, preguntas identificadas en conjunto por los administradores y los investigadores para facilitar la colaboración participativa; tercero, realizar investigaciones en sitios diferentes y ampliar con esto las habilidades de los administradores para llegar a múltiples actores; y cuarto, establecer un equipo multidisciplinario ya que la mayoría de los intereses de los administradores locales requieren información de múltiples disciplinas.

Can Historical Control Group Data Be Used to Replace Concurrent Controls in Animal Studies?

The availability of large amounts of high-quality control data from tightly controlled regulated animal safety data has created the idea to re-use these data beyond its classical applications of quality control, identification of treatment-related effects and assessing effect-size relevance for building virtual control groups (VCGs). While the ethical and cost-saving aspects of such a concept are immediately evident, the potential challenges need to be carefully considered to avoid any effect which could lower the sensitivity of an animal study to detect adverse events, safety thresholds, target organs, or biomarkers. In our brief communication, we summarize the current discussion regarding VCGs and propose a path forward how the replacement of concurrent control with VCGs resulting from historical data could be systematically assessed and to come to conclusions regarding the scientific value of the concept.

Measuring vagal activity in postictal bradycardia.

Alterations to cardiac electrical conduction are some of the most frequently observed systemic complications of seizures, with autonomic dysregulation cited as the principal driver for these alterations. In this prospective study, we use 6-lead continuous ECG monitoring in hospitalized patients with epilepsy to trend heart rate patterns in the postictal period. A total of 117 seizures in 45 patients met the criteria for analysis. There was a postictal heart rate increase of 61% (n = 72 seizures), and a decline in heart rate (deceleration) following 38.5% (n = 45). Using 6-lead ECGs for waveform analysis revealed that there was PR prolongation accompanying those seizures that were associated with postictal bradycardia.

Genomic innovation for crop improvement.

Crop production needs to increase to secure future food supplies, while reducing its impact on ecosystems. Detailed characterization of plant genomes and genetic diversity is crucial for meeting these challenges. Advances in genome sequencing and assembly are being used to access the large and complex genomes of crops and their wild relatives. These have helped to identify a wide spectrum of genetic variation and permitted the association of genetic diversity with diverse agronomic phenotypes. In combination with improved and automated phenotyping assays and functional genomic studies, genomics is providing new foundations for crop-breeding systems.

Evolutionary genomics of the cold-adapted diatom Fragilariopsis cylindrus.

The Southern Ocean houses a diverse and productive community of organisms. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean.

Nonmedical opioid use at the end of life: A tale of addiction and a last wish.

BACKGROUND: Nonmedical opioid use (NMOU) has been associated with opioid overdose deaths. This pattern of misuse can be seen in those using opioids for cancer-associated pain. We present a case that highlights the complexities associated with NMOU and a patient's care at the end of life. CASES DESCRIPTION: A patient with a metastatic solid tumor malignancy along with co-occurring history of polysubstance abuse was admitted to an acute palliative and supportive care unit (APSCU). The patient demonstrated behaviors concerning for NMOU during her hospital stay but had increased symptom expression concerning for worsening dyspnea while in the APSCU. Unfortunately, she used home opioids, which was unknown to the team at the time along with requesting for higher doses of opioids that were being prescribed. This caused a worsening respiratory status and affected her care. Using an interdisciplinary approach, the providers managed her symptoms and discharged her safely to see her child. CONCLUSION: This highlights the complexities of the alleviation of suffering in those with NMOU. It is important to continue to manage NMOU at the end of life due to its effects on quality of life. A multimodal approach is recommended to identify and care for these patients.

Reliability of urine drug testing among patients on buprenorphine transdermal patch.

BACKGROUND: Urine drug testing (UDT) plays a significant role in monitoring patients on chronic opioid therapy (COT) for non-medical opioid use (NMOU). UDT, at times, can be inconsistent and misleading. We present a case where a patient on a buprenorphine patch had false negative results. CASE DESCRIPTION: A female in her 70s with metastatic breast cancer presented with uncontrolled pain from a T6 compression fracture. She had no relief with tramadol 50 mg every 6 hours as needed. Due to an allergic reaction to hydromorphone, our team prescribed a buprenorphine patch of 5 µg/h. Subsequently, she expressed excellent pain control, and the clinician confirmed the patch placement on examination. She underwent a UDT during the visit. The UDT was negative for both buprenorphine and its metabolites. The literature review showed that false negative UDT results are relatively common among patients with low-dose buprenorphine patches. The combination of a thorough physical examination, a review of the Prescription Drug Monitoring Program, and reassuring scores on screening tools placed her at low risk for NMOU. DISCUSSION: Buprenorphine has a ceiling effect on respiratory depression and a lower risk for addiction. However, when used in low doses, the drug might not have enough metabolites in the urine, leading to a false negative UDT. Such results might affect patient-physician relationships. CONCLUSION: In addition to the UDT, a thorough history, screening for NMOU, physical exam, a review of PDMP, and a good understanding of opioid metabolism are necessary to help guide pain management.

The Relationship of Mentorship to Career Outcomes in Academic Psychiatry and Psychology: a Needs Assessment.

OBJECTIVE: Faculty development is designed to facilitate career advancement of junior faculty but there is limited empirical evidence on how to design an effective program. METHODS: As a first step in the design of an effective program, a needs assessment was conducted. Participants were faculty members of an academic psychiatry department. Participants completed a quantitative and qualitative survey assessing their experience with mentors, academic self-efficacy, career burnout and satisfaction, academic productivity, and perceived barriers to scholarship. RESULTS: Eighty percent (N = 104) of eligible faculty members completed the study survey (54% female; 81% White, 10% underrepresented in medicine). Less than half of the respondents (44%) reported having a current mentor. Number of mentors (r = .33; p < .01), mentorship meetings (r = .35; p < .01), and mentorship quality (r = .33; p < .01) were significantly correlated to a standardized measure of academic self-efficacy. Self-efficacy was significantly associated with academic productivity (r = .44; p < .001) and career satisfaction (r = .29; p < .05). The top barriers to scholarship productivity were time and lack of access to resources. Faculty members without a mentor endorsed more barriers to scholarship (p < .001) than those with a mentor. Themes that emerged from the qualitative data suggest that mentorship supports career advancement through coaching and professional development, invitations to collaborate and resource share, networking, and active teaching. CONCLUSION: Based on the relationship of mentoring to career outcomes, a robust faculty development program needs a formal academic mentorship program to improve career satisfaction and academic productivity.

Digital stress management in cancer: Testing StressProffen in a 12-month randomized controlled trial.

BACKGROUND: Cognitive-behavioral stress management interventions are associated with improved psychological well-being for cancer survivors. The availability of, access to, and outreach of these in-person interventions are limited, however. The current study, therefore, evaluated the efficacy of StressProffen, a digital application (app)-based stress management intervention for cancer survivors, in a 12-month randomized controlled trial. METHODS: Cancer survivors 1 year or less after their treatment (N = 172) were randomized to the StressProffen intervention (n = 84) or a usual-care control group (n = 88). The intervention was delivered in a simple blended care model: 1) 1 in-person introduction session, 2) 10 app-based cognitive-behavioral stress management modules, and 3) 2 follow-up phone calls. Stress (Perceived Stress Scale), anxiety and depression (Hospital Anxiety and Depression Scale), self-regulatory fatigue (Self-Regulatory Fatigue 18), and health-related quality of life (HRQOL; RAND-36) were examined at the baseline and at 6 and 12 months. Generalized linear models for repeated measures were fitted to compare effects over time. RESULTS: Participants were mainly female (82%), had a mean age of 52 years (standard deviation, 11.3 years; range, 20-78 years), and had a variety of cancer types (mostly breast cancer [48%]). Over the 12-month study time, the intervention group reported significantly decreased stress (P < .001), depression (P = .003), and self-regulatory fatigue (P = .002) as well as improved HRQOL (for 6 of 8 domains, P ≤ .015) in comparison with controls. The largest favored effects for the intervention group were observed at 6 months: stress (estimated mean difference [MD], -5.1; P < .001), anxiety (MD, -1.4; P = .015), depression (MD, -2.1; P < .001), self-regulatory fatigue (MD, -4.9; P < .001), and HRQOL (7 of 8 domains; P ≤ .037). CONCLUSIONS: Digital stress management interventions such as StressProffen have the potential to extend the outreach of psychological interventions and provide easily available and effective psychosocial support for cancer survivors.

Pulse-Picking Multimodal Nonlinear Optical Microscopy.

Nonlinear optical microscopy techniques can map chemical compositions in biological samples in a label-free manner. Commonly used nonlinear optical processes for imaging include multiphoton excitation fluorescence (MPEF), second harmonic generation (SHG), and coherent Raman scattering (CRS). Femtosecond lasers are typically used for MPEF and SHG due to the requirement of high peak power for excitation, while picosecond lasers are preferred for CRS due to the need for high spectral resolution. Therefore, it is challenging to integrate CRS with MPEF and SHG for chemical imaging. We develop a pulse-picking strategy based on an acousto-optic modulator that can program the duty cycle of the laser pulse train, significantly increasing the pulse peak power at low input average power. This approach offers strong enhancement of nonlinear optical signals and makes hyperspectral coherent anti-Stokes Raman scattering (CARS) microscopy compatible with MPEF and SHG for multimodal imaging at low laser average power. The pulse-picking method also enables the evaluation and comparison of phototoxicity of laser pulses at different average and peak power levels. The photo-perturbations to biological samples are evaluated using cellular dynamics and sample morphological changes, allowing the selection of optimal laser power for the best sensitivity and minimal phototoxicity.

Pathophysiologic Signature of Impending ICU Hypoglycemia in Bedside Monitoring and Electronic Health Record Data: Model Development and External Validation.

OBJECTIVES: We tested the hypothesis that routine monitoring data could describe a detailed and distinct pathophysiologic phenotype of impending hypoglycemia in adult ICU patients. DESIGN: Retrospective analysis leading to model development and validation. SETTING: All ICU admissions wherein patients received insulin therapy during a 4-year period at the University of Virginia Medical Center. Each ICU was equipped with continuous physiologic monitoring systems whose signals were archived in an electronic data warehouse along with the entire medical record. PATIENTS: Eleven thousand eight hundred forty-seven ICU patient admissions. INTERVENTIONS: The primary outcome was hypoglycemia, defined as any episode of blood glucose less than 70 mg/dL where 50% dextrose injection was administered within 1 hour. We used 61 physiologic markers (including vital signs, laboratory values, demographics, and continuous cardiorespiratory monitoring variables) to inform the model. MEASUREMENTS AND MAIN RESULTS: Our dataset consisted of 11,847 ICU patient admissions, 721 (6.1%) of which had one or more hypoglycemic episodes. Multivariable logistic regression analysis revealed a pathophysiologic signature of 41 independent variables that best characterized ICU hypoglycemia. The final model had a cross-validated area under the receiver operating characteristic curve of 0.83 (95% CI, 0.78-0.87) for prediction of impending ICU hypoglycemia. We externally validated the model in the Medical Information Mart for Intensive Care III critical care dataset, where it also demonstrated good performance with an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77-0.81). CONCLUSIONS: We used data from a large number of critically ill inpatients to develop and externally validate a predictive model of impending ICU hypoglycemia. Future steps include incorporating this model into a clinical decision support system and testing its effects in a multicenter randomized controlled clinical trial.