Development and Implementation of a Digital Quality Measure of Emergency Cancer Diagnosis.

PURPOSE: Missed and delayed cancer diagnoses are common, harmful, and often preventable. Automated measures of quality of cancer diagnosis are lacking but could identify gaps and guide interventions. We developed and implemented a digital quality measure (dQM) of cancer emergency presentation (EP) using electronic health record databases of two health systems and characterized the measure's association with missed opportunities for diagnosis (MODs) and mortality. METHODS: On the basis of literature and expert input, we defined EP as a new cancer diagnosis within 30 days after emergency department or inpatient visit. We identified EPs for lung cancer and colorectal cancer (CRC) in the Department of Veterans Affairs (VA) and Geisinger from 2016 to 2020. We validated measure accuracy and identified preceding MODs through standardized chart review of 100 records per cancer per health system. Using VA's longitudinal encounter and mortality data, we applied logistic regression to assess EP's association with 1-year mortality, adjusting for cancer stage and demographics. RESULTS: Among 38,565 and 2,914 patients with lung cancer and 14,674 and 1,649 patients with CRCs at VA and Geisinger, respectively, our dQM identified EPs in 20.9% and 9.4% of lung cancers, and 22.4% and 7.5% of CRCs. Chart reviews revealed high positive predictive values for EPs across sites and cancer types (72%-90%), and a substantial percent represented MODs (48.8%-84.9%). EP was associated with significantly higher odds of 1-year mortality for lung cancer and CRC (adjusted odds ratio, 1.78 and 1.83, respectively, 95% CI, 1.63 to 1.86 and 1.61 to 2.07). CONCLUSION: A dQM for cancer EP was strongly associated with both mortality and MODs. The findings suggest a promising automated approach to measuring quality of cancer diagnosis in US health systems.

Coupling a Live Cell Directed Evolution Assay with Coevolutionary Landscapes to Engineer an Improved Fluorescent Rhodopsin Chloride Sensor.

Our understanding of chloride in biology has been accelerated through the application of fluorescent protein-based sensors in living cells. These sensors can be generated and diversified to have a range of properties using laboratory-guided evolution. Recently, we established that the fluorescent proton-pumping rhodopsin wtGR from Gloeobacter violaceus can be converted into a fluorescent sensor for chloride. To unlock this non-natural function, a single point mutation at the Schiff counterion position (D121V) was introduced into wtGR fused to cyan fluorescent protein (CFP) resulting in GR1-CFP. Here, we have integrated coevolutionary analysis with directed evolution to understand how the rhodopsin sequence space can be explored and engineered to improve this starting point. We first show how evolutionary couplings are predictive of functional sites in the rhodopsin family and how a fitness metric based on a sequence can be used to quantify the known proton-pumping activities of GR-CFP variants. Then, we couple this ability to predict potential functional outcomes with a screening and selection assay in live Escherichia coli to reduce the mutational search space of five residues along the proton-pumping pathway in GR1-CFP. This iterative selection process results in GR2-CFP with four additional mutations: E132K, A84K, T125C, and V245I. Finally, bulk and single fluorescence measurements in live E. coli reveal that GR2-CFP is a reversible, ratiometric fluorescent sensor for extracellular chloride with an improved dynamic range. We anticipate that our framework will be applicable to other systems, providing a more efficient methodology to engineer fluorescent protein-based sensors with desired properties.

Antibiotics for acne vulgaris: using instagram to seek insight into the patient perspective.

OBJECTIVES: Monitoring of public social media posts is an underutilized method to understand patients' perspectives regarding their condition and treatment. We investigated information shared by Instagram users of oral and topical antibiotics for treatment of acne vulgaris. MATERIAL AND METHODS: We performed a retrospective observational study of public Instagram posts assigned common hashtags to denote the use of antibiotics therapy for acne over nearly eight years. RESULTS: Dissatisfaction was more prevalent among users of oral antibiotics (25.6%) compared to users of topical antibiotics (9.8%), and negative tone among this group was most commonly due to lack of improvement in skin appearance. Reported side effects paralleled known side effects for oral and topical antibiotics. CONCLUSIONS: Instagram may have utility in elucidating patient behavior and attitudes. Dermatologists should increase their social media presence in order to disqualify any incorrect information endorsed in 'popular' or commonly viewed posts.

On the Digital Psychopharmacology of Valproic Acid in Mice.

Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anxiety, anger and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. In this study, we applied instrumented home-cage monitoring to assess how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. Through a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. At 500-600 mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied to breeder pairs of mice throughout gestation, VPA prolonged the latency to viable litters without affecting litter size. Two-weeks old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Together, these data illustrate how automated home-cage assessments of spontaneous behavior capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating such rigorous assessments of psychological tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.

Home-cage monitoring ascertains signatures of ictal and interictal behavior in mouse models of generalized seizures.

Epilepsy is a significant contributor to worldwide disability. In epilepsy, disability can be broadly divided into two components: ictal (pertaining to the burden of unpredictable seizures and associated medical complications including death) and interictal (pertaining to more pervasive debilitating changes in cognitive and emotional behavior). In this study, we objectively and noninvasively appraise aspects of ictal and interictal behavior in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. Through daily intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) applied to C57BL/6J mice, we coordinately measure how "behavioral severity" (complex dynamic changes in movement and sheltering behavior) and convulsive severity (latency and occurrence of convulsive seizures) evolve or kindle with repeated injections. By closely studying long epochs between PTZ injections, we identify an interictal syndrome of nocturnal hypoactivity and increased sheltering behavior which remits with the cessation of seizure induction. We observe elements of this interictal behavioral syndrome in seizure-prone DBA/2J mice and in mice with a pathogenic Scn1a mutation (modeling Dravet syndrome). Through analyzing their responses to PTZ, we illustrate how convulsive severity and "behavioral" severity are distinct and independent aspects of the overall severity of a PTZ-induced seizure. Our results illustrate the utility of an ethologically centered automated approach to quantitatively appraise murine expressions of disability in mouse models of seizures and epilepsy. In doing so, this study highlights the very unique psychopharmacological profile of PTZ.