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Progressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the Pao 2 to the Fio 2 (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously (ratio of the Spo 2 to the Fio 2 [S/F ratio]), but it is affected by skin color and occult hypoxemia can occur in Black patients. Oxygen dissociation curves allow noninvasive estimation of P/F ratios (ePFRs) but remain unproven., Objectives: Measure overt and occult hypoxemia using ePFR., Design Setting and Participants: We retrospectively studied COVID-19 hospital encounters ( n = 5,319) at two academic centers (University of Virginia [UVA] and Emory University)., Main Outcomes and Measures: We measured primary outcomes (death or ICU transfer within 24 hr), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score [NEWS] and Sequential Organ Failure Assessment [SOFA]). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AORs) and area under the receiver operating characteristic curves (AUROCs). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test., Results: Overt hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p < 0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (0.70 [both sites]) or SOFA (0.68 [UVA]; 0.65 [Emory]) and similar to S/F ratio (0.76 [UVA]; 0.70 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p < 0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory]; p < 0.01)., Conclusions and Relevance: The ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models. By accounting for biased oximetry as well as clinicians' real-time responses to it (supplemental oxygen adjustment), ePFRs may reveal racial disparities attributable to occult hypoxemia., Competing Interests: Dr. Moore is supported by the National Institutes of Health (U01AI150508). Dr. Holder is supported by the National Institutes of Health (K23GM37182), and he has received speaker and consulting fees from Baxter International and Philips, respectively. Dr. Kamaleswaran was supported by the National Institutes of Health (R01GM139967). Dr. Clark is an employee of Nihon Kohden Digital Health Solutions (Irvine, CA). Dr. Moorman has equity in Medical Predictive Science Corporation, Charlottesville, VA, and consults for Nihon Kohden Digital Health Solutions, Irvine, CA, with proceeds donated to the University of Virginia Medical Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Current approaches to early detection of clinical deterioration in children have relied on intermittent track-and-trigger warning scores such as the Pediatric Early Warning Score (PEWS) that rely on periodic assessment and vital sign entry. There are limited data on the utility of these scores prior to events of decompensation leading to pediatric intensive care unit (PICU) transfer., Objective: The purpose of our study was to determine the accuracy of recorded PEWS scores, assess clinical reasons for transfer, and describe the monitoring practices prior to PICU transfer involving acute decompensation., Methods: We conducted a retrospective cohort study of patients ≤21 years of age transferred emergently from the acute care pediatric floor to the PICU due to clinical deterioration over an 8-year period. Clinical charts were abstracted to (1) determine the clinical reason for transfer, (2) quantify the frequency of physiological monitoring prior to transfer, and (3) assess the timing and accuracy of the PEWS scores 24 hours prior to transfer., Results: During the 8-year period, 72 children and adolescents had an emergent PICU transfer due to clinical deterioration, most often due to acute respiratory distress. Only 35% (25/72) of the sample was on continuous telemetry or pulse oximetry monitoring prior to the transfer event, and 47% (34/72) had at least one incorrectly documented PEWS score in the 24 hours prior to the event, with a score underreporting the actual severity of illness., Conclusions: This analysis provides support for the routine assessment of clinical deterioration and advocates for more research focused on the use and utility of continuous cardiorespiratory monitoring for patients at risk for emergent transfer., (©Rebecca L Kowalski, Laura Lee, Michael C Spaeder, J Randall Moorman, Jessica Keim-Malpass. Originally published in JMIR Pediatrics and Parenting (http://pediatrics.jmir.org), 22.02.2021.)

Objectives: Early detection of subacute potentially catastrophic illnesses using available data is a clinical imperative, and scores that report risk of imminent events in real time abound. Patients deteriorate for a variety of reasons, and it is unlikely that a single predictor such as an abnormal National Early Warning Score will detect all of them equally well. The objective of this study was to test the idea that the diversity of reasons for clinical deterioration leading to ICU transfer mandates multiple targeted predictive models., Design: Individual chart review to determine the clinical reason for ICU transfer; determination of relative risks of individual vital signs, laboratory tests and cardiorespiratory monitoring measures for prediction of each clinical reason for ICU transfer; and logistic regression modeling for the outcome of ICU transfer for a specific clinical reason., Setting: Cardiac medical-surgical ward; tertiary care academic hospital., Patients: Eight-thousand one-hundred eleven adult patients, 457 of whom were transferred to an ICU for clinical deterioration., Interventions: None., Measurements and Main Results: We calculated the contributing relative risks of individual vital signs, laboratory tests and cardiorespiratory monitoring measures for prediction of each clinical reason for ICU transfer, and used logistic regression modeling to calculate receiver operating characteristic areas and relative risks for the outcome of ICU transfer for a specific clinical reason. The reasons for clinical deterioration leading to ICU transfer were varied, as were their predictors. For example, the three most common reasons-respiratory instability, infection and suspected sepsis, and heart failure requiring escalated therapy-had distinct signatures of illness. Statistical models trained to target-specific reasons for ICU transfer performed better than one model targeting combined events., Conclusions: A single predictive model for clinical deterioration does not perform as well as having multiple models trained for the individual specific clinical events leading to ICU transfer., Competing Interests: Dr. Moorman is Chief Medical Officer and shareholder and Dr. Clark is Chief Scientific Officer and shareholder in Advanced Medical Predictive Devices, Diagnostics, and Displays, Charlottesville, VA. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Precision medicine (PM) has the potential to tailor healthcare to the individual patient by using their genetic information to guide treatment choices. However, this process is complex and difficult to understand for patients and providers alike. With a recent push in the healthcare community to understand the patient experience and engage patients in their care, it is important to give patients the opportunity to learn about PM. We performed a systematic review to identify previous work assessing the quality of patient-facing PM materials from 2008 to July 2018. Ten studies were identified, which used varying methods and measures. A qualitative assessment was conducted to compare key elements of the studies, including study design, characteristics of the participant population, what measurements were used to assess the PM materials, understandability, preference, psychological reactions, and the type of PM materials being assessed. The studies identified provide important groundwork by highlighting consistent aspects of design that aid in comprehension. Eight of the ten studies focused on the content and organization of genomic test results, while the remaining two assessed educational tools. Two main design elements that appeared across the studies were appropriately designed visual aids and simplified language. The studies identified were limited by the participant populations that were used, which were primarily white and well educated. Only one study attempted to oversample patient populations typically underrepresented in this type of research. Through our systematic review, it is evident that the breadth of knowledge in this field is limited in scope and that more work must be done to ensure that patients can engage in their care when faced with PM.

The subchronic toxicity of the trans isomer of N-(1,3,4,6,7-hexahydro-11bH-benzo[a] quinolizin-2-yl) propionanilide hydrochloride (TR2379), a new antihypertensive agent, was studied in rats and dogs. TR2379 was well tolerated for 13 weeks at daily p.o. doses up to 200 mg/kg in the rat and 70 mg/kg in the dog. However, severe toxic manifestations, including death, were elicited in the rat at 820 mg/kg and in the dog at 160 mg/kg. Toxicity in both species was characterized by a reduction in body weight gain and an increase in the weight of several organs, (liver, heart, kidneys, adrenals, and thyroids). Serum alkaline phosphatase, which was not assayed in the rat, was markedly increased in the dog. Microscopic examination of the various tissues revealed no evidence of organ pathology in either species.

Pathologic examination of sternums from young growing rats revealed a number of skeletal lesions involving both cartilage and bone elements. Degeneration or aseptic necrosis of the intersternebral cartilage was a frequent finding in most rats that were examined either at 130 or 180 days of age. Thickening of the sternal cortices and trabeculae containing prominent cement lines were less frequently occurring lesions in these sternums. These changes were absent in rats of 70 days of age. The etiology of the lesions is not understood, although several factors may be incriminated.

The toxicity of rioprostil was extensively investigated. Studies in rodents, dogs and monkeys indicate a low order of acute toxicity. Oral subchronic and chronic toxicity studies in rats and dogs produce effects that would be expected based on the pharmacological activity of the compound. In reproduction studies with rioprostil, male and female fertility is unaffected in rats at doses up to 2.0 mg/kg/day and there is no evidence of embryotoxicity, fetotoxicity, or teratogenicity in rats at doses up to 1.7 mg/kg/day. In rabbits a maternally toxic dose (1.5 mg/kg) also increases resorptions, reduces fetal weight, and increases the incidence of malformations. Evaluation of 24-month carcinogenicity studies in mice and rats at oral doses up to 2.0 and 1.5 mg/kg/day, respectively, are in progress. Mutagenicity studies are negative.

Histologic, histochemical, and electron microscopic studies of generalized ceroid-lipofuscinosis in a cynomolgus monkey are presented. Histologically, a wide variety of tissue cells contained numerous bright eosinophilic intracytoplasmic granules that varied in size from 0.5 micron to 4.0 microns in diameter. Histochemically, the granules gave a weakly positive reaction with periodic acid-Schiff and for lipids. They were weakly acid fast and capable of emitting autofluorescence. Ultrastructurally, the granules were single unit membrane-bound, and contained dense osmiophilic material with frequent concentric or fingerprint-type lamellar formation. The granules were different than hemofuscin, iron, and bilirubin. Tinctorially the granules were unique--they were bright red with hematoxylin and eosin and, thus, differed from typical age-related lipofuscin pigment.

Flavobacterium arborescens is a common rod-shaped, gram-negative bacterium which, when cultivated in a nutrient medium, is an efficient source of glucose isomerase (GI). GI is then used in the production of high fructose corn syrup. Studies were conducted to assure product safety and establish GRAS status for GI derived from F. arborescens . A viable cell suspension of F. arborescens and the cell-free medium in which the organism was cultured were administered i.v. to rats and rabbits. For feeding studies, the cells were immobilized using polycationic polymers and a crosslinking agent (i.e., chitosan, polyethylenimine and glutaraldehyde). GI, in the whole cell immobilized form, was offered at concentrations of 0, 1.5, 3.0 or 5.0% (wt/wt) of the diet to dogs for a minimum of 90 consecutive days and to rats over three generations. Animals were observed daily for signs of toxicosis; body weight and food consumption were monitored; biochemical tests, hematologic determinations, and urinalyses were done on blood and urine samples; and thorough gross and microscopic tissue examinations were performed at terminations. There were no signs of infection or toxicosis following i.v. administration of F. arborescens or the cell-free supernatant fluid. This, and the lack of toxicity in dogs and rats which received daily dietary concentrations of GI many times above the projected highest possible human exposure level, suggest that there should be virtually no risk of toxicity associated with the consumption of food and beverages containing high fructose syrup produced by GI derived from F. arborescens .

The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

Oral administration of 100 mg/kg of TR2379, N-(1,3,4,6,7-hexahydro-11bH-benzo[a]quinolizin-2-yl) propionanilide hydrochloride, for 20--29 days to 6 dogs resulted in significant elevations of alkaline phosphatase (AP) activity in serum and in liver microsomes. Results of biochemical and histochemical experiments revealed that the liver was the sole source of the increased AP activity but there was no evidence of liver damage. The subchronic (7-35 day) p.o. administration of TR2379 at 820 mg/kg to 20 rats did not produce elevation of AP activity in serum or liver. Relative liver weights (g/100 g body wt) of rats receiving TR2379 were significantly increased during the 2nd week and thereafter. The results of these studies suggest that high doses of TR2379 induce protein synthesis in dog and rat liver and induce AP activity in the dog but not in the rat. The elevation of AP in the dog is not considered to have toxicologic implications.

Rats received the equivalent of 100, 250, 500, or 700 mg/kg of 14C-aspirin orally as a suspension or as a solution of a buffered, effervescent, aspirin-containing product. Animals in each dose group were sacrificed at time intervals ranging from 0.5 to 24 hr after dosing. The 14C content of whole blood, plasma, and homogenized whole kidney (after perfusion) was determined. The concentration of total salicylate proved to be dose dependent and was lower in tissues from rats receiving the buffered, effervescent product, especially at the higher doses. The results suggest that salicylate-induced renal toxicity should be less likely to occur after administration of the buffered, effervescent formulation.

Fecal blood volume was determined daily in 11 dogs with single gastric ulcers. Beginning 11 days after production of the ulcers and dogs received, in crossover fashion, 2 placebo or ordinary 325-mg aspirin tablets orally twice daily during two 7-day treatment periods separated and followed by 5-day periods of no treatment. Mean daily fecal blood volumes of 0.52 and 3.25 ml were observed during periods of treatment with placebo and aspirin, respectively. However, in 7 previous studies in this laboratory a total of 24 normal dogs have received 7-day courses of treatment with 650 mg ordinary aspirin twice daily on 105 occasions; during these 105 treatment periods fecal blood volume averaged 2.90 ml/day. Thus, it is concluded that the effect of ordinary aspirin in dogs with gastric ulcers is essentially the same as the effect in normal dogs, and that there is no tendency for dogs with gastric ulcers to bleed massively in response to aspirin.

The effects of acute and repeated increasing oral doses of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) and guanethidine in the rat and dog have been described. On repeated oral administration guanethidine produced histopathological changes in cervical ganglia of rats and dogs which were clearly dose-dependent and reproduced lesions reported in the literature. Repeated oral administration of MA540 resulted in no histopathological changes in either species. The maximum tolerated oral dose for guanethidine was estimated to be 515 mg/kg in the rat and 26 mg/kg in the dog compared with an estimated maximum tolerated oral dose for MA540 of 1750 mg/kg in the rat and 460 mg/kg in the dog. On the basis of these findings it is suggested that subchronic studies with MA540 in the rat and dog should provide evidence which would justify the use of MA540 in man at daily oral doses as high as 9 mg/kg.