High-Throughput Assay for Predicting Diarrhea Risk Using a 2D Human Intestinal Stem Cell-Derived Model.

Gastrointestinal toxicities (GITs) are the most prevalent adverse events (AE) reported in clinical trials, often resulting in dose-limitations that reduce drug efficacy and delay development and treatment optimization. Preclinical animal models do not accurately replicate human GI physiology, leaving few options for early detection of GI side effects prior to human studies. Development of an accurate model that predicts GIT earlier in drug discovery programs would better support successful clinical trial outcomes. Chemotherapeutics, which exhibit high rates of clinical GIT, frequently target mitotic cells. Therefore, we hypothesized that a model utilizing proliferative cell populations derived from human intestinal crypts would predict the occurrence of clinical GITs with high accuracy. Here, we describe the development of a multiparametric assay utilizing the RepliGut® Planar system, an intestinal stem cell-derived platform cultured in an accessible high throughput Transwell™ format. This assay addresses key physiological elements of GIT by assessing cell proliferation (EdU incorporation), cell abundance (DAPI quantification), and barrier function (TEER). Using this approach, we demonstrate that primary proliferative cell populations reproducibly respond to marketed chemotherapeutics at physiologic concentrations. To determine the ability of this model to predict clinical diarrhea risk, we evaluated a set of 30 drugs with known clinical diarrhea incidence in three human donors, comparing results to known plasma drug concentrations. This resulted in highly accurate predictions of diarrhea potential for each endpoint (balanced accuracy of 91% for DAPI, 90% for EdU, 88% for TEER) with minimal variation across human donors. In vitro toxicity screening using primary proliferative cells may enable improved safety evaluations, reducing the risk of AEs in clinical trials and ultimately lead to safer and more effective treatments for patients.

Methylxanthine use in infants with hypoxic-ischemic encephalopathy: a retrospective cohort study.

Therapeutic hypothermia is the standard treatment for hypoxic-ischemic encephalopathy (HIE), but despite its widespread use, the rates of mortality and neurodevelopmental impairment for moderate to severe HIE remain around 30%. Methylxanthines, such as caffeine and aminophylline, have potential neuroprotective effects in the setting of hypoxic-ischemic injury. However, data on the safety and efficacy of methylxanthines in the setting of therapeutic hypothermia for HIE are limited. This retrospective multicenter study examined in-hospital outcomes in 52 infants with HIE receiving methylxanthines and therapeutic hypothermia. The frequency of mortality and in-hospital morbidities were similar to those of infants enrolled in clinical trials undergoing therapeutic hypothermia without adjunctive therapies. Clinical trials of methylxanthines for neuroprotection in HIE are needed to determine safety and efficacy and should explore optimal dosing and timing of methylxanthine administration.

Artificial Intelligence-based automated CT brain interpretation to accelerate treatment for acute stroke in rural India: An interrupted time series study.

In resource-limited settings, timely treatment of acute stroke is dependent upon accurate diagnosis that draws on non-contrast computed tomography (NCCT) scans of the head. Artificial Intelligence (AI) based devices may be able to assist non-specialist physicians in NCCT interpretation, thereby enabling faster interventions for acute stroke patients in these settings. We evaluated the impact of an AI device by comparing the time to intervention (TTI) from NCCT imaging to significant intervention before (baseline) and after the deployment of AI, in patients diagnosed with stroke (ischemic or hemorrhagic) through a retrospective interrupted time series analysis at a rural hospital managed by non-specialists in India. Significant intervention was defined as thrombolysis or antiplatelet therapy in ischemic strokes, and mannitol for hemorrhagic strokes or mass effect. We also evaluated the diagnostic accuracy of the software using the teleradiologists' reports as ground truth. Impact analysis in a total of 174 stroke patients (72 in baseline and 102 after deployment) demonstrated a significant reduction of median TTI from 80 minutes (IQR: 56·8-139·5) during baseline to 58·50 (IQR: 30·3-118.2) minutes after AI deployment (Wilcoxon rank sum test-location shift: -21·0, 95% CI: -38·0, -7·0). Diagnostic accuracy evaluation in a total of 864 NCCT scans demonstrated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) in detecting intracranial hemorrhage to be 0·89 (95% CI: 0·83-0·93), 0·99 (0·98-1·00), 0·96 (0·91-0·98) and 0·97 (0·96-0·98) respectively, and for infarct these were 0·84 (0·79-0·89), 0·81 (0·77-0·84), 0·58 (0·52-0·63), and 0·94 (0·92-0·96), respectively. AI-based NCCT interpretation supported faster abnormality detection with high accuracy, resulting in persons with acute stroke receiving significantly earlier treatment. Our results suggest that AI-based NCCT interpretation can potentially improve uptake of lifesaving interventions for acute stroke in resource-limited settings.

Attenuation correction and truncation completion for breast PET/MR imaging using deep learning.

Objective. Simultaneous PET/MR scanners combine the high sensitivity of MR imaging with the functional imaging of PET. However, attenuation correction of breast PET/MR imaging is technically challenging. The purpose of this study is to establish a robust attenuation correction algorithm for breast PET/MR images that relies on deep learning (DL) to recreate the missing portions of the patient's anatomy (truncation completion), as well as to provide bone information for attenuation correction from only the PET data.Approach. Data acquired from 23 female subjects with invasive breast cancer scanned with18F-fluorodeoxyglucose PET/CT and PET/MR localized to the breast region were used for this study. Three DL models, U-Net with mean absolute error loss (DLMAE) model, U-Net with mean squared error loss (DLMSE) model, and U-Net with perceptual loss (DLPerceptual) model, were trained to predict synthetic CT images (sCT) for PET attenuation correction (AC) given non-attenuation corrected (NAC) PETPET/MRimages as inputs. The DL and Dixon-based sCT reconstructed PET images were compared against those reconstructed from CT images by calculating the percent error of the standardized uptake value (SUV) and conducting Wilcoxon signed rank statistical tests.Main results. sCT images from the DLMAEmodel, the DLMSEmodel, and the DLPerceptualmodel were similar in mean absolute error (MAE), peak-signal-to-noise ratio, and normalized cross-correlation. No significant difference in SUV was found between the PET images reconstructed using the DLMSEand DLPerceptualsCTs compared to the reference CT for AC in all tissue regions. All DL methods performed better than the Dixon-based method according to SUV analysis.Significance. A 3D U-Net with MSE or perceptual loss model can be implemented into a reconstruction workflow, and the derived sCT images allow successful truncation completion and attenuation correction for breast PET/MR images.

Acoustic resonance therapy is safe and effective for the treatment of nasal congestion in rhinitis: A randomized sham-controlled trial.

BACKGROUND: Acoustic resonance therapy (ART) is a novel vibrational treatment that delivers patient-specific resonant frequency acoustic energy to the sinonasal cavities. In a pilot study, ART was effective for the acute treatment of nasal congestion. We conducted a sham-controlled randomized trial to validate the efficacy of ART when administered daily for 2 weeks. METHODS: A total of 52 adult patients were enrolled in a multi-center, randomized, double-blinded, sham-controlled, interventional study evaluating ART administered by a vibrational headband. Patients received either active treatment or a non-therapeutic sham treatment twice daily over 2 weeks. Clinical endpoints were the average change in nasal congestion sub-score of the Total Nasal Symptom Score (TNSS) and the average change in composite TNSS. RESULTS: ART resulted in a significantly greater mean change in the nasal congestion sub-score compared to sham (-0.87 [95% confidence interval [CI] -1.11, -0.62] vs. -0.44 [95% CI -0.64, -0.23], p = 0.008). ART also resulted in a significantly greater reduction in the composite TNSS versus sham, (-2.85 [95% CI -3.85, -1.85], vs. -1.32 [95% CI -2.27, -0.36], p = 0.027). The response rate, determined by a nasal congestion sub-score minimal clinically important difference of 0.23, was 80.8% for ART and 46.2% for sham, with an adjusted risk ratio of 1.95 (95% CI 1.26, 3.02, p = 0.003) in favor of ART. Safety endpoints showed no adverse events. CONCLUSION: ART is a safe and effective non-pharmacologic alternative for the treatment of nasal congestion.

Alfaxalone increases measured progesterone concentration in neutered male cats when determined by immunoreactivity.

OBJECTIVE: Alfaxalone is a commonly used anesthetic agent in small animals. In cats, alfaxalone can be administered as an IM agent to achieve clinically useful sedation or anesthesia, negating the need for IV injection in difficult patients. The molecular structure of alfaxalone is similar to the hormone progesterone (P4). It is hypothesized that alfaxalone would cross-react with the assay measuring progesterone causing a false elevation. ANIMALS: 8 healthy neutered male, domestic shorthair cats that were privately owned were enrolled in the study. METHODS: Male neutered cats were administered 3 mg/kg of alfaxalone IM. Blood samples were collected at set time points (baseline, 30 minutes, 60 minutes, 3 hours, 6 hours, and 10 hours after administration), and serum concentrations of progesterone immunoreactivity (IR) were determined using the Siemens Immulite 1000 automated immunoassay system. Statistical analysis was performed with repeated measures ANOVA and a Tukey-Cramer multiple comparisons test. A P value of < .05 was used for significance. RESULTS: Serum progesterone IR was significantly elevated at 30 minutes, 1 hour, and 3 hours (P < .05) when compared to baseline progesterone immunoreactivity. Progesterone immunoreactivity had returned to baseline by 6 hours. CLINICAL RELEVANCE: This study suggests that alfaxalone administered IM in cats may interfere with immunoassay measurement of serum progesterone for up to 6 hours. Caution should be used when interpreting serum progesterone immunoreactivity results in cats within 4 hours of alfaxalone.

Integrating sensory ecology and predator-prey theory to understand animal responses to fire.

Fire regimes are changing dramatically worldwide due to climate change, habitat conversion, and the suppression of Indigenous landscape management. Although there has been extensive work on plant responses to fire, including their adaptations to withstand fire and long-term effects of fire on plant communities, less is known about animal responses to fire. Ecologists lack a conceptual framework for understanding behavioural responses to fire, which can hinder wildlife conservation and management. Here, we integrate cue-response sensory ecology and predator-prey theory to predict and explain variation in if, when and how animals react to approaching fire. Inspired by the literature on prey responses to predation risk, this framework considers both fire-naïve and fire-adapted animals and follows three key steps: vigilance, cue detection and response. We draw from theory on vigilance tradeoffs, signal detection, speed-accuracy tradeoffs, fear generalization, neophobia and adaptive dispersal. We discuss how evolutionary history with fire, but also other selective pressures, such as predation risk, should influence animal behavioural responses to fire. We conclude by providing guidance for empiricists and outlining potential conservation applications.

Ultrasound dilution cardiac output and echocardiography findings in anesthetized mature alpacas (Vicugna pacos) during normotension, hypotension and hypertension.

Alpacas (Vicugna pacos) have physiologic adaptations to live at high altitude. These adaptations may result in unexpected responses to changes in cardiac performance and blood pressure during general anesthesia. There are few studies evaluating cardiovascular variables in anesthetized alpacas. The purpose of this study was to report cardiovascular performance in anesthetized mature alpacas during normotension, hypotension, and hypertension using ultrasound dilution and echocardiography. Six adult alpacas, 3 females and 3 castrated males, weighing 62.6 to 88.7 kg were anesthetized and maintained with isoflurane and placed in right lateral recumbency. Each alpaca underwent ultrasound dilution and echocardiography measurements during three cardiovascular phases, normotension, hypotension via increased isoflurane concentration, and hypertension via phenylephrine infusion. Variables were analyzed with a Friedman test and a post hoc Dunn's test when significant. A p < 0.05 was used for significance. Cardiac output, cardiac index, systemic vascular resistance, stroke volume, total ejection fraction, left ventricular internal diameter during diastole, and total stroke volume indexed to body weight were greater for hypertension compared to hypotension. Total ejection fraction, stroke volume, and left ventricular ejection time were greater for hypertions compared to normotension. There was no difference between ultrasound dilution and echocardiography determined cardiac output measurements within each cardiovascular phase. Phenylephrine appeared to have increased ventricular performance and/or increased preload in anesthetized, mature alpacas. For detecting change in cardiovascular status in anesthetized alpacas, ultrasound dilution and echocardiography may be useful.

Light modulates Drosophila lifespan via perceptual systems independent of circadian rhythms.

Across taxa, sensory perception modulates aging in response to important ecological cues, including food, sex, and danger. The range of sensory cues involved, and their mechanism of action, are largely unknown. We therefore sought to better understand how one potential cue, that of light, impacts aging in Drosophila melanogaster. In accordance with recently published data, we found that flies lived significantly longer in constant darkness. Extended lifespan was not accompanied by behavioral changes that might indirectly slow aging such as activity, feeding, or fecundity, nor were circadian rhythms necessary for the effect. The lifespans of flies lacking eyes or photoreceptor neurons were unaffected by light kept at normal housing conditions, and transgenic activation of these same neurons was sufficient to phenocopy the effects of environmental light on lifespan. The relationship between light and lifespan was not correlated with its intensity, duration, nor the frequency of light-dark transitions. Furthermore, high-intensity light reduced lifespan in eyeless flies, indicating that the effects we observed were largely independent of the known, non-specific damaging effects associated with light. Our results suggest that much like other environmental cues, light may act as a sensory stimulus to modulate aging.

Behavioral plasticity can facilitate evolution in urban environments.

Plasticity-led evolution is central to evolutionary theory. Although challenging to study in nature, this process may be particularly apparent in novel environments such as cities. We document abundant evidence of plastic behavioral changes in urban animals, including learning, contextual, developmental, and transgenerational plasticities. Using behavioral drive as a conceptual framework, our analysis of notable case studies suggests that plastic behaviors, such as altered habitat use, migration, diurnal and seasonal activity, and courtship, can have faciliatory and cascading effects on urban evolution via spatial, temporal, and mate-choice mechanisms. Our findings highlight (i) the need to incorporate behavioral plasticity more formally into urban evolutionary research and (ii) the opportunity provided by urban environments to study behavioral mechanisms of plasticity-led processes.

The Role of Social Determinants of Health in Moral Injury: Implications and Future Directions.

Purpose of Review: Exposure to potentially morally injurious events (PMIEs) and the development of moral injury have yet to be conceptualized as they relate to social determinants of health (SDoH).Recent Findings.In this paper, the extant literature on moral injury and SDoH is reviewed. Specific individual-level SDoH, including gender, sex, sexual orientation, race, and ethnicity, are explored relative to PMIEs and moral injury. The relationship among environmental SDoH, including childhood environment, justice involvement, and homelessness, is described. Summary: Assessment and treatment implications are discussed, and future research directions highlighting the need for additional work addressing health inequities in moral injury are presented.

The Role of Aquaculture and Capture Fisheries in Meeting Food and Nutrition Security: Testing a Nutrition-Sensitive Pond Polyculture Intervention in Rural Zambia.

This study tested the efficacy of a pond polyculture intervention with farming households in northern Zambia. Longitudinal data on fish consumption and the associated nutrient intake of households (N = 57) were collected over a six-month period (September 2019-March 2020). One group of people tested the intervention while another group that practiced monoculture tilapia farming, and a third group that did not practice aquaculture, acted as control groups. A similar quantity of fish was consumed on average; however, the associated nutrient intake differed, based on the quantity and type of species consumed, particularly for those who had access to pelagic small fish from capture fisheries. There was a decrease in fish consumption from December onward due to fisheries management restrictions. The ponds provided access to micronutrient-rich fish during this time. Pond polyculture can act as a complementary source of fish to capture fisheries that are subjected to seasonal controls, as well as to households that farm tilapia. Assessments of how aquatic foods can improve food and nutrition security often separate aquaculture and capture fisheries, failing to account for people who consume fish from diverse sources simultaneously. A nutrition-sensitive approach thus places food and nutrition security, and consumers, at the center of the analysis.

An Anthropomorphic Digital Reference Object (DRO) for Simulation and Analysis of Breast DCE MRI Techniques.

Advances in accelerated magnetic resonance imaging (MRI) continue to push the bounds on achievable spatial and temporal resolution while maintaining a clinically acceptable image quality. Validation tools, including numerical simulations, are needed to characterize the repeatability and reproducibility of such methods for use in quantitative imaging applications. We describe the development of a simulation framework for analyzing and optimizing accelerated MRI acquisition and reconstruction techniques used in dynamic contrast enhanced (DCE) breast imaging. The simulation framework, in the form of a digital reference object (DRO), consists of four modules that control different aspects of the simulation, including the appearance and physiological behavior of the breast tissue as well as the MRI acquisition settings, to produce simulated k-space data for a DCE breast exam. The DRO design and functionality are described along with simulation examples provided to show potential applications of the DRO. The included simulation results demonstrate the ability of the DRO to simulate a variety of effects including the creation of simulated lesions, tissue enhancement modeled by the generalized kinetic model, T1-relaxation, fat signal precession and saturation, acquisition SNR, and changes in temporal resolution.

Dermatology urgent care model reduces costs and healthcare utilization for psychodermatology patients - a retrospective chart review.

BACKGROUND: Patients with psychiatric dermatoses may be high users of healthcare, especially emergency services. A dermatology urgent care model may reduce healthcare utilization in this population. OBJECTIVE: To determine whether a dermatology urgent care model can reduce healthcare utilization among patients with psychiatric dermatoses. METHODS: We conducted a retrospective chart review of patients seen in dermatology urgent care at Oregon Health and Science University between 2018 and 2020 with diagnoses of Morgellons disease and neurotic excoriations. Rates of diagnosis-related healthcare visits and emergency department visits were annualized before and during engagement with the dermatology department. Rates were compared using paired t-tests. RESULTS: We found an 88.0% reduction in annual rates of healthcare visits (P<0.001) and 77.0% reduction in emergency room visits (P<0.003). Results were unchanged when controlled for gender identity, diagnosis, and substance use. LIMITATIONS: We could not account for healthcare use not included in electronic health record. CONCLUSION: Urgent care models in dermatology may reduce overuse of healthcare and emergency services among patients with psychiatric dermatoses.

Direct Costs of Healthcare among Patients with Deliberate Self-harm: A Pilot Study from a Tertiary Care Hospital in South India.

Background: Deliberate self-harm (DSH) in developing nations has a significant impact on health and economic conditions of patients and families. Materials and methods: This retrospective study aims to study the cost of hospitalization and the factors affecting the cost of medical care. Adult patients with a diagnosis of DSH were included. Results: A total of 107 patients were included with the most common type of poison consumed being pesticides (35.5%) followed by a tablet overdose (31.8%). There was a male preponderance with a mean (SD) age of 30.04 (9.03) years. The median cost of admission was ₹13,690 (USD 195.57); DSH with pesticide increased the cost of care by 67% as compared to non-pesticides. Other factors which increased the cost were need for intensive care, ventilation, use of vasopressors, and development of ventilator-associated pneumonia (VAP). Conclusions: Pesticide-based poisoning is the most frequent cause of DSH. Among different types of DSH, pesticide poisoning is associated with a higher direct cost of hospitalization. How to cite this article: Barnabas R, Yadav B, Jayakaran J, Gunasekaran K, Johnson J, Pichamuthu K, et al. Direct Costs of Healthcare among Patients with Deliberate Self-harm: A Pilot Study from a Tertiary Care Hospital in South India. Indian J Crit Care Med 2022;26(7):836-838.

Proton density water fraction as a reproducible MR-based measurement of breast density.

PURPOSE: To introduce proton density water fraction (PDWF) as a confounder-corrected (CC) MR-based biomarker of mammographic breast density, a known risk factor for breast cancer. METHODS: Chemical shift encoded (CSE) MR images were acquired using a low flip angle to provide proton density contrast from multiple echo times. Fat and water images, corrected for known biases, were produced by a six-echo CC CSE-MRI algorithm. Fibroglandular tissue (FGT) volume was calculated from whole-breast segmented PDWF maps at 1.5T and 3T. The method was evaluated in (1) a physical fat-water phantom and (2) normal volunteers. Results from two- and three-echo CSE-MRI methods were included for comparison. RESULTS: Six-echo CC-CSE-MRI produced unbiased estimates of the total water volume in the phantom (mean bias 3.3%) and was reproducible across protocol changes (repeatability coefficient [RC] = 14.8 cm3 and 13.97 cm3 at 1.5T and 3.0T, respectively) and field strengths (RC = 51.7 cm3 ) in volunteers, while the two- and three-echo CSE-MRI approaches produced biased results in phantoms (mean bias 30.7% and 10.4%) that was less reproducible across field strengths in volunteers (RC = 82.3 cm3 and 126.3 cm3 ). Significant differences in measured FGT volume were found between the six-echo CC-CSE-MRI and the two- and three-echo CSE-MRI approaches (p = 0.002 and p = 0.001, respectively). CONCLUSION: The use of six-echo CC-CSE-MRI to create unbiased PDWF maps that reproducibly quantify FGT in the breast is demonstrated. Further studies are needed to correlate this quantitative MR biomarker for breast density with mammography and overall risk for breast cancer.

Going Virtual: Objective Structured Teaching Exercises as an Innovative Method for Formative Resident Education.

BACKGROUND: The coronavirus disease 2019 pandemic forced residency programs to adapt teaching to the virtual arena. Objective Structured Teaching Exercises (OSTEs) are a simulation-based session we previously implemented in our in-person pediatric curriculum. We aimed to assess feasibility of and resident satisfaction with the transition to virtual learning for simulation-based OSTEs. METHODS: The pediatrics residency program at our hospital has a weekly academic half-day for residents where the OSTEs were held annually in person 2018 to 2019 and virtually in 2020. Surveys were collected from participating residents and faculty to compare teaching experience, feedback quality, and satisfaction with the session. RESULTS: Over 3 academic years, there were 159 total teaching sessions, 3 of which were OSTEs. The OSTE session was highly rated each year and was the second highest rated virtual session. Residents felt the OSTEs improved their teaching regardless of the virtual versus in-person platform (P = .77), and the quality of feedback as rated by the resident teacher was higher for virtual sessions (P < .001). CONCLUSIONS: Transitioning the OSTE to a virtual platform was both feasible and effective when compared to the in-person OSTE. In the transition to virtual learning, educators should consider opportunities for simulation-based teaching such as OSTEs.

Anesthetic Considerations for Working Dogs.

Working dogs pose unique concerns and challenges to the veterinary practitioner. In this article, the authors review the best practices and clinical pearls for anesthetizing working dogs for both routine and emergent procedures.