Hypercalcemia Secondary to Calcitriol Production From Dual Combination Immunotherapy in Pulmonary Metastatic Melanoma.

Nivolumab and ipilimumab are immunotherapy agents recommended for the treatment of metastatic melanoma. A rare adverse effect of these agents is hypercalcemia. The mechanism of immunotherapy-mediated hypercalcemia is thought to be due to ectopic calcitriol production from activated macrophages, similar to sarcoidosis. We present a case of a 76-year-old female with metastatic melanoma who developed severe hypercalcemia after completing a cycle of combined nivolumab and ipilimumab therapy. After other common causes of hypercalcemia in malignancy were ruled out, the decision was made to aggressively treat her hypercalcemia while inpatient and hold immunotherapy at discharge. Since holding immunotherapy, she has not had a repeat occurrence of hypercalcemia. This case stresses the importance of including immunotherapy adverse effects in the differential diagnosis for hypercalcemia in malignancy.

Transient Acquired Amegakaryocytic Thrombocytopenia in the Setting of Severe Sepsis: A Case Report.

Acquired amegakaryocytic thrombocytopenia (AATP) is a rare disorder in which severely low platelet levels occur due to reduced or complete absence of megakaryocytes in the bone marrow. The pathophysiology of this disease is not fully understood, although anti-thyroid peroxidase antibodies (anti-TPO) binding to cellular-myeloproliferative leukemia (c-mpl) receptors is a proposed mechanism. Currently, no standard published guideline for treatment exists, but immunosuppressive therapies have been used based on the proposed mechanism and associated conditions. We present a case of a 57-year-old male who presented to the hospital with a 3-day history of progressive weakness and dysphagia. He had recently been discharged from an outside health system after evaluation for suspected gastrointestinal bleeding, although esophagogastroduodenoscopy and colonoscopy did not uncover a source of bleeding. Fifteen days later, he was admitted to our hospital for septic shock and acute renal failure with suspected lower gastrointestinal bleeding (melena on presentation). He was found to have a rapidly declining platelet count with a nadir of 0. Due to severe thrombocytopenia, filgrastim was administered. A bone marrow biopsy revealed findings consistent with amegakaryocytosis with otherwise preserved cell lines. Hematologic labs improved with the initiation of appropriate treatment for severe sepsis. After performing an extensive workup, the likely etiology of transient AATP in this case was severe sepsis-induced immune dysregulation and bone marrow suppression.

Dual Oncological Challenges: Management of Simultaneous Lung Adenocarcinoma and Primary Cardiac Lymphoma.

Adenocarcinoma of the lung and primary cardiac lymphoma are both significant malignancies with serious health impacts. This case involves a 67-year-old woman who presented with progressive shortness of breath and fatigue. Initial computed tomography (CT) imaging identified possible cardiac and pulmonary masses, leading to her transfer to a specialized care center. Subsequent analysis confirmed adenocarcinoma of the lung, and further imaging and biopsy of the cardiac mass revealed diffuse large B-cell lymphoma. The patient received treatments targeted to each cancer, including chemotherapy and immunotherapy. This concurrence of malignancies highlights the importance of comprehensive diagnostic evaluations and personalized therapeutic strategies. Further research is needed to improve the management of patients with concurrent primary cancers.

Racial effects on masimo pulse oximetry: impact of low perfusion index.

PURPOSE:  Evaluate the SpO2-SaO2 difference between Black and White volunteer subjects having a low perfusion index (Pi) compared to those having a normal Pi. METHODS:  The Pi data were abstracted from electronic files collected on 7183 paired SpO2-SaO2 samples (3201 Black and 3982 White) from a recently reported desaturation study of 75 subjects (39 Black and 36 White) where SaO2 values were sequentially decreased from 100 to 70%. The Pi values from that dataset were divided into two groups (Pi ≤ 1 or Pi > 1) for analysis. A Pi value ≤ 1 was considered "low perfusion" and a Pi value > 1 was considered "normal perfusion". Statistical calculations included values of bias (mean difference of SpO2-SaO2), precision (standard deviation of the difference), and accuracy (root-mean-square error [ARMS]). During conditions of low perfusion (Pi ≤ 1, range [0.1 to 1]), overall bias and precision were + 0.48% ± 1.59%, while bias and precision were + 0.19 ± 1.53%, and + 0.91 ± 1.57%, for Black and White subjects, respectively. RESULTS:  During normal perfusion (Pi > 1, range [1 to 12]), overall bias and precision were + 0.18% ± 1.34%, while bias and precision were -0.26 ± 1.37%, and - 0.12 ± 1.31%, for Black and White subjects, respectively. ARMS was 1.37% in all subjects with normal perfusion and 1.64% in all subjects with low perfusion. CONCLUSION:  Masimo SET® pulse oximeters with RD SET® sensors are accurate for individuals of both Black and White races when Pi is normal, as well as during conditions when Pi is low. The ARMS for all conditions studied is well within FDA standards. This study was conducted in healthy volunteers during well-controlled laboratory desaturations, and results could vary under certain challenging clinical conditions.

A Prospective Randomized Controlled Pilot Simulation Study to Investigate the Effect of Audiovisual Decision Support on Diagnosis and Therapeutic Interventions.

INTRODUCTION: Combining audiovisual decision support during perioperative critical events might enhance provider diagnostic and therapeutic accuracy and efficiency. METHODS: This study is a prospective, randomized controlled pilot trial studying the impact of audiovisual decision support on anesthesia professional performance at NorthShore University HealthSystem's high fidelity simulation center. Twenty anesthesia professionals (>2 years of clinical experience in the current role) were randomized to 2 groups (current care model vs. audiovisual assistance) and underwent 3 periprocedural simulation scenarios, where patient deterioration occurs: anaphylaxis, amniotic fluid embolism, and cardiac arrest during dental case. RESULTS: Overall, there was a statistically significant decrease in the mean and median pooled times to diagnosis in both the amniotic fluid embolism and pediatric dental scenarios. There was a statistically significant increase in the number of participants in the intervention group who made diagnosis 3 before the end of the scene (P = 0.03) in the amniotic fluid embolism case. In the pediatric dental case, there was a statistically significant reduction in the median time to diagnosis 1 and diagnosis 3 in the intervention group versus control (P = 0.01 and P = 0.0002). A significant increase in the number of participants in the intervention group versus control made the correct diagnosis 2 before vital sign change 3 (P = 0.03), and more participants in the intervention group made the correct diagnosis 3 before the end of the scene when compared with control (P = 0.001). The median time to start intervention 2 during the dental case was statistically significantly greater in the intervention group versus the control (P = 0.05). All other endpoints were not statistically significant among the 3 simulation scenarios. Six questions were answered by all participants upon immediate completion of the simulation scenarios and revealed that 19 of 20 participants had delivered anesthesia care to patients similar to the 3 simulation scenarios and 18 of 20 participants reported that they would prefer audiovisual assistance to detect abnormalities in vital signs that subsequently provides appropriate diagnostic and therapeutic options. CONCLUSIONS: This pilot study suggested some significant improvement in anesthesia professional time to correct diagnosis and completion of identification of the correct diagnosis before the next vital change in the audiovisual cue group versus control, particularly in the outpatient dental case. In addition, the mean and median pooled times to diagnosis were significantly reduced by approximately 1 minute in both evaluated simulation scenarios. The postsimulation survey responses also suggest the desirability of an audiovisual decision support tool among the current anesthesia professional participants. However, overall, there were no significant differences in the time to intervention between groups in all simulation scenarios.

Racial effects on Masimo pulse oximetry: a laboratory study.

Recent publications have suggested that pulse oximeters exhibit reduced accuracy in dark-skinned patients during periods of hypoxemia. Masimo SET® (Signal Extraction Technology®) has been designed, calibrated, and validated using nearly equal numbers of dark and light skinned subjects, with the goal of eliminating differences between pulse oximetry saturation (SpO2) and arterial oxygen saturation (SaO2) values due to skin pigmentation. The accuracy concerns reported in dark-skinned patients led us to perform a retrospective analysis of healthy Black and White volunteers. Seventy-five subjects who self-identified as being racially Black or White underwent a desaturation protocol where SaO2 values were decreased from 100 to 70%, while simultaneous SpO2 values were recorded using Masimo RD SET® sensors. Statistical bias (mean difference) and precision (standard deviation of difference) were - 0.20 ± 1.40% for Black and - 0.05 ± 1.35% for White subjects. Plots of SpO2 versus SaO2 show no significant visible differences between races throughout the saturation range from 70 to 100%. Box plots grouped in 1% saturation bins, from 89-96%, and plotted against concomitant SaO2 values, show that occult hypoxemia (SaO2 < 88% when SpO2 = 92-96%) occurred in only 0.2% of White subject data pairs, but not in any Black subjects. There were no clinically significant differences in bias (mean difference of SpO2-SaO2) found between healthy Black and White subjects. Occult hypoxemia was rare and did not occur in Black subjects. Masimo RD SET® can be used with equal assurance in people with dark or light skin. These laboratory results were obtained in well-controlled experimental conditions in healthy volunteers-not reflecting actual clinical conditions/patients.

Correspondence to: performance of the new SmartCardia wireless, wearable oximeter: a comparison with arterial SaO2 in healthy volunteers.

In a recent publication in BMC Anesthesiology, Rincon, et al.present accuracy data for three pulse oximeters with sensors located at three different anatomic sites. Their results for the Masimo Radical with fingertip sensor are erroneous, and we present valid data here. Rincon, et al.show a Bias ± Precision of 2.02 ± 4.6, while the correct laboratory values are -0.01 ± 1.16. The most probable reason for these invalid data is that insufficient time was used at each saturation plateau to allow stabilization of SpO2 readings on a fingertip sensor. It has been shown in the literature that fingertip sensors require at least a full minute of stable oxygenation conditions before their readings will be the same as earlobe sensors.

Pro-Con Debate: Should Code Sharing Be Mandatory for Publication?

In this Pro-Con commentary article, we discuss whether or not code sharing should be mandatory for scientific publications. Scientific programming is an increasingly prevalent tool in research. However, there are not unified guidelines for code availability requirements. Some journals require code sharing. Others require code descriptions. Yet others have no policies around code sharing. The Pro side presented here argues that code sharing should be mandatory for all scientific publications involving code. This Pro argument comes in 2 parts. First, any defensible reason for not sharing code is an equally valid a reason for the manuscript itself not being published. Second, lack of code sharing requirements creates 2 tiers of science: one where reproducibility is required and one where it is not. Additionally, the Pro authors suggest that a debate over code sharing is itself a decade out-of-date due to the emerging availability of containerization and virtual environment sharing software. The Pro argument concludes with an appeal that authors release code to make their work more understandable by other researchers. The Con side presented here argues that computer source codes of medical technology equipment should not be subject to mandatory public disclosure. The source code is a crucial part of what makes a particular device unique and allows that device to outperform its competition. The Con authors believe that public disclosure of this proprietary information would destroy all incentives for businesses to develop new and improved technologies. Competition in the free marketplace is what drives companies to constantly improve their products, to develop new and better medical devices. The open disclosure of these "trade secret" details would effectively end that competitive drive. Why invest time, money, and energy developing a "better mousetrap" if your competitors can copy it and produce it the next day?

Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT.

As with all drugs, the route, form, and/or dose of a substance administered or applied can play a defining role in its overall pharmacology and use as a therapeutic. This review will focus on these factors as they relate to the psychedelic N,N-dimethyltryptamine (DMT). It will examine the positive and negative aspects of different formulations and routes of administration of DMT and the observed effects from such administrations in the form of ayahuasca teas; oral "pharmahuasca"; injections by intravenous (IV) and intramuscular (IM) routes; inhalation, insufflation; and other routes; and high-dose, low-dose, and "micro-dose" effects. The review will consider possible oral route of administration alternatives that would not require concomitant use of a monoamine oxidase inhibitor. The review will then address the current research findings for DMT from in vivo and in vitro studies as well as the possibility that these findings may be revealing the role of endogenous DMT in normal brain function.

Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD.

Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress, and inflammation. Animal models have recapitulated features of PTSD, but no comparative RNA sequencing analysis of differentially expressed genes (DEGs) in the brain between PTSD and animal models of traumatic stress has been carried out. We compared DEGs from the prefrontal cortex (PFC) of an established stress model to DEGs from the dorsolateral PFC (dlPFC) of humans. We observed a significant enrichment of rat DEGs in human PTSD and identified 20 overlapping DEGs, of which 17 (85%) are directionally concordant. N,N-dimethyltryptamine (DMT) is a known indirect antioxidant, anti-inflammatory, and neuroprotective compound with antidepressant and plasticity-facilitating effects. We tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and "pharmahuasca" (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and to modulate neuroplasticity-related gene expression in the model. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), pharmahuasca, or vehicle every other day for 5 days, following a 30 day stress regiment. We measured ROS production in the PFC and hippocampus (HC) by electron paramagnetic resonance spectroscopy and sequenced total mRNA in the PFC. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at 5HT2AR compared to 5-HT. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. Treatments normalized 9, 12, and 14 overlapping DEGs, and pathway analysis implicated that genes were involved in ROS production, inflammation, growth factor signaling, neurotransmission, and neuroplasticity.

Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain.

N,N-dimethyltryptamine (DMT), a psychedelic compound identified endogenously in mammals, is biosynthesized by aromatic-L-amino acid decarboxylase (AADC) and indolethylamine-N-methyltransferase (INMT). Whether DMT is biosynthesized in the mammalian brain is unknown. We investigated brain expression of INMT transcript in rats and humans, co-expression of INMT and AADC mRNA in rat brain and periphery, and brain concentrations of DMT in rats. INMT transcripts were identified in the cerebral cortex, pineal gland, and choroid plexus of both rats and humans via in situ hybridization. Notably, INMT mRNA was colocalized with AADC transcript in rat brain tissues, in contrast to rat peripheral tissues where there existed little overlapping expression of INMT with AADC transcripts. Additionally, extracellular concentrations of DMT in the cerebral cortex of normal behaving rats, with or without the pineal gland, were similar to those of canonical monoamine neurotransmitters including serotonin. A significant increase of DMT levels in the rat visual cortex was observed following induction of experimental cardiac arrest, a finding independent of an intact pineal gland. These results show for the first time that the rat brain is capable of synthesizing and releasing DMT at concentrations comparable to known monoamine neurotransmitters and raise the possibility that this phenomenon may occur similarly in human brains.

N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function.

This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the "natural" role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.

Assessing the Psychedelic "After-Glow" in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities.

Background: Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures. Methods: Using 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose. Results: Magnetic resonance spectroscopy showed post-acute reductions in glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex. Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Glutamate+glutamine reductions correlated with increases in the "nonjudging" subscale of the Five Facets Mindfulness Questionnaire. Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. Post-acute neural changes predicted sustained elevations in nonjudging 2 months later. Conclusions: These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca.

Cardiomyopathy in a Harris hawk (Parabuteo unicinctus).

CASE DESCRIPTION An adult sexually intact female Harris hawk (Parabuteo unicinctus) housed at a wildlife hospital was evaluated because of acute collapse during an educational exhibition. CLINICAL FINDINGS Physical examination and hematologic analysis revealed no abnormalities; radiography revealed findings consistent with a previous tibiotarsal fracture. Coelioscopy with histologic examination and fungal culture of lung and air sac samples revealed anthracosis but no fungal infection. The hawk was discharged and temporarily removed from the education program; 1 month later, upon reintroduction into the program, it collapsed again. Physical examination and hematologic findings were similar to those after the first episode. Transcoelomic and transesophageal echocardiography and CT angiocardiography findings were consistent with cardiomyopathy. TREATMENT AND OUTCOME Initial cardiac treatment included furosemide (0.5 mg/kg [0.23 mg/lb], PO, q 24 h) and pimobendan (10 mg/kg [4.5 mg/lb], PO, q 12 h). After 10 days of treatment, peak and trough plasma concentrations of pimobendan were measured at 25, 196 and 715.97 ng/mL, respectively; the dosage was decreased to 0.25 mg/kg (0.11 mg/lb), PO, every 12 hours. No overt signs of toxicosis were detected. A sample was collected to reevaluate plasma pimobendan concentration after 30 days of treatment; results were not obtained prior to the patient's death but revealed a peak concentration of 16.8 ng/mL, with an undetectable trough concentration. The hawk was found dead 6 months after initial evaluation. Necropsy revealed cardiomegaly, but histologic examination did not reveal an inciting cause of cardiac dysfunction. CLINICAL RELEVANCE Cardiac disease in raptors may be underreported. Transcoelomic and transesophageal echocardiography and CT angiography provided useful information for the diagnosis of cardiac disease in the hawk of this report.

Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans.

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus ß-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.