Hybrid models of chemotaxis with application to leukocyte migration.

Many chemical and biological systems involve reacting species with vastly different numbers of molecules/agents. Hybrid simulations model such phenomena by combining discrete (e.g., agent-based) and continuous (e.g., partial differential equation- or PDE-based) descriptors of the dynamics of reactants with small and large numbers of molecules/agents, respectively. We present a stochastic hybrid algorithm to model a stage of the immune response to inflammation, during which leukocytes reach a pathogen via chemotaxis. While large numbers of chemoattractant molecules justify the use of a PDE-based model to describe the spatiotemporal evolution of its concentration, relatively small numbers of leukocytes and bacteria involved in the process undermine the veracity of their continuum treatment by masking the effects of stochasticity and have to be treated discretely. Motility and interactions between leukocytes and bacteria are modeled via random walk and a stochastic simulation algorithm, respectively. Since the latter assumes the reacting species to be well mixed, the discrete component of our hybrid algorithm deploys stochastic operator splitting, in which the sequence of the diffusion and reaction operations is determined autonomously during each simulation step. We conduct a series of numerical experiments to ascertain the accuracy and computational efficiency of our hybrid simulations and, then, to demonstrate the importance of randomness for predicting leukocyte migration and fate during the immune response to inflammation.

AroER tri-screen™ is a novel functional assay to estimate both estrogenic and estrogen precursor activity of chemicals or biological specimens.

The purpose of the study is to define AroER tri-screen's utility for identifying endocrine-disrupting chemicals (EDCs) that target aromatase and/or estrogen receptor (ER), and to measure the total estrogenic activity in biological specimens. ER-positive, aromatase-expressing MCF-7 breast cancer cells were stably transfected with an estrogen responsive element (ERE)-driven luciferase reporter plasmid to yield a new high-throughput screening platform-the AroER tri-screen. AroER tri-screen was capable of identifying estrogen precursors, such as cortodoxone, which function as estrogens through a two-step conversion process in aromatase-expressing tissue. Furthermore, the system proved useful for assessing EDC activity in biologically relevant samples. Estimating these activities is critical because natural estrogens and estrogenic EDCs are important factors in ER-positive breast cancer risk. As our research demonstrates, incorporating functionally active aromatase into the AroER tri-screen produces a powerful and unique tool to (1) identify new EDCs targeting aromatase and/or ER; (2) discover novel EDCs activated by aromatase; and (3) estimate overall estrogenic activities in biological samples as a potential intermediate risk factor for breast cancer.

Recurrent, Severe Coital Headaches Associated With Bilateral Carotid Artery Aneurysms and the Effect of Endovascular Treatment.

Headaches are one of the most common chief complaints in the outpatient setting. Distinguishing between benign and life-threatening headaches can be difficult, particularly in the setting of a pre-existing history of headaches. Here, we present a 41-year-old female with a past medical history of migraines and uterine leiomyoma status post hysterectomy about nine months ago who presented to the clinic for severe coital headaches and worsening migraines starting eight months ago. Computer tomography angiogram (CTA) head and neck demonstrated bilateral para-ophthalmic internal carotid artery (ICA) aneurysms (right, 7.5, left 6 mm). A diagnostic cerebral angiogram (DSA) was subsequently done and confirmed the CTA findings. The patient underwent left and right flow-diverting stent placement two and four months later, respectively. One week after the right ICA stent placement, her headaches had improved to one to two times per week. At six months after the stent placement, she resumed her normal sex life and her migraines returned to baseline. Our case suggests that recurrent severe coital headaches are associated with bilateral carotid artery aneurysms. Thus, while assessing a patient with recurrent coital headaches, it is important to have a wide arsenal of differentials to rule out possibly catastrophic causes.

A safe insect-based Chikungunya fever vaccine affords rapid and durable protection in cynomolgus macaques.

Chikungunya virus (CHIKV), which induces chikungunya fever and chronic arthralgia, is an emerging public health concern. Safe and efficient vaccination strategies are needed to prevent or mitigate virus-associated acute and chronic morbidities for preparation of future outbreaks. Eilat (EILV)/CHIKV, a chimeric alphavirus which contains the structural proteins of CHIKV and the non-structural proteins of EILV, does not replicate in vertebrate cells. The chimeric virus was previously reported to induce protective adaptive immunity in mice. Here, we assessed the capacity of the virus to induce quick and durable protection in cynomolgus macaques. EILV/CHIKV protected macaques from wild-type (WT) CHIKV infection one year after a single dose vaccination. Transcriptome and in vitro functional analyses reveal that the chimeric virus triggered toll-like receptor signaling and T cell, memory B cell and antibody responses in a dose-dependent manner. Notably, EILV/CHIKV preferentially induced more durable, robust, and broader repertoire of CHIKV-specific T cell responses, compared to a live attenuated CHIKV 181/25 vaccine strain. The insect-based chimeric virus did not cause skin hypersensitivity reactions in guinea pigs sensitized to mosquito bites. Furthermore, EILV/CHIKV induced strong neutralization antibodies and protected cynomolgus macaques from WT CHIKV infection within six days post vaccination. Transcriptome analysis also suggest that the chimeric virus induction of multiple innate immune pathways, including Toll-like receptor signaling, type I IFN and IL-12 signaling, antigen presenting cell activation, and NK receptor signaling. Our findings suggest that EILV/CHIKV is a safe, highly efficacious vaccine, and provides both rapid and long-lasting protection in cynomolgus macaques.

Sex-Based Disparities in Acute Myocardial Infarction Treatment Patterns and Outcomes in Older Adults Hospitalized Across 6 High-Income Countries: An Analysis From the International Health Systems Research Collaborative.

BACKGROUND: Sex differences in acute myocardial infarction treatment and outcomes are well documented, but it is unclear whether differences are consistent across countries. The objective of this study was to investigate the epidemiology, use of interventional procedures, and outcomes for older females and males hospitalized with ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (NSTEMI) in 6 diverse countries. METHODS: We conducted a serial cross-sectional cohort study of 1 508 205 adults aged ≥66 years hospitalized with STEMI and NSTEMI between 2011 and 2018 in the United States, Canada, England, the Netherlands, Taiwan, and Israel using administrative data. We compared females and males within each country with respect to age-standardized hospitalization rates, rates of cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft surgery within 90 days of hospitalization, and 30-day age- and comorbidity-adjusted mortality. RESULTS: Hospitalization rates for STEMI and NSTEMI decreased between 2011 and 2018 in all countries, although the hospitalization rate ratio (rate in males/rate in females) increased in virtually all countries (eg, US STEMI ratio, 1.58:1 in 2011 and 1.73:1 in 2018; Israel NSTEMI ratio, 1.71:1 in 2011 and 2.11:1 in 2018). Rates of cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft surgery were lower for females than males for STEMI in all countries and years (eg, US cardiac catheterization in 2018, 88.6% for females versus 91.5% for males; Israel percutaneous coronary intervention in 2018, 76.7% for females versus 84.8% for males) with similar findings for NSTEMI. Adjusted mortality for STEMI in 2018 was higher for females than males in 5 countries (the United States, Canada, the Netherlands, Israel, and Taiwan) but lower for females than males in 5 countries for NSTEMI. CONCLUSIONS: We observed a larger decline in acute myocardial infarction hospitalizations for females than males between 2011 and 2018. Females were less likely to receive cardiac interventions and had higher mortality after STEMI. Sex disparities seem to transcend borders, raising questions about the underlying causes and remedies.

Evaluation of Intravenous Immunoglobulin Administration for Hyperbilirubinemia in Newborn Infants with Hemolytic Disease.

The primary objective of this research was to evaluate the use of intravenous immunoglobulin (IVIG) in infants with hemolytic disease, to assess compliance with the American Academy of Pediatrics (AAP) guideline recommendations, and to review the data on which the guidelines were based. This retrospective study evaluated all infants in the NICU (neonatal intensive care unit) who received IVIG between January 2018 and December 2020 (n = 71). Total serum bilirubin (TSB) levels surrounding the time of IVIG administration, rate of rise of bilirubin, and direct antiglobulin test (DAT) status were evaluated to determine the appropriateness of IVIG use based on the 2004 AAP recommendations that was current at the time of the study. Fifty-nine infants received IVIG for hyperbilirubinemia. Of them, 80% had an ABO mismatch, 19% had Rh mismatch, and 71% were DAT-positive. Phototherapy was started at an average of 7 h of age, and the first IVIG dose was administered at an average of 13 h of life; nearly 25% received a second IVIG dose. One infant (1.6%) met all three AAP guideline criteria of being DAT-positive, bilirubin within 3 of exchange level, and rising bilirubin despite intensive phototherapy. Twenty-five (42%) babies were DAT positive and met one of the other two criteria. Only 12% (n = 7) had a bilirubin within 3 of exchange level. Most infants who received IVIG for hyperbilirubinemia did not meet the AAP criteria, prompting us to develop an institution-specific IVIG clinical practice guideline. The 2022 AAP guideline was published after our study was completed, but it confirmed our belief that IVIG usage should be more restricted and the criteria more explicit.

Incidence and Risk Factors for Acute Kidney Injury in Hospitalized Children Receiving Piperacillin-Tazobactam.

OBJECTIVE: Drug-induced kidney injury contributes to morbidity and mortality in hospitalized children. Antibiotics such as TZP have been implicated in the development of acute kidney injury (AKI) in adults; however, data are limited in children. The purpose of this study was to determine the incidence of AKI in hospitalized children receiving TZP. METHODS: This was a retrospective cohort study of hospitalized children between 2 months and 19 years of age who received TZP for at least 48 hours. Acute kidney injury was defined as a 50% increase from the initial serum creatinine (SCr) prior to TZP initiation. Serum creatinine values were adjusted for fluid balance using a validated approach. Severity of AKI was characterized using the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria. Descriptive and inferential statistics were used to describe the incidence and risk factors of AKI, with an alpha = 0.05. RESULTS: A total of 65 subjects were included. Twenty-five (38.5%) required PICU admission. The incidence of AKI was 7.7% (n = 5) using adjusted SCr (13.37 cases/1000 patient-days). According to pRIFLE, 6.15% (n = 4) subjects met criteria for Risk (n = 3) or Injury (n = 1), and none developed Failure, Loss, or End-Stage (10.70 cases/1000 patient-days for Risk and Injury categories). No risk factors were identified. Hospital length of stay was longer in subjects who experienced AKI compared with those who did not (p = 0.04). CONCLUSIONS: The incidence of AKI in hospitalized children exposed to TZP was low. In those who did develop AKI, peak SCr occurred approximately 1 week after TZP initiation.

Are college campuses superspreaders? A data-driven modeling study.

The COVID-19 pandemic continues to present enormous challenges for colleges and universities and strategies for save reopening remain a topic of ongoing debate. Many institutions that reopened cautiously in the fall experienced a massive wave of infections and colleges were soon declared as the new hotspots of the pandemic. However, the precise effects of college outbreaks on their immediate neighborhood remain largely unknown. Here we show that the first two weeks of instruction present a high-risk period for campus outbreaks and that these outbreaks tend to spread into the neighboring communities. By integrating a classical mathematical epidemiology model and Bayesian learning, we learned the dynamic reproduction number for 30 colleges from their daily case reports. Of these 30 institutions, 14 displayed a spike of infections within the first two weeks of class, with peak seven-day incidences well above 1,000 per 100,000, an order of magnitude larger than the nation-wide peaks of 70 and 150 during the first and second waves of the pandemic. While most colleges were able to rapidly reduce the number of new infections, many failed to control the spread of the virus beyond their own campus: Within only two weeks, 17 campus outbreaks translated directly into peaks of infection within their home counties. These findings suggests that college campuses are at risk to develop an extreme incidence of COVID-19 and become superspreaders for neighboring communities. We anticipate that tight test-trace-quarantine strategies, flexible transition to online instruction, and-most importantly-compliance with local regulations will be critical to ensure a safe campus reopening after the winter break.

Osimertinib in Pulmonary Manifestations: Two Case Reports and Review of the Literature.

Osimertinib is an oral, irreversible epidermal growth factor receptor inhibitor that is associated with various pulmonary manifestations including transient asymptomatic pulmonary opacities (TAPOs) and pneumonitis. We present a case of a 61-year-old female with Stage IV lung adenocarcinoma, who developed bilateral ground glass opacities on her chest-computed tomography (CT) three months after initiating osimertinib. Her imaging findings were thought to represent lymphangitic carcinomatosis responding to chemotherapy rather than drug induced toxicity, and she was continued on osimertinib. Conversely, we present a second case of a 57-year-old female with Stage IV lung adenocarcinoma who developed osimertinib-induced pneumonitis and was successfully rechallenged with osimertinib and glucocorticoids. These cases, described herein, illustrate examples of the range of pulmonary manifestations of osimertinib, as well as the safety of rechallenging patients with osimertinib and glucocorticoids following the development of pneumonitis.

Interactions between kappa and mu opioid receptor agonists: effects of the ratio of drugs in mixtures.

RATIONALE: Pain is the leading reason for seeking health care, and mu opioid receptor agonists continue to be prescribed despite well-documented adverse effects. Kappa opioid receptor agonists have antinociceptive effects with little to no abuse liability and might be useful for treating pain in mixtures. Kappa:mu opioid mixtures might be useful if therapeutic effects of each drug can be selectively increased while reducing or avoiding the adverse effects that occur with larger doses of each drug alone. OBJECTIVE: This study characterized the effects of the kappa opioid receptor agonist spiradoline alone (0.32-56 mg/kg) and in 1:10, 1:3, 1:1, and 3:1 mixtures with the mu opioid receptor agonists morphine (1.0-32 mg/kg) and etorphine (1-10 µg/kg) on warm water tail-withdrawal latency, body temperature, responding for food, and fecal output in male Sprague-Dawley rats (n = 24). RESULTS: Antinociceptive effects were greater than additive for 1:10 and 1:3 spiradoline:morphine mixtures and for 1:10, 1:3, and 1:1 spiradoline:etorphine mixtures. The potency of spiradoline to produce hypothermia was greater with 1:3 and 3:1 spiradoline:etorphine mixtures but not with 1:10 or 1:1 mixtures or with any spiradoline:morphine mixture. The effects of 1:3 spiradoline:morphine on responding for food were additive, whereas 1:1 and 3:1 were greater than additive. Spiradoline did not significantly alter morphine-induced decreases in fecal output. CONCLUSIONS: Overall, mixtures of kappa and mu opioids might have therapeutic potential for treating pain, particularly when the mixture has a greater ratio of mu to kappa agonist. If adverse effects of each constituent drug are reduced or avoided, then kappa:mu mixtures might be advantageous to mu opioids alone.

Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant.

Purpose: Therapeutic strategies against hormonal receptor-positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized.Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis.Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivoConclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395-406. ©2017 AACR.

An Interesting Case of Tolosa-Hunt Syndrome in a Young Male.

Tolosa-Hunt syndrome is a rare disease with a limited number of cases reported in the literature. It typically presents with orbital pain associated with palsy of the third, fourth, or sixth cranial nerve. We present an interesting case of Tolosa-Hunt syndrome in a young male who responded well to high-dose steroids and in a few days had significant improvement in his retro-orbital pain and ocular movements.

Acute Pancreatitis Related to a Chemotherapy Drug.

Drug-induced acute pancreatitis is a rare cause of pancreatitis. We present a case of pancreatitis caused by pazopanib, a tyrosine kinase inhibitor used in the treatment of renal cell carcinoma. A 57-year-old male with no risk factors for pancreatitis and a past medical history of renal cell carcinoma who was being treated with pazopanib presented with epigastric pain with radiation to the back. Lipase was elevated to 7,960 units/L. Pazopanib was discontinued on arrival and his lipase levels decreased from 7,960 to 3,380 units/L one day after discontinuation. Abdominal pain resolved and patient tolerated a diet. This case illustrates the importance that medical professionals should be aware of acute pancreatitis as a rare but severe side effect of pazopanib and therefore should monitor and educate their patients accordingly.

Multiple Myeloma-Induced Hyperammonemic Encephalopathy.

Multiple myeloma (MM) typically presents with hypercalcemia, renal insufficiency, anemia, and bone lesions. Elevated ammonia level manifesting as altered mental status is a rare complication in MM. We report an interesting case of hyperammonemic encephalopathy in a 73-year-old male with advanced relapsing kappa-light chain MM.

Cardiomyopathy Related to a Weight Loss Supplement: A Case Report and Review of Literature.

There are various etiologies of dilated cardiomyopathy. However, in young patients without a strong family history of cardiovascular disease, alcohol or drug abuse, viral infections, and absence of endocrine and metabolic abnormalities, ischemia is an unlikely cause. We present an interesting case of a young female without traditional risk factors who developed dilated cardiomyopathy following administration of a weight loss supplement xenadrine and had resolution of symptoms after discontinuation of the supplement.

Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library.

Multiple mechanisms exist for endocrine disruption; one nonreceptor-mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17ß-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all 3 assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (eg, 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, 14 of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining 4 were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase.