TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome.

THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.

Mechanisms of mRNA processing defects in inherited THOC6 intellectual disability syndrome.

THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 facilitates the formation of the Transcription Export complex (TREX) tetramer, composed of four THO monomers. The TREX tetramer supports mammalian mRNA processing that is distinct from yeast TREX dimer functions. Human and mouse TIDS model systems allow novel THOC6-dependent TREX tetramer functions to be investigated. Biallelic loss-of-functon(LOF) THOC6 variants do not influence the expression and localization of TREX members in human cells, but our data suggests reduced binding affinity of ALYREF. Impairment of TREX nuclear export functions were not detected in cells with biallelic THOC6 LOF. Instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing novel insights into THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions that may inform TIDS neuropathology.

Epidemiology of cannabidiol related cases reported in the National Poison Data System - 2019-2020.

INTRODUCTION: Cannabidiol (CBD) has become a popular supplement in consumer products in recent years, resulting in part from normalization of the cultivation of low THC cannabis in 2018. However, the actual content of CBD-labeled products is frequently uncertain, as oversight of such products is minimal. To date, there is little pragmatic knowledge regarding exposures to products labeled as containing CBD. METHODS: Cases reported to Poison Control Centers from April 1, 2019 and March 31, 2020, the first year in which CBD was identified uniquely as a substance in the National Poison Data System, were analyzed for demographic, temporal, and clinical trends. RESULTS: Poison Control Centers handled 1581 cases exposures to CBD-containing products between April 1, 2019 and March 31, 2020. There was a significant trend of over 5 additional cases related to this substance per month (linear regression coefficient = 5.2, 95% CI: 1.52-8.98). Patients under age 13 years made up 44.0% of reported exposures. Mild CNS depression (10.3%), tachycardia (5.7%), dizziness/vertigo (5.3%), vomiting (4.9%), nausea (4.5%), and agitation (4.4%) were the most frequently reported symptoms. 13% of cases were coded as having "moderate" or "severe" medical outcomes. There were no fatalities. CONCLUSIONS: Cases reported to Poison Control Centers regarding exposures to CBD-labeled products have been increasing, representing an emerging trend of interest to Poison Control Center professionals, clinicians, and public health officials. Further monitoring of this trend is recommended.

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19).

OBJECTIVES: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes. METHODS: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit. RESULTS: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8. CONCLUSIONS: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

Red Blood Cell Distribution Width (RDW) Predicts COVID-19 Severity: A Prospective, Observational Study from the Cincinnati SARS-CoV-2 Emergency Department Cohort.

Since previous evidence has demonstrated that red blood cell distribution width (RDW) may be a useful prognostic parameter in many critical illnesses and infectious diseases, we investigated the utility of RDW for monitoring patients with coronavirus disease 2019 (COVID-19). The study population consisted of 49 COVID-19 patients, including 16 (32.6%) with severe illness, 12 (24.5%) with severe acute kidney injury (AKI), and 8 (16.3%) requiring renal replacement therapy (RRT). The predictive value of blood tests, performed during emergency department evaluation, was then addressed. A progressive increase of RDW was observed with advancing COVID-19 severity. The area under the curve (AUC) of RDW was 0.73 for predicting severe illness, 0.80 for severe AKI, and 0.83 for RRT, respectively. In multivariate analysis, elevated RDW was associated with 9-fold and 16-fold increased odds of severe COVID-19 and AKI, respectively. The results of this study suggest that RDW should be part of routine laboratory assessment and monitoring of COVID-19.

Physician Knowledge, Attitudes, and Practices Related to Chagas Disease in Tabasco, Mexico.

We designed and implemented a survey of physician knowledge, attitudes, and practices with respect to Chagas disease in the state of Tabasco, Mexico. Seventy-eight public sector physicians from across the state responded via Research Electronic Data Capture, an online survey capture tool. Improved performance on knowledge-based questions (P < 0.01) and an increase in decisions to screen (P = 0.04) were associated with previous training specific to this disease. Our results provide important descriptive information regarding knowledge, attitudes, and practices among a group of public sector Mexican doctors and highlight the importance of Chagas disease-specific physician training for identification and, ultimately, treatment of patients affected by this disease.

Pathophysiology of Leishmania Infection during Pregnancy.

The pathological processes resulting from parasitic infection are known to have important impacts on the mother child dyad during pregnancy. The roles of parasite transmission and the maternal immune response have been described in diseases such as malaria, toxoplasmosis, and trypanosomiasis. However, the impact of parasites of the genus Leishmania, etiological agents of the neglected tropical diseases tegumentary leishmaniasis (TL) and visceral leishmaniasis (VL), is comparatively less well known, though it is an increasingly recognized concern for infected mothers and their fetuses. In this review, we first consider the pathophysiology of placental infection and transplacental transmission of this parasite, and then discuss the role and mechanisms of the maternal immune system in simultaneously mediating maternal-fetal infection and adverse pregnancy outcomes.

Cost-effectiveness of meglumine antimoniate versus miltefosine caregiver DOT for the treatment of pediatric cutaneous leishmaniasis.

BACKGROUND: Oral miltefosine has been shown to be non-inferior to first-line, injectable meglumine antimoniate (MA) for the treatment of cutaneous leishmaniasis (CL) in children. Miltefosine may be administered via in-home caregiver Directly Observed Therapy (cDOT), while patients must travel to clinics to receive MA. We performed a cost-effectiveness analysis comparing miltefosine by cDOT versus MA for pediatric CL in southwest Colombia. METHODOLOGY/PRINCIPLE FINDINGS: We developed a Monte Carlo model comparing the cost-per-cure of miltefosine by cDOT compared to MA from patient, government payer, and societal perspectives (societal = sum of patient and government payer perspective costs). Drug effectiveness and adverse events were estimated from clinical trials. Healthcare utilization and costs of travel were obtained from surveys of providers and published sources. The primary outcome was cost-per-cure reported in 2015 USD. Treatment efficacy, costs, and adherence were varied in sensitivity analysis to assess robustness of results. Treatment with miltefosine resulted in substantially lower cost-per-cure from a societal and patient perspective, and slightly higher cost-per-cure from a government payer perspective compared to MA. Mean societal cost-per-cure were $531 (SD±$239) for MA and $188 (SD±$100) for miltefosine, a mean cost-per-cure difference of +$343. Mean cost-per-cure from a patient perspective were $442 (SD ±$233) for MA and $30 (SD±$16) for miltefosine, a mean difference of +$412. Mean cost-per-cure from a government perspective were $89 (SD±$55) for MA and $158 (SD±$98) for miltefosine, with a mean difference of -$69. Results were robust across a variety of assumptions in univariate and multi-way analysis. CONCLUSIONS/SIGNIFICANCE: Treatment of pediatric cutaneous leishmaniasis with miltefosine via cDOT is cost saving from patient and societal perspectives, and moderately more costly from the government payer perspective compared to treatment with MA. Results were robust over a range of sensitivity analyses. Lower drug price for miltefosine could result in cost saving from a government perspective.