Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial

Background Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. Methods This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3–5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. Discussion In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. Trial registration ClinicalTrials.gov NCT04397718. Registered on May 21, 202

Amygdala 14-3-3ζ as a Novel Modulator of Escalating Alcohol Intake in Mice

Alcoholism is a devastating brain disorder that affects millions of people worldwide. The development of alcoholism is caused by alcohol-induced maladaptive changes in neural circuits involved in emotions, motivation, and decision-making. Because of its involvement in these processes, the amygdala is thought to be a key neural structure involved in alcohol addiction. However, the molecular mechanisms that govern the development of alcoholism are incompletely understood. We have previously shown that in a limited access choice paradigm, C57BL/6J mice progressively escalate their alcohol intake and display important behavioral characteristic of alcohol addiction, in that they become insensitive to quinine-induced adulteration of alcohol. This study used the limited access choice paradigm to study gene expression changes in the amygdala during the escalation to high alcohol consumption in C57BL/6J mice. Microarray analysis revealed that changes in gene expression occurred predominantly after one week, i.e. during the initial escalation of alcohol intake. One gene that stood out from our analysis was the adapter protein 14-3-3ζ, which was up-regulated during the transition from low to high alcohol intake. Independent qPCR analysis confirmed the up-regulation of amygdala 14-3-3ζ during the escalation of alcohol intake. Subsequently, we found that local knockdown of 14-3-3ζ in the amygdala, using RNA interference, dramatically augmented alcohol intake. In addition, knockdown of amygdala 14-3-3ζ promoted the development of inflexible alcohol drinking, as apparent from insensitivity to quinine adulteration of alcohol. This study identifies amygdala 14-3-3ζ as a novel key modulator that is engaged during escalation of alcohol use

Nutritional indices in the gypsy moth ( Lymantria dispar (L.)) under field conditions and host switching situations

A large proportion of gypsy moths ( Lymantria dispar (L.)) are likely to experience multiple species diets in the field due to natural wandering and host switching which occurs with these insects. Nutritional indices in fourth and fifth instar gypsy moth larvae were studied in the field for insects that were switched to a second host species when they were fourth instars. The tree species used as hosts were northern pin oak ( Quercus ellipsoidalis E. J. Hill), white oak ( Q. alba L.), big-tooth aspen ( Populus grandidentata Michx.), and trembling aspen ( P. tremuloides Michx.). Conclusions of this study include: 1) Insects which fed before the host switch on northern pin oak performed better after the host switch than did insects with other types of early dietary experience. While the northern pin oak-started insects had very low relative food consumption rates on their second host species immediately after the switch, one instar later they had the highest ranked consumption rates. During both instars they had the second highest efficiencies of converting ingested and digested food to body mass. High food consumption rates and relatively high efficiency of food conversion helped these insects to obtain the highest ranked mean relative growth rates in the fifth instar compared to the relative growth rates obtained by insects from any of the other first host species. 2) Among the four host species examined, a second host of trembling aspen was most advantageous for the insects. Feeding on this species after the switch led to higher larval weights and higher relative growth rates for insects than did any of the other second host species. The insects on trembling aspen attained excellent growth despite only mediocre to low food conversion efficiencies. The low efficiencies were offset by high relative food consumption rates. 3) Low food consumption rates often tend to be paired with high efficiency of conversion and vice versa. 4) There is no discernable tendency for the first plant species eaten to cause long-term inductions which affect the ability of gypsy moths to utilize subsequent host plants. Insects did not tend to consume more, grow faster, or be more efficient if their second host plant was either the same as their rearing plant or congeneric to it. Methods are delineated which allow values of nutritional indices to be obtained for insects on intact host plants under field conditions. These methods are useful for the purpose of answering questions about the relative effects that different diet treatments have on insect response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47803/1/442_2004_Article_BF00323145.pd

Field triage to primary percutaneous coronary intervention: Factors influencing health-related quality of life for patients aged ≥70 and <70 years with non-complicated ST-elevation myocardial infarction

© 2016. Objective: To examine clinical and health-related quality of life (HRQOL) outcomes and predictors of HRQOL for uncomplicated field triage ST-elevation myocardial infarction (STEMI) patients aged ≥70 years and <70 years after primary percutaneous coronary intervention (PPCI). Background: Pre-hospital field triage for PPCI is associated with lower mortality but the impact of age and other factors on HRQOL remains unknown. Methods: 77 field triage STEMI patients were assessed for HRQOL using the Short Form-12 (SF-12) and the Seattle Angina Questionnaire (SAQ) at 4 weeks and 6 months after PPCI. Results: Regression analysis showed improvements in SF-12 domains and angina stability for older people. Age predicted lower physical function (. p = 0.001) and better SAQ QOL at 6 months (. p = 0.003). Conclusion: Age, length of hospitalization, recurrent angina and hypertension were important predictors of HRQOL with PPCI. Assessment of HRQOL combined with increased support for physical and emotional recovery is needed to improve clinical care for field triage PPCI patients

Implementation of U.S. Department of Energy physical protection upgrades in Lithuania and Uzbekistan

Since 1994, the U.S. Department of Energy (DOE) has provided cooperative assistance to the non-nuclear weapons states of the Former Soviet Union. This effort, within DOE`s program of Material Protection, Control, and Accounting (MPC&A), identified the Institute of Nuclear Physics (INP) in Uzbekistan and the Ignalina Nuclear Power Plant (INPP) in Lithuania as sites for cooperative MPC&A projects. The INP, located just outside of Tashkent, is the site of a 10-megawatt WWR-SM research reactor. This reactor is expected to remain operational as a major nuclear research and isotope production reactor for Central Asia. The INPP, located 100 kilometers northeast of the capital city of Vilnius, consists of two Russian-made RBMK reactors with a combined power output of 3,000 megawatts (electric). This power plant has been the subject of international safety and security concerns, which prompted DOE`s cooperative assistance effort. This paper describes U.S. progress in a multi-national effort directed at implementing physical protection upgrades in Lithuania and Uzbekistan. The upgrades agreed upon between DOE and the INP and between DOE and the INPP have been designed to interface with upgrades being implemented by other donor countries. DOE/INPP upgrade projects include providing training on U.S. approaches to physical protection, access control through the main vehicle portal, a hardened central alarm station, and improved guard force communications. DOE/INP upgrade projects in Uzbekistan include an access control system, a hardened fresh fuel storage vault, an interior intrusion detection and assessment system, and an integrated alarm display and assessment system

Corticosteroids in the Management of Severe Coccidioidomycosis.

BackgroundThere is limited data suggesting that recovery from severe pulmonary infection with Coccidioides may be hastened by the addition of systemic corticosteroids.MethodsWe present a case report of 2 patients with persistent and progressive coccidioidomycosis who demonstrated a dramatic response to adjunctive corticosteroid therapy.ResultsBoth patients had Coccidioides immitis cultured from respiratory samples. One was a 69-year-old man who had been treated with combination fluconazole and liposomal amphotericin for over 6 weeks, with persistent fever and pneumonia. The other was a 61-year-old man treated with fluconazole and then amphotericin for 3 weeks, with progression to acute respiratory distress syndrome and shock. Both received short courses of intravenous methylprednisolone and recovered to be discharged home.ConclusionsAs opposed to associated hypersensitivity, corticosteroid treatment in these cases was directed at modulating the ongoing destructive effects of unchecked inflammation. Rapid improvement was noted in both cases and raises the possibility that the addition of systemic corticosteroids may hasten recovery in patients with severe coccidioidomycosis

Corticosteroids in the Management of Severe Coccidioidomycosis.

BackgroundThere is limited data suggesting that recovery from severe pulmonary infection with Coccidioides may be hastened by the addition of systemic corticosteroids.MethodsWe present a case report of 2 patients with persistent and progressive coccidioidomycosis who demonstrated a dramatic response to adjunctive corticosteroid therapy.ResultsBoth patients had Coccidioides immitis cultured from respiratory samples. One was a 69-year-old man who had been treated with combination fluconazole and liposomal amphotericin for over 6 weeks, with persistent fever and pneumonia. The other was a 61-year-old man treated with fluconazole and then amphotericin for 3 weeks, with progression to acute respiratory distress syndrome and shock. Both received short courses of intravenous methylprednisolone and recovered to be discharged home.ConclusionsAs opposed to associated hypersensitivity, corticosteroid treatment in these cases was directed at modulating the ongoing destructive effects of unchecked inflammation. Rapid improvement was noted in both cases and raises the possibility that the addition of systemic corticosteroids may hasten recovery in patients with severe coccidioidomycosis