Bereavement in Pakistan during the COVID-19 pandemic: Psychometric analysis of the Pandemic Grief Scale-Urdu Version (PGS-UV).

With nearly 4 million deaths worldwide, COVID-19 has resulted in a great loss of life. For many of the bereaved, the grieving process has been especially difficult due to COVID-19 spatial distancing procedures and the traumatic circumstances of this particular form of loss. Consequently, a large number of the world's bereaved are experiencing dysfunctional levels of grief. To assess such grief, the Pandemic Grief Scale (PGS) was created to identify those affected who may benefit from professional support. This study aimed to psychometrically analyze the properties of the Urdu version of the scale, among a sample of 272 Pakistanis who lost a loved one to COVID-19 from March to June 2021. Results revealed that the scale was found to be a reliable and valid tool for assessing dysfunctional pandemic grief for both men and women. However, unique gender differences were found. Additional research should further confirm the psychometric properties of the PGS on other culturally diverse samples.

Coronaphobia among healthcare professionals in Mexico: A psychometric analysis.

The present study examined the validity of the coronaphobia phenomenon with healthcare professionals using a psychometric approach. Using SurveyMonkey, an adapted version of the Coronavirus Anxiety Scale-Healthcare version (CAS-HC) was administered to 231 adult healthcare professionals in Mexico. Confirmatory factor analysis demonstrated that dysfunctional coronavirus anxiety symptoms cohered into a reliable, single factor structure of coronaphobia. A receiver operating characteristic curve analysis indicated that the classification features of the CAS-HC were strong, but supported a less stringent cut-score for this population. Construct validity was supported by the positive correlations between the CAS-HC and measures of depression and generalized anxiety, while known groups validity was found with high CAS-HC scores exhibited by those working in emergency rooms, triage, and intensive care units. The findings collectively support the coronaphobia construct with healthcare professionals, and the finding that over one third of the participants in the study scored in the clinical range on this measure points to the critical importance of assessing and alleviating this form of distress in this vulnerable but indispensable workforce.

Persistent Complex Bereavement Disorder Symptoms Predict Grief Interview Emotions.

This study examined persistent complex bereavement disorder (PCBD) symptoms' ability to predict emotional reactions of 69 bereaved adults who participated in grief interviews. The results supported the predictive validity of PCBD symptoms for both self-report and behavioral observation measures of sadness but with only one behavioral measure of happiness. Furthermore, PCBD symptoms uniquely predicted sadness in all but one measure of that emotion while accounting for symptoms of depression, posttraumatic stress, and separation anxiety. Because interviews are the primary method of psychological evaluation for clinicians, these findings collectively support the validity of the PCBD construct.

Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein.

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.

Population pharmacokinetic modeling and simulations of berotralstat for prophylactic treatment of attacks of hereditary angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent episodes of swelling of the skin, larynx, gastrointestinal tract, genitals, and extremities that can be disruptive to patient quality of life. Dysregulation of plasma kallikrein activity leads to increased production and accumulation of bradykinin in HAE and causes attacks of angioedema. Plasma kallikrein is a serine protease essential for the formation of bradykinin. Berotralstat is a potent, highly selective, orally bioavailable small-molecule plasma kallikrein inhibitor that has been approved to prevent attacks of HAE in adults and children 12 years of age and older. Population pharmacokinetic (PK) analyses were conducted to describe the PK of berotralstat (BCX7353; Orladeyo™ ) and to evaluate the covariates that may explain variability in PK. The PK of berotralstat were characterized by population PK modeling of data from 13 clinical studies and a total of 771 healthy subjects and patients with HAE. The PK profile was well described by a three-compartment model with first-order absorption including an absorption lag time and linear elimination. Among the covariates tested, the effects of bilirubin and food were found not to be clinically significant and were removed from the model. Covariate analysis indicated significant effects of dose on bioavailability and weight on berotralstat clearance and volume. Despite the covariate effect of weight, simulations in adolescents and adults who were underweight, low weight, and overweight demonstrated similar predicted exposures to those observed at therapeutic doses in a clinical trial. Therefore, no dose adjustment is required in these HAE patient subpopulations.

Pharmacokinetics and Safety of the Nucleoside Analog Antiviral Drug Galidesivir Administered to Healthy Adult Subjects.

Galidesivir (BCX4430) is an adenosine nucleoside analog broadly active in cell culture against multiple RNA virus families, and active in animal models of viral diseases associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever. Current studies demonstrated the pharmacokinetics and safety of the first-in-human evaluations of galidesivir as intramuscular (IM) and intravenous (IV) formulations. Two double-blind, placebo-controlled, dose-ranging studies were conducted enrolling 126 healthy subjects. Study 1 evaluated the safety and tolerability of IM galidesivir over single day dosing, single day dosing ± lidocaine, and 7-day dosing with lidocaine. Study 2 evaluated the safety and tolerability of single ascending doses of IV galidesivir. Safety and tolerability were evaluated via clinical and laboratory monitoring. The plasma concentration-time profile of galidesivir at doses 0.3 to 10 mg/kg IM was characterized by rapid absorption, an initial rapid distribution and clearance phase, and an extended terminal elimination phase. The initial rapid distribution and extended terminal elimination were mimicked in the profile of galidesivir at doses 5 to 20 mg/kg IV. No fatal events or related serious adverse events were reported. No clinically significant dose-related trends in laboratory values, vital signs, electrocardiograms, or echocardiograms were noted. Galidesivir was safe and generally well tolerated.

Preliminary evaluation of septic-system absorption-field architecture types in a profile-limited soil.

Managing household wastewater is an issue that affects hundreds of thousands of people in rural communities nationwide, many of whom rely on septic systems as their primary means of household wastewater disposal. Septic system absorption field products with architectures quite different from traditional pipe-and-gravel systems are being installed in many states with variances from initial design specifications. The objective of this study was to evaluate the performance, as measured by the in-product height of stored solution, of four differing absorption-field product architecture types in a profile-limited soil that was loaded at the maximum allowable rate based on soil morphology. Five chamber, two gravel-less pipe, two polystyrene aggregate, and four pipe-and-gravel systems were installed in a profile-limited, Captina silt loam soil (fine-silty, siliceous, active, mesic Typic Fragiudult) and dosed with raw effluent at rates determined by current State of Arkansas regulations via individual peristaltic pumps. Free-solution monitoring ports were installed within each product, where the depth to free solution was measured periodically and used to evaluate product performance. Data collected from January through August 2009 indicated that preliminary system performance was unaffected by product architecture type. All products performed similarly under dry soil conditions. However, differences among individual products were observed during periods of hydrologic stress (i.e., wet soil conditions). Surfacing of effluent was not observed atop any product, indicating that the current loading rate design method is functioning properly. Preliminary results indicate that some alternative absorption-field products perform similarly to the traditional pipe-and-gravel system, thus providing flexibility and options for homeowners.

An update on the progress of galidesivir (BCX4430), a broad-spectrum antiviral.

Galidesivir (BCX4430) is an adenosine nucleoside analog that is broadly active in cell culture against several RNA viruses of various families. This activity has also been shown in animal models of viral disease associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever viruses. In many cases, the compound is more efficacious in animal models than cell culture activity would predict. Based on favorable data from in vivo animal studies, galidesivir has recently undergone evaluation in several phase I clinical trials, including against severe acute respiratory syndrome coronavirus 2, and as a medical countermeasure for the treatment of Marburg virus disease.

Activity of Galidesivir in a Hamster Model of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.

A novel class of fast-acting antimalarial agents: Substituted 15-membered azalides.

BACKGROUND AND PURPOSE: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low. EXPERIMENTAL APPROACH: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model. KEY RESULTS: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin. CONCLUSION AND IMPLICATIONS: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.

Incremental validity of coronaphobia: Coronavirus anxiety explains depression, generalized anxiety, and death anxiety.

The adverse psychological effects of COVID-19 have increased globally. Moreover, the psychological toll may be worsening for this health crisis due to the growing numbers of mass deaths and unemployment levels. Coronaphobia, a relatively new pandemic-related construct, has been shown to be strongly related to functional impairment and psychological distress. However, the extent to which coronaphobia is uniquely accountable for the psychological distress experienced during the COVID-19 crisis has not been systematically investigated. The current study examined this question of incremental validity using online data from 453 adult MTurk workers in the U.S. The results of a series of hierarchical multiple regression analyses demonstrated that coronaphobia explained additional variance in depression, generalized anxiety, and death anxiety, above sociodemographics, COVID-19 factors, and the vulnerability factors of neuroticism, health anxiety, and reassurance-seeking behaviors. These findings suggest that health professionals should be aware of coronaphobia as this expression of pandemic-related stress has reliably demonstrated incremental validity in accounting for major indicators of psychological distress.

Modeling pandemic depression and anxiety: The mediational role of core beliefs and meaning making.

Background: The aim of this research was to examine core belief violation and disrupted meaning making as primary cognitive processes regulating mental health during the pandemic. The study tested the hypothesis that both these cognitive processes function as mediating mechanisms, accounting for the adverse mental health effects of multiple pandemic stressors. Methods: A survey design (N = 2380) assessed demographic variables associated with poor pandemic mental health (gender, age, ethnicity, education), direct COVID stressors (diagnosis, death), indirect COVID stressors (unemployment, increased living costs, childcare loss), core belief violation, meaning made of the pandemic, coronavirus anxiety (CA), depression, and general anxiety. RESULTS: Core belief violation and disrupted meaning making explained the severity of depression, general anxiety, and CA to a significantly greater degree than did demographics, direct COVID stressors, and indirect COVID stressors combined. In addition, core belief violation and disrupted meaning making significantly mediated the impact of direct and indirect COVID stressors on all mental health outcomes. Specifically, each stressor was associated with increased core belief violation and decreased meaning making of the pandemic, in turn, those whose core beliefs were violated and those who made less meaning of the pandemic experienced greater depression, general anxiety, and CA. Limitations: The use of a cross-sectional design prohibited assessment of alternative causal orders. Conclusions: This study describes the first unifying model of pandemic mental health, establishing violation of core beliefs and the inability to make meaning of the pandemic as targets for clinical intervention in the context diverse pandemic stressors.

Clinically significant fear and anxiety of COVID-19: A psychometric examination of the Coronavirus Anxiety Scale.

The present study examined the psychometric properties of the Coronavirus Anxiety Scale (CAS) using an online survey of 398 adult Amazon MTurk workers in the U.S. Confirmatory factor analyses demonstrated that the CAS measures a reliable (α = 0.92), unidimensional construct with a structure that was shown to be invariant across gender, race, and age. Construct validity was demonstrated with correlations between CAS scores and demographics, coronavirus diagnosis, history of anxiety, coronavirus fear, functional impairment, alcohol/drug coping, religious coping, hopelessness, suicidal ideation, as well as social attitudes (e.g., satisfaction with President Trump). The CAS also demonstrated solid discrimination ability for functional impairment (AUC =0.88), while the original cut score of ≥9 (76% sensitivity and 90% specificity) showed the strongest diagnostic effectiveness among scores. Overall, these findings are largely consistent with the results of the first CAS investigation and support the validity of this mental health screener for COVID-19 related research and practice.

A direct-acting antiviral drug abrogates viremia in Zika virus-infected rhesus macaques.

Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection against Zika virus infection. Galidesivir exhibited favorable pharmacokinetics with no observed teratogenic effects in rats or rabbits at any dose tested. The antiviral efficacy of galidesivir observed in the blood and central nervous system of infected animals warrants continued evaluation of this compound for the treatment of flaviviral infections.

Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.

We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.

Antiparasitic compounds that target DNA.

Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48h after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death.

Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters.

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen endemic to sub-Saharan Africa and the Arabian Peninsula. There are no approved antiviral therapies or vaccines available to treat or prevent severe disease associated with RVFV infection in humans. The adenosine analog, galidesivir (BCX4430), is a broad-spectrum antiviral drug candidate with in vitro antiviral potency (EC50 of less than 50 µM) in more than 20 different viruses across eight different virus families. Here we report on the activity of galidesivir in the hamster model of peracute RVFV infection. Intramuscular and intraperitoneal treatments effectively limited systemic RVFV (strain ZH501) infection as demonstrated by significantly improved survival outcomes and the absence of infectious virus in the spleen and the majority of the serum, brain, and liver samples collected from infected animals. Our findings support the further development of galidesivir as an antiviral therapy for use in treating severe RVFV infection, and possibly other related phleboviral diseases.

Dications that target the DNA minor groove: compound design and preparation, DNA interactions, cellular distribution and biological activity.

Fluorescence microscopy of trypanosomes from drug treated mice shows that biologically active heterocyclic diamidines that target the DNA minor groove bind rapidly and specifically to parasite kinetoplast DNA (k-DNA). The observation that the kinetoplast is destroyed, generally within 24 hours, after drug treatment is very important for understanding the biological mechanism, and suggests that the diamidines may be inhibiting some critical opening/closing step of circular k-DNA. Given the uncertainties in the biological mechanism, we have taken an empirical approach to generating a variety of synthetic compounds and DNA minor groove interactions for development of improved and new biological activities. Furamidine, DB75, is a diphenyl-diamidine that has the curvature to match the DNA minor groove as expected in the classical groove interaction model. Surprisingly, a linear diamidine with a nitrogen rich linker has significantly stronger binding than furamidine due to favorable linker and water-mediated DNA interactions. The water interaction is very dependant on compound structure since other linear compounds do not have similar interactions. Change of one phenyl of furamidine to a benzimidazole does not significantly enhance DNA binding but additional conversion of the furan to a thiophene (DB818) yields a compound with ten times stronger binding. Structural analysis shows that DB818 has a very favorable curvature for optimizing minor groove interactions. It is clear that there are many ways for compounds to bind to k-DNA and exert specific effects on kinetoplast replication and/or transcription that are required to obtain an active compound.

Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism.

By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.