Nirmatrelvir and Molnupiravir Coadministration Modifies Preclinical Viral Exposure

Background: Implementation of vaccination programmes has had a transformational impact on control of the SARS-CoV-2 pandemic, but the need for effective antiviral drugs remains. Molnupiravir (MPV) targets viral RNA polymerase inhibiting replication via lethal mutagenesis and nirmatrelvir (NTV) is a protease inhibitor boosted with ritonavir when given clinically. This study aimed to assess the virological efficacy of NTV and MPV individually and in combination against the SARS-CoV-2 BA.1 Omicron variant in a K18-hACE2 mouse model. Method(s): K18-hACE2 mice were inoculated intranasally with 103 PFU of SARSCoV-2 BA.1 Omicron (B.1.1.529). After 24 hours, mice were orally dosed q12H, as outlined in Figure 1. At 2, 3, and 4-days post infection mice were sacrificed, and lung samples harvested. Animals were weighed and monitored daily throughout. Subsequently, viral replication in the lung was quantified using qRT-PCR to measure total (N-gene) and sub-genomic (E-gene) viral RNA. Data were normalized to 18S for quantitation. Viral exposures expressed as Areas Under viral load Curves (AUCs) were calculated by the trapezoidal method using mean values at each timepoint. Separate studies in Syrian golden hamsters using individual drugs were also conducted, and total serum IgG was measured by ELISA at 4-days post infection. Result(s): Mice gained weight in all groups post-treatment, with no significant difference between groups. A reduction in lung viral exposure was evident in all treatment groups compared to the vehicle control dosed mice (Figure 1). Coadministration of NTV with MPV displayed a trend towards lower lung viral exposure compared to the vehicle control with ~40-and ~45-fold reduction in AUC for N-and SgE-gene assays, respectively. Dosed individually, NTV and MPV reduced viral exposure 5.7-and 7.7-fold for the N-gene assay, respectively. Differences in total serum IgG concentrations were evident between vehicle and NTV-(34-fold reduction, P=0.018), and MPV-(4.2-fold reduction, P=0.053) treated hamsters. Conclusion(s): These data show virological efficacy of NTV and MPV against the SARS-CoV-2 BA.1 Omicron variant. The combination of NTV and MPV demonstrated a lower viral RNA exposure in the lung than either drug alone, albeit not statistically significant. Initial data indicate potential immune alterations in NTV and MPV dosed hamsters. Studies to clarify the utility of NTV/ MPV combinations and further characterize the impact of antiviral therapy on IgG are warranted.

NAFAMOSTAT AS NASAL CHEMOPROPHYLAXIS FOR SARS-CoV-2 IN HAMSTERS

Background: Chemoprophylaxis is a critical tool for many infectious diseases, and in COVID-19 may have particular benefit for vulnerable patients that do not maximally benefit from vaccination. Nafamostat inhibits TMPRSS2, which catalyses a critical cell entry pathway for SARS-CoV-2. This study sought to assess efficacy of intranasal nafamostat against airborne transmission of SARSCoV-2 in Syrian Golden hamsters. Method(s): Male hamsters were intranasally administered water or 5 mg/kg nafamostat in water twice daily for 5 days (sentinels). One day after treatment initiation, sentinels were co-housed with an untreated hamster that was intranasally inoculated with 1 x 104 PFU of Wuhan SARS-CoV-2 (donor). Sentinels were separated from the donor by a perforated divider, allowing airflow between zones but not contact. Hamsters were weighed and throat-swabbed throughout. At day 4, all animals were culled, and lung and nasal turbinates were harvested. N-RNA was quantified relative to 18S-RNA by qPCR. A 2-way ANOVA with Bonferroni correction was applied to compare weight changes in the nafamostat group to those in controls. An unpaired t-test was used to compare viral RNA in lung and nasal turbinate between groups. Result(s): SARS-CoV-2 viral RNA was significantly lower in the nasal turbinates of nafamostat-treated hamsters compared to water-treated controls (P = 0.012;Figure 1). Within the lung, SARS-CoV-2 RNA was undetectable in the nafamostat-treated hamsters, but was detectable in the water-treated controls. Viral RNA was undetectable in the swabs of the nafamostat-treated hamsters at all timepoints, but was quantifiable in the water-treated control group from day 3. Body weight of the nafamostat-treated hamsters was significantly lower (P = < 0.001) than in the water-treated animals throughout. SARS-CoV-2 viral RNA was detectable in the donor hamsters lung, nasal turbinate and swab samples confirming validity of the experiment. Conclusion(s): This study demonstrated a protective effect of intranasal nafamostat against airborne SARS-CoV-2 transmission in Syrian golden hamsters. A phase IIa study of intravenously administered nafamostat yielded no evidence of clinical efficacy in hospitalised patients, but further investigation of intranasally administered nafamostat in a prophylactic setting may be warranted.

INDIVIDUALS AND THEIR CAREGIVERS WITH PERSISTENT PAIN: A FEASIBILITY AND ACCEPTABILITY STUDY

Persistent pain interventions targeting the caregiving dyad (i.e., caregivers and care receivers) are scarce. Thus, the purpose of this pilot study was to assess the feasibility and acceptability of the Merging Yoga and self-management to develop Skills (MY-Skills) intervention for caregiving dyads experiencing persistent pain. MY-Skills is a group intervention and was delivered in-person or online (due to COVID-19) twice a week for eight weeks, with each two-hour session including self-management education followed by yoga. Benchmarks for feasibility were set a prioi and included: recruitment, attrition, attendance, safety, acceptability/satisfaction, and study completion. Thirteen participants (caregivers n=7, care-receivers n=6) completed the in-person intervention and 18 individuals (9 dyads) completed the online version. Feasibility benchmarks were met, except for recruitment, where >1000 individuals were screened for eligibility. Interventions may lead to improved wellbeing, yet further research is needed to establish efficacy of health-related outcomes for the caregiving dyad experiencing persistent pain.

FXR INHIBITION AS A NEW STRATEGY AGAINST COVID19 T Brevini1, M Maes2, GJ Webb3, CD Fuchs4, G Buescher5

Introduction: Vaccines revolutionised the management of COVID19. Nevertheless, they lack efficacy in high-risk or vulnerable groups (e.g., immunosuppressed patients), who may not mount an appropriate immune response. Monoclonal antibodies represent the gold-standard agents for such cases;but they are limited by availability, need for parenteral administration and the risk for viral escape because of spike protein mutations. Therefore, there is a pressing need for new prophylactic agents less prone to resistance.The viral receptor ACE2 represents an ideal target as it is essential for viral entry and transmission and because being a host protein it is not affected by viral mutations. However, the regulation of ACE2 remains elusive, due to the lack of appropriatein vitromodels. Cholangiocytes show one of the highest ACE2 expression levels in the body, representing an ideal platform for these studies. Here, we use cholangiocyte organoids as proof-of-principleto identify that the bile acid receptor FXR regulates ACE2 expression and SARS-CoV-2 infectionin vitro. We validate these findings in lung and gut organoids, animal models, human organs perfusedex situand patient cohorts. Aims & Methods: 1. Identify pathways controlling the transcriptional regulation of ACE2 2. Identify drugs modulating these pathways as novel prophylactic and therapeutic agents for COVID19. Organoids were propagated using established protocols. Marker expression was assessed using single-cell RNA sequencing, QPCR, and immunofluorescence. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Syrian golden hamsters were infected via direct inoculation and QPCR on oral swab, nasal turbinate and lung samples was used to measure SARS-CoV-2 infection. Human livers and lungs not used for transplantation were perfusedex-situusing normothermic perfusion. Nasopharyngeal swabs were used to measure ACE2 expression in nasal epithelial cells of healthy individuals taking UDCA at the standard therapeutic dose of 15 mg/kg/day. Patient registry data were compared using propensity score matching for sex, age, diabetes, NAFLD and Child- Turcotte-Pugh score. Result(s): We identified that FXR directly regulates ACE2 transcription in cholangiocyte organoids, while FXR inhibition with the approved drug ursodeoxycholic acid (UDCA), reduced ACE2 expression and SARS-CoV-2 infectionin vitro. We confirmed this mechanism in organoids from other COVID19-affected tissues, including the respiratory and intestinal systems. We validated our findingsin vivoin Syrian golden hamsters, showing that treatment with UDCA downregulates ACE2 and prevents SARS-CoV-2 infection. We confirmed that UDCA reduces ACE2 and SARS-CoV-2 infection in human lungs and livers perfusedex-situ. We performed a clinical study demonstrating that UDCA lowers ACE2 levels in the nasal epithelium of 6 healthy volunteers. Finally, we identified a correlation between UDCA and better clinical outcomes (hospitalisation, ICU admission and death) in COVID19 patients receiving UDCA for cholestatic diseases using the COVID-Hep and SECURELiver registry data. Conclusion(s): We identified FXR as a novel regulator of ACE2 expression. Using a bench-to-bedside approach combining in vitroand in vivomodels, exsituperfused human organs and clinical data we showed that FXR inhibition prevents or reduces SARS-CoV-2 infection and identified UDCA as an approved, cost-effective drug which could be repurposed for COVID19, paving the road for future clinical trials.

Lecturer self-efficacy beliefs: an integrative review and synthesis of relevant literature

This article reviews available research literature in the field of lecturer self-efficacy beliefs produced between 1988 and 2020. Given the growing interest in lecturer self-efficacy beliefs in recent years, and the global challenges the Higher Education sector will face following the current Covid-19 pandemic, the time to conduct such a review seems appropriate. Fifty-five empirical papers in English, Spanish and Portuguese were identified and examined. Findings show that papers investigated the beliefs of lecturers from 23 countries using mostly quantitative cross-sectional approaches involving questionnaires. Among the eight main themes that emerged, 'teaching self-efficacy' featured prominently and received most attention, while other aspects of the work of lecturers, including research, service-related and other administrative activities, were also considered. Concerning personal variables like gender, there was no consensus over whether different characteristics affected self-efficacy beliefs more than others. Conclusions point to the need for additional mixed-methods and qualitative studies with more refined and contextualised methodological approaches to better understand the field, to identify actual sources of self-efficacy themselves and to more fully inform policy, practice, the distribution of resources and building capacity.

Jordan: Background and U.S. Relations (Updated)

The Hashemite Kingdom of Jordan is a key U.S. partner in the Middle East. Although the United States and Jordan have never been linked by a formal treaty, the two countries have cooperated on a number of regional and international issues over the years. Jordan remains at peace with Israel and is a key interlocutor with the Palestinians. Jordan’s strategic importance to the United States is evident given ongoing instability in neighboring Syria and Iraq. Jordan also is a longtime U.S. partner in global counterterrorism operations. U.S.-Jordanian military, intelligence, and diplomatic cooperation seeks to empower political moderates, reduce sectarian conflict, and eliminate terrorist threats. U.S. officials frequently express their support for Jordan. U.S. support has helped Jordan address serious vulnerabilities, both internal and external. Jordan’s small size and lack of major economic resources have made it dependent on aid from Western and various Arab sources. President Trump has acknowledged Jordan’s role as a key U.S. partner in countering the Islamic State, as many U.S. policymakers advocate for continued robust U.S. assistance to the kingdom. Annual U.S. aid to Jordan has nearly quadrupled in historical terms over the last 15 years. The United States has provided economic and military aid to Jordan since 1951 and 1957, respectively. Total bilateral U.S. aid (overseen by the Departments of State and Defense) to Jordan through FY2018 amounted to approximately $22 billion. Jordan also hosts over 3, 000 U.S. troops. To date, Jordan has withstood the impact of Coronavirus Disease 2019 (COVID-19) with minimal loss of life (a reported nine deaths), but at a steep cost to its economy. Jordan’s small size and strong public health system arguably contributed to the country’s ability to manage the pandemic effectively. Jordan is one of the first Arab countries to reopen;as of June 2020 the state had lifted most restrictions on economic activity and certain public gatherings, such as religious worship. Analysts anticipate that Jordan’s Gross Domestic Product (GDP) will contract in 2020 by 3.5% after growing 2% last year. Losses in government revenue caused by fewer remittances and a weakened market for tourism are expected to widen the budget deficit in the years ahead. As the Trump Administration has enacted changes to longstanding U.S. policies on Israel and the Palestinians, which the Palestinians have criticized as unfairly punitive to them and biased toward Israel, Jordan has found itself in a difficult position. While King Abdullah II seeks to maintain strong relations with the United States, he rules over a country where the issue of Palestinian rights resonates with much of the population;more than half of all Jordanian citizens originate from either the West Bank or the area now comprising the state of Israel. In trying to balance U.S.-Jordanian relations with Palestinian concerns, King Abdullah II has refrained from directly criticizing the Trump Administration on its moves, while urging the international community to return to the goal of a two-state solution that would ultimately lead to an independent Palestinian state with East Jerusalem as its capital. Jordanian leaders have expressed strong opposition to a possible Israeli cabinet and Knesset vote on annexing West Bank territory-in coordination with the United States-after July 1, 2020. King Abdullah II has signaled that should Israel go ahead with annexation, Jordan is prepared to escalate its confrontation with Israel. As Jordan considers whether to revisit its ties to Israel, the range of possible options Jordan may be considering include withdrawing its ambassador from Israel, reducing security cooperation, cancelling its natural gas deal with Israel, and either partially or fully suspending the 1994 peace treaty. Congress may consider legislation pertaining to U.S. relations with Jordan. On February 18, 2016, President Obama signed the United States-Jordan Defense Cooperation Act of 2015 (P.L. 114-123), which authorizes expedited revie and an increased value threshold for proposed arms sales to Jordan for a period of three years. It amended the Arms Export Control Act to give Jordan temporarily the same preferential treatment U.S. law bestows upon NATO members and Australia, Israel, Japan, New Zealand, and South Korea. S. 28, the United States-Jordan Defense Cooperation Extension Act, would reauthorize the United States-Jordan Defense Cooperation Act (22 U.S.C. §275) through December 31, 2022. In the House, H.R. 4862 also would reauthorize the 2015 Act while also calling on the United States International Development Finance Corporation to issue a call for “proposals pursuing investment funds with a focus on Jordan.”. © 2016 by Nova Science Publishers, Inc.

Feminist geopolitics and the global-intimacies of pandemic times

COVID-19 has brought to unavoidable prominence what feminist geopolitics has long insisted, namely that the global and the intimate are always, everywhere, already entangled. Drawing on Anglo-American experiences of the pandemic, this paper aims to make two key arguments. The first is that feminist geopolitics is a conceptual approach that is perhaps uniquely placed to make sense of COVID geographies. The second is to propose that this account of COVID speaks back to recent debates about the future of feminist geopolitics. Reflecting on recent debates about possible futures for feminist geopolitics, the paper will make the case for a materially-engaged feminist geopolitics which nevertheless keeps the socially-marked body at the heart of analysis. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.