Development and validation of an LC-MS/MS method for quantification of favipiravir in human plasma.

Favipiravir (FVP) is a broad-spectrum antiviral that selectively inhibits viral RNA-dependent RNA polymerase, first trialled for the treatment of influenza infection. It has been shown to be effective against a number of RNA virus families including arenaviruses, flaviviruses and enteroviruses. Most recently, FVP has been investigated as a potential therapeutic for severe acute respiratory syndrome coronavirus 2 infection. A liquid chromatography tandem mass spectrometry method for the quantification of FVP in human plasma has been developed and validated for use in clinical trials investigating favipiravir as treatment for coronavirus disease-2019. Samples were extracted by protein precipitation using acetonitrile, using 13C, 15N- Favipiravir as internal standard. Elution was performed on a Synergi Polar-RP 150 × 2.1 mm 4 µm column using a gradient mobile phase programme consisting of 0.2% formic acid in water and 0.2% formic acid in methanol. The assay was validated over the range 500-50,000 ng/mL; this method was found to be precise and accurate and recovery of FVP from the matrix was high. Stability experiments confirmed and expanded on the known stability of FVP, including under heat treatment and for a period of 10 months at - 80 °C.

Physical Activity in Adults with Schizophrenia and Bipolar Disorder: A Large Cross-Sectional Survey Exploring Patterns, Preferences, Barriers, and Motivating Factors.

Adults with severe mental ill health may have specific attitudes toward physical activity. To inform intervention development, we conducted a survey to assess the physical activity patterns, preferences, barriers, and motivations of adults with severe mental ill health living in the community. Data were summarised using descriptive statistics, and logistic regressions were used to explore relationships between physical activity status and participant characteristics. Five-hundred and twenty-nine participants (58% male, mean age 49.3 years) completed the survey. Large numbers were insufficiently active and excessively sedentary. Self-reported levels of physical activity below that recommended in national guidelines were associated with professional inactivity, consumption of fewer than five portions of fruit and vegetables per day, older age, and poor mental health. Participants indicated a preference for low-intensity activities and physical activity that they can do on their own, at their own time and pace, and close to home. The most commonly endorsed source of support was social support from family and friends. Common motivations included improving mental health, physical fitness, and energy levels. However, poor mental and physical health and being too tired were also common barriers. These findings can inform the development of physical activity interventions for this group of people.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Functional HIV-1/HCV cross-reactive antibodies isolated from a chronically co-infected donor.

Despite prolific efforts to characterize the antibody response to human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) mono-infections, the response to chronic co-infection with these two ever-evolving viruses is poorly understood. Here, we investigate the antibody repertoire of a chronically HIV-1/HCV co-infected individual using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq). We identify five HIV-1/HCV cross-reactive antibodies demonstrating binding and functional cross-reactivity between HIV-1 and HCV envelope glycoproteins. All five antibodies show exceptional HCV neutralization breadth and effector functions against both HIV-1 and HCV. One antibody, mAb688, also cross-reacts with influenza and coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examine the development of these antibodies using next-generation sequencing analysis and lineage tracing and find that somatic hypermutation established and enhanced this reactivity. These antibodies provide a potential future direction for therapeutic and vaccine development against current and emerging infectious diseases. More broadly, chronic co-infection represents a complex immunological challenge that can provide insights into the fundamental rules that underly antibody-antigen specificity.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.

Sleep health among people with severe mental ill health during the COVID-19 pandemic: Results from a linked UK population cohort study

Objectives Sleep problems are a transdiagnostic feature of nearly all psychiatric conditions, and a strong risk factor for initial and recurrent episodes. However, people with severe mental ill health (SMI) are often excluded from general population surveys, and as such the extent and associates of poor sleep in this population are less well understood. This study explores sleep health in an SMI sample during the COVID-19 pandemic, using multiple regression to identify risk factors, including daily routine, wellbeing and demographics. Methods An existing cohort of people with an SMI diagnosis were sampled. Participants were invited to complete a self-report survey about their health and the impacts of COVID-19 and associated public health measures. Sleep duration, efficiency, and quality were measured using items from the Pittsburgh Sleep Quality Index (PSQI). Results Two hundred forty-nine adults (aged 21–84 years) completed the survey. Mean sleep duration and efficiency were similar to general population estimates, at 7 h 19 min and 78%, respectively. However, 43% reported “bad” sleep quality that was associated with being younger in age as well as disturbed routine and declined wellbeing. Indeed, 37% reported a disturbed routine during the pandemic. Conclusions High estimates of perceived poor sleep quality in the SMI population align with previous findings. Supporting people with SMI to maintain routine regularity may work to protect sleep quality and wellbeing. Future research should more closely examine sleep health in people with SMI, using accessible and scalable measures of objective and subjective sleep, examining longitudinal trends.

Influences on the physical and mental health of people with serious mental ill-health during the COVID-19 pandemic: a qualitative interview study.

PURPOSE: People with severe mental ill-health (SMI) experience profound health inequalities. The Optimizing Wellbeing in Self-isolation study (OWLS) explored the effects of the COVID-19 pandemic restrictions on people with SMI, including how and why their physical and mental health may have changed during the pandemic. METHODS: The OLWS study comprised two surveys and two nested qualitative studies. Of 367 people recruited to the study, 235 expressed interest in taking part in a qualitative interview. In the first qualitative study eighteen interviews were conducted with a purposive sample of participants. RESULTS: We identified six factors which influenced peoples' health, positively and negatively: Staying Physically Active; Maintaining a Balanced and Healthy Diet; Work or Not Working; Daily Routine and Good Sleep; Staying Connected to Family, Friends and the Local Community; and Habits, Addictions and Coping with Anxiety Created by the Pandemic. CONCLUSIONS: Different aspects of lifestyle are highly interconnected. For people with SMI, loss of routine and good sleep, poor diet and lack of exercise can compound each other, leading to a decline in physical and mental health. If people are supported to understand what helps them stay well, they can establish their own frameworks to draw on during difficult times.

Multispecialty multidisciplinary input into comorbidities along with treatment optimisation in heart failure reduces hospitalisation and clinic attendance.

AIMS: Heart failure (HF) is associated with comorbidities which independently influence treatment response and outcomes. This retrospective observational study (January 2020-June 2021) analysed the impact of monthly HF multispecialty multidisciplinary team (MDT) meetings to address management of HF comorbidities and thereby on provision, cost of care and HF outcomes. METHODS: Patients acted as their own controls, with outcomes compared for equal periods (for each patient) pre (HF MDT) versus post-MDT (multispecialty) meeting. The multispecialty MDT comprised HF cardiologists (primary, secondary, tertiary care), HF nurses, nephrologist, endocrinologist, palliative care, chest physician, pharmacist, clinical pharmacologist and geriatrician. Outcome measures were (1) all-cause hospitalisations, (2) outpatient clinic attendances and (3) cost. RESULTS: 334 patients (mean age 72.5±11 years) were discussed virtually through MDT meetings and follow-up duration was 13.9±4 months. Mean age-adjusted Charlson Comorbidity Index was 7.6±2.1 and Rockwood Frailty Score 5.5±1.6. Multispecialty interventions included optimising diabetes therapy (haemoglobin A1c-HbA1c pre-MDT 68±11 mmol/mol vs post-MDT 61±9 mmol/mol; p<0.001), deprescribing to reduce anticholinergic burden (pre-MDT 1.85±0.4 vs 1.5±0.3 post-MDT; p<0.001), initiation of renin-angiotensin aldosterone system inhibitors in HF with reduced ejection fraction (HFrEF) with advanced chronic kidney disease (9% pre vs 71% post-MDT; p<0.001). Other interventions included potassium binders, treatment of anaemia, falls assessment, management of chest conditions, day-case ascitic, pleural drains and palliative support. Total cost of funding monthly multispecialty meetings was £32 400 and resultant 64 clinic appointments cost £9600. The post-MDT study period was associated with reduction in 481 clinic appointments (cost saving £72150) and reduced all-cause hospitalisations (pre-MDT 1.1±0.4 vs 0.6±0.1 post-MDT; p<0.001), reduction of 1586 hospital bed-days and cost savings of £634 400. Total cost saving to the healthcare system was £664 550. CONCLUSION: HF multispecialty virtual MDT model provides integrated, holistic care across all healthcare tiers for management of HF and associated comorbidities. This approach is associated with reduced clinic attendances and all-cause hospitalisations, leading to significant cost savings.

Single-cell profiling of the antigen-specific response to BNT162b2 SARS-CoV-2 RNA vaccine.

RNA-based vaccines against SARS-CoV-2 have proven critical to limiting COVID-19 disease severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. Here we identify and characterize antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 using multiple single-cell technologies for in depth analysis of longitudinal samples from a cohort of healthy participants. Mass cytometry and unbiased machine learning pinpoint an expanding, population of antigen-specific memory CD4+ and CD8+ T cells with characteristics of follicular or peripheral helper cells. B cell receptor sequencing suggest progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlate with eventual SARS-CoV-2 IgG, and a participant lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms identify an antigen-specific cellular basis of RNA vaccine-based immunity.

Transformation Beyond COVID-19: Accessibility in Lived Experience Involvement in Research Post Pandemic. Experience, Reflections and Future Direction From the Closing the Gap Network and OWLS Study.

Research literature published during the COVID-19 pandemic highlights the loss of involvement opportunities for people with lived experience during the pandemic as well as the vital role lived experience advisors play at all times, including highlighting unseen aspects of the impacts of crises such as the COVID-19 pandemic. During the pandemic, researchers from the Closing the Gap Network (CtG) at the University of York worked to expand and diversify patient and public involvement (PPI) whist working on a study exploring the impact of the pandemic and associated restrictions on those with the most severe forms of mental ill health. CtG had a strong record of patient and public involvement pre-pandemic and researchers wanted to ensure that this continued during the pandemic. This paper describes the experience of lived experience involvement during the pandemic from multiple perspectives and makes recommendations for future involvement models, accessibility and recommendations for future research.

Pharmacokinetics of ß-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Saliva and nasal NHC were significantly correlated with plasma (P < .0001). Clinical Trials Registration. NCT04746183.

Efficient discovery of SARS-CoV-2-neutralizing antibodies via B cell receptor sequencing and ligand blocking.

Although several monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved for coronavirus disease 2019 (COVID-19) therapy, development was generally inefficient, with lead generation often requiring the production and testing of numerous antibody candidates. Here, we report that the integration of target-ligand blocking with a previously described B cell receptor-sequencing approach (linking B cell receptor to antigen specificity through sequencing (LIBRA-seq)) enables the rapid and efficient identification of multiple neutralizing mAbs that prevent the binding of SARS-CoV-2 spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The combination of target-ligand blocking and high-throughput antibody sequencing promises to increase the throughput of programs aimed at discovering new neutralizing antibodies.

A Year Into the Pandemic: The Diversity of Experience Amongst People With Severe Mental Ill Health.

BACKGROUND: The COVID-19 pandemic has amplified pre-existing health inequalities and people with severe mental ill health (SMI) are one of the groups at greatest risk. In this study, we explored the effects of the pandemic and pandemic restrictions on people with SMI during the first year of the pandemic. METHODS: We conducted a longitudinal study in a sample of people with SMI. The inception survey was carried out between July and December 2020. Participants were then re-surveyed between January and March 2021. People were contacted by telephone and invited to take part in the study over the phone, online or by postal questionnaire. Across both waves we asked participants about their physical and mental health, health risk behaviors, well-being, loneliness, and employment status. RESULTS: Three hundred and sixty-seven people with SMI completed the inception survey and 249 people completed the follow up. Whilst some people reported no change in their physical (77, 31%) or mental health (60, 24%) over the course of the pandemic 53 (21%) reported a continuing decline in physical health and 52 (21%) reported a continuing decline in mental health. Participants who maintained a daily routine or reported no decline in physical health were found to be associated with no deterioration in mental health (Daily routine OR 2.27, 95% CI 1.11-4.64; no reported physical health decline OR 0.54, 95% CI 0.17-0.70). Participants were less likely to be occupationally active in the first phase of the pandemic compared to before the pandemic and in the second phase of the pandemic. However, there was no one single experience of people with SMI and similar to studies in the general populations a range of different scenarios was experienced. CONCLUSIONS: We observed a series of factors that might amplify pre-existing health inequalities. Health systems should be mindful of this, and should redouble efforts to set in place changes to practice and policy, which can mitigate these inequalities. Examples might include; raising awareness of the importance of ensuring that people with SMI receive an annual physical health check and supporting people to maintain a daily routine.

Exploring Access to Mental Health and Primary Care Services for People With Severe Mental Illness During the COVID-19 Restrictions.

AIMS: To explore: how satisfied people with severe mental illness (SMI) are with the support received during the pandemic; understand any difficulties encountered when accessing both mental health and primary care services; consider ways to mitigate these difficulties; and assess the perceived need for future support from mental health services. MATERIALS AND METHODS: A representative sample was drawn from a large transdiagnostic clinical cohort of people with SMI, which was recruited between April 2016 and March 2020. The sample was re-surveyed a few months after the beginning of the restrictions. Descriptive frequency statistics were used to analyze the quantitative data. The free text responses were analyzed thematically. RESULTS: 367 participants responded to the survey. Two thirds were receiving support from mental health services with the rest supported in primary care or self-managing. A quarter thought they would need more mental health support in the coming year. Half had needed to used community mental health services during the pandemic and the majority had been able to get support. A minority reported that their mental health had deteriorated but they had either not got the supported they wanted or had not sought help. The biggest service change was the reduction in face-to-face appointments and increasing use of phone and video call support. Nearly half of those using mental health services found this change acceptable or even preferred it. However, acceptability was influenced by several factors, and participants were more likely to report that they had received all the support they needed, when seen in person. DISCUSSION: Although most participants were satisfied with the mental health support they had received, a minority were not. This, couple with findings on future need for mental health support has implications for post pandemic demand on services. Remote care has brought benefits but also risks that it could increase inequalities in access to services.

Loneliness among people with severe mental illness during the COVID-19 pandemic: Results from a linked UK population cohort study.

AIM/GOAL/PURPOSE: Population surveys underrepresent people with severe mental ill health. This paper aims to use multiple regression analyses to explore perceived social support, loneliness and factor associations from self-report survey data collected during the Covid-19 pandemic in a sample of individuals with severe mental ill health. DESIGN/METHODOLOGY/APPROACH: We sampled an already existing cohort of people with severe mental ill health. Researchers contacted participants by phone or by post to invite them to take part in a survey about how the pandemic restrictions had impacted health, Covid-19 experiences, perceived social support, employment and loneliness. Loneliness was measured by the three item UCLA loneliness scale. FINDINGS: In the pandemic sub-cohort, 367 adults with a severe mental ill health diagnosis completed a remote survey. 29-34% of participants reported being lonely. Loneliness was associated with being younger in age (adjusted OR = -.98, p = .02), living alone (adjusted OR = 2.04, p = .01), high levels of social and economic deprivation (adjusted OR = 2.49, p = .04), and lower perceived social support (B = -5.86, p < .001). Living alone was associated with lower perceived social support. Being lonely was associated with a self-reported deterioration in mental health during the pandemic (adjusted OR = 3.46, 95%CI 2.03-5.91). PRACTICAL IMPLICATIONS: Intervention strategies to tackle loneliness in the severe mental ill health population are needed. Further research is needed to follow-up the severe mental ill health population after pandemic restrictions are lifted to understand perceived social support and loneliness trends. ORIGINALITY: Loneliness was a substantial problem for the severe mental ill health population before the Covid-19 pandemic but there is limited evidence to understand perceived social support and loneliness trends during the pandemic.

The Role of Animal Ownership for People with Severe Mental Illness during the COVID-19 Pandemic: A Mixed-Method Study Investigating Links with Health and Loneliness.

Research has reported the benefits of companion animals for people with severe mental illness (SMI). However, this evidence base is fragmented and unclear. The COVID-19 pandemic presents an opportunity to explore the role of companion animals in the context of social distancing and isolation measures for people with SMI. Therefore, we aimed to investigate the links between mental and physical health and animal ownership in people with SMI and to explore animal owners' perceptions related to human-animal interactions during the pandemic restrictions. A survey was conducted with a previously assembled cohort of individuals with SMI in the UK. The survey included previously validated and new bespoke items measuring demographics, and outcomes related to mental and physical health, and human-animal interactions. The survey also included a question inviting free-text responses, allowing participants to describe any experiences of their human-animal relationships during the pandemic. Of 315 participants who consented to participate, 249 (79%) completed the survey. Of these, 115 (46.2%) had at least one companion animal. Regression analyses indicated that animal ownership was not significantly associated with well-being and loneliness. However, animal ownership was associated with a self-reported decline in mental health (b = 0.640, 95% CI [0.102-1.231], p = 0.025), but no self-reported change in physical health. Thematic analysis identified two main themes relating to the positive and negative impact of animal ownership during pandemic restrictions. Animal ownership appeared to be linked to self-reported mental health decline in people with SMI during the second wave of the pandemic in the UK. However, the thematic analysis also highlighted the perceived benefit of animal ownership during this time. Further targeted investigation of the role of human-animal relationships and the perceived human-animal bond for human health is warranted.

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.

Health risk behaviours among people with severe mental ill health during the COVID-19 pandemic: Analysis of linked cohort data.

BACKGROUND: People with severe mental ill health (SMI) experience a mortality gap of 15-20 years. COVID-19 has amplified population health inequalities, and there is concern that people with SMI will be disproportionately affected. Understanding how health risk behaviours have changed during the pandemic is important when developing strategies to mitigate future increases in health inequalities. METHODS: We sampled from an existing cohort of people with SMI. Researchers contacted participants by phone or post to invite them to take part in a survey about how the pandemic had affected them. We asked people about their health risk behaviours and how these had changed during the pandemic. We created an index of changed behaviours, comprising dietary factors, smoking, lack of exercise, and drinking patterns. By creating data linkages, we compared their responses during pandemic restrictions to responses they gave prior to the pandemic. OUTCOMES: 367 people provided health risk data. The mean age of the participants was 50.5 (range = 20 to 86, SD ± 15.69) with 51.0% male and 77.4% white British. 47.5% of participants reported taking less physical activity during the pandemic and of those who smoke 54.5% reported smoking more heavily. Self-reported deterioration in physical health was significantly associated with an increase in health risk behaviours (adjusted OR for physical health 1.59, 95%CI 1.22-2.07; adjusted OR for Age 0.99, 95%CI 0.98-1.00). INTERPRETATION: COVID-19 is likely to amplify health inequalities for people with SMI. Health services should target health risk behaviours for people with SMI to mitigate the immediate and long lasting impacts of the COVID-19 pandemic.

Use of the Internet and Digital Devices Among People With Severe Mental Ill Health During the COVID-19 Pandemic Restrictions.

Background: Restrictions due to the COVID-19 pandemic have led to everyday reliance on digitalisation of life, including access to health care services. People with severe mental ill health (SMI-e.g., bipolar or psychosis spectrum disorders) are at greater risk for digital exclusion and it is unknown to what extent they adapted to online service delivery. This study explored use of the Internet and digital devices during the pandemic restrictions and its association with physical and mental health changes. Methods: Three hundred sixty seven adults with an SMI diagnosis completed a survey (online or offline) and provided information on access to Internet connexion and devices, internet knowledge, online activities, and barriers to using the Internet. They also self-reported changes in mental and physical health since the beginning of the pandemic restrictions. Results: During the pandemic restrictions 61.6% were limited or non-users of the Internet. The majority had access to the Internet and digital devices but around half reported knowledge deficits. Most common activities were accessing information and entertainment (88.9%), staying in touch with friends and families (84.8%), and purchasing goods (other than food) (84.3%). Most common barriers were finding the Internet "not interesting" (28.3%) or "too difficult" (27.9%), as well as "security concerns" (22.1-24.3%). Using the Internet "a lot" (vs. "just a bit or not at all") during the pandemic was associated with younger age (18-30: Adj ORs 4.76; 31-45: 6.39; Ps < 0.001; vs. 66+), having a diagnosis of bipolar disorder (compared to psychosis; Adj OR = 3.88, P < 0.001), or reporting a decline in mental health (compared to no decline; Adj OR = 1.92, P = 0.01). Conclusion: Most people with SMI were limited or non-users of the Internet during the pandemic, which seems to be mainly attributable to lack of interest and skills, rather than lack of devices or connectivity. Older adults with psychosis should be the focus of interventions to support digital engagement in people with SMI.

Potent neutralization of SARS-CoV-2 variants of concern by an antibody with an uncommon genetic signature and structural mode of spike recognition.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable challenge to the clinical treatment of coronavirus disease (COVID-19). Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the linking B cell receptor to antigen specificity through sequencing (LIBRA-seq) technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 shows potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryoelectron microscopy (cryo-EM) structure of 54042-4 in complex with the SARS-CoV-2 spike reveals an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses uncommon genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings provide motivation for the development of 54042-4 as a lead candidate to counteract current and future SARS-CoV-2 VOCs.