Atomically accurate de novo design of single-domain antibodies (preprint)

Despite the central role that antibodies play in modern medicine, there is currently no way to rationally design novel antibodies to bind a specific epitope on a target. Instead, antibody discovery currently involves time-consuming immunization of an animal or library screening approaches. Here we demonstrate that a fine-tuned RFdiffusion network is capable of designing de novo antibody variable heavy chains (VHH's) that bind user-specified epitopes. We experimentally confirm binders to four disease-relevant epitopes, and the cryo-EM structure of a designed VHH bound to influenza hemagglutinin is nearly identical to the design model both in the configuration of the CDR loops and the overall binding pose.

Risk factors for severe COVID-19 outcomes: a study of immune-mediated inflammatory diseases, immunomodulatory medications, and comorbidities in a large US healthcare system (preprint)

Background COVID-19 outcomes, in the context of immune-mediated inflammatory diseases (IMIDs), are incompletely understood. Reported outcomes vary considerably depending on the patient population studied. It is essential to analyse data for a large population, while considering the effects of the pandemic time period, comorbidities, long term use of immunomodulatory medications (IMMs), and vaccination status. Methods In this retrospective case-control study, patients of all ages with IMIDs were identified from a large U.S. healthcare system. COVID-19 infections were identified based on SARS-CoV-2 NAAT test results. Controls without IMIDs were selected from the same database. Severe outcomes were hospitalisation, mechanical ventilation (MV), and death. We analysed data from 1 March 2020 to 30 August 2022, looking separately at both pre-Omicron and Omicron predominant periods. Factors including IMID diagnoses, comorbidities, long term use of IMMs, and vaccination and booster status were analysed using multivariable logistic regression (LR) and extreme gradient boosting (XGB). Findings Out of 2 167 656 patients tested for SARS-CoV-2, there were 290 855 with confirmed COVID-19 infection: 15 397 patients with IMIDs and 275 458 controls (patients without IMIDs). Age and most chronic comorbidities were risk factors for worse outcomes, whereas vaccination and boosters were protective. Patients with IMIDs had higher rates of hospitalisation and mortality compared with controls. However, in multivariable analyses, few IMIDs were rarely risk factors for worse outcomes. Further, asthma, psoriasis and spondyloarthritis were associated with reduced risk. Most IMMs had no significant association, but less frequently used IMM drugs were limited by sample size. XGB outperformed LR, with the AUROCs for models across different time periods and outcomes ranging from 0.77 to 0.92. Interpretation For patients with IMIDs, as for controls, age and comorbidities were risk factors for worse COVID-19 outcomes, whereas vaccinations were protective. Most IMIDs and immunomodulatory therapies were not associated with more severe outcomes. Interestingly, asthma, psoriasis and spondyloarthritis were associated with less severe COVID-19 outcomes than those expected for the population overall. These results can help inform clinical, policy and research decisions. Funding Pfizer, Novartis, Janssen, NIH

Young persons and healthcare professionals experience of virtual gastroenterology consultations: a multicentre survey conducted during the COVID-19 pandemic

ObjectiveTo explore Young Persons (YP) and healthcare professionals (HCP) experiences of virtual consultations (VC) and establish whether developmentally appropriate healthcare can be delivered virtually.MethodYP and HCP questionnaire surveys were designed and piloted. Electronic questionnaire links were sent by post, email or text message January–April 2021 to YP aged 13–25 years old, with predefined chronic gastrointestinal conditions, attending a gastroenterology/hepatology VC. HCP undertaking VC were invited to complete staff questionnaire. Results were anonymous and collated using Excel version 2302.ResultsFive UK hospital trusts participated, with 35 HCP responses. Of the 100 YP completing the survey 66% were female and 34% male aged between 13 years and 25 years (median: 18 years). 13% were new appointments and 87% follow ups, 29% were by video, 69% by phone and 2% gave no response. 80% of HCP spoke to YP directly but not privately (69%). 87% of YP and 88% HCP found VC useful. 83% of YP want VC again, although 20% preferred face to face. 43% of HCP required improved phone/internet connection. 77% of YP required hospital appointments for tests following VC.ConclusionsOverall respondents were satisfied with VC, finding them useful, convenient and time saving. Successful VC rely on appropriate patient selection and availability of reliable technology. Patient preference is key which may alter with time.

An online experimental medicine trial on the effect of 28-day simvastatin administration on emotional processing, reward learning, working memory and salivary cortisol in healthy volunteers at risk for depression: OxSTEP protocol.

BACKGROUND: Evidence suggests inflammation may be a key mechanism by which psychosocial stress, including loneliness, predisposes to depression. Observational and clinical studies have suggested simvastatin, with its anti-inflammatory properties, may have a potential use in the treatment of depression. Previous experimental medicine trials investigating 7-day use of statins showed conflicting results, with simvastatin displaying a more positive effect on emotional processing compared with atorvastatin. It is possible that statins require longer administration in predisposed individuals before showing the expected positive effects on emotional processing. AIMS: Here, we aim to test the neuropsychological effects of 28-day simvastatin administration versus placebo, in healthy volunteers at risk for depression owing to loneliness. METHOD: This is a remote experimental medicine study. One hundred participants across the UK will be recruited and randomised to either 28-day 20 mg simvastatin or placebo in a double-blind fashion. Before and after administration, participants will complete an online testing session involving tasks of emotional processing and reward learning, processes related to vulnerability to depression. Working memory will also be assessed and waking salivary cortisol samples will be collected. The primary outcome will be accuracy in identifying emotions in a facial expression recognition task, comparing the two groups across time.

The COVID Psychosocial Impacts Scale: A Reliable and Valid Tool to Examine the Psychosocial Impacts of the COVID-19 Pandemic.

This paper reports on the development and validation of the COVID Psychosocial Impacts Scale (CPIS), a self-report measure that comprehensively examines both positive and negative psychosocial impacts from the COVID-19 pandemic. This is the first part of the program of work in which the CPIS was administered and compared with a measure of psychological distress (Kessler Psychological Distress Scale, K-10) and wellbeing (World Health Organization Well-Being Index, WHO-5). The data were obtained online in 2020 and 2022 at two distinct time points to capture different exposures to the pandemic in the New Zealand population to a non-representative sample of 663 and 687 adults, respectively. Two hundred seventy-one participants took part in both surveys. Findings indicate a unidimensional structure within CPIS subscales and inter-relatedness among CPIS stress-related subscales. The scatter plots and correlation matrix indicate CPIS having a positive moderate correlation with K10 and a negative moderate correlation with WHO-5, indicative of construct validity. The paper outlines contextual factors surrounding CPIS development and makes suggestions for future iterations of CPIS. Further work will examine its psychometric properties across cultures.

High rates of SARS-CoV-2 infection in pregnant Ugandan women and association with stunting in infancy (preprint)

Background: SARS-CoV-2 has been well studied in resource-rich areas but many questions remain about effects of infection in African populations, particularly in vulnerable groups such as pregnant women. Methods: We describe SARS-CoV-2 immunoglobulin (Ig) G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in Uganda. Results: From December 2020 to February 2022, among 400 unvaccinated pregnant women, serologic assessments revealed that 128 (32%) were seronegative for anti-SARS-CoV-2 IgG and IgM at enrollment and delivery, 80 (20%) were infected either prior to or early in pregnancy, and 192 (48%) were infected or re-infected with SARS-CoV-2 during pregnancy. We observed preferential binding of plasma IgG to Wuhan-Hu-1-like antigens in individuals seroconverting up to early 2021, and to Delta variant antigens in a subset of individuals in mid-2021. Breadth of IgG binding to all variants improved over time. No participants experienced severe respiratory illness during the study. SARS-CoV-2 infection in early pregnancy was associated with lower median length-for-age Z-score at age 3 months compared with no infection or late pregnancy infection (-1.54 versus -0.37 and -0.51, p=0.009). Conclusion: Pregnant Ugandan women experienced high levels of SARS-CoV-2 infection without severe respiratory illness. Variant-specific serology testing demonstrated evidence of antibody affinity maturation at the population level. Early gestational SARS-CoV-2 infection was associated with shorter stature in early infancy.

Prevalence of SARS-CoV-2 Viremia in Presymptomatic Blood Donors in the Delta and Omicron Variant Eras.

Presymptomatic plasma samples from 1596 donors reporting coronavirus disease 2019 infection or symptoms after blood donation were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and anti-S and anti-N antibodies. Prior infection and vaccination both protected from developing SARS-CoV-2 RNAemia and from symptomatic infection. RNAemia rates did not differ in the Delta and Omicron variant eras.

Antibodies in healthcare personnel following severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection.

In a prospective cohort of healthcare personnel (HCP), we measured severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) nucleocapsid IgG antibodies after SARS-CoV-2 infection. Among 79 HCP, 68 (86%) were seropositive 14-28 days after their positive PCR test, and 54 (77%) of 70 were seropositive at the 70-180-day follow-up. Many seropositive HCP (95%) experienced an antibody decline by the second visit.

Ethnic and gender trends at the annual British Association of Urological Surgeons (BAUS) meeting: A review of BAUS programmes over a 13-year period (2009-2021)

Objective: In this paper, we wanted to review the annual British Association of Urological Surgeons (BAUS) programme to analyse the female and ethnic minority (EM) representation and find out whether there is ethnic and gender disparity, and if it does reflect the reality of the workforce. Method(s): To investigate gender and EM representation, we requested data for BAUS annual meetings over a 13-year period (2009-2021). All speakers and chairpersons for all four sub-sections including Endourology, Oncology, Andrology and Female, Neurological and Urodynamic urology (FNUU) were collated. We also looked at the geographic distribution of the speakers (London area, rest of England, Scotland, Northern Ireland and Wales). Data were analysed separately before and after the COVID-19 pandemic (cut-off March 2020), as in the latter 2 years, the meeting was held virtually. Result(s): A total of 2569 speakers (range: 135-323 speakers/year) were included in our analysis and 2187 (85%) speakers were from the United Kingdom. Of the UK speakers, more than three-quarters (76.6%, n = 1676) were males and females of White ethnicity and (23.4%, n = 511) were EM. The vast majority of speakers throughout the years were males (86%, n = 1891) with only 14% (n = 296) females regardless of their origin and ethnicity. The presence of EM females was only 1.9% (n = 43). The percentage of female representation rose consistently over time from 6.7% (n = 8) in 2009 to 21.1% (n = 44) in 2020, suggesting an upward trend. Regional distribution showed 31%, 63%, 3.6%, 1.6% and 0.2% from London, Rest of England, Scotland, Wales and Northern Ireland, respectively. Both gender and EM representation doubled in the last 2 years during the pandemic (p < 0.001). Conclusion(s): Annual BAUS meetings have seen a higher proportion of ethnic and gender representation in recent years. However, considering the workforce within urology, more needs to be done to address this historical disparity. Hopefully, the BAUS 10-point programme will provide a framework for addressing Equality, Diversity and Inclusion issues related to this bias. Level of Evidence: Not applicable.Copyright © British Association of Urological Surgeons 2022.

Singing for people with advance chronic respiratory diseases: Qualitative meta-synthesis

Introduction/Aim: Although there remains insufficient evidence regarding singing programs as effective strategies for achieving clinically significant health outcomes, this non-pharmacological intervention appears to be subjectively low-risk and well-tolerated by people with advanced chronic respiratory diseases (CRD). Method(s): A meta-synthesis was undertaken to examine the current qualitative evidence regarding the experiences of singing for lung health programs in adults with advanced CRD and their careers. Electronic databases (Medline, CINAHL, PsycINFO, and EMBASE) were searched for qualitative studies published in English. Qualitative data was extracted and analysed, which generated descriptive and analytical themes. Result(s): Themes identified from seven included studies consisted of anticipation and reluctance to participate;physical and psychological benefits;new sense of purpose and enjoyment;social connection and achievement;and broad views regarding program structure and content. The themes were categorised into three time points to explore participants' perspectives before, during and after engaging in the singing program. Over time participants transitioned from anxiety to mastery of their chronic condition as the singing program progressed. Participants, however, raised concerns regarding several singing technicalities, the lack of ongoing support after the singing programs' conclusion and the social impacts of transitioning the sessions online during the COVID-19 pandemic. Conclusion(s): The increasing body of qualitative literature suggests that participants enjoyed the singing program and derived psychological, social and health benefits, not necessarily captured in quantitative studies. Future work should explore participants' experiences through qualitative, longitudinal methods to gain further insight into the acceptability and feasibility of singing programs and inform broader implementation of the intervention.

The Suicidal Ideation Attributes Scale-Modified (SIDAS-M): Development and preliminary validation of a new scale for the measurement of suicidal ideation in autistic adults.

LAY ABSTRACT: Autistic people may be at higher risk of suicidal behavior than people in the general population. Suicidal behavior may include thinking about suicide or attempting to end one's own life by suicide. It is important to identify autistic people who may be thinking about suicide. People who are at risk of suicidal behavior can be identified by asking questions about whether they have been thinking about suicide. A specially designed questionnaire, or screening instrument, can help someone ask the best questions to find out if someone has been thinking about suicide. This information can help to identify supports to be put in place to prevent suicidal behavior, such as a suicide attempt. However, autistic people may interpret questions differently than non-autistic people. It is important to use screening tools that have been designed with, and for autistic people. In this study, we examined the Suicidal Ideation Attributes Scale (SIDAS). The SIDAS is an existing tool that was developed to screen for suicidal thinking in the general population. We modified SIDAS for use with autistic adults. We involved autistic people in the process of modifying SIDAS. We called the modified instrument the SIDAS-M. The results of our study showed SIDAS-M may be useful for screening for suicidal thinking in autistic adults who do not have an intellectual disability.

Identifying key leadership competencies for digital transformation: evidence from a cross-sectoral Delphi study of global managers

Purpose - Even with the recognized impact organizational leaders have on the outcome of digital transformation (DT), a comprehensive scholarly understanding of the competencies that leaders must possess to lead a DT to success is lacking. Design/methodology/approach - To derive and list the competencies considered by experts as necessary for managing DT, the authors recruited 18 international senior managers with relevant experience and applied the Delphi method to survey the managers. Upon the completion of three survey rounds and the authors modifying the response list until consensus was reached, 39 items were shortlisted as constituting key competencies for managing DT. Furthermore, the authors engaged in inductive theorizing to derive propositional statements using these findings.Findings - The practitioners agreed on visionary thinking, agility, understanding the value of data, data-driven decision-making, knowledge of strategy and accepting change as the most important requirements for managing DT. Through inductive theorizing, the authors further derived that the seven discovered clusters fell into two broader competencies - behavioral and strategic - and that each behavioral competency would have varying importance depending on the country and industry that the organization operates in.Research limitations/implications - As is typical for Delphi studies that involve multiple survey rounds, the study participant response rate was moderate. The implications of this study, in finding that a variety of leadership competencies are needed to ensure successful DT, validate prior research that people, not technology, drive DT.Practical implications - This study helps mitigate assumptions that successful DT processes are only possible by hiring technological experts, as doing so highlights the importance of behavioral leadership competencies.Originality/value - The study is one of the first to interlink digital leadership with DT by inductively theorizing behavioral and strategic competencies. The authors also establish that contexts are vital in determining which aspects of leadership competencies are deemed most important in driving DT.

Examining the psychosocial impacts of the COVID-19 pandemic: an international cross-sectional study protocol.

INTRODUCTION: The COVID-19 pandemic exposed people to significant and prolonged stress. The psychosocial impacts of the pandemic have been well recognised and reported in high-income countries (HICs) but it is important to understand the unique challenges posed by COVID-19 in low- and middle-income countries (LMICs) where limited international comparisons have been undertaken. This protocol was therefore devised to study the psychosocial impacts of the COVID-19 pandemic in seven LMICs using scales that had been designed for or translated for this purpose. METHODS AND ANALYSIS: This cross-sectional study uses an online survey to administer a novel COVID Psychosocial Impacts Scale (CPIS) alongside established measures of psychological distress, post-traumatic stress, well-being and post-traumatic growth in the appropriate language. Participants will include adults aged 18 years and above, recruited from Indonesia, Iraq, Iran, Malaysia, Pakistan, Somalia and Turkey, with a pragmatic target sample size of 500 in each country.Data will be analysed descriptively on sociodemographic and study variables. In addition, CPIS will be analysed psychometrically (for reliability and validity) to assess the suitability of use in a given context. Finally, within-subjects and between-subjects analyses will be carried out using multi-level mixed-effect models to examine associations between key sociodemographic and study variables. ETHICS AND DISSEMINATION: Ethical approval was granted by the Human Ethics Committee, University of Otago, New Zealand (Ref. No. 21/102). In addition, international collaborators obtained local authorisation or ethical approval in their respective host universities before data collection commenced.Participants will give informed consent before taking part. Data will be collected and stored securely on the University of Otago, New Zealand Qualtrics platform using an auto-generated non-identifiable letter-number string. Data will be available on reasonable request. Findings will be disseminated by publications in scientific journals and/or conference presentations. TRIAL REGISTRATION NUMBER: NCT05052333.

Understanding Australian Government Risk Communication Early in the COVID-19 Pandemic: Sociodemographics, Risk Attitudes and Media Consumption.

Effective risk communication is essential for government and health authorities to effectively manage public health during the Coronavirus disease (COVID-19) pandemic. Understanding the factors that influence people's perceptions of crisis-related risk messages is critical to identify gaps and inequalities in population risk communication. Using a longitudinal survey of a representative adult sample, we examined risk communication about COVID-19 during April-June 2020 in Australia across sociodemographic groups especially the at-risk groups, accounting for and exploring the effects of risk attitudes and media engagement. Our findings showed that individuals who were younger, more left-wing, more risk-tolerant, and had a current or a history of mental disorders perceived risk communication of the Australian Government to be lower quality. On the other hand, greater consumption of information from televisions was found to be associated with more positive attitudes toward government risk communication. Our results also revealed the importance of effective and high-quality risk communication in gaining the public endorsement of various public health directions. We discuss the implications of results in terms of the development of effective public communications that lead to health-protective behaviors and effectively scaffold public understanding of risk.

Classification of Covid-19 Vaccines tweets using Naïve Bayes Classification

Recently COVID-19 has become the most discussed topic in different social media platforms like Twitter, Facebook, Instagram etc. As time moves on, lot of messages and videos are posted in social media. As expected, most of the public followed these messages and becomes panic because of lack of information, misinformation about COVID-19 and its impact. This research study proposes a Twitter sentiment analysisbased on the most popular vaccines Covaxin, Covishield, and Pfizer. Most of the people expressed their feelings about vaccines in the twitter. Twitter API authentication is used here to extract the tweets. These extracted tweets are difficult to analyze, hence pre-processing has been done i.e., unstructured data is converted into structured format. After completion of preprocessing, the data is further classified by using Naïve Bayes algorithm. This algorithm performs data classification and divides it into three major classes as positive, negative, and neutral. The result shows that the covaxin yields 48.36% positive, 35.6% negative, and 16.04% neutral, Covishield yields 44.25% positive, 39.67% negative, and 16.08% neutral, Pfizer yields 42.95% positive, 39.45% negative, and 17.6% neutral sentiment. © 2022 IEEE.

Heart Transplantation from COVID-19 Positive Donors. A word of caution

Background During the COVID-19 pandemic, efforts to maintain solid-organ transplantation have continued, including the use of SARS-CoV-2 positive heart donors. Methods We present our institution's initial experience with SARS-CoV-2 positive heart donors. All donors met our institution's Transplant Center criteria, including a negative bronchoalveolar lavage (BAL) PCR result. All but one patient received postexposure prophylaxis (PEP) with anti-spike monoclonal antibody therapy, remdesivir, or both. Results A total of 6 patients received a heart transplant from a SARS-CoV-2 positive donor. One heart transplant was complicated by catastrophic secondary graft dysfunction requiring venoarterial extracorporeal membrane oxygenation and retransplant. The remaining five patients did well postoperatively and were discharged home. None of the patients had evidence of COVID-19 infection after surgery. Conclusion Heart transplants from SARS-CoV-2 PCR positive donors are feasible and safe with adequate screening and PEP.

County-level societal predictors of COVID-19 cases and deaths changed through time in the United States: A longitudinal ecological study

People of different racial/ethnic backgrounds, demographics, health, and socioeconomic characteristics have experienced disproportionate rates of infection and death due to COVID-19. This study tests if and how county-level rates of infection and death have changed in relation to societal county characteristics through time as the pandemic progressed. This longitudinal study sampled monthly county-level COVID-19 case and death data per 100,000 residents from April 2020 to March 2022, and studied the relationships of these variables with racial/ethnic, demographic, health, and socioeconomic characteristics for 3125 or 97.0% of U.S. counties, accounting for 96.4% of the U.S. population. The association of all county-level characteristics with COVID-19 case and death rates changed significantly through time, and showed different patterns. For example, counties with higher population proportions of Black, Native American, foreign-born non-citizen, elderly residents, households in poverty, or higher income inequality suffered disproportionately higher COVID-19 case and death rates at the beginning of the pandemic, followed by reversed, attenuated or fluctuating patterns, depending on the variable. Patterns for counties with higher White versus Black population proportions showed somewhat inverse patterns. Counties with higher female population proportions initially had lower case rates but higher death rates, and case and death rates become more coupled and fluctuated later in the pandemic. Counties with higher population densities had fluctuating case and death rates, with peaks coinciding with new variants of COVID-19. Counties with a greater proportion of university-educated residents had lower case and death rates throughout the pandemic, although the strength of this relationship fluctuated through time. This research clearly shows that how different segments of society are affected by a pandemic changes through time. Therefore, targeted policies and interventions that change as a pandemic unfolds are necessary to mitigate its disproportionate effects on vulnerable populations, particularly during the first six months of a pandemic.

Multiple measures of structural racism as predictors of U.S. county-level COVID-19 cases and deaths

Minoritized racial groups in the U.S. have experienced disproportionately higher rates of COVID-19 cases and deaths. Studies have linked structural racism as a critical factor causing these disproportionate health burdens. We analyse the relationships between county-level COVID-19 cases and deaths and five measures of structural racism on Black Americans: Black–White residential segregation, differences in educational attainment, unemployment, incarceration rates, and health insurance coverage between Black and White Americans. When controlling for socioeconomic, demographic, health and behavioural factors significant relationships were found between all measures of structural racism with cases and/or deaths except Black–White differences in health insurance coverage. Black–White disparities in educational attainment and incarceration were the strongest predictors. The results varied greatly across regions of the U.S. We also found strong relationships between COVID-19 and mobility and the proportion of foreign-born non-citizens. This work supports the important need to confront structural racism on multiple fronts to address health disparities.