The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection.

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. CONCLUSIONS: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

The impact of COVID-19 on the motivations of women seeking a uterus transplant.

Aim: The aim of this study was to investigate the change if any, in the motivations of women seeking a UTx and determine the impact of the COVID-19 pandemic. Methods: A cross-sectional survey. Results: 59% of women answered they were more motivated in achieving a pregnancy following the COVID-19 pandemic. 80% strongly agreed or agreed the pandemic had no impact on their motivation for a UTx, and 75% strongly agreed or agreed their desire for a baby strongly outweighs the risks of undergoing a UTx during a pandemic. Conclusion: Women continue to express a high level of motivation and desire for a UTx despite the risks imposed by the COVID-19 pandemic.

Social egg freezing: Motivations, treatment experiences and the impact of Covid-19 - a single-center experience.

INTRODUCTION: This study aims to assess the motivations and treatment experiences of women undergoing social egg freezing and to understand the impact of the Covid-19 pandemic. MATERIAL AND METHODS: Between January 2011 to December 2021, 191 social egg freezing patients were recruited from the Lister Fertility Clinic, London UK. Participants completed a validated questionnaire investigating patients' perspectives of social egg freezing. A response rate of 46.6% was achieved. RESULTS: In all, 93.9% of women expressed concern regarding age-related fertility decline which influenced their decision to undergo social egg freezing. The majority (89.5%) of women were not in a relationship at the time of social egg freezing and considered this a motivating factor. Also, 39.0% of participants had side effects related to treatment which affected work and social life. Participants were significantly more likely to experience side effects if they underwent multiple egg freezing cycles (χ2 , p < 0.01) or if they cryopreserved oocytes during the COVID-19 pandemic (χ2 , p < 0.05). Of the women, 64.0% wished to have cryopreserved oocytes at a younger age, a view significantly more likely if older than 37 years at first social egg freezing cycle (χ2 , p < 0.001). Also, 82.3% of women reported their decision to undergo social egg freezing was not delayed due to concerns regarding COVID-19 exposure during treatment; 44.1% considered the pandemic made them more willing to undergo social egg freezing. CONCLUSIONS: Most participants did not regret their decision to undergo social egg freezing but the majority wished they had cryopreserved oocytes at a younger age. This highlights the importance of early education to optimize outcomes and patient choice. The egg freezing process can be stressful, women may have concerns around social egg freezing and unprecedented situations such as the COVID-19 pandemic may alter treatment experience.

The impact of the COVID-19 pandemic on perinatal services and maternal mental health in the UK.

BACKGROUND: COVID-19 has created many challenges for women in the perinatal phase. This stems from prolonged periods of lockdowns, restricted support networks and media panic, alongside altered healthcare provision. AIMS: We aimed to review the evidence regarding the psychological impact on new and expecting mothers following changes to antenatal and postnatal service provision within the UK throughout the pandemic. METHOD: We conducted a narrative literature search of major databases (PubMed, Medline, Google Scholar). The literature was critically reviewed by experts within the field of antenatal and perinatal mental health. RESULTS: Changes to service provision, including the introduction of telemedicine services, attendance of antenatal appointments without partners or loved ones, and lack of support during the intrapartum period, are associated with increased stress, depression and anxiety. Encouraging women and their partners to engage with aspects of positive psychology through newly introduced digital platforms and virtual service provision has the potential to improve access to holistic care and increase mental well-being. An online course, designed by Imperial College Healthcare NHS Trust in response to changes to service provision, focuses on postnatal recovery inspiration and support for motherhood (PRISM) through a 5-week programme. So far, the course has received positive feedback. CONCLUSIONS: The pandemic has contributed to increased rates of mental illness among pregnant and new mothers in the UK. Although the long-term implications are largely unpredictable, it is important to anticipate increased prevalence and complexity of symptoms, which could be hugely detrimental to an already overburdened National Health Service.

COVID-19 Outcomes and Risk Factors Among People Living with HIV.

PURPOSE OF REVIEW: In this review, we examine the intersection of the HIV and COVID-19 epidemics with focus on COVID-19-related health outcomes and risk factors for SARS-CoV-2 among people living with HIV (PLWH). RECENT FINDINGS: Evidence to date do not suggest a higher incidence of SARS-CoV-2 infection among PLWH compared to the general population, although-once exposed-PLWH are at greater risk of severe COVID-19 outcomes. Key risk factors for severe COVID-19 include non-HIV comorbidities known to be associated with severe disease, as well as HIV-specific risk factors such as low CD4 + T-cell count, unsuppressed viral load, and tuberculosis co-infection. The disproportionate impact of the SARS-CoV-2 pandemic among Black, Latinx, and Native American/Alaskan Native PLWH could worsen pre-existing disparities in health outcomes among PLWH. Data on SARS-CoV-2 vaccine protection among PLWH needs additional study, although some studies suggest decreased humoral responses among those with low CD4 + T-cell counts, while there is a signal of increased vaccine breakthrough rates among PLWH in two large observational cohorts. Data on post-acute sequelae of SARS-CoV-2 (PASC) among PLWH is also limited. PLWH do not have a higher susceptibility to SARS-CoV-2, but once exposed, they are at higher risk of severe COVID-19 outcomes. Additional resources will need to be dedicated to the development of interventions to improve health outcomes and address disparities among PLWH impacted by the COVID-19 pandemic.

Effectiveness and cost-effectiveness of universal school-based mindfulness training compared with normal school provision in reducing risk of mental health problems and promoting well-being in adolescence: the MYRIAD cluster randomised controlled trial.

BACKGROUND: Systematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health. OBJECTIVE: The My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU). METHODS: MYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11-14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included. FINDINGS: Analysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI -0.05 to 0.06) for risk for depression; 0.02 (-0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (-0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed. CONCLUSIONS: Findings do not support the superiority of SBMT over TAU in promoting mental health in adolescence. CLINICAL IMPLICATIONS: There is need to ask what works, for whom and how, as well as considering key contextual and implementation factors. TRIAL REGISTRATION: Current controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z).

A population framework for predicting the proportion of people infected by the far-field airborne transmission of SARS-CoV-2 indoors.

The number of occupants in a space influences the risk of far-field airborne transmission of SARS-CoV-2 because the likelihood of having infectious and susceptible people both correlate with the number of occupants. This paper explores the relationship between occupancy and the probability of infection, and how this affects an individual person and a population of people. Mass-balance and dose-response models determine far-field transmission risks for an individual person and a population of people after sub-dividing a large reference space into 10 identical comparator spaces. For a single infected person, the dose received by an individual person in the comparator space is 10 times higher because the equivalent ventilation rate per infected person is lower when the per capita ventilation rate is preserved. However, accounting for population dispersion, such as the community prevalence of the virus, the probability of an infected person being present and uncertainty in their viral load, shows the transmission probability increases with occupancy and the reference space has a higher transmission risk. Also, far-field transmission is likely to be a rare event that requires a high emission rate, and there are a set of Goldilocks conditions that are just right when equivalent ventilation is effective at mitigating against transmission. These conditions depend on the viral load, because when they are very high or low, equivalent ventilation has little effect on transmission risk. Nevertheless, resilient buildings should deliver the equivalent ventilation rate required by standards as minimum.

Analysis of SARS-CoV-2 in Nasopharyngeal Samples from Patients with COVID-19 Illustrates Population Variation and Diverse Phenotypes, Placing the Growth Properties of Variants of Concern in Context with Other Lineages.

New variants of SARS-CoV-2 are continuing to emerge and dominate the global sequence landscapes. Several variants have been labeled variants of concern (VOCs) because they may have a transmission advantage, increased risk of morbidity and/or mortality, or immune evasion upon a background of prior infection or vaccination. Placing the VOCs in context with the underlying variability of SARS-CoV-2 is essential in understanding virus evolution and selection pressures. Dominant genome sequences and the population genetics of SARS-CoV-2 in nasopharyngeal swabs from hospitalized patients were characterized. Nonsynonymous changes at a minor variant level were identified. These populations were generally preserved when isolates were amplified in cell culture. To place the Alpha, Beta, Delta, and Omicron VOCs in context, their growth was compared to clinical isolates of different lineages from earlier in the pandemic. The data indicated that the growth in cell culture of the Beta variant was more than that of the other variants in Vero E6 cells but not in hACE2-A549 cells. Looking at each time point, Beta grew more than the other VOCs in hACE2-A549 cells at 24 to 48 h postinfection. At 72 h postinfection there was no difference in the growth of any of the variants in either cell line. Overall, this work suggested that exploring the biology of SARS-CoV-2 is complicated by population dynamics and that these need to be considered with new variants. In the context of variation seen in other coronaviruses, the variants currently observed for SARS-CoV-2 are very similar in terms of their clinical spectrum of disease. IMPORTANCE SARS-CoV-2 is the causative agent of COVID-19. The virus has spread across the planet, causing a global pandemic. In common with other coronaviruses, SARS-CoV-2 genomes can become quite diverse as a consequence of replicating inside cells. This has given rise to multiple variants from the original virus that infected humans. These variants may have different properties and in the context of a widespread vaccination program may render vaccines less effective. Our research confirms the degree of genetic diversity of SARS-CoV-2 in patients. By comparing the growth of previous variants to the pattern seen with four variants of concern (VOCs) (Alpha, Beta, Delta, and Omicron), we show that, at least in cells, Beta variant growth exceeds that of Alpha, Delta, and Omicron VOCs at 24 to 48 h in both Vero E6 and hACE2-A549 cells, but by 72 h postinfection, the amount of virus is not different from that of the other VOCs.

Digital haemophilia: Insights into the use of social media for haemophilia care, research and advocacy.

INTRODUCTION: The haemophilia community on Twitter is diverse, consisting of advocacy groups, patients, physicians, researchers and other users. However, the scope of this community is uncharacterized, and limited data is available regarding effective participation in this community. AIM: To assess the types of users active in the haemophilia community on Twitter, as well as major themes present in haemophilia-related tweets. METHODS: Forty-nine thousand five hundred and twelve tweets between September 2019 and September 2021 were classified using regular expressions. A subset of the classified tweets was manually analysed to identify prevalent discussion themes. RESULTS: Among the top 250 users by post count, the largest categories of users were support and advocacy groups, people with bleeding disorders and healthcare providers. The largest thematic categories of tweets were gene therapy, contaminated haemophilia blood products, haemophilia research, clinical management of haemophilia and COVID-19. While misinformation was rare, negative and incorrect perceptions of haemophilia were present among the general public. CONCLUSION: Our results demonstrate patterns of effective Twitter usage for patient care, research and advocacy purposes among the haemophilia community.

Amplicon and Metagenomic Analysis of Middle East Respiratory Syndrome (MERS) Coronavirus and the Microbiome in Patients with Severe MERS.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic infection that emerged in the Middle East in 2012. Symptoms range from mild to severe and include both respiratory and gastrointestinal illnesses. The virus is mainly present in camel populations with occasional zoonotic spill over into humans. The severity of infection in humans is influenced by numerous factors, and similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underlying health complications can play a major role. Currently, MERS-CoV and SARS-CoV-2 are coincident in the Middle East and thus a rapid way of sequencing MERS-CoV to derive genotype information for molecular epidemiology is needed. Additionally, complicating factors in MERS-CoV infections are coinfections that require clinical management. The ability to rapidly characterize these infections would be advantageous. To rapidly sequence MERS-CoV, an amplicon-based approach was developed and coupled to Oxford Nanopore long read length sequencing. This and a metagenomic approach were evaluated with clinical samples from patients with MERS. The data illustrated that whole-genome or near-whole-genome information on MERS-CoV could be rapidly obtained. This approach provided data on both consensus genomes and the presence of minor variants, including deletion mutants. The metagenomic analysis provided information of the background microbiome. The advantage of this approach is that insertions and deletions can be identified, which are the major drivers of genotype change in coronaviruses. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in late 2012 in Saudi Arabia. The virus is a serious threat to people not only in the Middle East but also in the world and has been detected in over 27 countries. MERS-CoV is spreading in the Middle East and neighboring countries, and approximately 35% of reported patients with this virus have died. This is the most severe coronavirus infection so far described. Saudi Arabia is a destination for many millions of people in the world who visit for religious purposes (Umrah and Hajj), and so it is a very vulnerable area, which imposes unique challenges for effective control of this epidemic. The significance of our study is that clinical samples from patients with MERS were used for rapid in-depth sequencing and metagenomic analysis using long read length sequencing.

Evaluation of a primary care-based collaborative care model (PARTNERS2) for people with diagnoses of schizophrenia, bipolar, or other psychoses: study protocol for a cluster randomised controlled trial.

BACKGROUND: Current NHS policy encourages an integrated approach to provision of mental and physical care for individuals with long term mental health problems. The 'PARTNERS2' complex intervention is designed to support individuals with psychosis in a primary care setting. AIM: The trial will evaluate the clinical and cost-effectiveness of the PARTNERS2 intervention. DESIGN & SETTING: This is a cluster randomised controlled superiority trial comparing collaborative care (PARTNERS2) with usual care, with an internal pilot to assess feasibility. The setting will be primary care within four trial recruitment areas: Birmingham & Solihull, Cornwall, Plymouth, and Somerset. GP practices are randomised 1:1 to either (a) the PARTNERS2 intervention plus modified standard care ('intervention'); or (b) standard care only ('control'). METHOD: PARTNERS2 is a flexible, general practice-based, person-centred, coaching-based intervention aimed at addressing mental health, physical health, and social care needs. Two hundred eligible individuals from 39 GP practices are taking part. They were recruited through identification from secondary and primary care databases. The primary hypothesis is quality of life (QOL). Secondary outcomes include: mental wellbeing, time use, recovery, and process of physical care. A process evaluation will assess fidelity of intervention delivery, test hypothesised mechanisms of action, and look for unintended consequences. An economic evaluation will estimate its cost-effectiveness. Intervention delivery and follow-up have been modified during the COVID-19 pandemic. CONCLUSION: The overarching aim is to establish the clinical and cost-effectiveness of the model for adults with a diagnosis of schizophrenia, bipolar, or other types of psychoses.

Modelling uncertainty in the relative risk of exposure to the SARS-CoV-2 virus by airborne aerosol transmission in well mixed indoor air.

We present a mathematical model and a statistical framework to estimate uncertainty in the number of SARS-CoV-2 genome copies deposited in the respiratory tract of a susceptible person, ∑ n , over time in a well mixed indoor space. By relating the predicted median ∑ n for a reference scenario to other locations, a Relative Exposure Index (REI) is established that reduces the need to understand the infection dose probability but is nevertheless a function of space volume, viral emission rate, exposure time, occupant respiratory activity, and room ventilation. A 7  h day in a UK school classroom is used as a reference scenario because its geometry, building services, and occupancy have uniformity and are regulated. The REI is used to highlight types of indoor space, respiratory activity, ventilation provision and other factors that increase the likelihood of far field ( > 2  m) exposure. The classroom reference scenario and an 8  h day in a 20 person office both have an REI ≃ 1 and so are a suitable for comparison with other scenarios. A poorly ventilated classroom (1.2 l s-1 per person) has REI > 2 suggesting that ventilation should be monitored in classrooms to minimise far field aerosol exposure risk. Scenarios involving high aerobic activities or singing have REI > 1 ; a 1  h gym visit has a median REI = 1 . 4 , and the Skagit Choir superspreading event has REI > 12 . Spaces with occupancy activities and exposure times comparable to those of the reference scenario must preserve the reference scenario volume flow rate as a minimum rate to achieve REI = 1 , irrespective of the number of occupants present.

Evaluating the use of telemedicine in gynaecological practice: a systematic review.

OBJECTIVES: The aim of this systematic review is to examine the use of telemedicine in the delivery and teaching of gynaecological clinical practice. To our knowledge, no other systematic review has assessed this broad topic. DESIGN: Systematic review of all studies investigating the use of telemedicine in the provision of gynaecological care and education. The search for eligible studies followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and focused on three online databases: PubMed, Science Direct and SciFinder. ELIGIBILITY CRITERIA: Only studies within gynaecology were considered for this review. Studies covering only obstetrics and with minimal information on gynaecology, or clinical medicine in general were excluded. All English language, peer-reviewed human studies were included. Relevant studies published up to the date of final submission of this review were considered with no restrictions to the publication year. DATA EXTRACTIONS AND SYNTHESIS: Data extracted included author details, year of publication and country of the study, study aim, sample size, methodology, sample characteristics, outcome measures and a summary of findings. Data extraction and qualitative assessment were performed by the first author and crossed checked by the second author. Quality assessment for each study was assessed using the Newcastle-Ottawa scale. RESULTS: A literature search carried out in August 2020 yielded 313 records published between 1992 and 2018. Following a rigorous selection process, only 39 studies were included for this review published between 2000 and 2018. Of these, 19 assessed gynaecological clinical practice, eight assessed gynaecological education, one both, and 11 investigated the feasibility of telemedicine within gynaecological practice. 19 studies were classified as good, 12 fair and eight poor using the Newcastle-Ottawa scale. Telecolposcopy and abortion care were two areas where telemedicine was found to be effective in potentially speeding up diagnosis as well as providing patients with a wide range of management options. Studies focusing on education demonstrated that telementoring could improve teaching in a range of scenarios such as live surgery and international teleconferencing. CONCLUSIONS: The results of this review are promising and demonstrate that telemedicine has a role to play in improving clinical effectiveness and education within gynaecology. Its applications have been shown to be safe and effective in providing remote care and training. In the future, randomised controlled studies involving larger numbers of patients and operators with measurable outcomes are required in order to be able to draw reliable conclusions.

Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Sequencing the viral genome as the outbreak progresses is important, particularly in the identification of emerging isolates with different pathogenic potential and to identify whether nucleotide changes in the genome will impair clinical diagnostic tools such as real-time PCR assays. Although single nucleotide polymorphisms and point mutations occur during the replication of coronaviruses, one of the biggest drivers in genetic change is recombination. This can manifest itself in insertions and/or deletions in the viral genome. Therefore, sequencing strategies that underpin molecular epidemiology and inform virus biology in patients should take these factors into account. A long amplicon/read length-based RT-PCR sequencing approach focused on the Oxford Nanopore MinION/GridION platforms was developed to identify and sequence the SARS-CoV-2 genome in samples from patients with or suspected of COVID-19. The protocol, termed Rapid Sequencing Long Amplicons (RSLAs) used random primers to generate cDNA from RNA purified from a sample from a patient, followed by single or multiplex PCRs to generate longer amplicons of the viral genome. The base protocol was used to identify SARS-CoV-2 in a variety of clinical samples and proved sensitive in identifying viral RNA in samples from patients that had been declared negative using other nucleic acid-based assays (false negative). Sequencing the amplicons revealed that a number of patients had a proportion of viral genomes with deletions.

COVID-19 pandemic: The impact on vulnerable children and young people in Australia.

The COVID-19 pandemic and associated system disruptions are impacting all children and young people (CYP) in Australia. For vulnerable groups of CYP, who already experience poorer health and well-being, these impacts are amplified. Challenges include reduced access to usual services, reduced community supports, financial instability, unemployment and other life circumstances that threaten to widen pre-existing inequities. This article aims to present the reasons for vulnerability of CYP during the pandemic, and to focus on actions by health professionals that mitigate additional challenges to their health and well-being. Using a rapid review of the literature and team-based discussions, eight vulnerable groups were identified: CYP with disabilities, mental health conditions and chronic diseases; CYP facing financial hardship; within the child protection system; Aboriginal; migrant and refugee; in residential care; rural; and isolated CYP. Recommendations for action are required at the level of governments, health professionals and researchers and include enhancing access to health and social supports, prioritising vulnerable CYP in resuming health activity and elevating the voice of CYP in designing the response. The pandemic can be conceptualised as an opportunity to create a more equitable society as we document the inequities that have been exacerbated. Vulnerable groups of CYP must be recognised and heard, and targeted actions must focus on improving their health outcomes during the pandemic and beyond.