Missed opportunities for pre-exposure prophylaxis (PrEP) and outcomes of people acquiring HIV with previous or recent PrEP use

Background: With NHS PrEP now available for those at risk, we aimed to identify missed opportunities for people newly diagnosed with HIV who attended sexual and reproductive health (SRH) services, and to determine the HIV outcomes associated with people acquiring HIV with previous or recent PrEP use. Method(s): A retrospective observational study reviewed all new HIV diagnoses from the last 2 years to see if they were eligible for PrEP and offered in SRH services. Data was collected using electronic medical records on HIV outcomes - virological suppression, resistance and antiretroviral choice. Result(s): There were 74 new HIV diagnoses. 41 people were eligible but only 10 were known to have accessed PrEP at our services. 21% were heterosexual and of black ethnicity - it was not possible to ascertain whether they were eligible for PrEP from the notes. Of the 10 people with recent PrEP use, 2 stopped due to side effects;headaches, vomiting, fatigue and renal toxicity concerns. For the remaining adherence concerns were reported - taking event based dosing (EBD) incorrectly and difficulty accessing services. 80% of people achieved virological suppression. 90% were put on a second generation integrase or protease inhibitor. No one developed nucleoside reverse transcriptase inhibitor (NRTI) resistance. 6 people eligible for PrEP had attended SRH services but not given PrEP. 2 attended during the IMPACT trial being full and referred to IwantPrEPnow. 2 attended during COVID where baseline bloods were done with follow up but subsequently tested positive. 2 people refused PrEP with 1 deeming themselves to be low risk. Conclusion(s): Our data highlights several missed opportunities for starting same-day PrEP which potentially may have prevented HIV acquisition. If PrEP is not issued on the day, adequate follow up must be ensured. Reassuringly those who acquired HIV with recent PrEP use have achieved good virological control without NRTI mutations. Counselling on potential side effects, EBD dosing and ongoing HIV risk are essential. Despite NHS PrEP available over 2 years, our data shows we are still failing to meet the demand of PrEP not only in men who have sex with men but also in other key at risk groups.

Altered lung physiology in two cohorts after COVID-19 infection as assessed by computed cardiopulmonography.

The longer-term effects of COVID-19 on lung physiology remain poorly understood. Here, a new technique, computed cardiopulmonography (CCP), was used to study two COVID-19 cohorts (MCOVID and C-MORE-LP) at both ∼6 and ∼12 mo after infection. CCP is comprised of two components. The first is collection of highly precise, highly time-resolved measurements of gas exchange with a purpose-built molecular flow sensor based around laser absorption spectroscopy. The second component is estimation of physiological parameters by fitting a cardiopulmonary model to the data set. The measurement protocol involved 7 min of breathing air followed by 5 min of breathing pure O₂. One hundred seventy-eight participants were studied, with 97 returning for a repeat assessment. One hundred twenty-six arterial blood gas samples were drawn from MCOVID participants. For participants who had required intensive care and/or invasive mechanical ventilation, there was a significant increase in anatomical dead space of ∼30 mL and a significant increase in alveolar-to-arterial Po₂ gradient of ∼0.9 kPa relative to control participants. Those who had been hospitalized had reductions in functional residual capacity of ∼15%. Irrespectively of COVID-19 severity, participants who had had COVID-19 demonstrated a modest increase in ventilation inhomogeneity, broadly equivalent to that associated with 15 yr of aging. This study illustrates the capability of CCP to study aspects of lung function not so easily addressed through standard clinical lung function tests. However, without measurements before infection, it is not possible to conclude whether the findings relate to the effects of COVID-19 or whether they constitute risk factors for more serious disease.NEW & NOTEWORTHY This study used a novel technique, computed cardiopulmonography, to study the lungs of patients who have had COVID-19. Depending on severity of infection, there were increases in anatomical dead space, reductions in absolute lung volumes, and increases in ventilation inhomogeneity broadly equivalent to those associated with 15 yr of aging. However, without measurements taken before infection, it is unclear whether the changes result from COVID-19 infection or are risk factors for more severe disease.

Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia.

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.

Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome.

Rationale: The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective: To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods: This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non-COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results: In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions: Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

Globe and Adnexal Trauma Terminology Survey.

Importance: Ocular trauma terminology should be periodically updated to enable comprehensive capturing and monitoring of ocular trauma in clinical and research settings. Objective: To update terminology for globe and adnexal trauma. Design, Setting, and Participants: A 2-round modified Delphi survey was conducted from January 1 to July 31, 2021, using an expert panel, including 69 ophthalmologists identified through their membership in ophthalmology (globe and adnexal trauma) societies. Consensus was defined as at least 67% expert agreement. A steering committee developed questions after identifying gaps in the current terminology via a targeted literature review. Round 1 sought consensus on existing and newly proposed terminology, and round 2 focused on unresolved questions from round 1. Experts included ophthalmologists who had managed, on average, 52 globe or adnexal trauma cases throughout their careers and/or published a total of 5 or more globe or adnexal trauma-related peer-reviewed articles. Main Outcomes and Measures: Expert consensus on ocular and adnexal terms. Results: A total of 69 experts participated in and completed round 1 of the survey. All 69 participants who completed round 1 were asked to complete round 2, and 58 responses were received. Consensus was reached for 18 of 25 questions (72%) in round 1 and 4 of 7 questions (57%) in round 2. Existing Birmingham Eye Trauma Terminology system terminology achieved consensus of 84% (58 of 69 experts) in round 1 and 97% (56 of 58 experts) in round 2. Experts agreed on the need for further refinement of the definition of zones of injury (55 of 69 [80%]), as the zone affected can have a substantial effect on visual and functional outcomes. There was consensus that the mechanism of injury (52 of 69 [75%]) and status of the lacrimal canaliculi (54 of 69 [78%]), nasolacrimal ducts (48 of 69 [69%]), lens (46 of 58 [80%]), retina (42 of 58 [73%]), and central and paracentral cornea (47 of 58 [81%]) be included in the revised terminology. Conclusions and Relevance: There was consensus (defined as at least 67% expert agreement) on continued use of the existing Birmingham Eye Trauma Terminology system definitions and that additional terms are required to update the current ocular trauma terminology.

The Impact of COVID-19 and the Rapid Adoption of Tele health on Provider Burnout in a Pediatric Healthcare Organization

Background: Clinician burnout is a serious problem in healthcare, which could be exacerbated by the consequences of the ongoing global COVID-19 pandemic, including the abrupt shifts in clinical practice (e.g., rapid increase in telehealth services). It is within this context that we conducted a survey of clinicians at a safety-net pediatric hospital to understand how these factors may have affected providers' experiences with and perceptions of burnout. Methods: The brief structured questionnaire was designed by a multidisciplinary team and was sent to all 378 providers at CHOC Children's in June 2020. Questions included demographics, experiences with and perceptions of burnout, and factors that may contribute to or mitigate burnout. After performing descriptive analyses, we used a binomial logistic regression model to test the primary hypotheses of this study: burnout is predicted by both providers' perceptions of the impact of the COVID-19 pandemic and their perceptions of the consequent transition to telehealth. Provider burnout was measured by the statement, “I am experiencing burnout,” with response options on a Likert scale from Strongly agree to Strongly disagree. This was converted to a binary variable for our analyses. Of note, and as others have done, we chose not to use the 22-item validated measure of burnout to avoid over-burdening clinicians. The study was reviewed and approved by the CHOC Institutional Review Board (#200675). Results: Eighty-four providers responded (22%), which is typical for surveys of clinicians. The majority of respondents identified as female (57%). Additionally, 70% of participants were between 35 and 54 years old, with about 10% <35 years and 20% >54 years. Almost all respondents (92%) were married or in a domestic partnership. Approximately 46% of respondents were Specialists, 33% General Pediatricians, and 20% Hospitalists. Fifty-six percent of respondents reported that they were experiencing burnout (N=84). Table 1 summarizes key descriptive results, and Figure 1 presents the results of the multivariable logistic regression model predicting self-reported provider burnout. The data show that, when controlling for the other variables in the model, the self-reported experience of burnout is predicted by three perceptions: COVID-19 has exacerbated provider burnout (p<0.001), the benefits of telehealth do not outweigh the challenges (p=0.045), and there is insufficient institutional support to reduce burnout (p<0.001). We also identified a statistically significant interaction, with those perceiving both sufficient institutional support and telehealth to be beneficial being less likely to report experiencing burnout (p=0.045). Conclusion: Increased institutional support should be provided to clinicians both now, as clinical practice continues to evolve during the COVID-19 pandemic, and more proactively during the inevitable future periods of crisis in an effort to reduce clinician burnout in these difficult times. Future research should assess the effectiveness of different institutional measures on clinician wellbeing.

Enhancing antibody responses by multivalent antigen display on thymus-independent DNA origami scaffolds (preprint)

Multivalent antigen display is a well-established design principle to enhance humoral immunity elicited by subunit vaccines. Protein-based virus-like particles (VLPs) are an important vaccine platform that implements this principle but also contain thymus-dependent off-target epitopes, thereby generating neutralizing and defocused antibody responses against the scaffold itself. Here, we present DNA origami as an alternative platform to display the receptor binding domain (RBD) of SARS-CoV-2. DNA-based scaffolds provide nanoscale control over antigen organization and, as thymus-independent antigens, are expected to induce only extrafollicular B-cell responses. Our icosahedral DNA-based VLPs elicited valency-dependent BCR signaling in two reporter B-cell lines, with corresponding increases in RBD-specific antibody responses following sequential immunization in mice. Mouse sera also neutralized the Wuhan strain of SARS-CoV-2--but did not contain boosted, DNA-specific antibodies. Thus, multivalent display using DNA origami can enhance immunogenicity of protein antigens without generating scaffold-directed immunological memory and may prove useful for rational vaccine design.

SARS-CoV-2 enzyme-linked immunosorbent assays as proxies for plaque reduction neutralisation tests.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread globally since its emergence in 2019. Most SARS-CoV-2 infections generate immune responses leading to rising levels of immunoglobulins (Ig) M, A and G which can be detected using diagnostic tests including enzyme-linked immunosorbent assays (ELISA). Whilst implying previous SARS-CoV-2 infection, the detection of Ig by ELISA does not guarantee the presence of neutralising antibodies (NAb) that can prevent the virus infecting cells. Plaque reduction neutralisation tests (PRNT) detect NAb, but are not amenable to mass testing as they take several days and require use of SARS-CoV-2 in high biocontainment laboratories. We evaluated the ability of IgG and IgM ELISAs targeting SARS-CoV-2 spike subunit 1 receptor binding domain (S1-RBD), and spike subunit 2 (S2) and nucleocapsid protein (NP), at predicting the presence and magnitude of NAb determined by PRNT. IgG S2 + NP ELISA was 96.8% [95% CI 83.8-99.9] sensitive and 88.9% [95% CI 51.8-99.7] specific at predicting the presence of NAbs (PRNT80 > 1:40). IgG and IgM S1-RBD ELISAs correlated with PRNT titre, with higher ELISA results increasing the likelihood of a robust neutralising response. The IgM S1-RBD assay can be used as a rapid, high throughput test to approximate the magnitude of NAb titre.

Presentation, clinical course and complications in trauma patients with concomitant COVID-19 infection.

BACKGROUND: This study investigated the impact of COVID-19 infection on hospitalized trauma patients. METHODS: A retrospective review of hospitalized trauma patients at a level I trauma center was performed from March-December 2020. Data pertaining to patient demographics, presentation and hospital course was compared between COVID positive and negative trauma patients. RESULTS: There were 4,912 patients and 179 (3.64%) were COVID-19 positive. Demographics and clinical presentation did not differ significantly between those with and without concomitant COVID-19. However, COVID positive trauma patients had higher rates of acute kidney injury (p = 0.016), sepsis (p = 0.016), unplanned intubation (p = 0.002) and unplanned return to the ICU (p = 0.01). The COVID positive cohort also had longer hospital stays (p < 0.01) with no significant difference in mortality. CONCLUSIONS: In the setting of an ongoing pandemic, awareness of the complications COVID positive trauma patients are predisposed to is important for providers.

The impact of COVID-19 on ophthalmology resident surgical experience: a retrospective cross-sectional analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused significant disruption to in-office and surgical procedures in the field of ophthalmology. The magnitude of the impact of the pandemic on surgical training among ophthalmology residents is not known. This study aims to quantify changes in average case logs among United States (U.S.) ophthalmology residency graduates prior to and during the COVID-19 pandemic. METHODS: Retrospective, cross-sectional analysis of aggregate, national data on case logs of U.S. ophthalmology residency graduates from 2012 to 2020. The yearly percent change in the average number of procedures performed in the Accreditation Council for Graduate Medical Education (ACGME) ophthalmology resident case logs were analyzed using linear regression on log-transformed dependent variables. The average percent change from 2019 to 2020 was compared to the average yearly percent change from 2012 to 2019 for procedures performed as the primary surgeon, and primary surgeon and surgical assistant (S + A), as well as procedures for which there are ACGME minimum graduating numbers. RESULTS: Across all procedures and roles, average case logs in 2020 were lower than the averages in 2019. While average total cases logged as primary surgeon increased yearly by 3.2% (95% CI: 2.7, 3.8%, p < 0.001) from 2012 to 2019, total primary surgeon case logs decreased by 11.2% from 2019 to 2020. Cataract (-22.0%) and keratorefractive (-21.1%) surgery experienced the greatest percent decrease in average primary surgeon cases logged from 2019 to 2020. Average total cases logged as S + A experienced an average yearly increase by 1.2% (95% CI: 0.9,1.6%, p < 0.001) prior to 2020, but decreased by 9.6% from 2019 to 2020. For ACGME minimum requirements, similar changes were observed. Specifically, the average case logs in YAG, SLT, filtering (glaucoma), and intravitreal injections had been increasing significantly prior to 2020 (p < 0.05 for all) but decreased in 2020. CONCLUSIONS: These findings demonstrate the vulnerability of ophthalmology residency programs to a significant interruption in surgical volume. There is a critical need for development of competency-based, rather than volume-based, requirements to evaluate readiness for independent practice.

SARS-CoV-2 viability on sports equipment is limited, and dependent on material composition.

The control of the COVID-19 pandemic in the UK has necessitated restrictions on amateur and professional sports due to the perceived infection risk to competitors, via direct person to person transmission, or possibly via the surfaces of sports equipment. The sharing of sports equipment such as tennis balls was therefore banned by some sport's governing bodies. We sought to investigate the potential of sporting equipment as transmission vectors of SARS-CoV-2. Ten different types of sporting equipment, including balls from common sports, were inoculated with 40 µl droplets containing clinically relevant concentrations of live SARS-CoV-2 virus. Materials were then swabbed at time points relevant to sports (1, 5, 15, 30, 90 min). The amount of live SARS-CoV-2 recovered at each time point was enumerated using viral plaque assays, and viral decay and half-life was estimated through fitting linear models to log transformed data from each material. At one minute, SARS-CoV-2 virus was recovered in only seven of the ten types of equipment with the low dose inoculum, one at five minutes and none at 15 min. Retrievable virus dropped significantly for all materials tested using the high dose inoculum with mean recovery of virus falling to 0.74% at 1 min, 0.39% at 15 min and 0.003% at 90 min. Viral recovery, predicted decay, and half-life varied between materials with porous surfaces limiting virus transmission. This study shows that there is an exponential reduction in SARS-CoV-2 recoverable from a range of sports equipment after a short time period, and virus is less transferrable from materials such as a tennis ball, red cricket ball and cricket glove. Given this rapid loss of viral load and the fact that transmission requires a significant inoculum to be transferred from equipment to the mucous membranes of another individual it seems unlikely that sports equipment is a major cause for transmission of SARS-CoV-2. These findings have important policy implications in the context of the pandemic and may promote other infection control measures in sports to reduce the risk of SARS-CoV-2 transmission and urge sports equipment manufacturers to identify surfaces that may or may not be likely to retain transferable virus.

International case control study of Sudden Unexpected Death in Epilepsy (SUDEP)

Purpose: To identify factors associated with an increased or decreased risk of SUDEP. Method: The EpiNet study group is undertaking a prospective case-control study, aiming to recruit 200 participants from approximately 40 international centres over four years. Patients with epilepsy from a pre-defined cohort who die of definite or probable SUDEP will be included. Cases must be alive when the cohort is defined. For each case, three true controls and one proxy control will be recruited from the same cohort. A structured telephone interview with the next-of-kin of SUDEP cases will be conducted. Controls will be asked about their epilepsy and lifestyle. Proxy controls will be asked about the control patient they know. Information regarding seizure type and medication, sleeping arrangements, nocturnal supervision, use of seizure-detection devices, socio-economic factors and other health issues will be entered into the EpiNet database. Pathologists' and coroners' data regarding circumstances and cause of death will also be recorded if available. The data will be analysed to identify risk factors for SUDEP. Odds ratios will be calculated using the Mantel-Haenszel method and logistic regression to control for covariates. 200 cases and 800 controls will detect an odds ratio of 1.7 over a control exposure range of 22-65%, with 80% power and 95% confidence level (2-sided). Result: The study is now underway in 8 countries through Asia-Oceania, Europe and North America. COVID-19 has adversely affected case enrolment, and new centres are being sought. Conclusions: SUDEP is second only to stroke as the leading neurological cause of years of potential life lost. The causes remain uncertain. A large prospective case-control study is the best way to determine the extent of the association between specific variables and SUDEP, in particular, those that could be modified to prevent this tragedy. Anyone interested in participating is welcome to contact: epinetadmin@adhb.govt.nz.

Twelve lateral flow immunoassays (LFAs) to detect SARS-CoV-2 antibodies.

BACKGROUND: There are an abundance of commercially available lateral flow assays (LFAs) that detect antibodies to SARS-CoV-2. Whilst these are usually evaluated by the manufacturer, externally performed diagnostic accuracy studies to assess performance are essential. Herein we present an evaluation of 12 LFAs. METHODS: Sera from 100 SARS-CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) positive participants were recruited through the FASTER study. A total of 105 pre-pandemic sera from participants with other infections were included as negative samples. RESULTS: At presentation sensitivity against RT-PCR ranged from 37.4 to 79% for IgM/IgG, 30.3-74% for IgG, and 21.2-67% for IgM. Sensitivity for IgM/IgG improved ≥ 21 days post symptom onset for 10/12 tests. Specificity ranged from 74.3 to 99.1% for IgM/IgG, 82.9-100% for IgG, and 75.2-98% for IgM. Compared to the EuroImmun IgG enzyme-linked immunosorbent assay (ELISA), sensitivity and specificity ranged from 44.6 to 95.4% and 85.4-100%, respectively. CONCLUSION: There are many LFAs available with varied sensitivity and specificity. Understanding the diagnostic accuracy of these tests will be vital as we come to rely more on the antibody status of a person moving forward, and as such manufacturer-independent evaluations are crucial.