Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UK.

BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.

Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

Proof-of-concept: SCENTinel 1.1 rapidly discriminates COVID-19-related olfactory disorders.

It is estimated that 20%-67% of those with COVID-19 develop olfactory disorders, depending on the SARS-CoV-2 variant. However, there is an absence of quick, population-wide olfactory tests to screen for olfactory disorders. The purpose of this study was to provide a proof-of-concept that SCENTinel 1.1, a rapid, inexpensive, population-wide olfactory test, can discriminate between anosmia (total smell loss), hyposmia (reduced sense of smell), parosmia (distorted odor perception), and phantosmia (odor sensation without a source). Participants were mailed a SCENTinel 1.1 test, which measures odor detection, intensity, identification, and pleasantness, using one of 4 possible odors. Those who completed the test (N = 287) were divided into groups based on their self-reported olfactory function: quantitative olfactory disorder only (anosmia or hyposmia, N = 135), qualitative olfactory disorder only (parosmia and/or phantosmia; N = 86), and normosmia (normal sense of smell; N = 66). SCENTinel 1.1 accurately discriminates quantitative olfactory disorders, qualitative olfactory disorders, and normosmia groups. When olfactory disorders were assessed individually, SCENTinel 1.1 discriminates between hyposmia, parosmia, and anosmia. Participants with parosmia rated common odors less pleasant than those without parosmia. We provide proof-of-concept that SCENTinel 1.1, a rapid smell test, can discriminate quantitative and qualitative olfactory disorders, and is the only direct test to rapidly discriminate parosmia.

A population-based matched cohort study of major congenital anomalies following COVID-19 vaccination and SARS-CoV-2 infection.

Evidence on associations between COVID-19 vaccination or SARS-CoV-2 infection and the risk of congenital anomalies is limited. Here we report a national, population-based, matched cohort study using linked electronic health records from Scotland (May 2020-April 2022) to estimate the association between COVID-19 vaccination and, separately, SARS-CoV-2 infection between six weeks pre-conception and 19 weeks and six days gestation and the risk of [1] any major congenital anomaly and [2] any non-genetic major congenital anomaly. Mothers vaccinated in this pregnancy exposure period mostly received an mRNA vaccine (73.7% Pfizer-BioNTech BNT162b2 and 7.9% Moderna mRNA-1273). Of the 6731 babies whose mothers were vaccinated in the pregnancy exposure period, 153 had any anomaly and 120 had a non-genetic anomaly. Primary analyses find no association between any vaccination and any anomaly (adjusted Odds Ratio [aOR] = 1.01, 95% Confidence Interval [CI] = 0.83-1.24) or non-genetic anomalies (aOR = 1.00, 95% CI = 0.81-1.22). Primary analyses also find no association between SARS-CoV-2 infection and any anomaly (aOR = 1.02, 95% CI = 0.66-1.60) or non-genetic anomalies (aOR = 0.94, 95% CI = 0.57-1.54). Findings are robust to sensitivity analyses. These data provide reassurance on the safety of vaccination, in particular mRNA vaccines, just before or in early pregnancy.

Burden of respiratory syncytial virus infection in older and high-risk adults: a systematic review and meta-analysis of the evidence from developed countries.

BACKGROUND: Respiratory syncytial virus (RSV) significantly impacts the health of older and high-risk adults (those with comorbidities). We aimed to synthesise the evidence on RSV disease burden and RSV-related healthcare utilisation in both populations. METHODS: We searched Embase and MEDLINE for papers published between 2000 and 2019 reporting the burden and clinical presentation of symptomatic RSV infection and the associated healthcare utilisation in developed countries in adults aged ≥60 years or at high risk. We calculated pooled estimates using random-effects inverse variance-weighted meta-analysis. RESULTS: 103 out of 3429 articles met the inclusion criteria. Among older adults, RSV caused 4.66% (95% CI 3.34-6.48%) of symptomatic respiratory infections in annual studies and 7.80% (95% CI 5.77-10.45%) in seasonal studies; RSV-related case fatality proportion (CFP) was 8.18% (95% CI 5.54-11.94%). Among high-risk adults, RSV caused 7.03% (95% CI 5.18-9.48%) of symptomatic respiratory infections in annual studies, and 7.69% (95% CI 6.23-9.46%) in seasonal studies; CFP was 9.88% (95% CI 6.66-14.43%). Data paucity impaired the calculation of estimates on population incidence, clinical presentation, severe outcomes and healthcare-related utilisation. CONCLUSIONS: Older and high-risk adults frequently experience symptomatic RSV infection, with appreciable mortality; however, detailed data are lacking. Increased surveillance and research are needed to quantify population-based disease burden and facilitate RSV treatments and vaccine development.

A population-based matched cohort study of early pregnancy outcomes following COVID-19 vaccination and SARS-CoV-2 infection.

Data on the safety of COVID-19 vaccines in early pregnancy are limited. We conducted a national, population-based, matched cohort study assessing associations between COVID-19 vaccination and miscarriage prior to 20 weeks gestation and, separately, ectopic pregnancy. We identified women in Scotland vaccinated between 6 weeks preconception and 19 weeks 6 days gestation (for miscarriage; n = 18,780) or 2 weeks 6 days gestation (for ectopic; n = 10,570). Matched, unvaccinated women from the pre-pandemic and, separately, pandemic periods were used as controls. Here we show no association between vaccination and miscarriage (adjusted Odds Ratio [aOR], pre-pandemic controls = 1.02, 95% Confidence Interval [CI] = 0.96-1.09) or ectopic pregnancy (aOR = 1.13, 95% CI = 0.92-1.38). We undertook additional analyses examining confirmed SARS-CoV-2 infection as the exposure and similarly found no association with miscarriage or ectopic pregnancy. Our findings support current recommendations that vaccination remains the safest way for pregnant women to protect themselves and their babies from COVID-19.

Hepatitis of unknown aetiology in children - epidemiological overview of cases reported in Europe, 1 January to 16 June 2022.

Following the report of an excess in paediatric cases of severe acute hepatitis of unknown aetiology by the United Kingdom (UK) on 5 April 2022, 427 cases were reported from 20 countries in the World Health Organization European Region to the European Surveillance System TESSy from 1 January 2022 to 16 June 2022. Here, we analysed demographic, epidemiological, clinical and microbiological data available in TESSy. Of the reported cases, 77.3% were 5 years or younger and 53.5% had a positive test for adenovirus, 10.4% had a positive RT-PCR for SARS-CoV-2 and 10.3% were coinfected with both pathogens. Cases with adenovirus infections were significantly more likely to be admitted to intensive care or high-dependency units (OR = 2.11; 95% CI: 1.18-3.74) and transplanted (OR = 3.36; 95% CI: 1.19-9.55) than cases with a negative test result for adenovirus, but this was no longer observed when looking at this association separately between the UK and other countries. Aetiological studies are needed to ascertain if adenovirus plays a role in this possible emergence of hepatitis cases in children and, if confirmed, the mechanisms that could be involved.

Proof-of-concept: SCENTinel 1.1 rapidly discriminates COVID-19 related olfactory disorders.

It is estimated that 20-67% of those with COVID-19 develop olfactory disorders, depending on the SARS-CoV-2 variant. However, there is an absence of quick, population-wide olfactory tests to screen for olfactory disorders. The purpose of this study was to provide a proof-of-concept that SCENTinel 1.1, a rapid, inexpensive, population-wide olfactory test, can discriminate between anosmia (total smell loss), hyposmia (reduced sense of smell), parosmia (distorted odor perception), and phantosmia (odor sensation without a source). Participants were mailed a SCENTinel 1.1 test, which measures odor detection, intensity, identification, and pleasantness, using one of four possible odors. Those who completed the test (N = 381) were divided into groups based on their self-reported olfactory function: quantitative olfactory disorder (anosmia or hyposmia, N = 135), qualitative olfactory disorder (parosmia and/or phantosmia; N = 86), and normosmia (normal sense of smell; N = 66). SCENTinel 1.1 accurately discriminates quantitative olfactory disorders, qualitative olfactory disorders, and normosmia groups. When olfactory disorders were assessed individually, SCENTinel 1.1 discriminates between hyposmia, parosmia and anosmia. Participants with parosmia rated common odors less pleasant than those without parosmia. We provide proof-of-concept that SCENTinel 1.1, a rapid smell test, can discriminate quantitative and qualitative olfactory disorders, and is the only direct test to rapidly discriminate parosmia.

Combined data analysis of fossil and living mammals: a Paleogene sister taxon of Placentalia and the antiquity of Marsupialia.

The Cretaceous-Paleogene (KPg) boundary, one of Earth's five major extinction events, occurred just before the appearance of Placentalia in the fossil record. The Gobi Desert, Mongolia and the Western Interior of North America have important fossil mammals occurring just before and after the KPg boundary (e.g. Prodiacodon, Deltatheridium) that have yet to be phylogenetically tested in a character-rich context with molecular data. We present here phylogenetic analyses of >6000 newly scored anatomical observations drawn from six untested fossils and added to the largest existing morphological matrix for mammals. These data are combined with sequence data from 27 nuclear genes. Results show the existence of a new eutherian sister clade to Placentalia, which we name and characterize. The extinct clade Leptictidae is part of this placental sister clade, indicating that the sister clade survived the KPg event to co-exist in ancient ecosystems during the Paleogene radiation of placentals. Analysing the Cretaceous metatherian Deltatheridium in this character-rich context reveals it is a member of Marsupialia, a finding that extends the minimum age of Marsupialia before the KPg boundary. Numerous shared-derived features from multiple anatomical systems support the assignment of Deltatheridium to Marsupialia. Computed tomography scans of exquisite new specimens better document the marsupial-like dental replacement pattern of Deltatheridium. The new placental sister clade has both Asian and North American species, and is ancestrally characterized by shared derived features such as a hind limb modified for saltatorial locomotion.

Association of cerebral venous thrombosis with recent COVID-19 vaccination: case-crossover study using ascertainment through neuroimaging in Scotland.

BACKGROUND: To investigate the association of primary acute cerebral venous thrombosis (CVT) with COVID-19 vaccination through complete ascertainment of all diagnosed CVT in the population of Scotland. METHODS: Case-crossover study comparing cases of CVT recently exposed to vaccination (1-14 days after vaccination) with cases less recently exposed. Cases in Scotland from 1 December 2020 were ascertained through neuroimaging studies up to 17 May 2021 and diagnostic coding of hospital discharges up to 28 April 2021, linked to national vaccination records. The main outcome measure was primary acute CVT. RESULTS: Of 50 primary acute CVT cases, 29 were ascertained only from neuroimaging studies, 2 were ascertained only from hospital discharges, and 19 were ascertained from both sources. Of these 50 cases, 14 had received the Astra-Zeneca ChAdOx1 vaccine and 3 the Pfizer BNT162b2 vaccine. The incidence of CVT per million doses in the first 14 days after vaccination was 2.2 (95% credible interval 0.9 to 4.1) for ChAdOx1 and 1 (95% credible interval 0.1 to 2.9) for BNT162b2. The rate ratio for CVT associated with exposure to ChAdOx1 in the first 14 days compared with exposure 15-84 days after vaccination was 3.2 (95% credible interval 1.1 to 9.5). CONCLUSIONS: These findings support a causal association between CVT and the AstraZeneca vaccine. The absolute risk of post-vaccination CVT in this population-wide study in Scotland was lower than has been reported for populations in Scandinavia and Germany; the explanation for this is not clear.

SCENTinel 1.0: Development of a Rapid Test to Screen for Smell Loss.

Commercially available smell tests are primarily used in research or in-depth clinical evaluations and are too costly and time-consuming for population surveillance in health emergencies like COVID-19. To address this need, we developed the SCENTinel 1.0 test, which rapidly evaluates 3 olfactory functions: detection, intensity, and identification. We tested whether self-administering the SCENTinel 1.0 test discriminates between individuals with self-reported smell loss and those with average smell ability (normosmic individuals) and provides performance comparable to the validated and standardized NIH Toolbox Odor Identification Test in normosmic individuals. Using Bayesian linear models and prognostic classification algorithms, we compared the SCENTinel 1.0 performance of a group of self-reported anosmic individuals (N = 111, 47 ± 13 years old, F = 71%) and normosmic individuals (N = 154, 47 ± 14 years old, F = 74%) as well as individuals reporting other smell disorders (such as hyposmia or parosmia; N = 42, 55 ± 10 years old, F = 67%). Ninety-four percent of normosmic individuals met our SCENTinel 1.0 accuracy criteria compared with only 10% of anosmic individuals and 64% of individuals with other smell disorders. Overall performance on SCENTinel 1.0 predicted belonging to the normosmic group better than identification or detection alone (vs. anosmic: AUC = 0.95, specificity = 0.94). Odor intensity provided the best single-feature predictor to classify normosmic individuals. Among normosmic individuals, 92% met the accuracy criteria at both SCENTinel 1.0 and the NIH Toolbox Odor Identification Test. SCENTinel 1.0 is a practical test able to discriminate individuals with smell loss and will likely be useful in many clinical situations, including COVID-19 symptom screening.

A dense sample of fossil primates (Adapiformes, Notharctidae, Notharctinae) from the Early Eocene Willwood Formation, Wyoming: Documentation of gradual change in tooth area and shape through time.

OBJECTIVES: The Willwood Formation of the southern Bighorn Basin, Wyoming is a fluvial rock sequence that spans approximately 3 million years of early Eocene time. It has yielded one the largest collections of fossil mammals in the world including thousands of dentitions of extinct lemur-like primates known as notharctines. In the southern Bighorn Basin, specimens of these primates have been collected on numerous paleontological expeditions and the stratigraphic levels yielding the dentitions have been carefully recorded. Notharctine dentitions represent a rare opportunity to study morphological variation in a single anatomical system through time among closely related individuals. MATERIALS AND METHODS: Prior studies of Bighorn Basin notharctines through time produced measurements of hundreds of specimens but I report here results from measurement and comparison of the dentitions and dentaries of more than 3,000 specimens, all stratigraphically mapped. RESULTS: Variation in premolar and molar area and variation in dentary depth are apparent throughout the section. Specimens with relatively small teeth and dentaries are known from the older part of the section. In younger rocks, variation in tooth area among specimens increases. Variation in tooth area is continuous and overlaps extensively both within and between stratigraphic levels. Other dental variables examined by inspection change in a mosaic and continuous fashion through the section. These features include variation in the presence and number of paraconids on the lower fourth premolar (p4), the size and shape of the entoconid notch on the lower first and second molars, and the relative development of the pseudohypocone, mesostyle, and cingula on the upper molars. DISCUSSION: These broad patterns can be identified despite notharctine alpha taxonomy being in need of extensive revision and, importantly, simplification. Such revision is beyond the scope of this article but is essential if we are to develop a taxonomy that is both free of stratigraphic influence and useful for rapid, repeatable species assignment. Boundaries among the patterns of tokogenesis, anagenesis, and cladogenesis are blurred in this dense sample of extinct primates. While pattern of evolution, a population-level phenomenon, may be difficult to falsify in the fossil record, this notharctine sample suggests that in the rare instance such as this, when the fossil record is densely sampled, change through time is continuous and more consistent with gradual evolution.

SCENTinel 1.0 : development of a rapid test to screen for smell loss.

BACKGROUND: Commercially available smell tests are primarily used in research or in-depth clinical evaluations, but are too costly and lengthy for population surveillance in health emergencies like COVID-19. We developed the SCENTinel 1 . 0 test which rapidly evaluates three olfactory functions (detection, intensity, and identification). We tested whether self-administering the SCENTinel 1 . 0 test discriminates between individuals with smell loss or average smell ability (normosmics), and provides comparable performance as the validated and standardized NIH Toolbox ® Odor Identification Test in normosmics. METHODS: Using Bayesian linear models and prognostic classification algorithms, we compared the SCENTinel 1 . 0 performance of a group of self-reported anosmics (N=111, 47±13yo, F=71%,) and normosmics (N=154, 47±14yo, F=74%), as well as individuals reporting other smell disorders (e.g., hyposmia, parosmia; N=42, 55±10yo, F=67%). RESULTS: Ninety-four percent of normosmics met our SCENTinel 1 . 0 accuracy criteria, while only 10% of anosmics and 64% of individuals with other smell disorders did. Overall performance on SCENTinel 1 . 0 predicted belonging to the normosmic group better than identification or detection alone (vs. anosmic: AUC=0.95, Sensitivity=0.72, Specificity=0.94). Odor intensity provided the best single-feature predictor to classify normosmics. Among normosmics, 92% met the accuracy criteria at both SCENTinel 1 . 0 and the NIH Toolbox ® Odor Identification Test. CONCLUSIONS: SCENTinel 1 . 0 is a practical test able to discriminate individuals with smell loss and is likely to be useful in many clinical situations, including COVID-19 symptom screening.

Report of the second international conference on next generation sequencing for adventitious virus detection in biologics for humans and animals.

The IABS-EU, in association with PROVAXS and Ghent University, hosted the "2nd Conference on Next Generation Sequencing (NGS) for Adventitious Virus Detection in Human and Veterinary Biologics" held on November 13th and 14th 2019, in Ghent, Belgium. The meeting brought together international experts from regulatory agencies, the biotherapeutics and biologics industries, contract research organizations, and academia, with the goal to develop a scientific consensus on the readiness of NGS for detecting adventitious viruses, and on the use of this technology to supplement or replace/substitute the currently used assays. Participants discussed the progress on the standardization and validation of the technical and bioinformatics steps in NGS for characterization and safety evaluation of biologics, including human and animal vaccines. It was concluded that NGS can be used for the detection of a broad range of viruses, including novel viruses, and therefore can complement, supplement or even replace some of the conventional adventitious virus detection assays. Furthermore, the development of reference viral standards, complete and correctly annotated viral databases, and protocols for the validation and follow-up investigations of NGS signals is necessary to enable broader use of NGS. An international collaborative effort, involving regulatory authorities, industry, academia, and other stakeholders is ongoing toward this goal.

Crowds Replicate Performance of Scientific Experts Scoring Phylogenetic Matrices of Phenotypes.

Scientists building the Tree of Life face an overwhelming challenge to categorize phenotypes (e.g., anatomy, physiology) from millions of living and fossil species. This biodiversity challenge far outstrips the capacities of trained scientific experts. Here we explore whether crowdsourcing can be used to collect matrix data on a large scale with the participation of nonexpert students, or "citizen scientists." Crowdsourcing, or data collection by nonexperts, frequently via the internet, has enabled scientists to tackle some large-scale data collection challenges too massive for individuals or scientific teams alone. The quality of work by nonexpert crowds is, however, often questioned and little data have been collected on how such crowds perform on complex tasks such as phylogenetic character coding. We studied a crowd of over 600 nonexperts and found that they could use images to identify anatomical similarity (hypotheses of homology) with an average accuracy of 82% compared with scores provided by experts in the field. This performance pattern held across the Tree of Life, from protists to vertebrates. We introduce a procedure that predicts the difficulty of each character and that can be used to assign harder characters to experts and easier characters to a nonexpert crowd for scoring. We test this procedure in a controlled experiment comparing crowd scores to those of experts and show that crowds can produce matrices with over 90% of cells scored correctly while reducing the number of cells to be scored by experts by 50%. Preparation time, including image collection and processing, for a crowdsourcing experiment is significant, and does not currently save time of scientific experts overall. However, if innovations in automation or robotics can reduce such effort, then large-scale implementation of our method could greatly increase the collective scientific knowledge of species phenotypes for phylogenetic tree building. For the field of crowdsourcing, we provide a rare study with ground truth, or an experimental control that many studies lack, and contribute new methods on how to coordinate the work of experts and nonexperts. We show that there are important instances in which crowd consensus is not a good proxy for correctness.

Giant taxon-character matrices: the future of morphological systematics.

Simões et al. () argued that large matrices are linked to the construction of "problematic" characters, and that those characters negatively affect tree topology. In their re-evaluation of two squamate datasets, however, Simões et al. () simply eliminated what they termed "problematic" characters, rather than recode them. This practice ignores potential sources of phylogenetic information and, if it were to be more widely followed, would inhibit the advancement of the field of systematics. Here, we defend the necessity and inevitability of large morphological (phenomic) datasets and discuss best practices for morphological data collection in contemporary phylogenetics.