Sporadic Creutzfeldt-Jakob disease in adults over 80 years: a 10-year review of United Kingdom surveillance.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease with public health implications. Mean age of onset is 68 years. Age-specific incidence declines after 80 years. This may arise from under-ascertainment or other biological features of the disease. Accurate characterisation of late-onset sCJD is important for early diagnosis, avoiding unnecessary investigations and improving ascertainment for public health purposes. OBJECTIVE: To phenotype the clinical features and investigation profile of sCJD in adults >80 years. METHODS: We analysed all probable and definite sCJD cases identified by the UK National CJD Research & Surveillance Unit over a 10-year period (2011-2021). Individuals were grouped by age of onset. Clinical features and investigation profiles were compared. RESULTS: 10.3% (123/1196) had an age of onset over 80. Median survival was shorter (3.2 vs 4.3 months; P < 0.001). Pyramidal signs (48.3% vs 34.2%; P = 0.008) and akinetic mutism (55.1% vs 33.2%; P < 0.001) were more frequent. Psychiatric symptoms (26.3% vs 39.6%; P = 0.01) and cerebellar signs (65.4% vs 78.6%, P = 0.007) were less frequent. Cognitive impairment and myoclonus were highly prevalent regardless of age. Between age groups, the diagnostic sensitivity of cerebrospinal fluid real-time quaking-induced conversion (CSF RT-QuIC) (92.9% vs 91.9%, P = 0.74) was comparable, electroencephalography was superior (41.5% vs 25.4%; P = 0.006) and MRI was inferior (67.8% vs 91.4%; P < 0.001). CONCLUSIONS: Late-onset sCJD has distinct clinical features, shorter survival and a different profile of investigation sensitivity. CSF RT-QuIC, MRI brain and specialist CJD review is recommended in older adults with a rapidly progressive neurological disorder. Autopsy is valuable when the cause remains elusive.

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme.

INTRODUCTION: Incorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients. METHODS: 250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC. RESULTS: 27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative. CONCLUSIONS: Individuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

Microbial production of the plant flavanone hesperetin from caffeic acid.

OBJECTIVE: Hesperetin is an important O-methylated flavonoid produced by citrus fruits and of potential pharmaceutical relevance. The microbial biosynthesis of hesperetin could be a viable alternative to plant extraction, as plant extracts often yield complex mixtures of different flavonoids making it challenging to isolate pure compounds. In this study, hesperetin was produced from caffeic acid in the microbial host Escherichia coli. We combined a previously optimised pathway for the biosynthesis of the intermediate flavanone eriodictyol with a combinatorial library of plasmids expressing three candidate flavonoid O-methyltransferases. Moreover, we endeavoured to improve the position specificity of CCoAOMT7, a flavonoid O-methyltransferase from Arabidopsis thaliana that has been demonstrated to O-methylate eriodictyol in both the para- and meta-position, thus leading to a mixture of hesperetin and homoeriodictyol. RESULTS: The best performing flavonoid O-methyltransferase in our screen was found to be CCoAOMT7, which could produce up to 14.6 mg/L hesperetin and 3.8 mg/L homoeriodictyol from 3 mM caffeic acid in E. coli 5-alpha. Using a platform for enzyme engineering that scans the mutational space of selected key positions, predicting their structures using homology modelling and inferring their potential catalytic improvement using docking simulations, we were able to identify a CCoAOMT7 mutant with a two-fold higher position specificity for hesperetin. The mutant's catalytic activity, however, was considerably diminished. Our findings suggest that hesperetin can be created from central carbon metabolism in E. coli following the introduction of a caffeic acid biosynthesis pathway.

Sustainable reference points for multispecies coral reef fisheries.

Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to lack research and monitoring capacity, preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for >2000 coral reefs, we estimate site-specific sustainable reference points for coral reef fisheries and use these and available catch estimates to assess the status of global coral reef fish stocks. We reveal that >50% of sites and jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the world's coral reef fisheries.

Conservation of vCJD Strain Properties After Extraction and In Vitro Propagation of PrPSc from Archived Formalin-Fixed Brain and Appendix Tissues Using Highly Sensitive Protein Misfolding Cyclic Amplification.

Three retrospective lymphoreticular tissue studies (Appendix I, II, and III) aimed to estimate the UK prevalence of variant Creutzfeldt-Jakob disease (vCJD), following exposure of the population to the bovine spongiform encephalopathy (BSE) agent, in the late 1980s and 1990s. These studies evaluated the presence of abnormal prion protein aggregates, in archived formalin-fixed paraffin-embedded (FFPE) appendectomy samples, by immunohistochemical detection. Although there was concordance in the estimated prevalence of vCJD from these studies, the identification of positive specimens from pre- and post-BSE-exposure periods in Appendix III study has raised questions regarding the nature and origin of the detected abnormal prion protein. We applied a robust and novel approach in the extraction of disease-associated prion protein (PrPSc) present in frozen and FFPE samples of brain and appendix from a patient with pathologically confirmed vCJD. The extracted material was used to seed the highly sensitive protein misfolding cyclic amplification assay (hsPMCA) to investigate the in vitro and in vivo propagation properties of the extracted abnormal prion protein. We demonstrate that PrPSc can be successfully extracted from FFPE appendix tissue and propagated in vitro. Bioassay in wild-type and gene-targeted mouse models confirmed that the extracted and amplified product is infectious and retains strain properties consistent with vCJD. This provides a highly sensitive and reliable platform for subsequent analysis of the archived FFPE appendix tissue derived from the Appendix II and III surveys, to further evaluate the nature of the abnormal PrP detected in the positive samples.

Improved Real-Time Quaking Induced Conversion for Early Diagnostics of Creutzfeldt-Jakob Disease in Denmark.

Cerebrospinal fluid-based real-time quaking-induced conversion (CSF RT-QuIC) is currently the most prominent method for early detection of sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disease. CSF RT-QuIC delivers high sensitivity (>90%) and specificity (100%), which has been demonstrated by large ring-trial studies testing probable and definitive sCJD cohorts. Following the inclusion of CSF RT-QuIC in the revised European CJD Surveillance Network diagnostic criteria for sCJD, it has become a standard diagnostic procedure in many prion disease reference or surveillance centers around the world. In this study, we present the implementation of the second-generation CSF RT-QuIC (commonly known as Improved QuIC or IQ) at the Danish Reference Center for Prion Diseases (DRCPD). The method's sensitivity and specificity were evaluated and validated by analyzing 63 CSF samples. These 63 samples were also analyzed at the National CJD Research and Surveillance Unit (NCJDRSU), based at the University of Edinburgh, UK; analysis was carried out using the first generation or previous CSF RT-QuIC method (PQ). The sensitivity and specificity of PQ during tests at the NCJDRSU were 92% and 100%, respectively. Using these 63 CSF samples, the agreement between the two RT-QuIC generations at DRCPD and NCJDRSU prion laboratories was 100%.

Sporadic Creutzfeldt-Jakob Disease in the young (50 and below): 10-year review of United Kingdom surveillance.

INTRODUCTION: Sporadic Creutzfeldt-Jakob Disease (sCJD) is the commonest human prion disease, with a median age of onset of 68 years. We characterise the clinical, investigation, and neuropathological features in young individuals with sCJD using data from UK national CJD surveillance. METHODS: Referrals between 2011 and 2021 were examined, with definite (post-mortem confirmed) or probable sCJD cases included. Clinical features, MRI, EEG, CSF RT-QuIC, 14-3-3, PRNP sequencing and neuropathological findings were examined. We compared younger (≤ 50 years age of onset) with older individuals. Records of Non-sCJD referrals were also reviewed. RESULTS: 46 (4%) young individuals were identified (age at onset 25-50) from 1178 cases. 15 (33%) were autopsy confirmed. Psychiatric disturbance (37% vs 22%, p = 0.02) and headache (11% vs 3%, p = 0.01) at presentation, and longer disease duration (by 1.45 months, 95% CI 0.43-2.79, logrank p = 0.007) were commoner. CSF RT-QuIC showed lower sensitivity (82% vs 93%, p = 0.02). There was no difference in sensitivity of MR brain or CSF 14-3-3. There were no significant co-pathologies in autopsy-confirmed cases. For non-sCJD referrals, 41 cases were of other CJD subtypes, and 7 non-prion diagnoses. CONCLUSIONS: Young-onset sCJD is more likely to present with neuropsychiatric symptoms and headache, longer disease duration, and lower sensitivity of RT-QuIC. These findings may be driven by the underlying molecular subtypes. Our results guide the evaluation of younger individuals presenting with rapidly progressive cognitive, neuropsychiatric, and motor decline, and emphasise the need for additional vigilance for atypical features by clinicians and CJD surveillance programmes worldwide.

Brain and Cerebrospinal Fluid α-Synuclein Real-Time Quaking-Induced Conversion Identifies Lewy Body Pathology in LRRK2-PD.

BACKGROUND: The neuropathology of Parkinson's disease (PD) associated with leucine-rich repeat kinase 2 (LRRK2) mutations (LRRK2-PD) is heterogeneous and varies with the type of mutation. There are only a few studies evaluating seeding aggregation assays to detect α-synuclein (α-syn) in patients with LRRK2-PD. OBJECTIVE: We aimed to investigate whether α-syn real-time quaking induced conversion (RT-QuIC) is a sensitive biomarker of synucleinopathy in LRRK2-PD. METHODS: We studied α-syn RT-QuIC in brain tissue and postmortem ventricular cerebrospinal fluid (CSF) of LRRK2-PD cases with and without Lewy-type pathology. RESULTS: The accuracy of α-syn RT-QuIC in substantia nigra and CSF samples of patients with LRRK2-PD was 100%. The test also obtained 100% sensitivity to detect misfolded α-syn in substantia nigra of cases with idiopathic PD and was negative in the substantia nigra of all the control brains without Lewy-type pathology. CONCLUSIONS: Substantia nigra and ventricular CSF RT-QuIC discriminates with high sensitivity and specificity LRRK2 cases with Lewy-type pathology from those without it. RT-QuIC assay could be of particular interest in the selection of cases for clinical trials in this genetic form of PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A functional vulnerability framework for biodiversity conservation.

Setting appropriate conservation strategies in a multi-threat world is a challenging goal, especially because of natural complexity and budget limitations that prevent effective management of all ecosystems. Safeguarding the most threatened ecosystems requires accurate and integrative quantification of their vulnerability and their functioning, particularly the potential loss of species trait diversity which imperils their functioning. However, the magnitude of threats and associated biological responses both have high uncertainties. Additionally, a major difficulty is the recurrent lack of reference conditions for a fair and operational measurement of vulnerability. Here, we present a functional vulnerability framework that incorporates uncertainty and reference conditions into a generalizable tool. Through in silico simulations of disturbances, our framework allows us to quantify the vulnerability of communities to a wide range of threats. We demonstrate the relevance and operationality of our framework, and its global, scalable and quantitative comparability, through three case studies on marine fishes and mammals. We show that functional vulnerability has marked geographic and temporal patterns. We underline contrasting contributions of species richness and functional redundancy to the level of vulnerability among case studies, indicating that our integrative assessment can also identify the drivers of vulnerability in a world where uncertainty is omnipresent.

'Things we are expected to just do and deal with': Using the medical humanities to encourage reflection on vulnerability and nurture clinical skills, collegiality, compassion, and self-care.

The Vulnerability in Medicine (ViM) program was developed to provide protected time and psychologically safe spaces for third-year medical students to consider challenges in the doctor-patient relationship and the clinical workplace. A suite of discussion-prompts presented in a small-group learning environment provides a springboard for students to reflect on their development as clinicians, understand the personhood of their patients, explore the therapeutic relationship, and consider emotional responses and personal, cultural, and social assumptions that impact on care. The program supports students to recognise vulnerability in themselves, the patient, their tutors, and the wider clinical team, as they face the challenge of aligning the clinician they want to become with ideals of professionalism and the imperfect clinical workplace. This 6­week program focuses on the vulnerability of patients, students, and doctors in a weekly tutorial interposed with clinical placements primarily in geriatric, rehabilitation, or palliative medicine. The tutorials draw from the medical humanities and use experiential, reflective, and narrative learning techniques. They are facilitated by generalist clinicians who model their own vulnerability, humanity, and reflective practice by sharing tutorial tasks equally with students. Students report feeling supported, and appreciate the opportunity to discuss ethical, psychosocial, and emotional aspects of medicine whilst reflecting on what medical practice means to them. Tutors experience a deeper appreciation of student journeys and their own vocations as clinicians and teachers. The sharing of vulnerability exposes the humanity of patients, students, and clinicians, and sustains our whole-person approach to the care of patients, students, and ourselves.

Concordance of cerebrospinal fluid real-time quaking-induced conversion across the European Creutzfeldt-Jakob Disease Surveillance Network.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) and this has led to its being included in revised European CJD Surveillance Network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC. METHODS: Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative. RESULTS: All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories, one had a disease duration >26 months with a negative 14-3-3, whilst the remaining case had a 4-month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study. CONCLUSIONS: This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, recombinant prion protein substrates and CSF volumes. The adoption of CSF RT-QuIC by all CJD surveillance centres is recommended.

Biological trade-offs underpin coral reef ecosystem functioning.

Human impact increasingly alters global ecosystems, often reducing biodiversity and disrupting the provision of essential ecosystem services to humanity. Therefore, preserving ecosystem functioning is a critical challenge of the twenty-first century. Coral reefs are declining worldwide due to the pervasive effects of climate change and intensive fishing, and although research on coral reef ecosystem functioning has gained momentum, most studies rely on simplified proxies, such as fish biomass. This lack of quantitative assessments of multiple process-based ecosystem functions hinders local and regional conservation efforts. Here we combine global coral reef fish community surveys and bioenergetic models to quantify five key ecosystem functions mediated by coral reef fishes. We show that functions exhibit critical trade-offs driven by varying community structures, such that no community can maximize all functions. Furthermore, functions are locally dominated by few species, but the identity of dominant species substantially varies at the global scale. In fact, half of the 1,110 species in our dataset are functionally dominant in at least one location. Our results reinforce the need for a nuanced, locally tailored approach to coral reef conservation that considers multiple ecological functions beyond the effect of standing stock biomass.

CPC-containing oral rinses inactivate SARS-CoV-2 variants and are active in the presence of human saliva.

Introduction. The importance of human saliva in aerosol-based transmission of SARS-CoV-2 is now widely recognized. However, little is known about the efficacy of virucidal mouthwash formulations against emergent SARS-CoV-2 variants of concern and in the presence of saliva.Hypothesis. Mouthwashes containing virucidal actives will have similar inactivation effects against multiple SARS-CoV-2 variants of concern and will retain efficacy in the presence of human saliva.Aim. To examine in vitro efficacy of mouthwash formulations to inactivate SARS-CoV-2 variants.Methodology. Inactivation of SARS-CoV-2 variants by mouthwash formulations in the presence or absence of human saliva was assayed using ASTM International Standard E1052-20 methodology.Results. Appropriately formulated mouthwashes containing 0.07 % cetylpyridinium chloride but not 0.2 % chlorhexidine completely inactivated SARS-CoV-2 (USA-WA1/2020, Alpha, Beta, Gamma, Delta) up to the limit of detection in suspension assays. Tests using USA-WA1/2020 indicates that efficacy is maintained in the presence of human saliva.Conclusions. Together these data suggest cetylpyridinium chloride-based mouthwashes are effective at inactivating SARS-CoV-2 variants. This indicates potential to reduce viral load in the oral cavity and mitigate transmission via salivary aerosols.

Investigation of SARS-CoV-2 Transmission Associated With a Large Indoor Convention - New York City, November-December 2021.

During November 19-21, 2021, an indoor convention (event) in New York City (NYC), was attended by approximately 53,000 persons from 52 U.S. jurisdictions and 30 foreign countries. In-person registration for the event began on November 18, 2021. The venue was equipped with high efficiency particulate air (HEPA) filtration, and attendees were required to wear a mask indoors and have documented receipt of at least 1 dose of a COVID-19 vaccine.* On December 2, 2021, the Minnesota Department of Health reported the first case of community-acquired COVID-19 in the United States caused by the SARS-CoV-2 B.1.1.529 (Omicron) variant in a person who had attended the event (1). CDC collaborated with state and local health departments to assess event-associated COVID-19 cases and potential exposures among U.S.-based attendees using data from COVID-19 surveillance systems and an anonymous online attendee survey. Among 34,541 attendees with available contact information, surveillance data identified test results for 4,560, including 119 (2.6%) persons from 16 jurisdictions with positive SARS-CoV-2 test results. Most (4,041 [95.2%]), survey respondents reported always wearing a mask while indoors at the event. Compared with test-negative respondents, test-positive respondents were more likely to report attending bars, karaoke, or nightclubs, and eating or drinking indoors near others for at least 15 minutes. Among 4,560 attendees who received testing, evidence of widespread transmission during the event was not identified. Genomic sequencing of 20 specimens identified the SARS-CoV-2 B.1.617.2 (Delta) variant (AY.25 and AY.103 sublineages) in 15 (75%) cases, and the Omicron variant (BA.1 sublineage) in five (25%) cases. These findings reinforce the importance of implementing multiple, simultaneous prevention measures, such as ensuring up-to-date vaccination, mask use, physical distancing, and improved ventilation in limiting SARS-CoV-2 transmission, during large, indoor events.†.

Validation of Revised International Creutzfeldt-Jakob Disease Surveillance Network Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease.

Importance: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation. Objective: To evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis). Design, Setting, and Participants: This diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021. Main Outcomes and Measures: Sensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age. Results: A total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P < .001) and had longer median (IQR) disease duration (118 [74.8-222.3] days vs 85 [51.5-205.5] days; P = .002); sex ratios were equivalent (253 [50.5%] male cases vs 74 [50.7%] male noncases). Sensitivity of revised criteria in in-life diagnosis (450 of 488 [92.2%] diagnoses; 95% CI, 89.5%-94.4%) was increased compared with prior criteria (378 of 488 [77.5%] diagnoses; 95% CI, 73.5%-81.1%; P < .001), while specificity (101 of 125 [80.8%] diagnoses; 95% CI, 72.8%-87.3%) was unchanged (102 of 125 [81.6%] diagnoses; 95% CI, 73.7%-88.0%; P > .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P < .001) while specificity was unchanged (67.3%; 95% CI, 52.9%-79.7% vs 69.2%; 95% CI, 54.9%-81.3%; P > .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age. Conclusions and Relevance: This diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance.

Range expansion and first observation of Tridacna noae (Cardiidae: Tridacninae) in American Samoa.

Giant clams are ecologically important, benefitting species of all trophic levels. But numerous populations have declined drastically in numbers due to past intensive exploitation that led to their listing in both CITES Appendix II and IUCN Red List of Threatened Species. However, giant clams are notoriously difficult to identify, and recent molecular work has revealed that morphological misidentification of giant clams have confounded current population assessments and extinction risk. The most recent study of the status of giant clams in the Samoan Archipelago was published in a journal over 20 years ago, without molecular corroboration of visual identifications. Using morphologic characteristics and ezRAD genetic techniques, we identify the existence of Tridacna noae in the Samoan Archipelago, presenting the first observation and a resulting range expansion. Accurately identifying the extant species in the archipelago is the first step toward a much-needed population status assessment to effectively manage these long-lived species.

Impact of the COVID-19 pandemic on Creutzfeldt-Jakob disease surveillance and patient care in the United Kingdom.

BACKGROUND AND PURPOSE: Creutzfeldt-Jakob disease (CJD) is lethal and transmissible. We assessed the impact of the COVID-19 pandemic on UK CJD surveillance. We hypothesized that (i) disruptions prolonged diagnostic latency; (ii) autopsy rates declined; and (iii) COVID-19 infection negatively affected diagnosis, care, and survival. METHODS: We retrospectively investigated the first year of the pandemic, using the preceding year as a comparator, quantifying numbers of individuals assessed by the UK National CJD Research & Surveillance Unit for suspected CJD, time to diagnosis, disease duration, and autopsy rates. We evaluated the impact of COVID-19 status on diagnosis, care, and survival in CJD. RESULTS: A total of 148 individuals were diagnosed with CJD in the pandemic (from a total of 166 individuals assessed) compared to 141 in the comparator (from 145 assessed). No differences were identified in disease duration or time to diagnosis. Autopsy rates were unchanged. Twenty individuals had COVID-19; 60% were symptomatic, and 10% had severe disease. Disruptions in diagnosis and care were frequently identified. Forty percent of COVID-19-positive individuals died; however, COVID-19 status did not significantly alter survival duration in CJD. CONCLUSIONS: The COVID-19 pandemic has not impacted UK CJD case ascertainment or survival, but diagnostic evaluation and clinical care of individuals have been affected.

Multistate Outbreak of SARS-CoV-2 Infections, Including Vaccine Breakthrough Infections, Associated with Large Public Gatherings, United States.

During July 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.617.2 variant infections, including vaccine breakthrough infections, occurred after large public gatherings in Provincetown, Massachusetts, USA, prompting a multistate investigation. Public health departments identified primary and secondary cases by using coronavirus disease surveillance data, case investigations, and contact tracing. A primary case was defined as SARS-CoV-2 detected <14 days after travel to or residence in Provincetown during July 3-17. A secondary case was defined as SARS-CoV-2 detected <14 days after close contact with a person who had a primary case but without travel to or residence in Provincetown during July 3-August 10. We identified 1,098 primary cases and 30 secondary cases associated with 26 primary cases among fully and non-fully vaccinated persons. Large gatherings can have widespread effects on SARS-CoV-2 transmission, and fully vaccinated persons should take precautions, such as masking, to prevent SARS-CoV-2 transmission, particularly during substantial or high transmission.

Comparative Metabolomics of Reproductive Organs in the Genus Aesculus (Sapindaceae) Reveals That Immature Fruits Are a Key Organ of Procyanidin Accumulation and Bioactivity.

Fruit from A. hippocastanum L. are used commercially for chronic venous insufficiency (CVI). The isomeric mixture of pentacyclic triterpenoid saponins (ß-aescin) exert anti-inflammatory effects. Hence, research has focused on ß-aescin, yet the diversity, accumulation, and bioactivity of organ-specific secondary metabolites represent missed pharmacological opportunities. To this end, we applied an untargeted metabolomics approach by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to the chemical profiles of flowers, immature fruits, and pedicels from 40 specimens across 18 species of Aesculus. Principal component analysis (PCA), orthogonal partial least squares (OPLS-DA), and molecular networking revealed stronger chemical differences between plant organs, than between species. Flowers are rich in glycosylated flavonoids, pedicels in organic acids and flavonoid aglycones, and immature fruits in monomeric flavan-3-ols and procyanidins. Although a high diversity of flavonoids and procyanidins was observed, the relative amounts differed by plant organ. Fruit extracts demonstrated the strongest antifungal (Saccharomyces cerevisiae) and antioxidant activity, likely from the procyanidins. Overall, secondary metabolite profiles are organ-specific, and fruits accumulate antifungal and antioxidant compounds. Due to the chemical similarity between species, similar effects may be achieved between species. This creates incentives for further exploration of the entire genus, in bioprospecting for potential therapeutic leads.