COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain.

OBJECTIVE: Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy. METHODS: Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods. RESULTS: SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11ß, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05). INTERPRETATION: COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

Learning loss and student dropouts during the COVID-19 pandemic: a review of the evidence two years after schools shut down

Following the outbreak and spread of COVID-19 in 2020, schools around the world closed for significant periods of time. Many scholars provided projections of the likely impacts on educational outcomes, with potentially dire impacts on learning loss and-especially in low-income contexts-dropout rates. Now, two years after schools began shutting down, we identify 40 empirical studies directly estimating student learning loss (29 studies) or dropout rates (15 studies) for students in pre-primary, primary, or secondary school in countries at any income level. Most estimates of average learning loss are negative, although-especially in low- and middle-income countries-this is not always the case, and average losses are not as significant as some models predicted. Furthermore, learning loss was consistently much higher among students with lower socioeconomic status in high-, middle-, and low-income countries, even in contexts with little or no average learning loss. In other words, the pandemic consistently boosted learning inequality. Dropout rates ranged dramatically, from under 1 percent to more than 35 percent, with much higher rates for older students, suggesting that pandemic school closures-together with other pandemic-related shocks-may have curtailed many adolescents' schooling careers. In some countries (e.g., Kenya and Nigeria), girls are at higher risk of dropping out. The vast majority of studies report results for students of primary school age (83 percent of studies), with fewer reporting results for students of secondary school age (45 percent) and even fewer studies (8 percent) for younger students.

Coronavirus in pregnancy and delivery: rapid review.

OBJECTIVES: There are limited case series reporting the impact on women affected by coronavirus during pregnancy. In women affected by severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), the case fatality rate appears higher in those affected in pregnancy compared with non-pregnant women. We conducted a rapid review to guide health policy and management of women affected by COVID-19 during pregnancy, which was used to develop the Royal College of Obstetricians and Gynaecologists' (RCOG) guidelines on COVID-19 infection in pregnancy. METHODS: Searches were conducted in PubMed and MedRxiv to identify primary case reports, case series, observational studies and randomized controlled trials describing women affected by coronavirus in pregnancy. Data were extracted from relevant papers. This review has been used to develop guidelines with representatives of the Royal College of Paediatrics and Child Health (RCPCH) and RCOG who provided expert consensus on areas in which data were lacking. RESULTS: From 9965 search results in PubMed and 600 in MedRxiv, 21 relevant studies, all of which were case reports or case series, were identified. From reports of 32 women to date affected by COVID-19 in pregnancy, delivering 30 babies (one set of twins, three ongoing pregnancies), seven (22%) were asymptomatic and two (6%) were admitted to the intensive care unit (ICU), one of whom remained on extracorporeal membrane oxygenation. No maternal deaths have been reported to date. Delivery was by Cesarean section in 27 cases and by vaginal delivery in two, and 15 (47%) delivered preterm. There was one stillbirth and one neonatal death. In 25 babies, no cases of vertical transmission were reported; 15 were reported as being tested with reverse transcription polymerase chain reaction after delivery. Case fatality rates for SARS and MERS were 15% and 27%, respectively. SARS was associated with miscarriage or intrauterine death in five cases, and fetal growth restriction was noted in two ongoing pregnancies affected by SARS in the third trimester. CONCLUSIONS: Serious morbidity occurred in 2/32 women with COVID-19, both of whom required ICU care. Compared with SARS and MERS, COVID-19 appears less lethal, acknowledging the limited number of cases reported to date and that one woman remains in a critical condition. Preterm delivery affected 47% of women hospitalized with COVID-19, which may put considerable pressure on neonatal services if the UK's reasonable worst-case scenario of 80% of the population being affected is realized. Based on this review, RCOG, in consultation with RCPCH, developed guidance for delivery and neonatal care in pregnancies affected by COVID-19, which recommends that delivery mode be determined primarily by obstetric indication and recommends against routine separation of affected mothers and their babies. We hope that this review will be helpful for maternity and neonatal services planning their response to COVID-19. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Using trust-based philanthropy with community-based organizations during the COVID-19 pandemic

Community-based organizations (CBOs) fill a critical role in acting as public health partners and trusted resources for their communities, especially in an emergency. The CDC Foundation, an independent, nonprofit organization, used trust-based philanthropy to manage more than 110 COVID-19 grants focused on equitable vaccine information, outreach, and access. The CDC Foundation team uses a trust-based philanthropy paradigm by applying five out of six of the grantmaking practices: do the homework;simplify and streamline paperwork;be transparent and responsive;solicit and act on feedback;and offer support beyond the check. By applying trust-based philanthropy practices, the CDC Foundation is empowering CBOs through flexible grant management and more equitable power dynamics as grantee and grantor. This has been essential to CBOs in their efforts of tackling health inequities during the COVID-19 pandemic and improving community resilience. Lessons learned will inform future collaborations with CBOs where the power dynamics are shared. © 2023 National Foundation for the Centers for Disease Control and Prevention. Journal of Philanthropy and Marketing published by John Wiley & Sons Ltd.

A two-ward acute care hospital outbreak of SARS-CoV-2 delta variant including a point-source outbreak associated with the use of a mobile vital signs cart and sub-optimal doffing of personal protective equipment.

BACKGROUND: The arrival of the Delta variant of SARS-CoV-2 was associated with increased transmissibility and illness of greater severity. Reports of nosocomial outbreaks of Delta variant COVID-19 in acute care hospitals have been described but control measures varied widely. AIM: Epidemiological investigation of a linked two-ward COVID-19 Delta variant outbreak was conducted to elucidate its source, risk factors, and control measures. METHODS: Investigations included epidemiologic analysis, detailed case review serial SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) testing of patients and healthcare workers (HCWs), viral culture, environmental swabbing, HCW-unaware personal protective equipment (PPE) audits, ventilation assessments, and the use of whole genome sequencing (WGS). FINDINGS: This linked two-ward outbreak resulted in 17 patient and 12 HCW cases, despite an 83% vaccination rate. In this setting, suboptimal adherence and compliance to PPE protocols, suboptimal hand hygiene, multi-bedded rooms, and a contaminated vital signs cart with potential fomite or spread via the hands of HCWs were identified as significant risk factors for nosocomial COVID-19 infection. Sudden onset of symptoms, within 72 h, was observed in 79% of all Ward 2 patients, and 93% of all cases (patients and HCWs) on Ward 2 occurred within one incubation period, consistent with a point-source outbreak. RT-PCR assays showed low cycle threshold (CT) values, indicating high viral load from environmental swabs including the vital signs cart. WGS results with ≤3 SNP differences between specimens were observed. CONCLUSION: Outbreaks on both wards settled rapidly, within 3 weeks, using a `back-to-basics' approach without extraordinary measures or changes to standard PPE requirements. Strict adherence to recommended PPE, hand hygiene, education, co-operation from HCWs, including testing and interviews, and additional measures such as limiting movement of patients and staff temporarily were all deemed to have contributed to prompt resolution of the outbreak.

A digital pathway for genetic testing in UK NHS patients with cancer: BRCA-DIRECT randomised study internal pilot.

BACKGROUND: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing. METHODS: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). RESULTS: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met. CONCLUSION: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses. TRIAL REGISTRATION NUMBER: ISRCTN87845055.

Estimating the Prevalence of Intimate Partner Violence at an Urban Hospital Before and During the COVID-19 Pandemic Using a Novel Natural Language Processing Algorithm

The impact of COVID-19 on intimate partner violence (IPV) in the United States is still relatively unknown, although some early data demonstrate that cases of IPV increased during COVID-19. The objective of this study was to measure the prevalence of IPV before and during the COVID-19 pandemic in a southeastern urban hospital. We performed a retrospective analysis of IPV encounters at a single high-volume Level I trauma hospital. IPV encounters were identified through a novel natural language processing algorithm using IPV-related words and phrases within unstructured clinical notes. IPV encounters from February to August 2019 (pre-COVID-19 period) were compared with encounters from February to August 2020 (COVID-19 period). The IPV visit rate during the COVID-19 period was higher than that during the pre-COVID-19 period (0.82% of all visits in 2020 vs. 0.72% of all visits in 2019). The number of IPV encounters for patients with no prior IPV visits was higher in 2020, whereas the number of revisits, patients with prior IPV encounters, was lower in 2020. There was an increased incidence of IPV during the COVID-19 pandemic with an increase in the number of patients presenting with first time IPV encounters. Future hospital and community pandemic preparedness protocols must include expansion of screening, resource allocation, and protective policies for those in unsafe situations.

Viral cultures for assessing fomite transmission of SARS-CoV-2: a systematic review and meta-analysis.

BACKGROUND: The role of fomites in the transmission of SARS-CoV-2 is unclear. AIM: To assess whether SARS-CoV-2 can be transmitted through fomites, using evidence from viral culture studies. METHODS: Searches were conducted in the World Health Organization COVID-19 Database, PubMed, LitCovid, medRxiv, and Google Scholar to December 31st, 2021. Studies that investigated fomite transmission and performed viral culture to assess the cytopathic effect (CPE) of positive fomite samples and confirmation of SARS-CoV-2 as the cause of the CPE were included. The risk of bias using a checklist modified from the modified Quality Assessment of Diagnostic Accuracy Studies - 2 (QUADAS-2) criteria was assessed. FINDINGS: Twenty-three studies were included. The overall risk of bias was moderate. Five studies demonstrated replication-competent virus from fomite cultures and three used genome sequencing to match fomite samples with human clinical specimens. The mean cycle threshold (CT) of samples with positive viral culture was significantly lower compared with cultured samples that returned negative results (standardized mean difference: -1.45; 95% confidence interval (CI): -2.00 to -0.90; I2 = 0%; P < 0.00001). The likelihood of isolating replication-competent virus was significantly greater when CT was <30 (relative risk: 3.10; 95% CI: 1.32 to 7.31; I2 = 71%; P = 0.01). Infectious specimens were mostly detected within seven days of symptom onset. One study showed possible transmission of SARS-CoV-2 from fomites to humans. CONCLUSION: The evidence from published studies suggests that replication-competent SARS-CoV-2 is present on fomites. Replication-competent SARS-CoV-2 is significantly more likely when the PCR CT for clinical specimens and fomite samples is <30. Further studies should investigate the duration of infectiousness of SARS-CoV-2 and the frequency of transmission from fomites.

Real-time genotyping-based breast cancer risk assessment in MyPeBS, an international randomized trial in the general population comparing risk-stratified to standard breast cancer screening (BCS)

Background: Risk-stratified BCS, integrating personal, familial variables and a polygenic risk score (PRS) is a promising strategy that may improve current BCS outcomes. Real-time risk assessment and field implementation are some of the main challenges for such an approach. Methods: MyPeBS is an ongoing EU-funded international randomized trial running in 6 countries. Eligible women (wn) aged 40-70 are randomized 1:1 between continuing standard organized BCS as recommended in their participating country/region and switching to risk-stratified BCS, in which BCS schedule and modalities are adapted to the individual predicted 5-year risk of invasive BC (IBC). Primary endpoint is 4-year incidence of stage 2 and higher BC. Secondary endpoints include PROs. 5-year IBC risk is estimated using the Mammorisk® BCSC-derived or the Tyrer Cuzick risk score and the centrally-determined PRS313 obtained from a saliva sample and calibrated for national BC incidence and age. We aim to describe 1) the feasibility of real-time assessment of BC risk and 2) the characteristics and risk profiles of the participants. Results: As of Sept. 7, 2021, 16,550 wn had been randomized. 29% were aged <50 (median age 54 (range 40-70), 13% had a previous benign breast biopsy, 40% a mammographic breast density C or D, 19% a 1st degree family history of breast or ovarian cancer;72% had tertiary education. 36% were estimated at low risk (<1% risk of IBC at 5 years), 29% at average risk, and 35% at high (34%) or very high risk (1%) (>1.67% and >6% risk, respectively). Only 2.5% of DNA extractions were not usable for genotyping, due to DNA concentration or quality;and 98.8% of the eligible DNA samples were successfully genotyped. Median turnover time from saliva sampling to risk result available was 11 weeks despite the COVID pandemic (currently 7 weeks). Conclusions: Real-time BC risk assessment based on a large set of polymorphisms, family, screening and hormonal history, and breast density is feasible within organized screening programmes. Participants are so far representative of different categories with some over-representation of highly educated participants. Clinical trial identification: NCT03672331. Legal entity responsible for the study: Unicancer. Funding: European Commission and French National Cancer Institute. Disclosure: S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca;Financial Interests, Institutional, Invited Speaker: Exact Sciences;Financial Interests, Institutional, Advisory Board: Novartis;Financial Interests, Institutional, Advisory Board: Pierre fabre;Financial Interests, Institutional, Advisory Board: Orion;Financial Interests, Institutional, Advisory Board: Sanofi;Financial Interests, Institutional, Advisory Board: Rappta;Financial Interests, Institutional, Advisory Board: Cellectis;Financial Interests, Institutional, Advisory Board: Isis/servier;Financial Interests, Institutional, Invited Speaker: Pfizer;Financial Interests, Institutional, Invited Speaker: Seagen;Financial Interests, Institutional, Invited Speaker: Lilly;Financial Interests, Institutional, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Invited Speaker: MSD;Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare;Financial Interests, Institutional, Invited Speaker: Roche Genentech;Financial Interests, Institutional, Invited Speaker: BMS;Financial Interests, Institutional, Invited Speaker: Puma;Financial Interests, Institutional, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Invited Speaker: Orion;Financial Interests, Institutional, Invited Speaker: Sanofi;Financial Interests, Institutional, Funding: GE;Financial Interests, Institutional, Invited Speaker: Pfizer;Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho;Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM. D. Keatley: Financial Interests, Personal, Advisory Board: Public Advisory Board of Heealth Data UK. E. Gauthier: Financial Interests, Personal, Stocks/Shares: Predilife;Financial Interests, Personal, Full or part-time Employment: Predilife. S. Michiels: Financial Interests, Personal, Advisory Role: IDDI;Financial Interests, Personal, Advisory Role: Amaris;Financial Interests, Personal, Advisory Role: Roche;Financial Interests, Personal, Advisory Role: Sensorion;Financial Interests, Personal, Advisory Role: Biophytis;Financial Interests, Personal, Advisory Role: Servier;Financial Interests, Personal, Advisory Role: Yuhan. All other authors have declared no conflicts of interest.

Kappa omicron lambda lambda eta theta epsilon nu tau epsilon zeta in Acts 17.34 and the Establishment of the Athenian Church

It is commonly stated that while the author of Acts records some conversions that resulted from Paul's Athenian ministry, it is unlikely that a church was established in the city. This article argues, through an analysis of the use of the kappa omicron lambda lambda alpha omega word family in Luke-Acts, the Septuagint, early Christian writings and other relevant texts, that Luke uses the participle kappa omicron lambda lambda eta theta epsilon nu tau epsilon zeta as a way of signifying that a Christian community was indeed gathered together in Athens at this time. Leaving other social groups to join Paul and the other new believers, the new group is fused together by their shared faith, forming a new faith community in this ancient city.

Comfortable Cohorts and Tractable Teams: Making Large Computing Theory Courses Feel Small

Instructors of introductory theoretical computing courses need to overcome lower initial student motivation ("Why do I need to learn this if I just want to be a programmer?'') and higher student discomfort ("I'm not really a 'math person'.'') to provide an engaging, inclusive, and effective learning experience for students. We present a structure for teaching large ($\sim$300 students) theory of computation courses that enables rich student collaboration and frequent student-staff interaction. We developed this structure to adapt a course that we had previously taught in large lecture format to work in a fully-virtual environment, as mandated by our university's Covid lockdown. Our experience with it led us to adopt many elements of this structure in subsequent and future courses, including those that meet in person. We anecdotally observed that this structure improves students' understanding and enthusiasm for the material. It also facilitated easier teaching assistant recruitment and retention. This paper relates our experience with forming cohorts, designing assignments, and managing teaching assistants, and discusses application of insights gained from this experience to future in-person and virtual courses. © 2022 Owner/Author.

Identifying men affected by changes in PSA screening in the COVID-19 pandemic

Introduction & Objectives: The COVID19 pandemic has had enormous impacts on the health of our population. With health services under significant strain, prostate cancer was subject to strict changes in referral criteria. In our network the PSA thresholds for cancer referral criteria were raised, to >10ng/mL and >20ng/mL for those aged <70 years and 70-75 years respectively, for 3 months. Materials & Methods: We modelled the effects of these restricted referral criteria on patients, applying them to our prospective multicentre database of consecutive men referred to our cancer network from 04/2017-07/2020. We calculated the total numbers and proportions of significant cancers - by grade or T-stage - that may have been missed when these restrictions were applied. Four definitions of ‘significance’ were used;Gleason 3+4, 4+3, UCL1 (>/=4+3 OR maximum cancer core length (MCCL) >/=6mm) and UCL2 (>/=3+4 OR MCCL >/=4mm). Results: 2107/3014 (69.9%) of patients would not have been referred under the restricted referral criteria, including 199 (9.4%) and 486 (23.1%) significant cancers depending on the definition of significance. During the restricted period, this represents an expected 162 men who would not have been referred, including between 15 and 37 significant cancers by grade, and 1 and 7 by T-stage. Conclusions: The COVID19 pandemic had significant impact on our prostate cancer pathways. Potentially, up to 1 in 4 men who ordinarily would have had curable disease identified early, and treated, will not have done. Efforts must be made to identify these men before they represent with disease states of poorer prognosis.

Losing the elearning safety net: Teaching an MBA class without an educational technician

The forced transition caused by the safety lockdowns associated with the COVID-19 pandemic imposed “emergency eLearning” on many university faculty members. This transition had many facets including moving away from face-to-face instruction to fully online and hybrid or blended forms of eLearning. For programs that were already leveraging blended teaching, using simultaneous synchronous and asynchronous teaching in the same classroom, the major change was the loss of an educational technician to operate and monitor the technology used for these hybrid teaching models. This paper outlines some of the changes required to navigate this transition and the positive and negative consequences associated with this forced move to eLearning. © 15th International Conference e-Learning, EL 2021 - Held at the 15th Multi-Conference on Computer Science and Information Systems, MCCSIS 2021. All rights reserved.

Emergency elearning during a pandemic: Tales of a forced transition

This paper explores the impact on faculty and students of the forced transition to eLearning caused by the COVID-19 pandemic. A review of the literature on eLearning modalities and the issues involved in transitioning from face-to-face instruction is followed by a series of reports on the experiences of 10 faculty in making the change from traditional instruction to various modalities of eLearning. The methodology employed is an adaptation of the grounded theory approach used in sociology. The results indicate that the primary advantages to the transition to eLearning were the flexibility afforded both faculty and students and the ability to continue delivering quality instruction during the pandemic. The primary negatives were the difficulty in engaging students in the new delivery modalities and the significant challenges involved in proctoring exams. Prior experience with online and blended learning on the part of the faculty and students made the transition smoother. © 15th International Conference e-Learning, EL 2021 - Held at the 15th Multi-Conference on Computer Science and Information Systems, MCCSIS 2021. All rights reserved.