Covid19-Sources

Persistent symptoms following the acute phase of COVID-19 present a major burden to both the affected and the wider community. We conducted a cohort study including over 856,840 first COVID-19 cases, 72,422 re-infections and more than 3.1 million first negative-test controls from primary care electronic health records from Spain and the UK (Sept 2020 to Jan 2022 (UK)/March 2022 (Spain)). We characterised post-acute COVID-19 symptoms and identified key symptoms associated with persistent disease. We estimated incidence rates of persisting symptoms in the general population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential by comparing their frequency in COVID-19 cases vs. matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections.Our study shows that the proportion of COVID-19 cases affected by persistent post-acute COVID-19 symptoms declined over the study period. Risk for altered smell/taste was consistently higher in patients with COVID-19 vs test-negative controls. Persistent symp- toms were more common after reinfection than following a first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.

Nature - Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human...

The survey identified 34 cases of acute encephalopathy associated with COVID-19 infection among those under 18 between January 2020 and May 2022.

Deutschland steuert auf den vierten Winter seit der weltweiten Ausbreitung des Coronavirus zu. Die Fallzahlen steigen, doch welche Varianten gehen um?

The post–COVID-19 condition (PCC) is a disabling syndrome affecting at least 5%–10% of subjects who survive COVID-19. SARS-CoV-2 mediated vagus nerve dysfunction could explain some PCC symptoms, such as dysphonia, dysphagia, dyspnea, dizziness, tachycardia, orthostatic hypotension, gastrointestinal disturbances, or neurocognitive complaints. Participants were mostly women (24 of 30, 80%), and the median age was 44 years (interquartile range [IQR] 35–51 years). Their most prevalent symptoms were cognitive dysfunction 25 of 30 (83%), dyspnea 24 of 30 (80%), and tachycardia 24 of 30 (80%). Compared with COVID-19-recovered and uninfected controls, respectively, subjects with PCC were more likely to show thickening and hyperechogenic vagus nerve in neck ultrasounds (cross-sectional area [CSA] [mean ± standard deviation]: 2.4 ± 0.97mm2 vs. 2 ± 0.52mm2 vs. 1.9 ± 0.73 mm2; p 0.08), reduced esophageal-gastric-intestinal peristalsis (34% vs. 0% vs. 21%; p 0.02), gastroesophageal reflux (34% vs. 19% vs. 7%; p 0.13), and hiatal hernia (25% vs. 0% vs. 7%; p 0.05). Subjects with PCC showed flattening hemidiaphragms (47% vs. 6% vs. 14%; p 0.007), and reductions in maximum inspiratory pressure (62% vs. 6% vs. 17%; p ≤ 0.001), indicating respiratory muscle weakness. The latter findings suggest additional involvement of the phrenic nerve.

SARS-CoV-2 omicron XBB sublineages efficiently evade immunity from infection or vaccination, requiring vaccine adaptation. Updated monovalent omicron XBB.1.5-containing vaccines were approved in September, 2023. Although preliminary manufacturer data suggest neutralisation of currently emerging sublineages, real-world evidence is scarce,1 and persisting immune imprinting2,3 might compromise elicitation of antibodies against new SARS-CoV-2 sublineages. We monitored immune responses in 65 health-care workers from our ongoing CoCo Study4 who were vaccinated with 30 μg of the updated BNT162b2 omicron XBB.1.5 vaccine (Raxtozinameran, BioNTech, Mainz, Germany) in September, 2023, and analysed 53 individuals 8–10 days after vaccination (appendix p 12).

What are the rates of ongoing COVID-19 symptoms in 2023 and beyond?

As part of an ongoing partnership with the Census Bureau, the National Center for Health Statistics (NCHS) recently added questions to assess the prevalence of post-COVID-19 conditions (long COVID), on the experimental Household Pulse Survey. This 20-minute online survey was designed to complement the ability of the federal statistical system to rapidly respond and provide relevant information about the impact of the coronavirus pandemic in the U.S. Data collection began on April 23, 2020.

Evolution of SARSCoV2 Omicron spike:⬆️infectivity &⬆️immune evasion &⬆️no of mutations compared to previous (VOCs) characterize Omicron variant-evolution has lengthened fallout;diff from previous VOCs-outcompete other variants, https://t.co/NmV7zTmS7f— Prof. Dr. Sanjeev Bagai (@BagaiDr) November 22, 2023

There is no evidence that an individual is worse off for having avoided earlier infection

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neurotropic potential, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. The results herein suggest that evolving omicron variants may have increasing neurotropic potential.

Information on the protein-based severe acute respiratory syndrome (SARS-CoV-2) vaccine-NVX-CoV2373 (Novavax), as a heterologous booster remains limit…

Background Rapid antigen tests (RATs) for SARS-CoV-2 have been used to combat the still ongoing Covid-19 pandemic. This study is the extension of the COVAG study originally performed from February 1 to March 31, 2021. We compared two RATs, the Panbio COVID-19 Ag Rapid Test (Abbott) and the SD Biosensor Q SARS-CoV-2 Rapid Antigen Test (Roche), against RT-PCR on the foil of new variants. Methods We included 888 all-comers at a diagnostic center between October 20, 2021, and March 18, 2022. RT-PCR-positive samples with a Ct value ≤ 32 were examined for SARS-CoV-2 variants. Findings The sensitivity of the Abbott-RAT and Roche-RAT were 65% and 67%, respectively. For both RATs, lower Ct values were significantly correlated with higher sensitivity. For samples with Ct values ≤ 25, the sensitivities of the Roche-RAT and of the Abbott-RAT were 96% and 95%, for Ct values 25-30 both were 19%, and for Ct values ≥ 30 they were 6% and 2%, respectively. The RATs had substantially higher sensitivities in symptomatic than asymptomatic participants (76, 77%, vs. 29, 31%, for Abbott-RAT, Roche-RAT, respectively) and in participants referred to testing by their primary care physician (84%, 85%) compared to participants who sought testing due to referral by the health department (55%, 58%) or a warning by the Corona-Warn-App (49%, 49%). In persons with self-reported previous Covid-19 sensitivities were markedly lower than in patients without previous Covid-19: 27% vs. 75% for Roche-RAT and 27% vs. 73% for Abbott-RAT. Depending on the vaccination status, the sensitivity of the RATs is 67.6%, 61.5% and 70.6% for non-vaccinated, vaccinated and boostered participants, respectively. For the considered subpopulation of 888 participants, we find no significant correlation between vaccination status and sensitivity. The Omicron variant was detected with a sensitivity of 94% and 92%, the delta variant with a sensitivity of 80% and 80% for Abbott-RAT and Roche-RAT, respectively. This difference is attributable to the lower Ct values of the Omicron samples compared to the Delta samples. When adjusted for the Ct value, a multivariate logistic regression did not show a significant difference between Omicron and Delta. In terms of sensitivity, we found no significant difference between the wild-type and the Omicron and Delta variants, but a significantly lower sensitivity to the alpha variant compared to the other variants. For a Ct value ≤ 25 the sensitivities were 95.2% and 96.0% for the Abbott-RAT and the Roche-RAT, respectively (Table 4). For a Ct value of 25-30 both RATs had a sensitivity of 18.8%. For a Ct value of 30-32, the sensitivities were 0.0% and 7.1% respectively, for Ct values ≥32 the sensitivities were 3.0% and 6.0% for Abbott-RAT and Roche-RAT, respectively. The specificities were 99% overall. Interpretation: The sensitivity of the RATs for asymptomatic carriers is unsatisfactory questioning their use for screening. When used in symptomatic patients or when requested by a primary care physician the sensitivities were higher. Our study does not suggest that the vaccination status influences the sensitivity of RATs. ### Competing Interest Statement CW, HB, AS, NL, EW, MR, and WM were employed by SYNLAB Holding Germany GmbH or its regional subsidiaries. AD is the owner of Company Dr. Dressel Consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ### Funding Statement The costs of the study were defrayed by SYNLAB Holding Deutschland GmbH. The management had no role in writing of the report or the decision to submit for publication. There was no financial support to SYNLAB Holding Deutschland GmbH from the manufacturers of the assays used in this evaluation and there has been no other financial support for this work that could have influenced its outcome. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by Ethics Committee II (Mannheim) of the University of Heidelberg (reference number 2020-417MF) and the German Institute for Drugs and Medical Devices I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available to researchers upon justified request and formal agreement to make sure that rules of good scientific practice are obeyed, and that credit is given to the people who have been in charge of the design and the organization of the study. Interested researchers are invited to address their request or proposal to WM (winfried.maerz{at}synlab.com). The authors confirm that they accessed and validated these data and that all other researchers can access the data in the same manner the authors did.

The rise of the JN.1 variant

Nature - A study shows that US children who received mRNA COVID-19 vaccines have some protection against developing long-lasting symptoms of the coronavirus SARS-CoV-2.

Companies have been ignoring the enormous long Covid risk for too long. Now they're paying for it – literally. Implementing the Swiss cheese system could make them largely Covid-proof in no time. So what needs to be done?

The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (V˙˙O2) at maximum fat oxidation (g min−1) than the healthy controls (P 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = −0.105 [95% confidence interval −0.174; −0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Nature Italy - In addition to the known ACE2 receptor, the SARS-CoV-2 virus can also bind to the RAGE receptor found in white blood cells.

Phosphoproteomics analysis of SARS-CoV-2-infected Vero E6 cells reveals host cellular pathways hijacked by viral infection, leading to the identification of small molecules that target dysregulated pathways and elicit potent antiviral efficacy.

Continued high-level spread of SARS-CoV-2 has enabled an accumulation of changes within the Spike glycoprotein, leading to resistance to neutralising antibodies and concomitant changes to entry requirements that increased viral transmission fitness. Herein, we demonstrate a significant change in angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) dependent entry by primary SARS-CoV-2 isolates that occurred upon arrival of Omicron lineages. Mechanistically we show this shift to be a function of two distinct ACE2 pools based on cleavage by TMPRSS2. In engineered cells overexpressing ACE2 and TMPRSS2, ACE2 cleavage by TMPRSS2 led to either augmentation or attenuation of viral infectivity of pre-Omicron and Omicron lineages, respectively. Mutagenesis of the TMPRSS2 cleavage site in ACE2 restored infectivity across all Omicron lineages through enabling ACE2 binding that facilitated TMPRSS2 activation of viral fusion. Our data supports the evolution of Omicron lineages towards the use of pools of ACE2 with the latter consistent with its role as a chaperone for many tissue specific amino acid transport proteins. ![Figure][1] Graphical Abstract: Cleaved ACE2 pool model and evolution of SARS-CoV-2 tropism. A. &-B. ACE2 cleaved pool model to reconcile the evolving entry requirements of SARS-CoV-2 and changes in viral tropism in vivo . A. Both SARS-CoV-1 and early SARS-CoV-2 (pre-Omicron) lineages undergo cleavage of ACE2 (blue protein) by TMPRSS2 (green protein) which promotes viral entry. In other settings in which ACE2 is not cleaved by TMPRSS2, viral entry still proceeds. Therefore, regardless of the cleavage state of ACE2, TMPRSS2 cleavage and activation of Spike S2 can proceed (“on” conformation) in pre-Omicron variants. B. For Omicron lineages, cleavage of ACE2 by TMPRSS2 does not lead to TMPRSS2 Spike S2 activation (“off” confirmation”). Whilst this supports attenuation in tissue where ACE2 is cleavage sensitive due to its role in soluble ACE2 regulation (e.g. lung), replication in other tissues proceeds. Independent of RAS, ACE2 can also act as a chaperone for several tissue-specific amino acid transporters which engage at and around the TMPRSS2 cleavage site, thus blocking the ACE2 cleavage site from TMPRSS2. To mimic the lack of ACE2 cleavage in this setting, we mutated the TMPRSS2 cleavage site in ACE2 and demonstrated that Omicron viral infection and TMPRSS2 Spike S2 activation can occur in the presence of non-cleaved ACE2 (“on” conformation). C. Cleaved (black dashed line) versus non-cleaved ACE2 (blue line) usage by SARS-CoV-2 variants throughout the pandemic. The appearance of globally dominant variants over time is presented as a backdrop (Nextstrain). Here, e arly SARS-CoV-2 lineages are observed to be augmented by the action of ACE2/TMPRSS2 cleavage. This augmentation steadily declines and crosses over to attenuation upon the arrival of the first Omicron lineage BA.1. Further attenuation is then observed with the appearance of the recombinant lineages such as O micron XBB and XBF. Concurrently, ACE2 resistant to TMPRSS2 cleavage has supported TMPRSS2 Spike S2 activation entry across all SARS-CoV-2 lineages equally. ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

Debate rages over whether SARS-CoV-2 can insert bits of its RNA into the human genome

COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with68 prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14. We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple pulmonary and extrapulmonary tissues early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our80 data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.

Scientific Reports - Association between BNT162b2 vaccination and health-related quality of life up to 18 months post-SARS-CoV-2 infection in Israel

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection damages the heart, increasing the risk of adverse cardiovascular events. Female sex protects against complications of infection; females are less likely to experience severe illness or death, although their risk for postacute sequelae of COVID-19 (“long COVID”) is higher than in males. Despite the important role of the heart in COVID-19 outcomes, molecular elements in the heart impacted by SARS-CoV-2 are poorly understood. Similarly, the role sex has on the myocardial effects of SARS-CoV-2 infection has not been investigated at a molecular level. We intranasally inoculated female and male ferrets with SARS-CoV-2 and assessed myocardial stress signals, inflammation, and the innate immune response for 14 days. Myocardial phosphorylated GSK3α/β decreased at day 2 postinfection (pi) in male ferrets, whereas females showed no changes. Myocardial levels of p62/SQSTM1 decreased in male ferrets at days 2, 7, and 14 pi while lower baseline levels in females increased on day 2. Phosphorylated ERK1/2 increased in cardiomyocyte nuclei in females on days 2 and 14 pi, whereas male ferrets had no changes. Only hearts from females increased fibrosis on day 14 pi. Immune and inflammation markers increased in hearts, with some sex differences. These results are the first to identify myocardial stress responses following SARS-CoV-2 infection and reveal sex differences that may contribute to differential outcomes. Future research is required to define the pathways involving these stress signals to fully understand the myocardial effects of COVID-19 and identify targets that mitigate cardiac injury following SARS-CoV-2 infection. NEW & NOTEWORTHY Cardiovascular disease is a leading risk factor for severe COVID-19, and cardiovascular pathologies are among the most common adverse outcomes following SARS-CoV-2 infection. Females and males have different outcomes and adverse cardiovascular events following SARS-CoV-2 infection. This study shows sex differences in stress proteins p62/SQSTM1, ERK1/2, and GSK3α/β, along with innate immunity and inflammation in hearts of ferrets infected with SARS-CoV-2, identifying mechanisms of COVID-19 cardiac injury and cardiac complications of long COVID.

Importance/Background: The coronavirus disease (COVID-19) pandemic is a critical public health issue. Evidence has shown that metformin favorably influences COVID-19 outcomes. This study aimed to assess the benefits and risks of metformin in COVID-19 patients.Methods: We searched the PubMed, Embase, Cochrane Library, and Chinese Biomedical Literature Database from inception to February 18, 2021. Observational studies assessing the association between metformin use and the outcomes of COVID-19 patients were included. The primary outcome was mortality, and the secondary outcomes included intubation, deterioration, and hospitalization. Random-effects weighted models were used to pool the specific effect sizes. Subgroup analyses were conducted by stratifying the meta-analysis by region, diabetic status, the adoption of multivariate model, age, risk of bias, and timing for adding metformin.Results: We identified 28 studies with 2,910,462 participants. Meta-analysis of 19 studies showed that metformin is associated with 34% lower COVID-19 mortality [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.56–0.78; I2 = 67.9%] and 27% lower hospitalization rate (pooled OR, 0.73; 95% CI, 0.53–1.00; I2 = 16.8%). However, we did not identify any subgroup effects. The meta-analysis did not identify statistically significant association between metformin and intubation and deterioration of COVID-19 (OR, 0.94; 95% CI, 0.77–1.16; I2 = 0.0% for intubation and OR, 2.04; 95% CI, 0.65–6.34; I...

Eine randomisiert-kontrollierte US-Studie zeigt, dass Metformin bei ambulant behandelten übergewichtigen und adipösen SARS-CoV-2-Infizierten offenbar vor der späteren Entwicklung von Long-COVID schützen kann. Wurde eine Metformin-Therapie innerhalb von drei Tagen nach Beginn der Akuterkrankung begonnen, sank das Risiko für Langzeitsymptome um 63 %.

The study found Paxlovid is now less effective at keeping patients out of the hospital, but still remains highly effective at stopping death.

Easy access to health data in the WHO European Region. In English and Russian.

Post-viral syndromes are associated with serotonin reduction, which may contribute to the neurological and cognitive symptoms seen in individuals with Long COVID.

Nature - Blood plasma protein data was combined with machine learning models for a simple method to determine differences in organ-specific aging; the study provides a basis for the prediction of...