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Long Covid-19

Machine learning to understand risks for severe COVID-19 outcomes: a retrospective cohort study of immune-mediated inflammatory diseases, immunomodulatory medications, and comorbidities in a large US health-care system
Wei Q, Mease PJ, Chiorean M, Iles-Shih L, Matos WF, Baumgartner A, Molani S, Hwang YM, Belhu B, Ralevski A and Hadlock J
In the context of immune-mediated inflammatory diseases (IMIDs), COVID-19 outcomes are incompletely understood and vary considerably depending on the patient population studied. We aimed to analyse severe COVID-19 outcomes and to investigate the effects of the pandemic time period and the risks associated with individual IMIDs, classes of immunomodulatory medications (IMMs), chronic comorbidities, and COVID-19 vaccination status.
Immunotherapy Toxicity Management in Clinical Practice: Building the Clinical Infrastructure for Immune-related Adverse Event Evaluation and Care
Klionsky Y, Simon Meara A and Reid P
Cancer immunotherapy is revolutionary for survival but has complications due to immunogenicity with unpredictable and potentially long-lasting autoimmune side effects known as immune-related adverse events (irAEs). Currently, treatment beyond corticosteroids can be complicated by the diversity of providers who are needed across a variety of clinical settings to manage irAEs. We outline the role of critical players in the management of irAEs, discuss the current limitations that exist, and propose various methodologies that can be adapted across clinical settings to tackle these needs. We aim to better understand who can be affected by irAEs and tailor diagnostics and therapeutics appropriately.
FIT negative clinic as a safety net for low-risk patients with colorectal cancer: impact on endoscopy and radiology utilisation-a retrospective cohort study
Nigam GB, Meran L, Bhatnagar I, Evans S, Malik R, Cianci N, Pakpoor J, Manganis C, Shine B, James T, Nicholson BD, East JE and Palmer RM
Faecal immunochemical testing (FIT) is recommended by the National Institute for Health and Care Excellence to triage symptomatic primary care patients who have unexplained symptoms but do not meet the criteria for a suspected lower gastrointestinal cancer pathway. During the COVID-19 pandemic, FIT was used to triage patients referred with urgent 2-week wait (2ww) cancer referrals instead of a direct-to-test strategy. FIT-negative patients were assessed and safety netted in a FIT negative clinic.
Potential Anti-Inflammatory and Anti-Fatigue Effects of an Oral Food Supplement in Long COVID Patients
Noce A, Marrone G, Di Lauro M, Vita C, Montalto G, Giorgino G, Chiaramonte C, D'Agostini C, Bernardini S and Pieri M
Long coronavirus disease (COVID) syndrome leads to chronic inflammatory state onset that can have a multisystem impact and compromise organ function. Moreover, long COVID syndrome is often characterized by the presence of chronic fatigue, which affects subjects' daily activities and worsens their quality of life. The aim of our double-blind, placebo-controlled randomized trial (protocol code RS 150.21, approved on 4 November 2021) was to evaluate the beneficial effects of the consumption of 2 cps/day, for two months, of an oral food supplement (OFS), based on , rosehip, propolis, royal jelly and zinc, in long COVID patients, compared to a two-month placebo period. The OFS's vitamin C content was equal to 22.17 mg/g (8.87 mg/capsule). The OFS's total polyphenol content was 43.98 mg/g gallic acid equivalents. At the end of the in vivo study, we highlighted a significant decrease in the inflammatory parameters in the OFS period, compared to the placebo period (neutrophil-to-lymphocyte ratio, = 0.0455; monocyte to-lymphocyte ratio, = 0.0005; C-reactive protein, = 0.0145). Our study also highlighted a significant increase in vitamin D serum values ( = 0.0005) and, at the same time, an improvement in patients' life quality and a reduction in fatigue, monitored by the fatigue severity scale. This study showed the OFS's beneficial effects on the inflammatory state, fatigue and quality of life in long COVID patients.
Correction: "They seemed to be like cogs working in different directions": a longitudinal qualitative study on long COVID healthcare services in the United Kingdom from a person-centred lens
Fang C, Akhtar Baz S, Sheard L and Carpentieri JD
Outdoor air pollution as a risk factor for testing positive for SARS-CoV-2: A nationwide test-negative case-control study in the Netherlands
Simões M, Zorn J, Hogerwerf L, Velders GJM, Portengen L, Gerlofs-Nijland M, Dijkema M, Strak M, Jacobs J, Wesseling J, de Vries WJ, Mijnen-Visser S, Smit LAM, Vermeulen R and Mughini-Gras L
Air pollution is a known risk factor for several diseases, but the extent to which it influences COVID-19 compared to other respiratory diseases remains unclear. We performed a test-negative case-control study among people with COVID-19-compatible symptoms who were tested for SARS-CoV-2 infection, to assess whether their long- and short-term exposure to ambient air pollution (AAP) was associated with testing positive (vs. negative) for SARS-CoV-2. We used individual-level data for all adult residents in the Netherlands who were tested for SARS-CoV-2 between June and November 2020, when only symptomatic people were tested, and modeled ambient concentrations of PM10, PM2.5, NO and O at geocoded residential addresses. In long-term exposure analysis, we selected individuals who did not change residential address in 2017-2019 (1.7 million tests) and considered the average concentrations of PM10, PM2.5 and NO in that period, and different sources of PM (industry, livestock, other agricultural activities, road traffic, other Dutch sources, foreign sources). In short-term exposure analysis, individuals not changing residential address in the two weeks before testing day (2.7 million tests) were included in the analyses, thus considering 1- and 2-week average concentrations of PM10, PM2.5, NO and O before testing day as exposure. Mixed-effects logistic regression analysis with adjustment for several confounders, including municipality and testing week to account for spatiotemporal variation in viral circulation, was used. Overall, there was no statistically significant effect of long-term exposure to the studied pollutants on the odds of testing positive vs. negative for SARS-CoV-2. However, significant positive associations of long-term exposure to PM10 and PM2.5 from specifically foreign and livestock sources, and to PM10 from other agricultural sources, were observed. Short-term exposure to PM10 (adjusting for NO) and PM2.5 were also positively associated with increased odds of testing positive for SARS-CoV-2. While these exposures seemed to increase COVID-19 risk relative to other respiratory diseases, the underlying biological mechanisms remain unclear. This study reinforces the need to continue to strive for better air quality to support public health.
A New Auto-Regressive Multi-Variable Modified Auto-Encoder for Multivariate Time-Series Prediction: A Case Study with Application to COVID-19 Pandemics
de Oliveira EV, Aragão DP and Gonçalves LMG
The SARS-CoV-2 global pandemic prompted governments, institutions, and researchers to investigate its impact, developing strategies based on general indicators to make the most precise predictions possible. Approaches based on epidemiological models were used but the outcomes demonstrated forecasting with uncertainty due to insufficient or missing data. Besides the lack of data, machine-learning models including random forest, support vector regression, LSTM, Auto-encoders, and traditional time-series models such as Prophet and ARIMA were employed in the task, achieving remarkable results with limited effectiveness. Some of these methodologies have precision constraints in dealing with multi-variable inputs, which are important for problems like pandemics that require short and long-term forecasting. Given the under-supply in this scenario, we propose a novel approach for time-series prediction based on stacking auto-encoder structures using three variations of the same model for the training step and weight adjustment to evaluate its forecasting performance. We conducted comparison experiments with previously published data on COVID-19 cases, deaths, temperature, humidity, and air quality index (AQI) in São Paulo City, Brazil. Additionally, we used the percentage of COVID-19 cases from the top ten affected countries worldwide until May 4th, 2020. The results show 80.7% and 10.3% decrease in RMSE to entire and test data over the distribution of 50 trial-trained models, respectively, compared to the first experiment comparison. Also, model type#3 achieved 4th better overall ranking performance, overcoming the NBEATS, Prophet, and Glounts time-series models in the second experiment comparison. This model shows promising forecast capacity and versatility across different input dataset lengths, making it a prominent forecasting model for time-series tasks.
Optimizing the Selection of Mass Vaccination Sites: Access and Equity Consideration
Aljohani B and Hall R
In the early phases of the COVID-19 pandemic, vaccine accessibility was limited, impacting large metropolitan areas such as Los Angeles County, which has over 10 million residents but only nine initial vaccination sites, which resulted in people experiencing long travel times to get vaccinated. We developed a mixed-integer linear model to optimize site selection, considering equitable access for vulnerable populations. Analyzing 277 zip codes between December 2020 and May 2021, our model incorporated factors such as car ownership, ethnic group disease vulnerability, and the Healthy Places Index, alongside travel times by car and public transit. Our optimized model significantly outperformed actual site allocations for all ethnic groups. We observed that White populations faced longer travel times, likely due to their residences being in more remote, less densely populated areas. Conversely, areas with higher Latino and Black populations, often closer to the city center, benefited from shorter travel times in our model. However, those without cars experienced greater disadvantages. While having many vaccination sites might improve access for those dependent on public transit, that advantage is diminished if people must search among many sites to find a location with available vaccines.
Organ-Dysfunction Markers in Mild-to-Moderate COVID-19 Convalescents
Wiśniewska A, Kijak A, Nowak K, Lulek M, Skwarek A, Małecka-Giełdowska M, Śmiarowski M, Wąsik S and Ciepiela O
: A coronavirus disease 2019 (COVID-19) outbreak led to a worldwide pandemic. COVID-19 not only caused acute symptoms during the severe phase of the disease, but also induced long-term side effects on the functioning of many organs and systems. Symptoms that were associated with the disease and present at least 3 months after recovery were named long COVID. The aim of this study was to assess if mild-to-moderate COVID-19 may lead to the dysfunction of respiratory, cardiovascular, neural, and renal systems in healthy blood donors who recovered from the disease at least 6 months earlier. Here, we examined 294 adults among volunteer blood donors divided into convalescents ( = 215) and healthy controls ( = 79). Concentrations of soluble CD163, TGF beta, Lp-PLA2, NCAM-1, S100, NGAL, and creatinine were measured either by ELISA or automated methods. The probability value < 0.05 was considered as statistically significant. We found significant differences in Lp-PLA2, S100, and NCAM-1 between convalescents and never-infected subjects. Lp-PLA2 and NCAM-1 were lower, and S100 higher, in convalescents than in the control group. Mild-to-moderate COVID-19 convalescents are at a low risk of developing lung fibrosis or chronic kidney disease. However, they should regularly carry out their prophylaxis examinations for early detection of possible negative outcomes of COVID-19.
Assessment of the Impact of SARS-CoV-2 Infection on the Sexual Function of Women, Levels of Oxytocin and Prolactin: A Prospective Cohort Study
Żak K, Starek E, Korga-Plewko A, Rasoul-Pelińska K, Abramiuk M, Michalczuk M, Rajtak A, Kotarski J, Frankowska K, Bis L, Ostrowska-Leśko M and Bobiński M
(1) : There is a lack of direct evidence on whether SARS-CoV-2 affects women's sexual function through a biological-organic mechanism. Existing studies on the topic are few and have produced contradictory results. This study aims to explore the possible relationship between sex hormones and sexual function in patients who have been infected with SARS-CoV-2. Moreover, we aimed to determine whether these changes are related to the clinical course of COVID-19 and whether they are temporary or long-lasting. (2) : A study was conducted on 104 women, including 64 women infected with COVID-19 and a control group of 40 healthy women, between January 2021 and August 2022. Blood samples were collected to measure prolactin and oxytocin levels, and a clinical assessment was performed 3 and 6 months later. Sexual function self-assessment was captured based on the FSFI scale. (3) : Our study found that patients with severe COVID-19 had better sexual satisfaction scores one month after recovery but no discernible difference after six months. High levels of serum prolactin were observed in patients with active COVID-19 but became similar to a control group after one month and remained stable over time. Higher prolactin levels were significantly associated with increased arousal and hydration. Individuals with severe COVID-19 had notably low levels of plasma oxytocin, but there was no correlation between oxytocin levels and sexual satisfaction. (4) : The gynecologic symptoms, as well as disturbances in oxytocin and prolactin levels, might be observed in a short time after infection. However, SARS-CoV-2 infection has no lasting effect on sexual function, oxytocin, and prolactin levels among women.
The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19
Gómez-Moyano E, Pavón-Morón J, Rodríguez-Capitán J, Bardán-Rebollar D, Ramos-Carrera T, Villalobos-Sánchez A, Pérez de Pedro I, Ruiz-García FJ, Mora-Robles J, López-Sampalo A, Pérez-Velasco MA, Bernal-López MR, Gómez-Huelgas R, Jiménez-Navarro M, Romero-Cuevas M, Costa F, Trenas A and Pérez-Belmonte LM
The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients. These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome.
Targeting the High-Density Lipoprotein Proteome for the Treatment of Post-Acute Sequelae of SARS-CoV-2
Grote K, Schaefer AC, Soufi M, Ruppert V, Linne U, Mukund Bhagwat A, Szymanski W, Graumann J, Gercke Y, Aldudak S, Hilfiker-Kleiner D, Schieffer E and Schieffer B
Here, we target the high-density lipoprotein (HDL) proteome in a case series of 16 patients with post-COVID-19 symptoms treated with HMG-Co-A reductase inhibitors (statin) plus angiotensin II type 1 receptor blockers (ARBs) for 6 weeks. Patients suffering from persistent symptoms (post-acute sequelae) after serologically confirmed SARS-CoV-2 infection (post-COVID-19 syndrome, PCS, n = 8) or following SARS-CoV-2 vaccination (PVS, n = 8) were included. Asymptomatic subjects with corresponding serological findings served as healthy controls (n = 8/8). HDL was isolated using dextran sulfate precipitation and the HDL proteome of all study participants was analyzed quantitatively by mass spectrometry. Clinical symptoms were assessed using questionnaires before and after therapy. The inflammatory potential of the patients' HDL proteome was addressed in human endothelial cells. The HDL proteome of patients with PCS and PVS showed no significant differences; however, compared to controls, the HDL from PVS/PCS patients displayed significant alterations involving hemoglobin, cytoskeletal proteins (MYL6, TLN1, PARVB, TPM4, FLNA), and amyloid precursor protein. Gene Ontology Biological Process (GOBP) enrichment analysis identified hemostasis, peptidase, and lipoprotein regulation pathways to be involved. Treatment of PVS/PCS patients with statins plus ARBs improved the patients' clinical symptoms. After therapy, three proteins were significantly increased (FAM3C, AT6AP2, ADAM10; FDR < 0.05) in the HDL proteome from patients with PVS/PCS. Exposure of human endothelial cells with the HDL proteome from treated PVS/PCS patients revealed reduced inflammatory cytokine and adhesion molecule expression. Thus, HDL proteome analysis from PVS/PCS patients enables a deeper insight into the underlying disease mechanisms, pointing to significant involvement in metabolic and signaling disturbances. Treatment with statins plus ARBs improved clinical symptoms and reduced the inflammatory potential of the HDL proteome. These observations may guide future therapeutic strategies for PVS/PCS patients.
The Effects of Six Weeks Pulmonary Rehabilitation on Functional and Psychological Outcomes in Long-COVID Patients: Preliminary Results from Serbian Single Center Study
Mujovic N, Nikolic D, Markovic F, Stjepanovic M, Zekovic M, Ali HSH, Zivanovic D, Savic M and Laban M
In this study, we aimed to evaluate the effects of six weeks of pulmonary rehabilitation on functional and psychological outcomes in long-COVID patients. The prospective clinical study included 46 patients that were diagnosed with COVID-19. A respiratory rehabilitation program was implemented for six weeks. Further valuables were tested before the beginning of the rehabilitation program (admission) and six weeks after (discharge): SpO, heart rate, respiratory rate, Visual Analogue Scale (VAS) score, Borg score, Sit-to-Stand (StS) test number of repetition, distance of 6-Minute Walking Test (6MWT), Patient Health Questionnaire (PHQ) 9 score and Generalized anxiety disorder (GAD) anxiety score. These parameters were tested before the rehabilitation program on admission and at discharge and after the rehabilitation program on admission and at discharge. The results were presented with standard descriptive and analytical methods. Differences between the continuous variables before and after physical rehabilitation intervention were tested using the Wilcoxon test. Graphical analysis is presented with a box plot. On discharge, in comparison with admission, the values of SpO were significantly lower ( = 0.007) before the 6MWT, and VAS scores were significantly higher ( = 0.036), while after the 6MWT, VAS scores were significantly lower ( < 0.001) as were Borg scores ( = 0.016). On discharge, in comparison with admission, the respiratory rate was significantly higher ( = 0.005) before the StS test, and Borg scores were significantly lower ( = 0.001), while after the StS test, SpO levels were significantly higher ( = 0.036) and VAS scores were significantly lower ( < 0.001), as were Borg scores ( = 0.008). After discharge, the values of the StS test were significantly higher ( = 0.011), PHQ9 scores were significantly lower ( < 0.001) and GAD anxiety scores were significantly lower as well ( = 0.005), while the distances measured in meters on the 6MWT were significantly increased ( < 0.001). A structured rehabilitation program in our study was shown to have beneficial effects on physiological, psychological and functional improvements in patients with long-COVID, and therefore it is advisable for these patients.
Pathophysiological Mechanisms in Long COVID: A Mixed Method Systematic Review
Diar Bakerly N, Smith N, Darbyshire JL, Kwon J, Bullock E, Baley S, Sivan M and Delaney B
Long COVID (LC) is a global public health crisis affecting more than 70 million people. There is emerging evidence of different pathophysiological mechanisms driving the wide array of symptoms in LC. Understanding the relationships between mechanisms and symptoms helps in guiding clinical management and identifying potential treatment targets.
Clinical-based phenotypes in children with pediatric post-COVID-19 condition
Noij LCE, Blankestijn JM, Lap CR, van Houten MA, Biesbroek G, der Zee AM, Abdel-Aziz MI, van Goudoever JB, Alsem MW, Brackel CLH, Oostrom KJ, Hashimoto S and Terheggen-Lagro SWJ
Pediatric post coronavirus disease 2019 (COVID-19) condition (PPCC) is a heterogeneous syndrome, which can significantly affect the daily lives of children. This study aimed to identify clinically meaningful phenotypes in children with PPCC, to better characterize and treat this condition.
SARS-CoV-2 Omicron BA.1 Variant Infection of Human Colon Epithelial Cells
Antia A, Alvarado DM, Zeng Q, Casorla-Perez LA, Davis DL, Sonnek NM, Ciorba MA and Ding S
The Omicron variant of SARS-CoV-2, characterized by multiple subvariants including BA.1, XBB.1.5, EG.5, and JN.1, became the predominant strain in early 2022. Studies indicate that Omicron replicates less efficiently in lung tissue compared to the ancestral strain. However, the infectivity of Omicron in the gastrointestinal tract is not fully defined, despite the fact that 70% of COVID-19 patients experience digestive disease symptoms. Here, using primary human colonoids, we found that, regardless of individual variability, Omicron infects colon cells similarly or less effectively than the ancestral strain or the Delta variant. The variant induced limited type III interferon expression and showed no significant impact on epithelial integrity. Further experiments revealed inefficient cell-to-cell spread and spike protein cleavage in the Omicron spike protein, possibly contributing to its lower infectious particle levels. The findings highlight the variant-specific replication differences in human colonoids, providing insights into the enteric tropism of Omicron and its relevance to long COVID symptoms.
Unveiling the nexus: Understanding post-COVID parkinsonism and its neurological ramifications
Kow CS, Ramachandram DS, Hasan SS and Thiruchelvam K
This article explores the potential link between COVID-19 and parkinsonism, synthesizing existing evidence and recent research findings. It highlights limitations in current understanding, emphasizes the direct impact of the virus on dopamine neurons, and calls for continued research to elucidate long-term neurological implications and optimize patient care strategies.
New-onset or relapse of uveitis after rapid spreading of COVID-19 infection in China and risk factor analysis for relapse
Wang K, Li J, Guo K and Zhang X
The aim of this study was to report the clinical profile of new-onset and relapse of uveitis following rapid spreading of coronavirus disease 2019 (COVID-19) infection due to change of anti-COVID-19 policies in China and investigate potential risk factors for inflammation relapse.
Changing epidemiology of parvovirus B19 in the Netherlands since 1990, including its re-emergence after the COVID-19 pandemic
Russcher A, van Boven M, Benincà E, Verweij EJTJ, Molenaar-de Backer MWA, Zaaijer HL, Vossen ACTM and Kroes ACM
Parvovirus B19V (B19V) infection during pregnancy can be complicated by potentially life-threatening fetal hydrops, which can be managed by intrauterine transfusion (IUT). This study investigates the long-term temporal patterns in the epidemiology of B19V and evaluates the impact on fetal hydrops, by combining data on B19V infections from the Dutch Sentinel Surveillance system in the period 1990 to 2023, Dutch blood banking data and hospital data on fetal hydrops. Using wavelet analysis, we identified annual epidemic cycles in the Netherlands in the period 1990-2019 and we identified superimposed multiannual cycles in the period 1990-2009. After 2009, no multiannual cycle could be identified, although the incidence fluctuated and correlates with number of IUT performed. As of 2020, weekly reports of B19V infection demonstrated a historically low incidence and B19V-DNA positive blood donors were nearly absent. From May 2020 to May 2023, no IUT for B19V-related hydrops was performed. In the spring of 2023, B19V infections re-emerged, reaching pre-pandemic epidemic levels. Due to the changes in B19V epidemiology over the last 30 years and the near-absence of B19V during the COVID-19 pandemic, the resulting low immunity levels may lead to rebound outbreaks. Alertness to severe complications such as fetal hydrops is warranted.
Cognitive performance of post-covid patients in mild, moderate, and severe clinical situations
de Pádua Serafim A, Saffi F, Soares ARA, Morita AM, Assed MM, de Toledo S, Rocca CCA and Durães RSS
Studying individuals with varying symptoms, from mild to severe, can provide valuable insights into the spectrum of cognitive outcomes after COVID-19. We investigated the cognitive performance of adults who recovered from the novel coronavirus disease (COVID-19) without prior cognitive complaints, considering mild (not hospitalized), moderate (ward), and severe (intensive care unit) symptoms.
Lessons we learned during the past four challenging years in the COVID-19 era: pharmacotherapy, long COVID complications, and vaccine development
Ghasemiyeh P and Mohammadi-Samani S
About four years have passed since the detection of the first cases of COVID-19 in China. During this lethal pandemic, millions of people have lost their lives around the world. Since the first waves of COVID-19 infection, various pharmacotherapeutic agents have been examined in the management of COVID-19. Despite all these efforts in pharmacotherapy, drug repurposing, and design and development of new drugs, multiple organ involvement and various complications occurred during COVID-19. Some of these complications became chronic and long-lasting which led to the "long COVID" syndrome appearance. Therefore, the best way to eradicate this pandemic is prophylaxis through mass vaccination. In this regard, various vaccine platforms including inactivated vaccines, nucleic acid-based vaccines (mRNA and DNA vaccines), adenovirus-vectored vaccines, and protein-based subunit vaccines have been designed and developed to prevent or reduce COVID-19 infection, hospitalization, and mortality rates. In this focused review, at first, the most commonly reported clinical presentations of COVID-19 during these four years have been summarized. In addition, different therapeutic regimens and their latest status in COVID-19 management have been listed. Furthermore, the "long COVID" and related signs, symptoms, and complications have been mentioned. At the end, the effectiveness of available COVID-19 vaccines with different platforms against early SARS-CoV-2 variants and currently circulating variants of interest (VOI) and the necessity of booster vaccine shots have been summarized and discussed in more detail.
Plasma Proteomics Elucidated a Protein Signature in COVID-19 Patients with Comorbidities and Early-Diagnosis Biomarkers
Urbiola-Salvador V, Lima de Souza S, Macur K, Czaplewska P and Chen Z
Despite great scientific efforts, deep understanding of coronavirus-19 disease (COVID-19) immunopathology and clinical biomarkers remains a challenge. Pre-existing comorbidities increase the mortality rate and aggravate the exacerbated immune response against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, which can result in more severe symptoms as well as long-COVID and post-COVID complications. In this study, we applied proteomics analysis of plasma samples from 28 patients with SARS-CoV-2, with and without pre-existing comorbidities, as well as their corresponding controls to determine the systemic protein changes caused by the SARS-CoV-2 infection. As a result, the protein signature shared amongst COVID-19 patients with comorbidities was revealed to be characterized by alterations in the coagulation and complement pathways, acute-phase response proteins, tissue damage and remodeling, as well as cholesterol metabolism. These altered proteins may play a relevant role in COVID-19 pathophysiology. Moreover, several novel potential biomarkers for early diagnosis of the SARS-CoV-2 infection were detected, such as increased levels of keratin K22E, extracellular matrix protein-1 (ECM1), and acute-phase response protein α-2-antiplasmin (A2AP). Importantly, elevated A2AP may contribute to persistent clotting complications associated with the long-COVID syndrome in patients with comorbidities. This study provides new insights into COVID-19 pathogenesis and proposes novel potential biomarkers for early diagnosis that could be facilitated for clinical application by further validation studies.
Platelet-Rich Plasma (PRP) in the Treatment of Long COVID Olfactory Disorders: A Comprehensive Review
Maniaci A, Lavalle S, Masiello E, Lechien JR, Vaira L, Boscolo-Rizzo P, Musa M, Gagliano C and Zeppieri M
Long COVID has brought numerous challenges to healthcare, with olfactory dysfunction (OD) being a particularly distressing outcome for many patients. The persistent loss of smell significantly diminishes the affected individual's quality of life. Recent attention has been drawn to the potential of platelet-rich plasma (PRP) therapy as a treatment for OD. This comprehensive review aims to evaluate the effectiveness of PRP therapy in ameliorating OD, especially when associated with long-term COVID-19. We executed a comprehensive search of the literature, encompassing clinical trials and observational studies that utilized PRP in treating OD limited to COVID-19. We retrieved and comprehensively discussed data such as design, participant demographics, and reported outcomes, focusing on the efficacy and safety of PRP therapy for OD in COVID-19 patients. Our comprehensive analysis interestingly found promising perspectives for PRP in OD following COVID-19 infection. The collective data indicate that PRP therapy contributed to a significant improvement in olfactory function after COVID-19 infection. The evidence amassed suggests that PRP is a promising and safe therapeutic option for OD, including cases attributable to Long COVID-19. The observed uniform enhancement of olfactory function in patients receiving PRP highlights the necessity for well-designed, controlled trials. Such studies would help to refine treatment protocols and more definitively ascertain the efficacy of PRP in a broader, more varied patient cohort.
Proposal and Definition of an Intelligent Clinical Decision Support System Applied to the Prediction of Dyspnea after 12 Months of an Acute Episode of COVID-19
Casal-Guisande M, Comesaña-Campos A, Núñez-Fernández M, Torres-Durán M and Fernández-Villar A
Long COVID is a condition that affects a significant proportion of patients who have had COVID-19. It is characterised by the persistence of associated symptoms after the acute phase of the illness has subsided. Although several studies have investigated the risk factors associated with long COVID, identifying which patients will experience long-term symptoms remains a complex task. Among the various symptoms, dyspnea is one of the most prominent due to its close association with the respiratory nature of COVID-19 and its disabling consequences. This work proposes a new intelligent clinical decision support system to predict dyspnea 12 months after a severe episode of COVID-19 based on the SeguiCovid database from the Álvaro Cunqueiro Hospital in Vigo (Galicia, Spain). The database is initially processed using a CART-type decision tree to identify the variables with the highest predictive power. Based on these variables, a cascade of expert systems has been defined with Mamdani-type fuzzy-inference engines. The rules for each system were generated using the Wang-Mendel automatic rule generation algorithm. At the output of the cascade, a risk indicator is obtained, which allows for the categorisation of patients into two groups: those with dyspnea and those without dyspnea at 12 months. This simplifies follow-up and the performance of studies aimed at those patients at risk. The system has produced satisfactory results in initial tests, supported by an AUC of 0.75, demonstrating the potential and usefulness of this tool in clinical practice.
Fibrinaloid Microclots and Atrial Fibrillation
Kell DB, Lip GYH and Pretorius E
Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis). Clots are, of course, a well-known of atrial fibrillation. We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF. We consider known 'risk factors' for AF, and in particular, exogenous stimuli such as infection and air pollution by particulates, both of which are known to cause AF. The external accompaniments of both bacterial (lipopolysaccharide and lipoteichoic acids) and viral (SARS-CoV-2 spike protein) infections are known to stimulate fibrinaloid microclots when added in vitro, and fibrinaloid microclots, as with other amyloid proteins, can be cytotoxic, both by inducing hypoxia/reperfusion and by other means. Strokes and thromboembolisms are also common consequences of AF. Consequently, taking a systems approach, we review the considerable evidence in detail, which leads us to suggest that it is likely that microclots may well have an aetiological role in the development of AF. This has significant mechanistic and therapeutic implications.
The Aftermath of COVID-19: Exploring the Long-Term Effects on Organ Systems
Golzardi M, Hromić-Jahjefendić A, Šutković J, Aydin O, Ünal-Aydın P, Bećirević T, Redwan EM, Rubio-Casillas A and Uversky VN
Post-acute sequelae of SARS-CoV-2 infection (PASC) is a complicated disease that affects millions of people all over the world. Previous studies have shown that PASC impacts 10% of SARS-CoV-2 infected patients of which 50-70% are hospitalised. It has also been shown that 10-12% of those vaccinated against COVID-19 were affected by PASC and its complications. The severity and the later development of PASC symptoms are positively associated with the early intensity of the infection.
COVID-19 booster vaccine uptake and reduced risks for long-COVID: A cross-sectional study of a U.S. adult population
Xie Z, Stallings-Smith S, Patel S, Case S and Hong YR
Long-COVID (having symptoms lasting 3 months or longer post-infection) is an emerging public health concern, yet research on whether COVID-19 booster vaccines can mitigate this condition is limited. This study examined associations between booster uptake and long-COVID prevalence among U.S. adults. Data were analyzed from 8757 adults aged 18 years or older with a history of COVID-19 infection from the 2022 National Health Interview Survey. Weighted prevalence and logistic regression models examined relationships between self-reported COVID-19 booster vaccination status and long-COVID, adjusting for sociodemographics and health factors. 19.5 % reported experiencing long-COVID. Individuals receiving the COVID-19 booster vaccine had significantly lower adjusted odds of long-COVID (OR 0.75, 95 % CI 0.61-0.93) compared to unvaccinated individuals. Overall, these findings suggest that COVID-19 booster vaccination is associated with a reduced prevalence of long-COVID among the U.S. adult population, underscoring the importance of optimizing booster uptake to mitigate the long-term impacts of COVID-19.
A report on neurogenic bladder in COVID-19 vaccine-associated acute transverse myelitis
Zainudin MF, Hasim MR, Martin CE and Chandrabose T
Acute transverse myelitis (ATM) is a rare neurological complication of Coronavirus disease (COVID-19) vaccines. Various vaccines have been linked to ATM, such as non-replicating viral vectors, ribonucleic acid, and inactivated vaccines. An ATM case is presented here involving the BNT162b2 vaccine leading to asymmetrical incomplete paraplegia and neurogenic bladder.
Spiritual Support Staff Influence Stress Among Hospital-Based Health Care Personnel: A Cross-Sectional Study
Rangel T, Timmerman R, Bock D, Keller M and Long J
Stress negatively affects well-being, relating to poor physical, emotional, and occupational outcomes for health care personnel. Health care professionals faced extreme stressors in the context of the COVID-19 pandemic, making occupational stress relief a top priority for hospital administrators. Many health systems employ specially trained spiritual support staff as one strategy to alleviate work-related stressors. It is unclear whether health care personnels' perceptions of the availability of spiritual care staff influence self-reported stress.
Unraveling the Complexities of Severe Acute Respiratory Syndrome Coronavirus 2: A Comprehensive Ophthalmic and Systemic Perspective
Neri P, Perez Y, Agarwal A and Pichi F
The editorial explores the profound implications of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, which emerged in December 2019 and rapidly evolved into a global health crisis. Despite initial focus on respiratory symptoms, the virus revealed significant ocular implications, prompting a reevaluation of the eye's role in its transmission, diagnosis, and systemic effects. The paradoxical nature of SARS-CoV-2-simultaneously novel and familiar within the coronavirus family-has been central to guiding the global medical response, including the swift development of vaccines. The pandemic has intensified research into the eye's susceptibility to viral infections, enhancing our understanding of virus-host interactions and the systemic impacts of viral diseases. The editorial delves into the pathophysiology of SARS-CoV-2, highlighting its potential to trigger autoinflammatory and autoimmune reactions with significant ocular repercussions. It examines the rapid vaccine development and deployment, the associated ocular side effects, and the ongoing research necessary to mitigate these outcomes. As the World Health Organization declared the end of COVID-19 as a public health emergency, the focus has shifted toward understanding the virus's long-term implications, including its effects on ocular health. This work underscores the critical role of interdisciplinary collaboration in addressing the systemic impacts of viral infections. It emphasizes the importance of ophthalmology in the broader context of public health and highlights the need for continued vigilance, research, and adaptation in a postpandemic world. The editorial calls for an integrated approach to health care, emphasizing the lessons learned from the SARS-CoV-2 pandemic to prepare for future health challenges, with a particular focus on the intersection of virology, immunology, and ophthalmology.
Researchers See Hope in Symptom-Guided Exercise for Long COVID With Postexertional Malaise
Bock A
Risk of major adverse cardiovascular events after SARS-CoV-2 infection in British Columbia: a population-based study
Velásquez García HA, Wong S, Jeong D, Binka M, Naveed Z, Wilton J, Hawkins NM and Janjua NZ
COVID-19 is associated with increased risk of post-acute cardiovascular outcomes. Population-based evidence for long periods of observation is still limited.
Outcome, predictors and longitudinal trajectories of subjects with critical illness polyneuropathy and myopathy (CINAMOPS): study protocol of an observational cohort study in a clinical and post-clinical setting
Bergmann J, Egger M, Müller F and Jahn K
Critical illness polyneuropathy and myopathy (CIP/CIM) are frequent complications in the intensive care unit (ICU) with major consequences for the progress and outcome of subjects. CIP/CIM delays the weaning process, prolongs the hospital stay and increases the mortality rate. Additionally, it may have long-term consequences beyond the hospitalisation phase with prolonged disability. Even though there is growing interest in CIP/CIM, research about the clinical and post-clinical course as well as the middle-term and long-term outcomes of subjects with CIP/CIM is scarce. A large prospective study of critically ill subjects is needed with accurate diagnosis during the acute stage and comprehensive assessment during long-term follow-up.
Physical activity and mental health in individuals with multimorbidity during COVID-19: an explanatory sequential mixed-method study
Ambrosio L, Faulkner J, Morris JH, Stuart B, Lambrick D, Compton E and Portillo MC
To understand the physical activity and mental health of individuals living with long-term conditions during the COVID-19 pandemic.
Screening Strategies to Reduce COVID-19 Mortality in Nursing Homes
Dong S, Jutkowitz E, Giardina J and Bilinski A
Nursing home residents continue to bear a disproportionate share of COVID-19 morbidity and mortality, accounting for 9% of all US COVID-19 deaths in 2023, despite comprising only 0.4% of the population.
The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China
Zuo W, He D, Liang C, Du S, Hua Z, Nie Q, Zhou X, Yang M, Tan H, Xu J, Yu Y, Zhan Y, Zhang Y, Gu X, Zhu W, Zhang H, Li H, Sun W, Sun M, Liu X, Liu L, Cao C, Li R, Li J, Zhang Y, Zhang Y, Guo J, Zhao L, Zhang CP, Liu H, Wang S, Xiao F, Wang Y, Wang Z, Li H and Cao B
Growing evidence suggests that symptoms associated with post-COVID-19 condition (also known as long COVID) can affect multiple organs and systems in the human body, but their association with viral persistence is not clear. The aim of this study was to investigate the persistence of SARS-CoV-2 in diverse tissues at three timepoints following recovery from mild COVID-19, as well as its association with long COVID symptoms.
Long COVID and SARS-CoV-2 persistence: new answers, more questions
Buonsenso D and Tantisira KG
A Host Receptor Nanodisc-Based Biosensor Platform for the Detection of a Specific Virus and Its Variants
Yoo J, Park I, Jwa S, Lee SH, Hong S and Park TH
The host receptor is a key element in the initial stage of the virus entry into the host. The use of this host receptor is valuable as a sensing element for selectively and sensitively detecting specific viruses. Also, viruses tend to escape neutralizing antibodies through viral mutation but still utilize the cell entry process using the same host receptors, so it would be a powerful detection tool even for the mutant viruses. The angiotensin-converting enzyme 2 (ACE2) receptor, which is the representative host receptor, performs an essential function in facilitating viral penetration by interacting with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. In this study, we introduce a novel approach, where we fabricated a carbon nanotube field-effect transistor (CNT-FET) sensor and combined it with ACE2 receptor-embedded nanodisc (ND). ACE2 was produced using an expression system, purified, and integrated into the ND platform. ACE2 NDs showed robust functionality through interactions with a pseudotyped virus (PV) containing the spike protein, enabling sensitive detection of both SARS-CoV-2 and its genetic variations at 10 PFU/mL. The ACE ND-based sensor exhibited excellent selectivity by accurately differentiating SARS-CoV-2 wild-type and variants (Omicron, Delta) from other viruses (ZIKA and MERS-CoV). As a result of comparative analysis, ACE2 ND showed approximately 49% superior long-term functionality up to the second week compared to that of soluble ACE2. These findings highlight the high selectivity and sensitivity of host receptor-based sensors for detecting viral variants and provide a promising tool to prevent the spread of unknown viruses.
Psychiatric Symptoms, Treatment Uptake, and Barriers to Mental Health Care Among US Adults With Post-COVID-19 Condition
Naik H, Tran KC, Staples JA, Perlis RH and Levin A
Psychiatric symptoms are reportedly common among adults with post-COVID-19 condition (PCC). However, nationally representative data regarding symptom prevalence, treatment uptake, and barriers to care are needed to inform the development of care models.
Identification of Age-Related Characteristic Genes Involved in Severe COVID-19 Infection Among Elderly Patients Using Machine Learning and Immune Cell Infiltration Analysis
Li H, Zhao J, Xing Y, Chen J, Wen Z, Ma R, Han F, Huang B, Wang H, Li C, Chen Y and Ning X
Elderly patients infected with severe acute respiratory syndrome coronavirus 2 are at higher risk of severe clinical manifestation, extended hospitalization, and increased mortality. Those patients are more likely to experience persistent symptoms and exacerbate the condition of basic diseases with long COVID-19 syndrome. However, the molecular mechanisms underlying severe COVID-19 in the elderly patients remain unclear. Our study aims to investigate the function of the interaction between disease-characteristic genes and immune cell infiltration in patients with severe COVID-19 infection. COVID-19 datasets (GSE164805 and GSE180594) and aging dataset (GSE69832) were obtained from the Gene Expression Omnibus database. The combined different expression genes (DEGs) were subjected to Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Diseases Ontology functional enrichment analysis, Gene Set Enrichment Analysis, machine learning, and immune cell infiltration analysis. GO and KEGG enrichment analyses revealed that the eight DEGs (IL23A, PTGER4, PLCB1, IL1B, CXCR1, C1QB, MX2, ALOX12) were mainly involved in inflammatory mediator regulation of TRP channels, coronavirus disease-COVID-19, and cytokine activity signaling pathways. Three-degree algorithm (LASSO, SVM-RFE, KNN) and correlation analysis showed that the five DEGs up-regulated the immune cells of macrophages M0/M1, memory B cells, gamma delta T cell, dendritic cell resting, and master cell resisting. Our study identified five hallmark genes that can serve as disease-characteristic genes and target immune cells infiltrated in severe COVID-19 patients among the elderly population, which may contribute to the study of pathogenesis and the evaluation of diagnosis and prognosis in aging patients infected with severe COVID-19.
Metacognitive Management of Attention in Online Learning
Hays MJ, Kustes SR and Bjork EL
Performance during training is a poor predictor of long-term retention. Worse yet, conditions of training that produce rapidly improving performance typically do not produce long-lasting, generalizable learning. As a result, learners and instructors alike can be misled into adopting training or educational experiences that are suboptimal for producing actual learning. Computer-based educational training platforms can counter this unfortunate tendency by providing only productive conditions of instruction-even if they are unintuitive (e.g., spacing instead of massing). The use of such platforms, however, introduces a different liability: being easy to interrupt. An assessment of this possible liability is needed given the enormous disruption to modern education brought about by COVID-19 and the subsequent widespread emergency adoption of computer-based remote instruction. The present study was therefore designed to (a) explore approaches for detecting interruptions that can be reasonably implemented by an instructor, (b) determine the frequency at which students are interrupted during a cognitive-science-based digital learning experience, and (c) establish the extent to which the pandemic and ensuing lockdowns affected students' metacognitive ability to maintain engagement with their digital learning experiences. Outliers in time data were analyzed with increasing complexity and decreasing subjectivity to identify when learners were interrupted. Results indicated that only between 1.565% and 3.206% of online interactions show evidence of learner interruption. And although classroom learning was inarguably disrupted by the pandemic, learning in the present, evidence-based platform appeared to be immune.
Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches
Molnar T, Lehoczki A, Fekete M, Varnai R, Zavori L, Erdo-Bonyar S, Simon D, Berki T, Csecsei P and Ezer E
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.
Modelling COVID-19 Vaccination in the UK: Impact of the Autumn 2022 and Spring 2023 Booster Campaigns
Mendes D, Machira Krishnan S, O'Brien E, Padgett T, Harrison C, Strain WD, Manca A, Ustianowski A, Butfield R, Hamson E, Reynard C and Yang J
The delivery of COVID-19 vaccines was successful in reducing hospitalizations and mortality. However, emergence of the Omicron variant resulted in increased virus transmissibility. Consequently, booster vaccination programs were initiated to decrease the risk of severe disease and death among vulnerable members of the population. This study aimed to estimate the effects of the booster program and alternative vaccination strategies on morbidity and mortality due to COVID-19 in the UK.
Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Nunes JM, Kell DB and Pretorius E
Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.
Influence of substance use on male reproductive health and offspring outcomes
Lo JO, Hedges JC, Chou WH, Tager KR, Bachli ID, Hagen OL, Murphy SK, Hanna CB and Easley CA
The prevalence of substance use globally is rising and is highest among men of reproductive age. In Africa, and South and Central America, cannabis use disorder is most prevalent and in Eastern and South-Eastern Europe, Central America, Canada and the USA, opioid use disorder predominates. Substance use might be contributing to the ongoing global decline in male fertility, and emerging evidence has linked paternal substance use with short-term and long-term adverse effects on offspring development and outcomes. This trend is concerning given that substance use is increasing, including during the COVID-19 pandemic. Preclinical studies have shown that male preconception substance use can influence offspring brain development and neurobehaviour through epigenetic mechanisms. Additionally, human studies investigating paternal health behaviours during the prenatal period suggest that paternal tobacco, opioid, cannabis and alcohol use is associated with reduced offspring mental health, in particular hyperactivity and attention-deficit hyperactivity disorder. The potential effects of paternal substance use are areas in which to focus public health efforts and health-care provider counselling of couples or individuals interested in conceiving.
Qualitative interview study of rheumatology patients' experiences of COVID-19 shielding to explore the physical and psychological impact and identify associated support needs
Silverthorne CA, Jones B, Brooke M, Coates LC, Orme J, Robson JC, Tillett W and Dures E
Many clinically extremely vulnerable rheumatology patients have only recently ceased shielding from COVID-19, while some continue to minimise in-person contact. The objective of this study was to understand the impact of shielding and associated support needs in patients with rheumatic conditions and to understand how rheumatology teams can meet these needs both currently and in future pandemics.
Exogenous Insulin Antibody Syndrome (EIAS) Presenting in an Elderly, Long-Term Patient with Type 1 Diabetes Mellitus that Resolved with Low-Cost Outpatient Therapy with Mycophenolate Mofetil and Regular Insulin by Pump
Jerkins T, Stockham K and Bell DSH
Exogenous insulin antibody syndrome (EIAS) has until recently been a rarely described complication of exogenous insulin therapy. EIAS results not only in hyperglycemia, but also in hypoglycemia and occasionally in ketoacidosis (DKA). The incidence of EIAS is increasing probably due to an overall increase in autoimmunity associated with the coronavirus disease 2019 (Covid-19) epidemic resulting in increasing binding of insulin by antibodies. Herein, we describe a case of EIAS occurring in an elderly patient with longstanding type 1 diabetes mellitus (T1DM) who had progressive loss of glycemic control. It responded positively, as we have previously described, to oral mycophenolate mofetil and the use of soluble regular insulin delivered by continuous subcutaneous insulin infusion (CSII). Therefore, EIAS is an increasingly frequent cause of hyperglycemia with and without DKA, and hypoglycemia in subjects with T1DM. Once diagnosed, they can be treated with mycophenolate mofetil and soluble insulin in an outpatient setting, which will decrease the rate of hospitalization and lower the expense of therapy.
Farmworker Mobility and COVID-19 Vaccination Strategies: Yuma County, Arizona, 2021
Franc KA, Phippard AE, Ruedas P, Pinto SJ, Mehta K, Montiel S, Contreras S, Katz H, McIntyre E, Lopez B, Kreutzberg-Martinez M, Steiner D, Gomez D and Merrill R
Farmworkers, a group of essential workers, experience a disproportionately high burden of COVID-19 due to their living and working conditions. This project characterized farmworker mobility in and around Yuma County, Arizona, to identify opportunities to improve farmworker access to COVID-19 vaccination. We collected qualitative and geospatial data through a series of in-person and virtual focus group discussions, key informant interviews, and intercept interviews with participatory mapping. Participants included farmworkers, employers, and representatives of local institutions who serve or interact with farmworkers. We identified participants through purposive and referential sampling and grouped people by sociodemographic characteristics for interviews. We used qualitative and geospatial analyses to identify common themes and mobility patterns. The team interviewed 136 people from February 26 to April 2, 2021. Common themes emerged about how farmworkers have little or no access to COVID-19 vaccination unless offered at their workplaces or at locations where they congregate at convenient times. Further, farmworkers described how their demanding work schedules, long commute times, and caretaker commitments make it challenging to access vaccination services. Geospatial analyses identified three geographic areas in Yuma County where farmworkers reported living and working that did not have a COVID-19 vaccine clinic within walking distance. Coordination between local public health authorities and key partners, including employers and trusted representatives from local community-based organizations or the Mexican consulate, to offer vaccination at worksites or other locations where farmworkers congregate can help improve access to COVID-19 vaccines and booster doses for this population.
Perception of In-Person Prerounding Amongst Neurology Residents Across Two Academic Centers
Chen A, Prasad S, Bowley M, Krupat E and Galetta K
In-person prerounding has long been a routine practice for residents in the field of neurology. However, with the emergence of the COVID-19 pandemic, many institutions, including our two academic neurology centers, have shifted to computer rounding. This study aims to assess the effects of computer rounding alone compared to a combination of computer rounding and in-person prerounding from the perspective of neurology residents.
Understanding the psychological impact of identifying carrier status on young adults: A qualitative study exploring peer reactions
Bowen E, Langston J, Fletcher H, Domek J and Ulph F
The benefits and harms of identifying carriers in childhood have long been debated with European Guidelines advising against this practice. Yet over a thousand carriers are identified via newborn bloodspot screening per year in the United Kingdom alone. One of the concerns about identification is the impact it has on an individual's identity. This, in part, will be determined by how parents and peers view carriers, particularly during young adulthood. To address the paucity of research looking at how carriers are perceived by peers, this study sought to explore the views of young adults, who themselves are not carriers, toward carriers. As the narratives around COVID-19 increased, the salience of the term "carrier", the impact of such narratives on perceptions, was also explored. Twenty-five 18-25 year olds participated in a diary-interview study in the United Kingdom during 2021 to explore their perceptions of carriers via hypothetical scenarios. Data were analyzed using thematic analysis. Interviewees believed carriers would experience stigma-including societal and self-stigma. This was because people used existing illness beliefs to make sense of carrier status about which they had low levels of understanding. Interviewees believed carriers would experience challenges in familial and romantic relationships due to others' judgments. They also believed parents of carriers would experience a burden around making reproductive decisions, with clear views on what society would view as acceptable choices. Importantly interviewees felt knowledge of ones' own carrier status conferred complex communication challenges within relationships. These findings suggest an urgent need for more research and support for young adults entering a key stage in life for identity formation who have knowledge of their carrier status. The results suggest that support targeted toward the carrier regarding navigating complex communication and targeted more broadly to avoid stigma based on misunderstanding should be researched and developed.
Construction and efficacy testing of DNA vaccines containing HLA-A*02:01-restricted SARS-CoV-2 T-cell epitopes predicted by immunoinformatics
Tan D, Kang N, Zhu Y, Hou J, Wang H, Xu H, Zu C, Gao Z, Liu M, Liu N, Deng Q, Lu H, Liu J and Xie Y
Vaccines play essential roles in the fight against the COVID-19 pandemic. The development and assessment of COVID-19 vaccines have generally focused on the induction and boosting of neutralizing antibodies targeting the SARS-CoV-2 spike (S) protein. Due to rapid and continuous variation in the S protein, such vaccines need to be regularly updated to match newly emerged dominant variants. T-cell vaccines that target MHC I- or II-restricted epitopes in both structural and non-structural viral proteins have the potential to induce broadly cross-protective and long-lasting responses. In this work, the entire proteome encoded by SARS-CoV-2 (Wuhan-hu-1) is subjected to immunoinformatics-based prediction of HLA-A*02:01-restricted epitopes. The immunogenicity of the predicted epitopes is evaluated using peripheral blood mononuclear cells from convalescent Wuhan-hu-1-infected patients. Furthermore, predicted epitopes that are conserved across major SARS-CoV-2 lineages and variants are used to construct DNA vaccines expressing multi-epitope polypeptides. Most importantly, two DNA vaccine constructs induce epitope-specific CD8 T-cell responses in a mouse model of HLA-A*02:01 restriction and protect immunized mice from challenge with Wuhan-hu-1 virus after hACE2 transduction. These data provide candidate T-cell epitopes useful for the development of T-cell vaccines against SARS-CoV-2 and demonstrate a strategy for quick T-cell vaccine candidate development applicable to other emerging pathogens.
CREATE'ing improvements in first-year students' science efficacy via an online introductory course experience
Garzke J and Steinwand BJ
With a primary objective to engage students in the process of science online, we transformed a long-standing laboratory course for first-year science students into a more accessible, immersive experience of current biological research using a narrow and focused set of primary literature and the Consider, Read, Elucidate a hypothesis, Analyze and interpret data, Think of the next Experiment (CREATE) pedagogy. The efficacy of the CREATE approach has been demonstrated in a diversity of higher education settings and courses. It is, however, not yet known if CREATE can be successfully implemented online with a large, diverse team of faculty untrained in the CREATE pedagogy. Here, we present the transformation of a large-enrollment, multi-section, multi-instructor course for first-year students in which the instructors follow different biological research questions but work together to reach shared goals and outcomes. We assessed students' (i) science self-efficacy and (ii) epistemological beliefs about science throughout an academic year of instruction fully administered online as a result of ongoing threats posed by COVID-19. Our findings demonstrate that novice CREATE instructors with varying levels of teaching experience and ranks can achieve comparable outcomes and improvements in students' science efficacy in the virtual classroom as a teaching team. This study extends the use of the CREATE pedagogy to large, team-taught, multi-section courses and shows its utility in the online teaching and learning environment.
COVID-19 Vaccination-Related Myocarditis: What We Learned From Our Experience and What We Need to Do in The Future
Park JH and Kim KH
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has led to a global health crisis with substantial mortality and morbidity. To combat the COVID-19 pandemic, various vaccines have been developed, but unexpected serious adverse events including vaccine-induced thrombotic thrombocytopenia, carditis, and thromboembolic events have been reported and became a huddle for COVID-19 vaccination. Vaccine-related myocarditis (VRM) is a rare but significant adverse event associated primarily with mRNA vaccines. This review explores the incidence, risk factors, clinical presentation, pathogenesis, management strategies, and outcomes associated with VRM. The incidence of VRM is notably higher in male adolescents and young adults, especially after the second dose of mRNA vaccines. The pathogenesis appears to involve an immune-mediated process, but the precise mechanism remains mostly unknown so far. Most studies have suggested that VRM is mild and self-limiting, and responds well to conventional treatment. However, a recent nationwide study in Korea warns that severe cases, including fulminant myocarditis or death, are not uncommon in patients with COVID-19 VRM. The long-term cardiovascular consequences of VRM have not been well understood and warrant further investigation. This review also briefly addresses the critical balance between the substantial benefits of COVID-19 vaccination and the rare risks of VRM in the coming endemic era. It emphasizes the need for continued surveillance, research to understand the underlying mechanisms, and strategies to mitigate risk. Filling these knowledge gaps would be vital to refining vaccination recommendations and improving patient care in the evolving COVID-19 pandemic landscape.
Long COVID Characteristics and Experience: A Descriptive Study from the Yale LISTEN Research Cohort
Sawano M, Wu Y, Shah RM, Zhou T, Arun AS, Khosla P, Kaleem S, Vashist A, Bhattacharjee B, Ding Q, Lu Y, Caraballo C, Warner F, Huang C, Herrin J, Putrino D, Michelsen T, Fisher L, Adinig C, Iwasaki A and Krumholz HM
To describe the experience of people with long COVID symptomatology and characterize the psychological, social, and financial challenges they experience.
Loneliness and Mortality Risk Among Cancer Survivors in the United States: A Retrospective, Longitudinal Study
Zhao J, Reese JB, Han X and Yabroff KR
Loneliness, a subjective feeling of being isolated, is a prevalent concern for elderly people and more so among cancer survivors because a cancer diagnosis and its subsequent treatment may result in long-term adverse health effects. This study aimed to examine the association of loneliness and mortality risk among cancer survivors in the United States.
Long COVID exhibits clinically distinct phenotypes at 3-6 months post-SARS-CoV-2 infection: results from the P4O2 consortium
Blankestijn JM, Abdel-Aziz MI, Baalbaki N, Bazdar S, Beekers I, Beijers RJHCG, Bloemsma LD, Cornelissen MEB, Gach D, Houweling L, Holverda S, Jacobs JJL, Jonker R, van der Lee I, Linders PMA, Mohamed Hoesein FAA, Noij LCE, Nossent EJ, van de Pol MA, Schaminee DW, Schols AMWJ, Schuurman LT, Sondermeijer B, Geelhoed JJM, van den Bergh JP, Weersink EJM, de Wit-van Wijck Y, Maitland-van der Zee AH and
Four months after SARS-CoV-2 infection, 22%-50% of COVID-19 patients still experience complaints. Long COVID is a heterogeneous disease and finding subtypes could aid in optimising and developing treatment for the individual patient.
Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial
Xu J, Wang BY, Yu SH, Chen SJ, Yang SS, Liu R, Chen LJ, Hou J, Chen Z, Zhao WH, He AL, Mi JQ and Chen SJ
The autologous anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up.
Analysing the patient experience of COVID-19: Exploring patients' experiences of hospitalisation and their quality of life post discharge
Reay A, Dismore L, Aujayeb A, Dotchin C, Tullo E, Steer J and Swainston K
We sought to gain an understanding of the patient experience during their hospital stay for COVID-19, and the impact of COVID-19 on quality of life post discharge.
Unleashing the potential of mRNA therapeutics for inherited neurological diseases
Monfrini E, Baso G, Ronchi D, Meneri M, Gagliardi D, Quetti L, Verde F, Ticozzi N, Ratti A, Di Fonzo A, Comi GP, Ottoboni L and Corti S
Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments. Notably, mRNA therapy exhibits significant potential as a mutation-agnostic approach that can address virtually any monogenic loss-of-function disease. Therapeutic mRNA carries the information for a healthy copy of the defective protein, bypassing the problem of targeting specific genetic variants. Moreover, unlike conventional gene therapy, mRNA-based drugs are delivered through a simplified process that requires only transfer to the cytoplasm, thereby reducing the mutagenic risks related to DNA integration. Additionally, mRNA therapy exerts a transient effect on target cells, minimizing the risk of long-term unintended consequences. The remarkable success of mRNA technology for developing COVID-19 vaccines has rekindled interest in mRNA as a cost-effective method for delivering therapeutic proteins. However, further optimization is required to enhance mRNA delivery, particularly to the central nervous system, while minimizing adverse drug reactions and toxicity. In this comprehensive review, we delve into past, present, and ongoing applications of mRNA therapy for neurological monogenic loss-of-function diseases. We also discuss the promises and potential challenges presented by mRNA therapeutics in this rapidly advancing field. Ultimately, we underscore the full potential of mRNA therapy as a game-changing therapeutic approach for neurological disorders.
Gustatory dysfunction and long COVID in Chinese patients with COVID-19: A 6-month follow-up study
Wei J, Lu C, Ding Y, Lu Y, Yang X, Zhang X and Tang G
To evaluate long COVID of gustatory dysfunction and the associated risk factors regarding onset and recovery in Chinese patients.
Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial
Kessing LV, Knudsen MB, Rytgaard HCW, Torp-Pedersen C and Berk M
Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.
Association of socioeconomic disadvantage and ethnicity with perinatal neonatal, and infant mortality in Slovakia
Bosakova L, Rosicova K and Filakovska Bobakova D
Infant mortality rates are reliable indices of the child and general population health status and health care delivery. The most critical factors affecting infant mortality are socioeconomic status and ethnicity. The aim of this study was to assess the association between socioeconomic disadvantage, ethnicity, and perinatal, neonatal, and infant mortality in Slovakia before and during the COVID-19 pandemic.
Exploring the Prevalence of Tinnitus and Ear-Related Symptoms in China After the COVID-19 Pandemic: Online Cross-Sectional Survey
Wang D, Li P, Huang X, Liu Y, Mao S, Yin H, Wang N, Luo Y and Sun S
Tinnitus is a complex and heterogeneous disease that has been identified as a common manifestation of COVID-19. To gain a comprehensive understanding of tinnitus symptoms in individuals following COVID-19 infection, we conducted an online survey called the China Ear Nose and Throat Symptom Survey in the COVID-19 Pandemic (CENTSS) among the Chinese population.
Psychiatric outcomes in outpatients affected by long COVID: A link between mental health and persistence of olfactory complaint
Metelkina-Fernandez V, Dumas LE, Vandersteen C, Chirio D, Gros A, Fernandez A, Askenazy F and Manera V
Anosmia was one of the main symptoms of coronavirus disease 2019 (COVID-19). A psychiatric history ( depression) may be an independent contributor to the risk of COVID-19 diagnosis, and COVID-19 survivors appear to have an increased risk of neuropsychiatric sequelae (bidirectional association).
Neuropsychological functioning of pediatric patients with long COVID
Luedke JC, Vargas G, Jashar DT, Malone LA, Morrow A and Ng R
: To determine the neurocognitive profile for youth with long COVID presenting with cognitive concerns. : This study is a case series of 54 pediatric patients (65% female, = 13.48, = 3.10, 5-19) with long COVID who were referred for neuropsychological testing from a post-COVID-19 multidisciplinary clinic. The outcomes of interest were neuropsychological test scores and parent ratings of mood, attention, and executive functioning. The percentage of patients with neuropsychological test scores below the 9th percentile (below average range) and those with at-risk or clinically significant scores (T-scores > 59) on parent-informant inventories were computed. : A portion of children with long COVID showed weaknesses in sustained attention (29%) and divided attention (35%). This portion of patients did not significantly differ when comparing patients with and without pre-existing attention and mood concerns. A high percentage of parents reported at-risk to clinically significant concerns for cognitive regulation (53%), depression (95%), anxiety (85%), and inattention (66%) on standardized questionnaires. : The present case series showed that approximately a third of children with long COVID demonstrate objective weaknesses on sustained and divided attention tasks but were largely intact in other domains of neuropsychological functioning. Importantly, children with long COVID had similar difficulties in attention, regardless of pre-existing attention or mood concerns. Parents reported high rates of mood, anxiety, and executive functioning difficulties which likely impact daily functioning. Attention and emotional regulation should be closely monitored and treated as necessary in pediatric patients with long COVID to aid functional recovery.
Transformation of Mandatory Physiotherapy Internship into A Structured Competency-Based Program: A Pilot Study
Nair SP, Kini R and P Panhale V
Health professions education is challenging in terms of developing ways to construct and assess the amalgamation of knowledge, skills and attitudes that result in novice graduates to be self-aware and confident to practice without supervision. Currently, the Physiotherapy internship program in India does not have a comprehensive competency-based framework. With the current batch of interns facing the wrath of the COVID-19 pandemic during their undergraduate training, it is a matter of concern to ensure they have developed the required competencies to handle patients independently.
Clinical features of patients with rheumatic and musculoskeletal diseases during the coronavirus disease 2019 pandemic and the association of its relapse with infection: Across-sectional study
Zhang Y, Xu P, Huang J and Hu Z
The aim of this study was to investigate the clinical features of patients with rheumatic and musculoskeletal diseases (RMDs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the relationship between RMDs relapse and SARS-CoV-2 infection.
From Psychostasis to the Discovery of Cardiac Nerves: The Origins of the Modern Cardiac Neuromodulation Concept
Paradiso B, Pauza DH, Limback C, Ottaviani G and Thiene G
This review explores the historical development of cardiology knowledge, from ancient Egyptian psychostasis to the modern comprehension of cardiac neuromodulation. In ancient Egyptian religion, psychostasis was the ceremony in which the deceased was judged before gaining access to the afterlife. This ritual was also known as the "weighing of the heart" or "weighing of the soul". The Egyptians believed that the heart, not the brain, was the seat of human wisdom, emotions, and memory. They were the first to recognize the cardiocentric nature of the body, identifying the heart as the center of the circulatory system. Aristotle (fourth century BC) considered the importance of the heart in human physiology in his philosophical analyses. For Galen (third century AD), the heart muscle was the site of the vital spirit, which regulated body temperature. Cardiology knowledge advanced significantly in the 15th century, coinciding with Leonardo da Vinci and Vesalius's pioneering anatomical and physiological studies. It was William Harvey, in the 17th century, who introduced the concept of cardiac circulation. Servet's research and Marcello Malpighi's discovery of arterioles and capillaries provided a more detailed understanding of circulation. Richard Lower emerged as the foremost pioneer of experimental cardiology in the late 17th century. He demonstrated the heart's neural control by tying off the vagus nerve. In 1753, Albrecht von Haller, a professor at Göttingen, was the first to discover the heart's automaticity and the excitation of muscle fibers. Towards the end of the 18th century, Antonio Scarpa challenged the theories of Albrecht von Haller and Johann Bernhard Jacob Behrends, who maintained that the myocardium possessed its own "irritability", on which the heartbeat depended, and was independent of neuronal sensitivity. Instead, Scarpa argued that the heart required innervation to maintain life, refuting Galenic notions. In contemporary times, the study of cardiac innervation has regained prominence, particularly in understanding the post-acute sequelae of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection (PASC), which frequently involves cardiorespiratory symptoms and dysregulation of the intrinsic cardiac innervation. Recently, it has been recognized that post-acute sequelae of acute respiratory infections (ARIs) due to other pathogens can also be a cause of long-term vegetative and somatic symptoms. Understanding cardiac innervation and modulation can help to recognize and treat long COVID and long non-COVID-19 (coronavirus disease 2019) ARIs. This analysis explores the historical foundations of cardiac neuromodulation and its contemporary relevance. By focusing on this concept, we aim to bridge the gap between historical understanding and modern applications. This will illuminate the complex interplay between cardiac function, neural modulation, cardiovascular health, and disease management in the context of long-term cardiorespiratory symptoms and dysregulation of intrinsic cardiac innervations.
Long-Term Corneal Endothelial Parameters of COVID-19 Patients With Ocular Surface Symptoms
Kılıçarslan O, Yılmaz Çebi A, Doğan C and Arslan OŞ
This study aimed to investigate the long-term effects of COVID-19 on corneal endothelial cell morphology in patients with ocular symptoms to assess possible corneal involvement in patients who recovered.
Long-term monitoring of SARS-CoV-2 seroprevalence and variants in Ethiopia provides prediction for immunity and cross-immunity
Merkt S, Ali S, Gudina EK, Adissu W, Gize A, Muenchhoff M, Graf A, Krebs S, Elsbernd K, Kisch R, Betizazu SS, Fantahun B, Bekele D, Rubio-Acero R, Gashaw M, Girma E, Yilma D, Zeynudin A, Paunovic I, Hoelscher M, Blum H, Hasenauer J, Kroidl A and Wieser A
Under-reporting of COVID-19 and the limited information about circulating SARS-CoV-2 variants remain major challenges for many African countries. We analyzed SARS-CoV-2 infection dynamics in Addis Ababa and Jimma, Ethiopia, focusing on reinfection, immunity, and vaccination effects. We conducted an antibody serology study spanning August 2020 to July 2022 with five rounds of data collection across a population of 4723, sequenced PCR-test positive samples, used available test positivity rates, and constructed two mathematical models integrating this data. A multivariant model explores variant dynamics identifying wildtype, alpha, delta, and omicron BA.4/5 as key variants in the study population, and cross-immunity between variants, revealing risk reductions between 24% and 69%. An antibody-level model predicts slow decay leading to sustained high antibody levels. Retrospectively, increased early vaccination might have substantially reduced infections during the delta and omicron waves in the considered group of individuals, though further vaccination now seems less impactful.
Multimorbidity in middle-aged women and COVID-19: binary data clustering for unsupervised binning of rare multimorbidity features and predictive modeling
Benny D, Giacobini M, Costa G, Gnavi R and Ricceri F
Multimorbidity is typically associated with deficient health-related quality of life in mid-life, and the likelihood of developing multimorbidity in women is elevated. We address the issue of data sparsity in non-prevalent features by clustering the binary data of various rare medical conditions in a cohort of middle-aged women. This study aims to enhance understanding of how multimorbidity affects COVID-19 severity by clustering rare medical conditions and combining them with prevalent features for predictive modeling. The insights gained can guide the development of targeted interventions and improved management strategies for individuals with multiple health conditions.
The gut microbiome associates with phenotypic manifestations of post-acute COVID-19 syndrome
Su Q, Lau RI, Liu Q, Li MKT, Yan Mak JW, Lu W, Lau ISF, Lau LHS, Yeung GTY, Cheung CP, Tang W, Liu C, Ching JYL, Cheong PK, Chan FKL and Ng SC
The mechanisms underlying the many phenotypic manifestations of post-acute COVID-19 syndrome (PACS) are poorly understood. Herein, we characterized the gut microbiome in heterogeneous cohorts of subjects with PACS and developed a multi-label machine learning model for using the microbiome to predict specific symptoms. Our processed data covered 585 bacterial species and 500 microbial pathways, explaining 12.7% of the inter-individual variability in PACS. Three gut-microbiome-based enterotypes were identified in subjects with PACS and associated with different phenotypic manifestations. The trained model showed an accuracy of 0.89 in predicting individual symptoms of PACS in the test set and maintained a sensitivity of 86% and a specificity of 82% in predicting upcoming symptoms in an independent longitudinal cohort of subjects before they developed PACS. This study demonstrates that the gut microbiome is associated with phenotypic manifestations of PACS, which has potential clinical utility for the prediction and diagnosis of PACS.
Towards understanding post-COVID-19 condition: A systematic meta-analysis of transcriptomic alterations with sex-specific insights
Rusu EC, Monfort-Lanzas P, Bertran L, Barrientos-Riosalido A, Solé E, Mahmoudian R, Aguilar C, Briansó S, Mohamed F, Garcia S, Camaron J and Auguet T
Post COVID-19 Condition (PCC), characterized by lingering symptoms post-acute COVID-19, poses clinical challenges, highlighting the need to understand its underlying molecular mechanisms. This meta-analysis aims to shed light on the transcriptomic landscapes and sex-specific molecular dynamics intrinsic to PCC.
A randomized clinical trial investigating the impact of magnesium supplementation on clinical and biochemical measures in COVID-19 patients
Rostami S, Alavi SM, Daghagheleh R, Maraghi E and Hosseini SA
This study sought to examine the impact of magnesium supplementation on clinical outcomes and biochemical factors among hospitalized patients with COVID-19.
Achalasia Following SARS-CoV-2 Infection: A Case Report and Review of Literature
Huang J, Su H, Lin J, Zhu F, Jiang X and Pan J
The COVID-19 pandemic caused by the SARS-CoV-2 virus has led to health complications beyond respiratory symptoms, revealing multi-organ involvement, including potential gastrointestinal implications.
Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa
Chopra P, Tomar AK, Thapliyal A, Ranjan P, Datta SK and Yadav S
Following an initial recovery, COVID-19 survivors struggle with a spectrum of persistent medical complications, including fatigue, breathlessness, weight loss, hair loss, and attention deficits. Additionally, there is growing evidence of adverse effects of COVID-19 on the male reproductive system. This investigation seeks to understand the long-term ramifications on male fertility by examining hormonal profiles, semen parameters, and sperm proteome of recovered COVID-19 patients compared to controls. The serum hormone profiles between the two groups showed minimal variations except for prolactin, cortisol, and testosterone levels. Testosterone levels were slightly lower, while prolactin and cortisol were elevated in COVID-19 cases compared to controls. Though semen parameters exhibited no significant disparities between the COVID-19 and control groups, quantitative proteomics analysis revealed changes in sperm proteins. It identified 190 differentially expressed proteins, of which 161 were upregulated and 29 downregulated in COVID-19 cases. Western blotting analysis validated the differential expression of serpin B4 and calpain 2. Bioinformatics analysis signifies cellular stress in the spermatozoa of COVID-19 recovered patients and thus, SOD and MDA levels in semen were measured. MDA levels were found to be significantly elevated, indicating lipid peroxidation in COVID-19 samples. While the effects of COVID-19 on semen parameters may exhibit a potential for reversal within a short duration, the alterations it inflicts on sperm proteome are persisting consequences on male fertility. This study paves the path for further research and emphasizes the significance of comprehending the complex molecular processes underlying the long-term consequences of COVID-19 on male reproductive health.
Systemic glucocorticoids link to long-term microvascular injury in COVID-19
Yang Q, Xia CY, Cai Y, Zhang YF, Li DT, Wu SQ and Hu P
Practical Recommendations for Exercise Training in Patients with Long COVID with or without Post-exertional Malaise: A Best Practice Proposal
Gloeckl R, Zwick RH, Fürlinger U, Schneeberger T, Leitl D, Jarosch I, Behrends U, Scheibenbogen C and Koczulla AR
People with long COVID may suffer from a wide range of ongoing symptoms including fatigue, exertional dyspnea, reduced exercise performance, and others. In particular, impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program. However, clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID. Currently, there is no guideline or consensus available on how to apply exercise training in this cohort. Therefore, we conducted a literature review in the PubMed library using the following search terms: "COVID", "post-COVID", "long COVID" and "exercise" searching for studies from January 2020 to January 2024. Data from 46 trials were included. Exercise training regimes were very heterogeneous and none of these studies reported on the management of PEM in the context of an exercise training program. Based on the feedback from an additional survey that was answered by 14 international experts in the field of exercise training in long COVID, combined with the authors´ own extensive practical experience, a best practice proposal for exercise training recommendations has been developed. This proposal differentiates exercise procedures according to the presence of no, mild/moderate or severe PEM in people with long COVID. These recommendations may guide allied healthcare professionals worldwide in initiating and adjusting exercise training programs for people with long COVID, stratified according to the presence and severity of PEM.
Post-COVID Trajectory of Pentraxin 3 Plasma Levels Over 6 Months and Their Association with the Risk of Developing Post-Acute Depression and Anxiety
De Lorenzo R, Mazza MG, Sciorati C, Leone R, Scavello F, Palladini M, Merolla A, Ciceri F, Bottazzi B, Garlanda C, Benedetti F, Rovere-Querini P and Manfredi AA
Clinical manifestations of coronavirus disease 2019 (COVID-19) often persist after acute disease resolution. Underlying molecular mechanisms are unclear. The objective of this original article was to longitudinally measure plasma levels of markers of the innate immune response to investigate whether they associate with and predict post-COVID symptomatology.
Adoption and Use of Telemedicine and Digital Health Services Among Older Adults in Light of the COVID-19 Pandemic: Repeated Cross-Sectional Analysis
Haimi M and Sergienko R
As the population ages and the prevalence of long-term diseases rises, the use of telecare is becoming increasingly frequent to aid older people.
Markov chain-based impact analysis of the pandemic Covid-19 outbreak on global primary energy consumption mix
Ahmad H, Liaqat R, Alhussein M, Muqeet HA, Aurangzeb K and Ashraf HM
The historic evolution of global primary energy consumption (GPEC) mix, comprising of fossil (liquid petroleum, gaseous and coal fuels) and non-fossil (nuclear, hydro and other renewables) energy sources while highlighting the impact of the novel corona virus 2019 pandemic outbreak, has been examined through this study. GPEC data of 2005-2021 has been taken from the annually published reports by British Petroleum. The equilibrium state, a property of the classical predictive modeling based on Markov chain, is employed as an investigative tool. The pandemic outbreak has proved to be a blessing in disguise for global energy sector through, at least temporarily, reducing the burden on environment in terms of reducing demand for fossil energy sources. Some significant long term impacts of the pandemic occurred in second and third years (2021 and 2022) after its outbreak in 2019 rather than in first year (2020) like the penetration of other energy sources along with hydro and renewable ones in GPEC. Novelty of this research lies within the application of the equilibrium state feature of compositional Markov chain based prediction upon GPEC mix. The analysis into the past trends suggests the advancement towards a better global energy future comprising of cleaner fossil resources (mainly natural gas), along with nuclear, hydro and renewable ones in the long run.
Decoding Post-Viral Fatigue: The Basal Ganglia's Complex Role in Long-COVID
Rudroff T
Long-COVID afflicts millions with relentless fatigue, disrupting daily life. The objective of this narrative review is to synthesize current evidence on the role of the basal ganglia in long-COVID fatigue, discuss potential mechanisms, and highlight promising therapeutic interventions. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases. Mounting evidence from PET, MRI, and functional connectivity data reveals basal ganglia disturbances in long-COVID exhaustion, including inflammation, metabolic disruption, volume changes, and network alterations focused on striatal dopamine circuitry regulating motivation. Theories suggest inflammation-induced signaling disturbances could impede effort/reward valuation, disrupt cortical-subcortical motivational pathways, or diminish excitatory input to arousal centers, attenuating drive initiation. Recent therapeutic pilots targeting basal ganglia abnormalities show provisional efficacy. However, heterogeneous outcomes, inconsistent metrics, and perceived versus objective fatigue discrepancies temper insights. Despite the growing research, gaps remain in understanding the precise pathways linking basal ganglia dysfunction to fatigue and validating treatment efficacy. Further research is needed to advance understanding of the basal ganglia's contribution to long-COVID neurological sequelae and offer hope for improving function across the expanding affected population.
Association between Gut Microbiota Composition and Long-Term Vaccine Immunogenicity following Three Doses of CoronaVac
Zhang LN, Tan JT, Ng HY, Liao YS, Zhang RQ, Chan KH, Hung IF, Lam TT and Cheung KS
Neutralizing antibody level wanes with time after COVID-19 vaccination. We aimed to study the relationship between baseline gut microbiota and immunogenicity after three doses of CoronaVac.
Device-Associated Infections in COVID-19 Patients: Frequency of Resistant Bacteria, Predictors and Mortality in Medellín, Colombia
Ocampo DP, Echeverri-Toro LM, Jiménez JN, Salazar L, Vargas C, Roncancio G, Roa MA and Vanegas JM
Increased antimicrobial use during the COVID-19 pandemic has raised concerns about the spread of resistant bacteria. This study analyzed the frequency of device-associated infections (DAI) caused by resistant bacteria, the predictors of these infections, and 30-day all-cause mortality in patients with and without COVID-19.
Effects of Hyperbaric Oxygen Therapy on Long COVID: A Systematic Review
Wu BQ, Liu DY, Shen TC, Lai YR, Yu TL, Hsu HL, Lee HM, Liao WC and Hsia TC
The coronavirus disease (COVID-19) pandemic has resulted in an increasing population that is experiencing a wide range of long-lasting symptoms after recovery from the acute infection. Long COVID refers to this specific condition and is associated with diverse symptoms, such as fatigue, myalgias, dyspnea, headache, cognitive impairment, neurodegenerative symptoms, anxiety, depression, and a sense of despair. The potential of hyperbaric oxygen therapy (HBOT) to improve chronic fatigue, cognitive impairments, and neurological disorders has been established; therefore, the use of HBOT to treat long COVID has also been studied. We conducted a literature search between 1 January 2019 and 30 October 2023, focusing on the clinical efficacy and utility of HBOT for treating long COVID and found ten clinical studies that fit the review topic, including one case report, five one-group pretest-posttest design studies, one safety report from a randomized controlled trial (RCT), and three complete reports of RCTs. Most studies found that HBOT can improve quality of life, fatigue, cognition, neuropsychiatric symptoms, and cardiopulmonary function. Although HBOT has shown some benefits for long COVID symptoms, further rigorous large-scale RCTs are required to establish precise indications, protocols, and post-treatment evaluations.
Hybrid-Capture Target Enrichment in Human Pathogens: Identification, Evolution, Biosurveillance, and Genomic Epidemiology
Quek ZBR and Ng SH
High-throughput sequencing (HTS) has revolutionised the field of pathogen genomics, enabling the direct recovery of pathogen genomes from clinical and environmental samples. However, pathogen nucleic acids are often overwhelmed by those of the host, requiring deep metagenomic sequencing to recover sufficient sequences for downstream analyses (e.g., identification and genome characterisation). To circumvent this, hybrid-capture target enrichment (HC) is able to enrich pathogen nucleic acids across multiple scales of divergences and taxa, depending on the panel used. In this review, we outline the applications of HC in human pathogens-bacteria, fungi, parasites and viruses-including identification, genomic epidemiology, antimicrobial resistance genotyping, and evolution. Importantly, we explored the applicability of HC to clinical metagenomics, which ultimately requires more work before it is a reliable and accurate tool for clinical diagnosis. Relatedly, the utility of HC was exemplified by COVID-19, which was used as a case study to illustrate the maturity of HC for recovering pathogen sequences. As we unravel the origins of COVID-19, zoonoses remain more relevant than ever. Therefore, the role of HC in biosurveillance studies is also highlighted in this review, which is critical in preparing us for the next pandemic. We also found that while HC is a popular tool to study viruses, it remains underutilised in parasites and fungi and, to a lesser extent, bacteria. Finally, weevaluated the future of HC with respect to bait design in the eukaryotic groups and the prospect of combining HC with long-read HTS.
Evaluation of Binding and Neutralizing Antibodies for Inactivated SARS-CoV-2 Vaccine Immunization
Zhao H, Jiang G, Li C, Che Y, Long R, Pu J, Zhang Y, Li D, Liao Y, Yu L, Zhao Y, Yuan M, Li Y, Fan S, Liu L and Li Q
The circulating severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variant presents an ongoing challenge for surveillance and detection. It is important to establish an assay for SARS-CoV-2 antibodies in vaccinated individuals. Numerous studies have demonstrated that binding antibodies (such as S-IgG and N-IgG) and neutralizing antibodies (Nabs) can be detected in vaccinated individuals. However, it is still unclear how to evaluate the consistency and correlation between binding antibodies and Nabs induced by inactivated SARS-CoV-2 vaccines. In this study, serum samples from humans, rhesus macaques, and hamsters immunized with inactivated SARS-CoV-2 vaccines were analyzed for S-IgG, N-IgG, and Nabs. The results showed that the titer and seroconversion rate of S-IgG were significantly higher than those of N-IgG. The correlation between S-IgG and Nabs was higher compared to that of N-IgG. Based on this analysis, we further investigated the titer thresholds of S-IgG and N-IgG in predicting the seroconversion of Nabs. According to the threshold, we can quickly determine the positive and negative effects of the SARS-CoV-2 variant neutralizing antibody in individuals. These findings suggest that the S-IgG antibody is a better supplement to and confirmation of SARS-CoV-2 vaccine immunization.
Vaccine Responses in Patients with Liver Cirrhosis: From the Immune System to the Gut Microbiota
Airola C, Andaloro S, Gasbarrini A and Ponziani FR
Vaccines prevent a significant number of deaths annually. However, certain populations do not respond adequately to vaccination due to impaired immune systems. Cirrhosis, a condition marked by a profound disruption of immunity, impairs the normal immunization process. Critical vaccines for cirrhotic patients, such as the hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcal, and coronavirus disease 19 (COVID-19), often elicit suboptimal responses in these individuals. The humoral response, essential for immunization, is less effective in cirrhosis due to a decline in B memory cells and an increase in plasma blasts, which interfere with the creation of a long-lasting response to antigen vaccination. Additionally, some T cell subtypes exhibit reduced activation in cirrhosis. Nonetheless, the persistence of memory T cell activity, while not preventing infections, may help to attenuate the severity of diseases in these patients. Alongside that, the impairment of innate immunity, particularly in dendritic cells (DCs), prevents the normal priming of adaptive immunity, interrupting the immunization process at its onset. Furthermore, cirrhosis disrupts the gut-liver axis balance, causing dysbiosis, reduced production of short-chain fatty acids (SCFAs), increased intestinal permeability, and bacterial translocation. Undermining the physiological activity of the immune system, these alterations could impact the vaccine response. Enhancing the understanding of the molecular and cellular factors contributing to impaired vaccination responses in cirrhotic patients is crucial for improving vaccine efficacy in this population and developing better prevention strategies.
Fluoxetine and Sertraline Potently Neutralize the Replication of Distinct SARS-CoV-2 Variants
Thümmler L, Beckmann N, Sehl C, Soddemann M, Braß P, Bormann M, Brochhagen L, Elsner C, Hoertel N, Cougoule C, Ciesek S, Widera M, Dittmer U, Lindemann M, Horn PA, Witzke O, Kadow S, Kamler M, Gulbins E, Becker KA and Krawczyk A
The pandemic caused by SARS-CoV-2 is still a major health problem. Newly emerging variants and long-COVID-19 represent a challenge for the global health system. In particular, individuals in developing countries with insufficient health care need easily accessible, affordable and effective treatments of COVID-19. Previous studies have demonstrated the efficacy of functional inhibitors of acid sphingomyelinase against infections with various viruses, including early variants of SARS-CoV-2. This work investigated whether the acid sphingomyelinase inhibitors fluoxetine and sertraline, usually used as antidepressant molecules in clinical practice, can inhibit the replication of the former and recently emerged SARS-CoV-2 variants in vitro. Fluoxetine and sertraline potently inhibited the infection with pseudotyped virus-like particles and SARS-CoV-2 variants D614G, alpha, delta, omicron BA.1 and omicron BA.5. These results highlight fluoxetine and sertraline as priority candidates for large-scale phase 3 clinical trials at different stages of SARS-CoV-2 infections, either alone or in combination with other medications.
Who Is the Intermediate Host of RNA Viruses? A Study Focusing on SARS-CoV-2 and Poliovirus
Brogna C, Bisaccia DR, Costanzo V, Lettieri G, Montano L, Viduto V, Fabrowski M, Cristoni S, Prisco M and Piscopo M
The COVID-19 pandemic has sparked a surge in research on microbiology and virology, shedding light on overlooked aspects such as the infection of bacteria by RNA virions in the animal microbiome. Studies reveal a decrease in beneficial gut bacteria during COVID-19, indicating a significant interaction between SARS-CoV-2 and the human microbiome. However, determining the origins of the virus remains complex, with observed phenomena such as species jumps adding layers to the narrative. Prokaryotic cells play a crucial role in the disease's pathogenesis and transmission. Analyzing previous studies highlights intricate interactions from clinical manifestations to the use of the nitrogen isotope test. Drawing parallels with the history of the Poliovirus underscores the need to prioritize investigations into prokaryotic cells hosting RNA viruses.
Investigating ABO Blood Groups and Secretor Status in Relation to SARS-CoV-2 Infection and COVID-19 Severity
Ferous S, Siafakas N, Boufidou F, Patrinos GP, Tsakris A and Anastassopoulou C
The ABO blood groups, Lewis antigens, and secretor systems are important components of transfusion medicine. These interconnected systems have been also shown to be associated with differing susceptibility to bacterial and viral infections, likely as the result of selection over the course of evolution and the constant tug of war between humans and infectious microbes. This comprehensive narrative review aimed to explore the literature and to present the current state of knowledge on reported associations of the ABO, Lewis, and secretor blood groups with SARS-CoV-2 infection and COVID-19 severity. Our main finding was that the A blood group may be associated with increased susceptibility to SARS-CoV-2 infection, and possibly also with increased disease severity and overall mortality. The proposed pathophysiological pathways explaining this potential association include antibody-mediated mechanisms and increased thrombotic risk amongst blood group A individuals, in addition to altered inflammatory cytokine expression profiles. Preliminary evidence does not support the association between ABO blood groups and COVID-19 vaccine response, or the risk of developing long COVID. Even though the emergency state of the pandemic is over, further research is needed especially in this area since tens of millions of people worldwide suffer from lingering COVID-19 symptoms.
Forensic Pathology and Legal Issues in COVID-19: Case Report and Literature Review
Kingsley-Godwin MJ, Tsranchev II, Belovezhdov V, Timonov P, Fasova A, Goshev M, Mileva B and Alexandrov A
Autopsy investigations of deaths following nosocomial coronavirus disease 2019 (COVID-19) infection have enormous medical and social significance, as autopsies are essential for the correct statistical recording of COVID-19 deaths, presenting new lessons, which is important to policymakers and in the improvement of public health in general.  Our study is based on the presentation of a case of a road traffic accident involving an elderly 73-year-old female with a complication of nosocomial COVID-19 infection and death leading to forensic pathological investigation. This involved autopsy, histopathological examinations, and other tests, and highlighting the importance of medicolegal matters, including the legal and ethical practicalities encountered in healthcare. This article highlights the fact that patients who have sustained various traumatic injuries accompanied by nosocomial COVID-19 infection have higher risks of morbidity and mortality. The significance of the role of a Forensic Pathologist in dealing with the analysis of injuries and the performance of autopsies to determine the cause, mechanism, and manner of death. In addition, the important lesson of testing patients for COVID-19 more regularly during a long hospital admission period, to offer early treatment and isolation, including avoiding the further spread of the COVID-19 infection variants to patients and healthcare professionals, thereby minimising and preventing hospital-acquired infection and death is stressed.
A "call to bear the burden of a long twilight struggle": a special issue on social determinants of health assessment and intervention
Hudson MF
Disease burden attributable to respiratory syncytial virus outbreaks in long-term care
Ferrante C, Bancej C and Atchessi N
Respiratory syncytial virus (RSV) disease burden is significant among children; however, RSV can also cause excess morbidity and mortality among older adults. Populations in long-term care homes (LTCHs) may be at greater risk of exposure and increased infection severity. The objectives of this article are to identify evidence regarding disease burden and outcome severity attributable to RSV outbreaks among residents and staff in LTCHs; and to highlight reported population and outbreak characteristics.
Outcomes for Women Denied Postpartum Tubal Ligation During the Initial COVID-19 Surge
Cosgriff L, Plummer M, Concepcion G and Danvers AA
To evaluate the utilization and outcomes of postpartum long-acting reversible contraception (PPLARC) following unmet postpartum bilateral tubal ligation (PPBTL) requests during a time in which elective surgeries were canceled due to the initial COVID-19 surge.
Case report: Atypical case of autoimmune glial fibrillary acidic protein astrocytopathy following COVID-19 vaccination refractory to immunosuppressive treatments
Morishima Y, Hata T, Nakajima S, Shindo K, Tsuchiya M, Watanabe T, Tahara I, Kondo T, Kimura A, Shimohata T and Ueno Y
A 54-year-old Japanese man presented with headache and fever the day after SARS-CoV-2 vaccination. He became deeply unconscious within a week. Brain MRI showed periventricular linear enhancements and a few spotty lesions in the cerebral white matter. Cerebrospinal fluid (CSF) testing showed mild pleocytosis. He was treated with intravenous methylprednisolone and plasma exchange. However, the white matter lesions enlarged to involve the brainstem and cerebellum, and long cord spinal lesions appeared. Anti-glial fibrillary acidic protein (GFAP) antibody was positive in the CSF and serum, and he was therefore diagnosed as autoimmune GFAP-astrocytopathy (GFAP-A). In addition, high-dose immunoglobulin therapy was administered twice, but his symptoms did not improve; the white matter lesions enlarged further, and modified Rankin Scale score increased to 5. A brain biopsy specimen showed infiltration of macrophages and CD lymphocytes together with neuron and oligodendrocytic injuries and glial scar. Although GFAP-A generally responds well to steroids, the present case developed GFAP-A following SARS-CoV-2 vaccination, with refractory to intensive immunosuppressive therapy and atypical pathologic findings of infiltration of CD lymphocytes and demyelination.
Critical success factors for creating sustainable digital health applications: A systematic review of the German case
Schramm L and Carbon CC
The Covid-19 pandemic has accelerated the adoption of digital technologies to address social needs, leading to increased investments in digital healthcare applications. Germany implemented a special law called the "Digitales Versorgungsgesetz" (DVG-Digital Supply Act) in 2019, which enables the reimbursement of digital health applications, including digital therapeutics (DTx), through a fast-track process. The Federal Institute for Drugs and Medical Devices (BfArM), the German federal authority responsible for overseeing digital health applications, has implemented legislative adjustments since the law's introduction, which have increased requirements for these applications and potentially led to the removal of some from the directory as well as a slowdown in the addition of new ones. To counteract this trend, this work aimed to identify key success factors for digital health applications (DiGAs).
[Avascular necrosis of the hip secondary to long-standing COVID]
García-Dobarganes-Barlow FE, Valadez-Soto JM, Saavedra-Islas N, García-Romo VM, Mata-Coronado J, Villavicencio-Ocampo E and Encalada-Díaz MI
Long COVID is a term used to describe the long-terms effects of COVID-19 infection that continue for weeks or months after the patient has recovered from COVID-19. Long COVID is defined by the persistence of symptoms beyond 12 weeks from the onset of the disease. Corticosteroids are part of the treatment in this period with good results in controlling the disease; however, it is a predisposing factor for the development of avascular necrosis. We present a clinic case of a young man of 39 years old with diagnosis of avascular necrosis in his left hip, before the administration of corticosteroids for the treatment of COVID-19. There is a lack of consensus about the dosage and duration of steroids required to develop avascular necrosis. Some authors have reported that cumulative dose of 2,000 mg prednisone (or its equivalent) was required for avascular necrosis development. For patients with advanced avascular necrosis stages total hip arthroplasty is an attractive option with excellent outcomes in terms of pain relief and survivorship.
Long COVID-19 and mnemonic effects: an integrative literature review
Martins WRM, Cardoso TV, Oliveira AL, Fernandes GS, Fontes IFL, Dantas JG, Miranda JS, Martins JE, Antunes LN and Leite TG
The effectiveness of the COVID-19 vaccines in the prevention of post-COVID conditions in children and adolescents: a systematic literature review and meta-analysis
Gutfreund MC, Kobayashi T, Callado GY, Pardo I, Hsieh MK, Lin V, Perencevich EN, Salinas JL, Edmond MB, Mendonça E, Rizzo LV and Marra AR
We performed a systematic literature review and meta-analysis on the effectiveness of coronavirus disease 2019 (COVID-19) vaccination against post-COVID conditions (long COVID) in the pediatric population.

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