Retrospective Analysis of Clostridioides difficile Infection Rates in Hospitalized Patients during COVID-19 Pandemic. A Unicenter Study in Reus, Spain (preprint)

.Background: Clostridioides difficile infections (CDI) vary in severity from mild diarrhea to life-threatening conditions like pseudomembranous colitis or toxic megacolon, often leading to sepsis and death. The COVID-19 pandemic prompted changes in healthcare practices, potentially affecting CDI incidence, though reported data are inconclusive. We studied factors influencing CDI incidence and outcomes at a university hospital throughout the COVID-19 pandemic years. Methods: We conducted a retrospective study on all adult hospitalized CDI cases from January 1, 2020, to December 31, 2022. We collected demographic information, comorbid conditions, and concurrent infections. Results: While overall CDI and COVID-19 rates decreased in 2022, a nota-ble increase in CDI infections was observed among oncological patients and those undergoing some aggressive treatments, such as colon or gastroscopies. The prevalence of comorbidities remained unmodified, and there were declines in prior gastrointestinal surgeries and proton pump inhibitor prescriptions. Factors associated with patient fatality or prolonged hospitaliza-tion included older age, cancer, chronic kidney disease, higher Charlson and McCabe indices, elevated C-reactive protein, and low albumin concentrations. Conclusion: Our study shows the evolving landscape of CDI during the COVID-19 pandemic and emphasizes the impact of de-layed diagnoses and treatments exacerbated by telemedicine adoption. Identified risk factors for CDI-related mortality or prolonged hospital stays underscore the importance of targeted inter-ventions in high-risk populations.

The Aftermath of COVID-19: Exploring Long-Term Effects on the Organ Systems (preprint)

Background: 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 hospitalized. It has also been shown that 10-12% of those vaccinated against COVID-19 were affected with PASC and its complications. The severity and the later development of PASC symptoms is positively associated with the early intensity of the infection. Results: The generated health complications caused by PASC involve a vast variety of organ systems. Patients affected by PASC have been diagnosed with neuropsychiatric and neurological symptoms. Cardiovascular system also has been involved and several diseases such as myocarditis, pericarditis, and coronary artery diseases were reported. Chronic hematological problems such as thrombotic endothelialitis and hypercoagulability were described as a condition that could increase the risk of clotting disorders and coagulopathy in PASC patients. Chest pain, breathlessness, and cough in PASC patients were associated with respiratory system in long COVID-19 causing respiratory distress syndrome. The observed immune complications were notable, involving several diseases. Renal system also was impacted and result in raising the risk of diseases such as thrombotic issues, fibrosis, and sepsis. Endocrine gland malfunction can lead to diabetes, thyroiditis, and male infertility. Symptoms such as diarrhea, nausea, loss of appetite and taste were also among reported observations due to several gastrointestinal disorders. Skin abnormalities might be an indication of infection and long-term implications such as persistent cutaneous complaints were linked to PASC. Conclusions: Long COVID is a multidimensional syndrome with considerable public health implications, affecting several physiological systems and demanding thorough medical therapy as well as more study to address its underlying causes and long-term effects.

Deciphering Abnormal Platelet Subpopulations in Inflammatory Diseases through Machine Learning and Single-Cell Transcriptomics (preprint)

The study focuses on understanding the transcriptional heterogeneity of activated platelets and its impact on diseases like sepsis, COVID-19, and systemic lupus erythematosus (SLE). Recognizing the limited knowledge in this area, our research aims to dissect the complex transcriptional profiles of activated platelets to aid in developing targeted therapies for abnormal and pathogenic platelet subtypes. We analyzed single-cell transcriptional profiles from 47,977 platelets derived from 413 samples of patients with these diseases, utilizing Deep Neural Network (DNN) and eXtreme Gradient Boosting (XGB) to distinguish transcriptomic signatures predictive of fatal or survival outcomes. Our approach included source data annotations and platelet markers, along with SingleR and Seurat for comprehensive profiling. Additionally, we employed Uniform Manifold Approximation and Projection (UMAP) for effective dimensionality reduction and visualization, aiding in the identification of various platelet subtypes and their relation to disease severity and patient outcomes. Our results highlighted distinct platelet subpopulations that correlate with disease severity, revealing that changes in platelet transcription patterns can intensify endotheliopathy, increasing the risk of coagulation in fatal cases. Moreover, these changes also seem to impact lymphocyte function, indicating a more extensive role for platelets in inflammatory and immune responses. This study sheds light on the crucial role of platelet heterogeneity in serious health conditions, paving the way for innovative therapeutic approaches targeting platelet activation, which could potentially improve patient outcomes in diseases characterized by altered platelet function.

Global research trends on sepsis and septic shock during 2003–2022: A data-driven bibliometric analysis (preprint)

Background Sepsis is a major medical condition that contributes to substantial morbidity and mortality rates worldwide. Research to better understand and manage these complex conditions has intensified over the past two decades. This bibliometric analysis aims to map global research trends in sepsis and septic shock from 2003 to 2022, providing insights into the evolution of the field.Methods This study conducted a comprehensive search for publications on sepsis and septic shock using the Web of Science Core Collection. Data were analysed using VOSviewer for bibliometric mapping, focusing on publication trends, country, institutional contributions, journal sources, citation analysis, and keyword co-occurrence.Results In total, 78,108 publications were retrieved, with a notable increase in annual output over the study period. The United States ranked first in publication volume, followed by China, Germany, and the United Kingdom. Harvard University was the most prolific institution. Critical Care Medicine emerged as the leading journal in terms of publication count. The most cited articles and references were predominantly related to definition, epidemiology, and management guidelines for sepsis. Recent research hotspots included COVID-19, machine learning applications, NLRP3 inflammasome, autophagy, gut microbiota, and microRNA (miRNA).Conclusions Our bibliometric analysis identifies global research trends in sepsis over the past 20 years, with evolving hotspots and increasing global collaboration. Key findings highlight continuous efforts to understand the complex pathophysiology of sepsis and septic shock. COVID-19, machine learning applications, NLRP3 inflammasome, autophagy, gut microbiota, and microRNA (miRNA) are hotspots.

Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial & Role of Central Endpoint Adjudication (preprint)

Background: Despite progress in reducing Infant mortality in India, neonatal mortality decline is slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming prevention of neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention, including probiotic supplementation. This article communicates the decision by ProSPoNS trial investigators to establish a Central Endpoint Adjudication committee as an addendum to the published protocol in 'Trials 2021.' Methods:  In the pursuit of clarity regarding the primary outcome of Sepsis/PSBI in a clinical trial, a crucial decision was reached during the investigators' meeting at MGIMS Sevagram on 17th-18th August 2023. The unanimous consensus was to explicitly define "Physician diagnosed sepsis" as the primary study outcome, encompassing Sepsis/PSBI. This alignment aimed to synchronize the primary objective and outcome with the stated hypothesis, necessitating the establishment of a Central Endpoint Adjudication (CEA) process across all six trial sites. To enact this, the CEA committee, chaired by an external Subject Expert and comprising Site Principal Investigators, a Trial Statistician, and a Microbiologist, will employ four criteria to determine 'Physician diagnosed sepsis' for each sickness event in a study participant. These criteria include Blood culture status, Sepsis screen status, PSBI/non-PSBI signs and symptoms, and the Clinical course during the event, including antibiotic usage. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No.5/7/915/2012 Version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. Results:  The challenges faced in the trial implementation, such as complex multi-centric design, heterogeneity / extreme variation across sites, inconsistency with definition of sepsis in the neonatal/young infant population, remote vs. on-site training/monitoring during the Covid-19 Pandemic have been described and potential solutions to some of the challenges in clinical trials suggested. Conclusions: The decision to utilize the guidance of a Central Endpoint Adjudication Committee has been suggested as a way forward in the ProSPoNS and other multicentre complex clinical trials. Trial registration: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.

The Role of Serum Albumin and Blood Urea Nitrogen to Serum Albumin Ratio in Prediction of Disease Severity and Thirty--day Mortality in Patients with COVID--19 (preprint)

Background: Considering the role of higher blood urea nitrogen and lower serum albumin (SA) levels in deceased COVID-19 patients, increased blood urea nitrogen to SA (B/A) ratio may help to determine those at higher risk of becoming critically ill. This study evaluated the association of SA level and B/A ratio with disease severity and 30–day mortality and also their predictive value for disease severity in COVID–19 patients. Methods: 433 adult patients with COVID–19, admitted to a referral medical center in Tehran, Iran, from February to May 2020 were included. The laboratory markers were measured on admission. Disease severity was categorized into mild disease, severe pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and septic shock. The mortality was followed up for thirty days after admission. Results: Thirty–day mortality rate was 27.25%. The frequency of mild, severe pneumonia, ARDS, sepsis, and septic shock was 30.72%, 36.95%, 24.02%, 6.00%, and 2.31%, respectively. Mean B/A ratio was different among different disease severities. The odds of thirty-day mortality increased by 16% by each unit increase in B/A ratio and decreased by 57% by each unit increase in SA level. B/A ratio had the AUC of 0.45 for disease severity prediction with 71% sensitivity and 22% specificity. Conclusion: The results showed that B/A ratio and SA levels are associated with mortality in COVID–19 patient, while they had low predictive value for disease severity. High B/A ratio is, additionally, associated with disease severity. Therefore, we suggest to use this marker for clinical assessment of patients with COVID–19.

MIS-C, inherited metabolic diseases and methylmalonic acidemia: a case report and review of the literature (preprint)

Bacground Methylmalonic acidemia (MMA) secondary to mutase deficiency, mut0, is an inborn error of metabolism causing complete enzyme deficiency. Multisystem Inflammatory Syndrome in Children (MIS-C) is a hyperinflammatory syndrome characterized by fever, inflammation, multiorgan impairment that manifests 14–60 days after the SARS-CoV-2 infection in patients aged < 21 years. Case presentation We describe the clinical case of a 2-year-old child with MMA secondary to mutase deficiency, with the documented homozygous mutation c.2179 C > T of MMUT gene, associated to mut0 phenotype. One month after SARS-CoV-2 infection, he presented fever, rash, significant increase of C-reactive protein (CRP), ferritin, triglycerides, (interleukin) IL-6, PRO-BNP, compatible with the diagnosis of MIS-C. He was treated with intravenous immunoglobulins (2gr/Kg), methylprednisolone (2 mg/Kg/day), with rapid clinical improvement. Ten days later, he showed the worsening of clinical conditions, with the recurrence of fever, vasculitic rash with palmoplantar extension, further increase of ferritin (1033 ug/l), IL-6 (146 pg/ml), PRO-BNP (5117 pg/ml), triglycerides, anemia, thrombocytopenia, metabolic acidosis with hyperlactatemia (180 mg/dl), increased urinary methylmalonic acid (200 mmol/mCreat), multiorgan failure. He was treated with sodium bicarbonate, thiamine, coenzyme Q, vitamin C, methylprednisolone and anakinra (2 mg/Kg/day). Three days after the start of anakinra, he showed a significant improvement of clinical and biochemical parameters and defervescence. 20 days later, a sepsis from Staphylococcus Aureus and Candida Albicans required the interruption of anakinra, with the worsening of the clinical and haematological parameters and the exitus. Conclusions Only a few cases of patients with inherited metabolic diseases (IMD) and MIS-C are described. However, to our knowledge, this is the first case of MIS-C in MMA described. The description of these clinical cases is a precious lesson for pediatricians to manage IMD therapeutic emergencies. Anakinra must be considered as a safe treatment of choice in IMD patients with MIS-C. The use of anakinra in patients with a severe form of MMA is safe and can be employed to treat MIS-C, gaining a substantial clinical and biochemical improvement.

How did CariesCare International performed under pandemic conditions in children: 1-year multicenter single-group interventional study (preprint)

Background:In 2020, CariesCare International (CCI) -derived from ICCMS- was plannedto be tested for caries-control effectiveness in children by means of a multicenter randomized clinical trial (RCT). Nevertheless, due to the pandemic, RCTs proved unfeasible and aerosol-generating procedures (AGP) were associated with a spread of COVID-19. Consequently, the study design required to be modified to a single-interventional study and CCI had to be adapted excluding AGP and reducing on-site consultation (CCI-adapted). Objective: This 12-month multicenter single-group interventional study aimed at assessing the effect of a pandemic CCI-adapted protocol on caries control in children. Methods: Twenty-one Latin American and European centers with n³20 3-8-year-old children per center were invited to participate; 17 obtained IRB and signed written informed consents. Trained examiners assessed at baseline (T0) and 1-year follow-up (T1y) (blind to the intervention): CCI-caries risk, oral-health-related practices; dmf/DMFS with ICDAS-merged-Epi visual caries severity and activity criteria; dental sepsis and toothache. Individual- and tooth-surface-level personalized care plan was then performed by dental practitioners previously trained in CCI-adapted. After 5 months, parents’ and dentists’ dental-care-process acceptance (Treatment Evaluation Inventory) was assessed. The one-year caries-control effect of CCI-adapted was assessed in terms of tooth-surface and individual-level caries-progression control; oral-health behavior improvement, and caries-care system acceptability. Results: Sixteen centers finished the study (94.1%; Latin America: n=13; Europe: n=3), with 337 children (78.6%;mean age of 5.5±1.6 years). There was a T0 to T1y significant decrease (p<0.05) in the mean number of tooth surfaces with caries lesions (7.7±9.1 to 2.8±4.6), with active caries lesions (6.8±8.8 to 0.8±2.2), and a tooth-surface caries-progression control of 99.3%. In the majority of children there was a significant (p<0.05) control of: caries progression (79.5%), high-caries risk (86.6%), and non-adequate oral-health behavior (72.7%). There was a very high (parents) and a high-very high (dentists) acceptability of CCI. Conclusion: Given the challenge of the pandemic, this single-group interventional CCI-adapted study showed one-year control of caries progression, caries risk, and high parents’ and dentists’ CCI acceptance. Trial registration:Retrospectively‐registered‐ClinicalTrials.gov NCT04666597 07/12/2020 (Protocol version 2): https://register.clinicaltrials. gov/prs/app/action/SelectProtocol?sid=S000AGM4&selectaction=Edit&uid=U00019IE&ts=2&cx=uwje3h

Comparison of the type and prevalence of cardiac involvement among children hospitalized with COVID-19 and Multisystem Inflammatory Syndrome in Children: A cross-sectional study (preprint)

Background: Since the outbreak of COVID-19 in late 2019, more than 772 million individuals have been infected. There are numerous reports and studies about the complications and effects of this viral disease on different systems of the body. One of the important complications of COVID-19 in children is a condition named “Multisystem Inflammatory syndrome in Children (MIS-C)” which has some manifestations similar to Kawasaki disease or sepsis. Methods: In this study, we retrospectively compared the cardiac complications of COVID-19 and MIS-C in individuals under 18 years old of age, admitted to the Children’s Hospital of Bandar-Abbas, Iran, in an 18-months period of time. Results: The prevalence of mitral regurgitation in MIS-C and COVID-19 groups was 36.4% and 15.6%, respectively. The prevalence of tricuspid regurgitation in MIS-C and COVID-19 groups was 62.8% and 34.6%, respectively. The prevalence of positive result for troponin enzyme level in MIS-C and COVID-19 groups was 24.2% and 7.4%, respectively. Conclusion: This study showed that the prevalence of cardiac involvement in MIS-C patients was greater than COVID-19 patients. Additionally, the most cardiac complications among these groups of patients were tricuspid regurgitation and mitral regurgitation.

Combination of multiple omics and machine learning identifies diagnostic genes for ARDS and COVID-19 (preprint)

BACKGROUND Acute respiratory distress syndrome (ARDS) is a common acute clinical syndrome of the respiratory system with a high mortality rate and difficult prognosis.COVID-19 is a serious respiratory infectious disease caused by coronaviruses in a global pandemic. Some studies have suggested a possible association between COVID-19 and ARDS, but few studies have investigated the mechanism of interaction between them.METHODS Microarray data of ARDS (GSE32707 and GSE66890) and COVID-19 (GSE213313) were downloaded from the GEO database and searched for common differential genes for enrichment analysis.WGCNA was used to identify co-expression modules and genes associated with ARDS and COVID-19. RF and LASSO were performed for candidate gene identification. Machine learning XGBoost improved the diagnosis of hub genes in ARDS and COVID-19. The degree of immune cell infiltration in ARDS and COVID-19 samples was assessed using the CIBERSORT algorithm, and the relationship between hub genes and infiltrating immune cells was investigated. Changes in pathway activity per cell were visualized using Seurat standard flow down clustering (seurat) to visualize peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data from patients with sepsis-combined ARDS and patients with sepsis alone.RESULTS Limma difference analysis identified 314 up-regulated genes and 241 down-regulated genes in ARDS and COVID-19.WGCNA identified the purple-red co-expression module as the core module of ARDS and COVID-19. Five candidate genes, namely HIST1H2BK, TCF4, OLFM4, KIF14 and HK1, were screened using two machine learning algorithms, RF and LASSO. XGBoost constructed diagnostic models to evaluate the hub genes with high diagnostic efficacy in ARDS and COVID-19. Single-cell sequencing revealed the presence of alterations in five immune subpopulations, including monocytes, B cells, T cells, NK cells and platelets, with high expression levels and cellular occupancy of TCF4 and HK1, which are involved in oxidative reactions.

Addressing the aftermath of the COVID-19 pandemic: A quality improvement collaborative to optimize the use of antibacterials in Argentine Intensive Care Units (preprint)

BackgroundReducing antimicrobial resistance is a global priority that become even more important after the COVID-19 pandemic. To date there is a scarce volume of evidence from antimicrobial stewardship programs from less resourced settings where this phenomenon is bigger. Our aim was to improve the quality of antibacterials prescription in intensive care units (ICUs) in a middle-income country. MethodsWe established a quality improvement collaborative (QIC) model involving nine ICUs over an 11-month period, with a 16-week baseline (BP) and 32-week Intervention (IP) periods. Our co-designed intervention package included audits and feedback on antibacterial use, facility-specific treatment guidelines, antibacterial timeouts, pharmacy-based interventions, and education. The intervention was delivered in two learning sessions with three action periods, along with coaching support and basic quality improvement training. ResultsWe enrolled 912 patients, with 357 in baseline period (BP) and 555 in implementation period (IP). The latter had higher APACHE II (17 (12, 21) vs. 15 (11, 20); p=0.036) and SOFA scores (6 (4, 9) vs. 5 (3, 8); p=0.006), sepsis (36.1% vs. 31.6%, p<0.001), and septic shock (40.0% vs. 33.8%, p<0.001). Days of antibacterial therapy were similar between groups (IP 1112.2, BP 1133.4, RR 0.98 (0.95-1.02); p=0.2973) and the antibacterial Daily Define Dose was lower in IP group (IP, 1193.0; BP, 1301.0; RR, 0.92 (0.89, 0.95); p=0.0001). The rate of adequate antibacterial adjustment was higher during the IP (62.0% vs. 45.3%, p<0.001). We observed a lower rate of ventilation-associated pneumonia and catheter-associated urinary tract infections related to multidrug-resistant organisms (MDRO) in the IP. There was a noticeable improvement in the Infection Prevention and Control (IPC) Assessment Framework compared to baseline. ConclusionThe implementation of a post pandemic antimicrobial stewardship program in ICUs via a QIC demonstrated success in improving antibacterials utilization, reducing HAIs related to MDRO while also enhancing IPC measures. What is already known on this topicO_LIHealthcare-associated infections represent a global healthcare issue, particularly prevalent in low- and middle-income countries, where their occurrence is nearly three times higher. C_LIO_LIApproximately 50% of antimicrobial use is deemed unnecessary or inappropriate, necessitating the development of widely accessible stewardship methods. C_LIO_LIThe misuse and overuse of antibacterials adversely affect patients admitted to intensive care units (ICUs). C_LIO_LIFurther research is urgently required to determine the most effective ways to implement ASPs in LMICs. C_LI What this study addsO_LIBy establishing a quality improvement collaborative (QIC), we showcased an improvement in antibacterial utilization within ICUs in a low- to middle-income country. C_LIO_LIAdditionally, a reduction in healthcare-associated infections is evident. C_LIO_LIMoreover, the QIC effectively strengthened the capabilities of infection control and prevention in participating ICUs. C_LI How this study might affect research, practice, or policyO_LIThis study is among the initial endeavors in a middle-income country to evaluate the efficacy and essential strategies for establishing antimicrobial stewardship programs. C_LIO_LIThis study could serve as a foundational reference for upcoming teams aiming to introduce similar programs in the region. C_LI

Compassion Versus Infection Prevention and Control in Hospital Visiting; A False Dichotomy? A Case Study of Informal Caregiving in a Ugandan Regional Referral Hospital (preprint)

This paper addresses the role of visitors or ‘attendants’ in the transmission and management of infection risk in a public referral hospital in Uganda. The study built on research on maternal sepsis which found that over 50% antibiotics administered in the hospital were for Healthcare Associated Infections (HAIs). The data was collected during the COVID-19 pandemic which introduced new risks and heightened concern about social movements within hospitals and between hospitals and communities. In the first study of its kind, observational data was collected on a 24/7 basis to capture the presence and roles of attendants in a low resource setting exposing both the infection risks associated with these forms of movement but also the absolute necessity of attendants in the management of infection risk in such contexts. The paper responds directly to a recent call for a ‘new conversation on infection prevention and compassion’ (Storr et al, 2023;408).

Deciphering Abnormal Platelet Subpopulations in Inflammatory Diseases through Machine Learning and Single-Cell Transcriptomics (preprint)

IntroductionThe transcriptional heterogeneity of activated platelets, play a significant role in contributing to negative outcomes in sepsis, COVID-19, and autoimmune diseases such as systemic lupus erythematosus (SLE). Despite this, our understanding of these heterogeneous platelet responses remains limited. In this study, we aim to investigate the diverse transcriptional profiles of activated platelets in these diseases, with the goal of deciphering this platelet heterogeneity for new therapeutic strategies to target abnormal and pathogenic platelet subtypes. Materials and methodsWe obtained the single cell transcriptional profiles of blood platelets from patients with COVID-19, sepsis, and SLE. Utilizing machine learning algorithms, Deep Neural Network (DNN) and eXtreme Gradient Boosting (XGB), we discerned the distinct transcriptomic signatures indicative of fatal versus survival clinical outcomes. Our methodological framework incorporated source data annotations and platelet markers and used SingleR and Seurat for detailed profiling. Additionally, we implemented Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and visualization, aiding in the detection of various platelet subtypes and their correlation with disease status and patient outcomes. ResultsOur study identified distinct platelet subpopulations that are associated with disease severity. We demonstrated that alterations in platelet transcription patterns can exacerbate endotheliopathy, potentially heightening the risk of coagulation in fatal patients. Moreover, these changes can also influence lymphocyte function, indicating a more extensive role for platelets in inflammatory and immune responses. ConclusionsEnhanced transcriptional heterogeneity in activated platelets is linked to adverse outcomes in conditions such as sepsis, COVID-19, and autoimmune diseases. The discovery of these unique platelet subpopulations paves the way for innovative therapeutic strategies targeting platelet activation, which could potentially improve patient outcomes. Summary sentenceSingle-Cell RNA Sequencing Analysis of Platelets from COVID-19, Sepsis, and SLE Reveals Disease Signatures and Treatment Options to Prevent Patient Mortality. Graphical AbstractsO_LIThe platelet to T cell ratio proportion in PBMC was identified as the most potent predictor for distinguishing survivors from fatal patients, underscores the potential of this ratio as a prognostic biomarker. C_LIO_LIThe discovery of different platelet subgroups, especially active coagulation, hypoxic, and quiescent clusters, in fatal COVID-19 patients, indicates potential targeted treatment strategies. C_LIO_LIIn patients with severe and fatal conditions, we observed three key phenomena: the aggregation of platelets with monocytes, the amplification of endothelial dysfunction by platelets, and a decrease in lymphocyte activation and differentiation due to platelets. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/572680v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@141ca55org.highwire.dtl.DTLVardef@4ad1aborg.highwire.dtl.DTLVardef@b400forg.highwire.dtl.DTLVardef@9ad44e_HPS_FORMAT_FIGEXP M_FIG C_FIG

Non-classical CD45RBlo memory B-cells are the majority of circulating antigen-specific B-cells following mRNA vaccination and COVID-19 infection. (preprint)

Resting memory B-cells can be divided into classical and non-classical groups based on differential expression of markers such as CD27 and CD11c, while activated memory B-cells express a combination of markers, making their ontogeny hard to determine. Here by longitudinal analysis of COVID-19, bacterial sepsis, and BNT162b2 mRNA vaccine recipients by mass cytometry and CITE-seq we describe a three-branch structure of resting B-cell memory consisting of “classical” CD45RB+ memory and two branches of CD45RBlo memory further defined by expression of CD23 and CD11c respectively. Stable differences in CD45RB upon activation allowed tracking of activated B-cells and plasmablasts derived from CD45RB+ classical and CD45RBlo non-classical memory B-cells. In both COVID-19 patients and mRNA vaccination, CD45RBlo B-cells formed the majority of SARS-CoV2 specific memory B-cells and correlated with serum antibodies while CD45RB+ memory was most strongly activated by bacterial Sepsis. These results suggest that diverse non-classical CD45RBlo memory B-cells consisting of branches of CD11c+Tbet+ and CD23+ fractions form a critical part of responses to viral infection and vaccination.

Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis (preprint)

Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression in concert with emergency hematopoiesis. Epigenetic changes, notably in the form of histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation to this process remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes previously implicated as major drivers of immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8). Methylome alterations are driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed through treatment with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Importantly, these changes are recapitulated in septic mice following cecal slurry injection, resulting in stable changes at critical immune genes that support the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.

Community-onset urinary tract infection in females in the context of COVID-19: a longitudinal population cohort study exploring case presentation, management, and outcomes (preprint)

Background COVID-19 affected the epidemiology of other infectious diseases and how they were managed. Urinary tract infection (UTI) is one of the most common infections treated in the community in England. We investigated the impact of the COVID-19 pandemic on UTI primary care consultations and outcomes in female patients. Methods and findings We analysed General Practice (GP) consultation and hospital admission records using the Whole Systems Integrated Care (WSIC) data in North West London between 2016 and 2021. We quantified the changes in UTI GP consultation rates using time series analysis before and during the pandemic. We assessed the outcomes of UTI, measured by subsequent bacteraemia and sepsis within 60 days, for consultations delivered face-to-face or remotely, with or without diagnostic tests recommended by the national guidelines, and with or without antibiotic treatment. Between January 2016 and December 2021, we identified 375,859 UTI episodes in 233,450 female patients. Before the COVID-19 pandemic (January 2016-February 2020), the UTI GP consultation rate stayed level at 522.8 cases per 100,000 population per month, with a seasonal pattern of peaking in October. Since COVID-19, (March 2020-December 2021), monthly UTI GP consultations declined when COVID-19 cases surged and rose when COVID-19 case fell. During the pandemic, the UTI consultations delivered face-to-face reduced from 72.0% to 29.4%, the UTI consultations with appropriate diagnostic tests, including urine culture and urinalysis, reduced from 17.3% to 10.4%, and the UTI cases treated with antibiotics reduced from 52.0% to 47.8%. The likelihood of antibiotics being prescribed was not affected by whether the consultation was delivered face-to-face or remotely but associated with whether there was a diagnostic test. Regardless of whether the UTI consultation occurred before or during the pandemic, the absence of antibiotic treatment for UTI is associated with a 10-fold increase in the risk of having bacteraemia or sepsis within 60 days, though the patients who consulted GPs for UTI during the pandemic were older and more co-morbid. Across the study period (January 2016-December 2021), nitrofurantoin remained the first-line antibiotic option for UTI. The percentage of non-prophylactic acute UTI antibiotic prescriptions with durations that exceeded the guideline recommendations was 58.7% before the pandemic, and 49.4% since. This led to 830,522 total excess days of treatment, account for 63.3% of all non-prophylactic acute antibiotics prescribed for UTI. Before the pandemic, excess antibiotic days of UTI drugs had been reducing consistently. However, this decline slowed down during the pandemic. Having a diagnostic test was associated with 0.6 less excess days of antibiotic treatment. Conclusions This analysis provides a comprehensive examination of management and outcomes of community-onset UTI in female patients, considering the changes in GP consultations during the COVID-19 pandemic. Our findings highlighted the importance of appropriate urine testing to support UTI diagnosis in symptomatic patients and initiation of antibiotic treatment with appropriate course duration. Continued monitoring is required to assess the overall impact on patients and health systems from the changed landscape of primary care delivery.

Accuracy of automated computer-aided risk scoring systems to estimate the risk of COVID-19: a retrospective cohort study (preprint)

Background: In the UK National Health Service (NHS), the patient’s vital signs are monitored and summarised into a National Early Warning Score (NEWS) score. A set of computer-aided risk scoring systems (CARSS) was developed and validated for predicting in-hospital mortality and sepsis in unplanned admission to hospital using NEWS and routine blood tests results. We sought to assess the accuracy of these models to predict the risk of COVID-19 in unplanned admisisons during the first phase of the pandemic. Methods: Adult (>=18 years) non-elective admissions discharged (alive/deceased) between 11-March-2020 to 13-June-2020 from two acute hospitals with an index NEWS electronically recorded within ±24 hours of admission. We identified COVID-19 admission based on ICD-10 code ‘U071’ which was determined by COVID-19 swab test results (hospital or community). We assessed the performance of CARSS (CARS_N, CARS_NB, CARM_N, CARM_NB) for predicting the risk of COVID-19 in terms of discrimination (c-statistic) and calibration (graphically). Results: The risk of in-hospital mortality following emergency medical admission was 8.4% (500/6444) and 9.6% (620/6444) had a diagnosis of COVID-19. For predicting COVID-19 admissions, the CARS_N model had the highest discrimination 0.73 (0.71 to 0.75) and calibration slope 0.81 (0.72 to 0.89) compared to other CARSS models: CARM_N (discrimination:0.68 (0.66 to 0.70) and calibration slope 0.47 (0.41 to 0.54)), CARM_NB (discrimination:0.68 (0.65 to 0.70) and calibration slope 0.37 (0.31 to 0.43)), and CARS_NB (discrimination:0.68 (0.66 to 0.70) and calibration slope 0.56 (0.47 to 0.64)). Conclusions: The CARS_N model is reasonably accurate for predicting the risk of COVID-19. It may be clinically useful as an early warning system at the time of admission especially to triage large numbers of unplanned hospital admissions because requires no additional data collection and is readily automated.

Long-term outcomes of hospitalized SARS-CoV-2/COVID-19 patients with and without neurological involvement: 3-year follow-up assessment (preprint)

Background and ObjectivesAcute neurological manifestations are a common complication of acute COVID-19 disease. This study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. MethodsPatients infected by SARS-CoV-2 between March 1 and April 16, 2020 and hospitalized in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to January 23, 2023 (3 years post COVID-19). This cohort consisted of 414 COVID-19 patients with significant neurological manifestations and 1199 propensity-matched COVID- 19 patients without neurological manifestations. Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were clinical neuroimaging findings (hemorrhage, active stroke, prior stroke, mass effect, and microhemorrhage, white-matter changes, microvascular disease, and volume loss). Predictive models were used to identify risk factors of mortality post-discharge. ResultsMore patients in the neurological cohort were discharged to acute rehabilitation (10.54% vs 3.68%, p<0.0001), skilled nursing facilities (30.67% vs 20.78%, p=0.0002) and fewer to home (55.27% vs 70.21%, p<0.0001) compared to the matched controls. Incidence of readmission for any medical reason (65.70% vs 60.72%, p=0.036), stroke (6.28% vs 2.34%, p<0.0001), and MACE (20.53% vs 16.51%, p=0.032) was higher in the neurological cohort post-discharge. Neurological patients were more likely to die post-discharge (58 (14.01%) vs 94 (7.84%), p=0.0001) compared to controls (HR=2.346, 95% CI=(1.586, 3.470), p<0.0001). The major causes of death post-discharge were heart disease (14.47%), sepsis (13.82%), influenza and pneumonia (11.18%), COVID-19 (8.55%) and acute respiratory distress syndrome (7.89%). Factors associated with mortality after leaving the hospital were belonging to the neurological cohort (OR=1.802 (1.237, 2.608), p=0.002), discharge disposition (OR=1.508, 95% CI=(1.276, 1.775), p<0.0001), congestive heart failure (OR=2.281 (1.429, 3.593), p=0.0004), higher COVID-19 severity score (OR=1.177 (1.062, 1.304), p=0.002), and older age (OR=1.027 (1.010, 1.044), p=0.002). There were no group differences in gross radiological findings, except the neurological cohort showed significantly more age-adjusted brain volume loss (p<0.05) compared to controls. DiscussionCOVID-19 patients with neurological manifestations have worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for COVID-19 patients with neurological manifestations.

[Informativeness estimation for the main clinical and laboratory parameters in patients with severe COVID-19].

AIM: To conduct a retrospective assessment of the clinical and laboratory data of patients with severe forms of COVID-19 hospitalized in the intensive care and intensive care unit, in order to assess the contribution of various indicators to the likelihood of death. MATERIALS AND METHODS: A retrospective assessment of data on 224 patients with severe COVID-19 admitted to the intensive care unit was carried out. The analysis included the data of biochemical, clinical blood tests, coagulograms, indicators of the inflammatory response. When transferring to the intensive care units (ICU), the indicators of the formalized SOFA and APACHE scales were recorded. Anthropometric and demographic data were downloaded separately. RESULTS: Analysis of obtained data, showed that only one demographic feature (age) and a fairly large number of laboratory parameters can serve as possible markers of an unfavorable prognosis. We identified 12 laboratory features the best in terms of prediction: procalcitonin, lymphocytes (absolute value), sodium (ABS), creatinine, lactate (ABS), D-dimer, oxygenation index, direct bilirubin, urea, hemoglobin, C-reactive protein, age, LDH. The combination of these features allows to provide the quality of the forecast at the level of AUC=0.85, while the known scales provided less efficiency (APACHE: AUC=0.78, SOFA: AUC=0.74). CONCLUSION: Forecasting the outcome of the course of COVID-19 in patients in ICU is relevant not only from the position of adequate distribution of treatment measures, but also from the point of view of understanding the pathogenetic mechanisms of the development of the disease.