Tag: covid-19

How does post COVID differ from other post-viral conditions in childhood and adolescence (0-20 years old)? A systematic review

Abstract:

Background: Post Coronavirus disease (COVID) and other post-viral infection syndromes present an overlap of pathogenesis, onset, progression, and symptom profile. We aimed to systematically describe studies on post-viral conditions and determine the entity of post COVID compared to other post-viral conditions in children.

Methods: We conducted a systematic search of the Embase, MEDLINE, Cochrane Library, and GoogleScholar databases (January 1946-3 November 2023), according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The main outcomes were differences in condition duration, symptom type, and development of chronic symptoms. This systematic review was registered on PROSPERO (CRD42023401789).

Findings: 35/5051 studies were included, with 42,934 children, adolescents and young adults (0-20 years old) overall. Twenty-eight studies focused on post COVID symptoms, followed by five papers on Respiratory Syncytial Virus (RSV) and Rhinovirus, one study on Epstein-Barr Virus (EBV), and one on gastrointestinal viruses. Studies on post COVID mainly reported data on older children/adolescents, describing long-lasting symptoms, including fatigue, neurologic, cardiorespiratory, musculoskeletal, mental health, and gastrointestinal symptoms. The maximum described symptoms duration was eighteen months, with an average follow-up of seven months. The development of chronic symptoms was reported by 30 studies (93.8%) for 10,473/28,474 patients (36.8%). Recovery was achieved in 18,001/28,474 cases (63.2%). The study on EBV reported persistent fatigue in adolescents for a similar duration (6 months, 46% chronic). Studies on RSV and Rhinovirus were mainly done in children under three years, with development of recurrent wheezing (up to 3 years).

Interpretation: Post-viral fatigue was a shared feature between post COVID and post EBV conditions. A better understanding of post COVID as a unique condition, sharing features with other post-viral syndromes, is needed. The healthcare burden and socio-economic consequences for children and their families warrant further investigation and development of appropriate healthcare management plans. The foremost requirement is the establishment of consistent and shareable definitions, as well as a consensus on outcomes, to effectively evaluate follow-up and quantify the burden of different viral infections.

Source: Minotti C, McKenzie C, Dewandel I, Bekker C, Sturniolo G, Doni D, Giaquinto C, Van Der Zalm MM, Donà D. How does post COVID differ from other post-viral conditions in childhood and adolescence (0-20 years old)? A systematic review. EClinicalMedicine. 2024 Feb 2;68:102436. doi: 10.1016/j.eclinm.2024.102436. PMID: 38333536; PMCID: PMC10850405. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10850405/ (Full text)

Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals

Abstract:

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown.

Methods: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC.

Results: During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular.

Conclusions: We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC.

Source: Leung JM, Wu MJ, Kheradpour P, Chen C, Drake KA, Tong G, Ridaura VK, Zisser HC, Conrad WA, Hudson N, Allen J, Welberry C, Parsy-Kowalska C, Macdonald I, Tapson VF, Moy JN, deFilippi CR, Rosas IO, Basit M, Krishnan JA, Parthasarathy S, Prabhakar BS, Salvatore M, Kim CC. Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals. Front Immunol. 2024 Jan 22;15:1348041. doi: 10.3389/fimmu.2024.1348041. PMID: 38318183; PMCID: PMC10838987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10838987/ (Full text)

Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19

Abstract:

Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking.

Materials and methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code.

Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed. A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58-0.85]; P = 4 ×10-4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 – 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Source: Sidky H, Hansen KA, Girvin AT, Hotaling N, Michael SG, Gersing K, Sahner DK; N3C consortium. Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19. Comput Struct Biotechnol J. 2024 Jan 9;24:115-125. doi: 10.1016/j.csbj.2023.12.045. PMID: 38318198; PMCID: PMC10839808. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10839808/ (Full text)

Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID)

Abstract:

Background: Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections.

Methods: A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the ‘exposed cohorts’ and ‘reference cohort’ was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC.

Results: Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final ‘matched’ analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts.

Conclusions: Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

Source: Pazukhina E, Rumyantsev M, Baimukhambetova D, Bondarenko E, Markina N, El-Taravi Y, Petrova P, Ezhova A, Andreeva M, Iakovleva E, Bobkova P, Pikuza M, Trefilova A, Abdeeva E, Galiautdinova A, Filippova Y, Bairashevskaia A, Zolotarev A, Bulanov N, DunnGalvin A, Chernyavskaya A, Kondrikova E, Kolotilina A, Gadetskaya S, Ivanova YV, Turina I, Eremeeva A, Fedorova LA, Comberiati P, Peroni DG, Nekliudov N, Genuneit J, Reyes LF, Brackel CLH, Mazankova L, Miroshina A, Samitova E, Borzakova S, Carson G, Sigfrid L, Scott JT, McFarland S, Greenhawt M, Buonsenso D, Semple MG, Warner JO, Olliaro P, Osmanov IM, Korsunskiy AA, Munblit D; Sechenov StopCOVID Research Team. Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID). BMC Med. 2024 Feb 1;22(1):48. doi: 10.1186/s12916-023-03221-x. PMID: 38302974; PMCID: PMC10835884. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835884/ (Full text)

Role of Ferroptosis in the Progression of COVID-19 and the Development of Long COVID

Abstract:

Objectives: To examine the role of ferroptosis on the pathogenesis and progression of COVID-19.

Materials and methods: A total of 127 patients who were hospitalized for COVID-19 were categorized into two groups according to the intensity of oxygen therapy (high-flow or low-flow). Clinical characteristics, laboratory parameters, plasma markers, and peripheral blood mononuclear cell (PBMC) markers were measured at baseline and one or two weeks after treatment. Telephone follow-up was performed 3 months after discharge to assess long COVID.

Results: Patients receiving high-flow oxygen therapy had greater levels of neutrophils; D-dimer; C reactive protein; procalcitonin; plasma protein levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-17, and acyl-CoA synthetase long-chain family member 4 (ACSL4); and PBMC mRNA level of TNF-α; but had lower levels of lymphocytes and plasma glutathione peroxidase 4 (GPX4). There were negative correlations of plasma GPX4 and cystine/glutamate transporter-11 (SLC7A11) with TNF-α, IL-6, and IL-17, and positive correlations of ACSL4 with inflammatory markers in plasma and PBMCs. The plasma levels of TNF-α, IL-6, IL-17, and ACSL4 were significantly lower after treatment than at baseline, but there were higher post-treatment levels of lymphocytes, GPX4, and SLC7A11. Patients with long COVID had a lower baseline level of plasma SLC7A11.

Conclusion: Ferroptosis is activated during the progression of COVID-19, and a low baseline level of a ferroptosis marker (SLC7A11) may indicate an increased risk for long COVID-19. Ferroptosis has potential as a clinical indicator of long COVID and as a therapeutic target.

Source: Zhao W, Wang S, Han Y, Zhang H, Cao J, Dong S, Li D, Lei M, Liu C, Gao Y. Role of Ferroptosis in the Progression of COVID-19 and the Development of Long COVID. Curr Med Chem. 2024 Jan 3. doi: 10.2174/0109298673281662231208102354. Epub ahead of print. PMID: 38310391. https://pubmed.ncbi.nlm.nih.gov/38310391/

Association of vaccine status, reinfections, and risk factors with Long COVID syndrome

Abstract:

The COVID-19 pandemic had a profound global impact, characterized by a high fatality rate and the emergence of enduring consequences known as Long COVID. Our study sought to determine the prevalence of Long COVID syndrome within a population of Northeastern Mexico, correlating it with patients’ comorbidities, number of COVID-19 reinfection, and vaccination status. Employing an observational cross-sectional approach, we administered a comprehensive questionnaire covering medical history, demographics, vaccination status, COVID-related symptoms, and treatment.

Our participant cohort included 807 patients, with an average age of 41.5 (SD 13.6) years, and women accounting 59.3% of the cohort. The follow-up was 488 (IQR 456) days. One hundred sixty-eight subjects (20.9%) met Long COVID criteria. Long COVID-19 was more prevalent when subjects had reinfections (p = 0.02) and less frequent when they had a complete vaccination scheme (p = 0.05).

Through logistic regression, we found that male gender (OR 0.5, p ≤ 0.001), blood types of AB- (OR 0.48, p = 0.003) and O- (OR 0.27, p ≤ 0.001) in comparison with A+ and two doses of vaccines (OR 0.5, p = 006) to be protective factors against Long COVID; while higher BMI (OR 1.04, p = 0.005) was a risk factor.

We saw that the prevalence of Long COVID was different within vaccinated patients and specific blood types, while being female and a higher BMI were associated with an increased risk of having long-COVID.

Source: Romero-Ibarguengoitia ME, Rodríguez-Torres JF, Garza-Silva A, Rivera-Cavazos A, Morales-Rodriguez DP, Hurtado-Cabrera M, Kalife-Assad R, Villarreal-Parra D, Loose-Esparza A, Gutiérrez-Arias JJ, Mata-Porras YG, Ojeda-Salazar DA, Sanz-Sánchez MA, González-Cantú A, Azzolini E, Rescigno M. Association of vaccine status, reinfections, and risk factors with Long COVID syndrome. Sci Rep. 2024 Feb 2;14(1):2817. doi: 10.1038/s41598-024-52925-4. PMID: 38307886; PMCID: PMC10837423. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10837423/ (Full text)

Patient Experiences Navigating Care Coordination For Long COVID: A Qualitative Study

Abstract:

Background: Little is known about how to best evaluate, diagnose, and treat long COVID, which presents challenges for patients as they seek care.

Objective: Understand experiences of patients as they navigate care for long COVID.

Design: Qualitative study involving interviews with patients about topics related to seeking and receiving care for long COVID.

Participants: Eligible patients were at least 18 years of age, spoke English, self-identified as functioning well prior to COVID infection, and reported long COVID symptoms continued to impact their lives at 3 months or more after a COVID infection.

Approach: Patients were recruited from a post-COVID recovery clinic at an academic medical center from August to September 2022. Interviews were audio-recorded, transcribed, and analyzed using thematic analysis.

Key results: Participants (n=21) reported experiences related to elements of care coordination: access to care, evaluation, treatment, and ongoing care concerns. Some patients noted access to care was facilitated by having providers that listened to and validated their symptoms; other patients reported feeling their access to care was hindered by providers who did not believe or understand their symptoms. Patients reported confusion around how to communicate their symptoms when being evaluated for long COVID, and they expressed frustration with receiving test results that were normal or diagnoses that were not directly attributed to long COVID. Patients acknowledged that clinicians are still learning how to treat long COVID, and they voiced appreciation for providers who are willing to try new treatment approaches. Patients expressed ongoing care concerns, including feeling there is nothing more that can be done, and questioned long-term impacts on their aging and life expectancy.

Conclusions: Our findings shed light on challenges faced by patients with long COVID as they seek care. Healthcare systems and providers should consider these challenges when developing strategies to improve care coordination for patients with long COVID.

Source: MacEwan SR, Rahurkar S, Tarver WL, Forward C, Eramo JL, Teuschler L, Gaughan AA, Rush LJ, Stanwick S, McConnell E, Schamess A, McAlearney AS. Patient Experiences Navigating Care Coordination For Long COVID: A Qualitative Study. J Gen Intern Med. 2024 Feb 2. doi: 10.1007/s11606-024-08622-z. Epub ahead of print. PMID: 38308155. https://link.springer.com/article/10.1007/s11606-024-08622-z (Full text)

Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study

Abstract:

Background: Long-COVID is defined by persistent symptoms following COVID-19 infection. Approximately 71% of individuals with long-COVID experience ongoing fatigue, post-exertional malaise, and cognitive impairments, which share pathological similarities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This similarity has prompted studies to explore the characteristics of long-COVID to gain a better understanding of ME/CFS. To gain insights, we investigated the clinical and laboratory characteristics of individuals with fatigue-dominant long-COVID.

Methods: We enrolled 100 subjects (36 males, 64 females) with long-COVID who had a higher score than 60 in modified Korean version of the Chalder Fatigue Scale (mKCFQ11) and higher than 5 in fatigue-focused Visual Analogue Scale (VAS). To investigate fatigue symptoms, the mKCFQ11, the Multidimensional Fatigue Inventory (MFI-20), and VAS for fatigue and brain-fog, along with the Short Form Survey (SF-12) were employed. We also measured three cytokines and cortisol levels for immunological and endocrinological indicators. As a cross-sectional observational study, the data were collected at a single point in time.

Results: The mean scores on the measurements showed severe fatigue, and these scores were significantly correlated, with no differences based on sex, the post-COVID period, or age. Among the laboratory tests, plasma cortisol levels had a significant negative correlation with fatigue scores and a positive correlation with living quality. The negative correlation between cortisol levels and mKCFQ11 scores appeared to be more specific to mental fatigue than physical, which conflicted with other measurements.

Conclusion: Our findings provide the first insights into the characteristics of fatigue in individuals with long-COVID, particularly in terms of fatigue severity and cortisol levels. These results serve as valuable reference data for clinicians dealing with fatigue symptoms in long-COVID patients and for researchers exploring post-viral fatigue symptoms, including ME/CFS, in the future.

Source: Lee JS, Choi Y, Joung JY, Son CG. Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study. Am J Med. 2024 Feb 6:S0002-9343(24)00057-3. doi: 10.1016/j.amjmed.2024.01.025. Epub ahead of print. PMID: 38331137. https://pubmed.ncbi.nlm.nih.gov/38331137/

Postacute Sequelae of SARS-CoV-2 in Children

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children.

This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition. We highlight the pediatric components of the National Institutes of Health-funded Researching COVID to Enhance Recovery Initiative, which seeks to characterize the natural history, mechanisms, and long-term health effects of PASC in children and young adults to inform future treatment and prevention efforts. These initiatives include electronic health record cohorts, which offer rapid assessments at scale with geographical and demographic diversity, as well as longitudinal prospective observational cohorts, to estimate disease burden, illness trajectory, pathobiology, and clinical manifestations and outcomes.

Source: Suchitra Rao, MBBS, MSCS; Rachel S. Gross, MD, MS; Sindhu Mohandas, MD; Cheryl R. Stein, PhD; Abigail Case, MD; Benard Dreyer, MD; Nathan M. Pajor, MD; H. Timothy Bunnell, PhD; David Warburton, MD; Elizabeth Berg, MD; Jonathan B. Overdevest, MD; Mark Gorelik, MD; Joshua Milner, MD; Sejal Saxena, BA; Ravi Jhaveri, MD; John C. Wood, MD, PhD; Kyung E. Rhee, MD, MSc, MA; Rebecca Letts, BA; Christine Maughan, BS; Nick Guthe, BA; Leah Castro-Baucom, MA; Melissa S. Stockwell, MD, MPH. Postacute Sequelae of SARS-CoV-2 in Children. Pediatrics e2023062570. https://doi.org/10.1542/peds.2023-062570 https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2023-062570/196606/Postacute-Sequelae-of-SARS-CoV-2-in-Children (Full text)

Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19

Highlights:

  • A subset of patients experienced persistent fatigue symptoms after COVID-19.
  • Treatment with low-dose naltrexone (LDN) and NAD+ was well tolerated.
  • Treatment increased SF-36 quality of life scores.
  • Treatment also improved fatigue symptom scores.
  • A subset of patients were clinically responsive.

Abstract:

A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted.

In this pilot study, we assessed whether treatment with low-dose naltrexone (LDN, 4.5 mg/day) and supplementation with NAD + through iontophoresis patches could improve fatigue symptoms and quality of life in 36 patients with persistent moderate/severe fatigue after COVID-19.

We detected a significant increase from baseline in SF-36 survey scores after 12 weeks of treatment (mean total SF-36 score 36.5 [SD: 15.6] vs. 52.1 [24.8]; p < 0.0001), suggestive of improvement of quality of life. Furthermore, participants scored significantly lower on the Chalder fatigue scale after 12 weeks of treatment (baseline: 25.9 [4.6], 12 weeks: 17.4 [9.7]; p < 0.0001).

We found a subset of 52 % of patients to be responders after 12 weeks of treatment. Treatment was generally safe, with mild adverse events previously reported for LDN, which could be managed with dose adjustments. The iontophoresis patches were associated with mild, short-lived skin irritation in 25 % of patients.

Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19. Larger randomized controlled trials will have to confirm our data and determine which patient subpopulations might benefit most from this strategy.

Source: Anar Isman, Andy Nyquist, Bailey Strecker, Girish Harinath, Virginia Lee, Xingyu Zhang, Sajad Zalzala. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain, Behavior, & Immunity – Health, Volume 36, 2024, 100733, ISSN 2666-3546, https://doi.org/10.1016/j.bbih.2024.100733. https://www.sciencedirect.com/science/article/pii/S2666354624000115 (Full text)