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Tumor-Infiltrating Clonal Hematopoiesis.
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear. METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors. RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth. CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).
Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.
BACKGROUND: Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition. Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial. METHODS: FEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable. DISCUSSION: FEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based. TRIAL REGISTRATION: EudraCT number: 2021-004056-42. ISRCTN: 88,102,629.
Serum and mucosal antibody-mediated protection and identification of asymptomatic respiratory syncytial virus infection in community-dwelling older adults in Europe.
INTRODUCTION: Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) and reinfects adults throughout life, posing a risk for hospitalization in older adults (>60 years) with frailty and comorbidities. METHODS: To investigate serum and mucosal antibodies for protection against RSV infections, baseline serum samples were compared for RSV-pre- and -post-fusion (F) binding, and RSV-A2 neutralizing IgG antibodies between symptomatic RSV-ARTI (N = 30), non-RSV (RSV negative) ARTI (N = 386), and no ARTI (N = 338). Mucosal RSV-pre-F IgA and IgG levels, as well as serum RSV-G IgG antibodies, were analyzed to determine their association with protection from symptomatic RSV-ARTI in a subset study. RESULTS: Using a receiver operating characteristic (ROC) analysis, we established thresholds of 1.4- to 1.6-fold change (FC) for RSV-pre-F and -post-F, and RSV-A2 neutralizing IgG antibodies, respectively, enabling the identification of asymptomatic RSV cases with high sensitivity and specificity (>80% and >90%, respectively). As a result, serum RSV-pre-F, RSV-G IgG, and mucosal pre-F binding IgA antibodies showed correlations with protection against symptomatic RSV infection. RSV-pre-F IgG antibodies were correlated with protection from RSV infections irrespective of the symptoms. DISCUSSION: This study provides insights into antibody-mediated protection for symptomatic RSV infection in a community-dwelling older-adult population and establishes a threshold to identify asymptomatic RSV infection using a data-driven approach.
The respiratory microbiome is linked to the severity of RSV infections and the persistence of symptoms in children.
Respiratory syncytial virus (RSV) is the leading cause of infant respiratory infections and hospitalizations. To investigate the relationship between the respiratory microbiome and RSV infection, we sequence nasopharyngeal samples from a birth cohort and a pediatric case-control study (Respiratory Syncytial virus Consortium in Europe [RESCEU]). 1,537 samples are collected shortly after birth ("baseline"), during RSV infection and convalescence, and from healthy controls. We find a modest association between baseline microbiota and the severity of consecutive RSV infections. The respiratory microbiota during infection clearly differs between infants with RSV and controls. Haemophilus, Streptococcus, and Moraxella abundance are associated with severe disease and persistence of symptoms, whereas stepwise increasing abundance of Dolosigranulum and Corynebacterium is associated with milder disease and health. We conclude that the neonatal respiratory microbiota is only modestly associated with RSV severity during the first year of life. However, the respiratory microbiota at the time of infection is strongly associated with disease severity and residual symptoms.
Communicating about paediatric infectious diseases at the beginning of the 20th century.
The Charta of paediatric infectious diseases, which was printed in Athens, Greece in 1912, contains instructions for school students on the prevention of paediatric infectious diseases occurring in Greece at the beginning of the 20th century. It consists of four sections: i) The official circular of the Department of the School of Hygiene of the Hellenic Ministry of Education on the protection of school students from acute infectious diseases signed by the minister on January 31, 1912; ii) an introductory section on the definition of infectious diseases, the modes of their transmission and the conditions required for the inactivation of microbial activity; iii) a section with general preventative measures against paediatric infectious diseases; and iv) a section with information and specialized measures against specific paediatric infectious diseases. It also contains colourful images of children with different infectious diseases, including smallpox, measles, diphtheria, varicella, eye trachoma and other infectious diseases involving the skin. The Charta of paediatric infectious diseases is exhibited at the Museum of School Students' Life in Aliveri, on the island of Euboea in Greece and was recently reprinted in the context of the 10th workshop on paediatric virology organized by the Institute of Paediatric Virology on November 9, 2024.
180-day efficacy of nirsevimab against hospitalisation for respiratory syncytial virus lower respiratory tract infections in infants (HARMONIE): a randomised, controlled, phase 3b trial.
BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection and hospitalisations in infants worldwide. The primary analyses of HARMONIE showed that nirsevimab reduced infant hospitalisations due to RSV-associated lower respiratory tract infection through the RSV season. This analysis aims to evaluate nirsevimab's efficacy at 180 days after dosing, a period exceeding the typical 5-month RSV season. METHODS: HARMONIE is an ongoing, open-label, parallel arm, randomised, controlled, phase 3b study conducted in France, Germany, and the UK. Infants aged 12 months or younger, born at a gestational age of at least 29 weeks, were randomly assigned (1:1) to receive either a single intramuscular dose of nirsevimab (50 mg for children <5 kg or 100 mg for children ≥5 kg) or standard care (without RSV prophylaxis) before or during their first RSV season. Randomisation was electronically done, stratified by country and age-group. The primary efficacy endpoint for this analysis was the incidence of hospitalisations due to RSV-associated lower respiratory tract infection up to 180 days after nirsevimab administration or randomisation in all randomised participants. Safety up to 365 days following nirsevimab administration was also assessed. This trial is ongoing and registered with ClinicalTrials.gov, number NCT05437510. FINDINGS: Between Aug 8, 2022, and Feb 28, 2023, 8057 infants were randomly assigned to either the nirsevimab group (n=4038) or the standard care group (n=4019). The median age at randomisation was 4·00 months (IQR 1·0-7·0; range 0·0-12·0, and 4195 (52·1%) were male and 3862 (47·9%) were female. Up to 180 days, 12 (0·3%) of 4038 infants in the nirsevimab group and 68 (1·7%) of 4019 infants in the standard care group had been hospitalised for RSV-associated lower respiratory tract infection, corresponding to a nirsevimab efficacy of 82·7% (95% CI 67·8-91·5; p<0·0001). Most participants experienced grade 1 (2759 [68·7%] of 4016 in the nirsevimab group; 2696 [67·1%] of 4018 in the standard care group) or grade 2 (1447 [36·0%] of 4016 in the nirsevimab group; 1436 [35·7%] of 4018 in the standard care group) treatment-emergent adverse events, and no apparent safety concerns were raised up to 365 days after dosing. INTERPRETATION: Nirsevimab offers consistent and sustained protection against hospitalisation due to RSV-associated lower respiratory tract infection for at least 6 months. This finding provides global health systems greater flexibility when implementing nirsevimab, providing substantial benefit in the ongoing effort to reduce the burden of infant RSV and the potential wider public health value. FUNDING: Sanofi and AstraZeneca.
Recent advances in the prevention and treatment of respiratory syncytial virus disease.
Respiratory syncytial virus (RSV) is associated with considerable healthcare burden; as such, prevention and treatment of RSV have long been considered a priority. Historic failures in RSV vaccine development had slowed the research field. However, the discovery of the conformational change in the RSV fusion protein (F) has led to considerable advancements in the field. The RSV pharmaceutical landscape has drastically changed in recent years with successful trials of both vaccines and second-generation mAbs leading to licensing and roll-out of these agents in several countries. RSV preventative and therapeutic measures will likely have a significant impact on RSV-related morbidity and mortality. However, there are still gaps in the protection that these immunizations offer that should be addressed. Many unanswered questions about RSV infection dynamics and subsequent disease should be a focus of ongoing research. This review discusses the currently licensed RSV pharmaceuticals and others that have recently progressed to clinical trials.
Higher dose corticosteroids in hospitalised COVID-19 patients requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial.
BACKGROUND: Low dose corticosteroids (e.g., 6 mg dexamethasone) have been shown to reduce mortality for hypoxic COVID-19 patients. We have previously reported that higher dose corticosteroids cause harm in patients with clinical hypoxia but not receiving ventilatory support (the combination of non-invasive mechanical ventilation, including high-flow nasal oxygen, continuous positive airway pressure and bilevel positive airway pressure ventilation, and invasive mechanical ventilation or extra-corporeal membrane oxygenation), but the balance of efficacy and safety in patients receiving ventilatory support is uncertain. METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) assessed multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients receiving ventilatory support were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. Recruitment closed on 31 March 2024 when funding for the trial ended. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FINDINGS: Between 25 May 2021 and 9 January 2024, 477 COVID-19 patients receiving ventilatory support were randomly allocated to receive usual care plus higher dose corticosteroids vs. usual care alone (of whom 99% received corticosteroids during the follow-up period). Of those randomised, 221 (46%) were in Asia, 245 (51%) in the UK and 11 (2%) in Africa. 143 (30%) had diabetes mellitus. Overall, 86 (35%) of 246 patients allocated to higher dose corticosteroids vs. 86 (37%) of 231 patients allocated to usual care died within 28 days (rate ratio [RR] 0.87; 95% CI 0.64-1.18; p = 0.37). There was no significant difference in the proportion of patients discharged from hospital alive within 28 days (128 [52%] in the higher dose corticosteroids group vs. 120 [52%] in the usual care group; RR 1.04, 0.81-1.33]; p = 0.78). Among those not on invasive mechanical ventilation at baseline, there was no clear reduction in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (76 [37%] of 206 vs. 93 [45%] of 205; RR 0.79 [95% CI 0.63-1.00]; p = 0.05). INTERPRETATION: In patients hospitalised for COVID-19 receiving ventilatory support, we found no evidence that higher dose corticosteroids reduced the risk of death compared to usual care, which included low dose corticosteroids. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute for Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).
Antiviral Treatment and Risk of Hearing Loss in Asymptomatic and Mild Symptomatic Infants With Congenital Cytomegalovirus.
BACKGROUND: To assess hearing outcomes at 24 months of age in infants with mild congenital cytomegalovirus (cCMV) infection, depending on whether they have received antiviral treatment or not. METHODS: A retrospective study within the European Registry of Children with cCMV was performed. Included children had cCMV diagnosed in utero/in the first 21 days of life, with normal physical examination, alanine aminotransferase <80 U/L and platelets >100,000 cs/mm 3 and absence of hearing loss (HL) at birth. Cranial ultrasound (cUS) and/or cranial magnetic resonance imaging was normal or with minor findings (isolated lenticulostriate vasculopathy and/or germinolysis/caudothalamic or subependymal cysts, and/or focal/multifocal white matter involvement). The main outcome was the presence of HL at 24 months of age. RESULTS: One hundred ninety-six patients met inclusion criteria. A total of 34.7% received antiviral treatment with valganciclovir/ganciclovir. Children treated had lower gestational age, birth weight and head circumference, and maternal primary infection was less frequent. Among treated children, 21.3% presented minor findings in cUS versus 6.3% in nontreatment group ( P = 0.003). Nine patients (4.6%) developed HL at 24 months. Among children with HL, 20% presented minor findings in cUS versus 11.3% in non-HL group ( P = NS). HL rate was similar in treated and nontreated groups (4.6% vs. 6.3%; P = 0.6). CONCLUSIONS: One-third of the children were treated with antivirals and infants with minor neuroimaging findings at birth were more likely to receive antiviral. There were no differences in the prevalence of HL at 2 years of age between treated and not-treated children. Minor neuroimaging findings were not clearly associated with an increased risk of delayed onset HL.
Latent Profiles of Early Language Development in a Large Finnish-Speaking Sample of the FinnBrain Birth Cohort Study.
PURPOSE: Research on early language development has primarily used two categories to group at-risk children, differing by the age at which risk is identified. Late talkers are toddlers with late onset of language development, some of whom may catch up with peers. Developmental language disorder is used to refer to children above the age of 4 years. To this day, the longitudinal relationship between the two categories remains unclear. In this study, we explored early language trajectories in a large birth cohort using exploratory methodology to gain better understanding of the types and prevalence of language trajectories from 14 months to 5 years of age, with particular interest in risk trajectories that cluster statistically. METHOD: We conducted latent profile analysis (LPA) on seven language variables collected between 1 and 5 years of age (N = 1,281). Multinomial logistic regression procedure was used to identify child and family characteristics that predicted profile memberships. RESULTS: The LPA yielded three profiles of language development described as persistent low, stable average, and stable high. Female sex, longer duration of pregnancy, and higher maternal socioeconomic status increased the odds of belonging to the stable high-language profile, whereas male sex and not being first born increased the odds of belonging to persistent low language profile. CONCLUSIONS: Contrary to previous research, we did not observe increasing or decreasing profiles, suggesting that toddler language difficulties tend to persist at age 5 years, at least in this birth cohort. This suggests commencing language intervention early instead of the wait-and-see approach. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.29441471.
Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5.
Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines.
Distinct neutralization sensitivity between adult and infant transmitted/founder HIV-1 subtype C viruses to broadly neutralizing monoclonal antibodies.
Broadly neutralizing antibodies (bnAbs), passively administered or elicited through vaccination, are a promising strategy for novel HIV prevention, treatment or inducing ART-free remission. However, HIV diversity and evolution are a barrier to the efficacy of bnAbs and there is therefore an urgent need for continuous virus surveillance to identify bnAbs with optimal neutralization breadth and potency against transmitted/founder (TF) viruses, especially in high-burden regions. We determined the neutralization sensitivity of TF viruses isolated within seven days after first detection of heterosexually acquired infection from young women 18-23 years old (n = 39) and within 1 month after birth from in-utero infected infants (n = 21) from FRESH and Baby Cure cohorts respectively, in KwaZulu-Natal, South Africa, where HIV-1 subtype C predominates. Neutralization sensitivities of 47 viruses from FRESH and 21 viruses from Baby Cure were assessed against nine bnAbs targeting different regions on the HIV-1 Env trimer. HIV-1 env sequences within and between bnAb epitopes were compared with database. The bnAbs VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10E8 and PGT151 displayed higher neutralization breadth and potency than other bnAbs against FRESH TF viruses (>70% coverage, starting concentration of 10 μg/ml). Furthermore, VRC07-523LS showed higher neutralization breadth and potency than other bnAbs against Baby Cure TF viruses (p = 0.02). Interestingly, CAP256-VRC26.25 and PGT151 had lower neutralization coverage against infant TF viruses (<60% coverage). Moreover, 40% of infants TF had escape mutations within the V2 loop compared to 28% observed in FRESH and these mutations may explain the observed differences in neutralization sensitivities. However, few mutations were observed in gp120-gp41 interface in both adults and infants. Our findings suggest that intervention studies may have to consider different antibody combinations in adult versus paediatric settings. Moreover, high transmission of escape variants in both vertical and heterosexual transmissions is of concern. This information may be important in the selection of bnAbs that will undergo clinical testing in subtype C settings.
Antifungal Use in Immunocompromised Children in Europe: A 12-Week Multicenter Weekly Point Prevalence Survey (CALYPSO)
We prospectively analyzed antifungal use in immunocompromised children through a multicenter 12-week weekly point-prevalence survey in 31 hematology-oncology (HO) and hematopoietic stem cell/solid organ transplant (HSCT/SOT) units of 18 hospitals in 11 European countries. All patients hospitalized and receiving systemic antifungals were included. Ward policies, and weekly ward/patient data were collected. All 21 HO and 10 HSCT/SOT units had prophylaxis policies for high-risk patients (27/31 used azoles, 14/31 echinocandins and 15/31 liposomal amphotericin B [LAMB]). Among 572 courses recorded, prophylaxis was indicated in 439/572 (77%) and treatment in 133/572 (62/133 empirical, 43/133 pre-emptive, 28/133 targeted). Among patients receiving prophylaxis, 56% belonged to the non-high-risk group. Most common reasons for empirical, pre-emptive and targeted treatment were antibiotic-resistant febrile neutropenia (52%), abnormalities on chest-CT with/without positive galactomannan (77%) and candidiasis (82%), respectively. Fluconazole and LAMB were the most frequently prescribed agents both for prophylaxis (31%, 21%) and treatment (32%, 23%). Underdosing of micafungin for treatment in 50% of prescriptions and of fluconazole for treatment and prophylaxis in 70% of cases was noticed. In conclusion, most antifungal prescribing was for prophylaxis, with fluconazole being the main antifungal prescribed. Inadequate doses of antifungal prescribing and prophylaxis of non-high-risk patients could be targets for improvement.
Exon skipping peptide-conjugated morpholinos downregulate dynamin 2 to rescue centronuclear myopathy
Abstract Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and disorganization of myofibers. These conditions can result from dominant mutations in the DNM2 gene encoding the GTPase dynamin, making them potential targets for antisense therapy. Preclinical studies suggested decreasing DNM2 as a therapy but a recent clinical trial with antisense oligonucleotides did not effectively address the disease and showed some non-muscle toxicity. Here, to promote DNM2 downregulation in muscle versus other tissues, we used an exon skipping peptide-conjugated phosphorodiamidate morpholino (PPMO) targeting Dnm2 exon 6 splicing in the Dnm2R369W/+ mouse model for the moderate CNM form. PPMOs intravenous administration at early age (4 weeks) significantly downregulated intact (i.e. normally spliced) Dnm2 mRNA (∼50%) and DNM2 protein levels in muscle. This intervention led to a rescue of muscle force, thereby preventing disease progression. PPMO administration at a later age (8 weeks), when mice demonstrated established phenotypes, efficiently decreased intact Dnm2 mRNA and protein levels in muscle, resulting in reversal of the disease phenotype and significant improvement in muscle force (from 11 mN/mg to nearly 16 mN/mg). Overall, our results indicate that PPMOs targeting Dnm2 splicing effectively decrease intact Dnm2 mRNA and protein levels in muscle and rescue muscle force in Dnm2R369W/+ mice, suggesting a promising translational approach for patients with DNM2 mutations and potentially other forms of CNM. More generally, it provides the concept of using the exon skipping strategy to decrease the protein expression of a target gene, rather than producing a shorter functional protein as is generally done.