Recent publications
Background
A three-antigen DNA-prime/chimpanzee adenovirus 63 (ChAd63) boost vaccine containing pre-erythrocytic Plasmodium falciparum (Pf) circumsporozoite protein (CSP), Pf apical membrane antigen-1 (AMA1) and malaria multiple epitopes (ME) fused to Pf thrombospondin-related adhesion protein (ME-TRAP) elicited higher vaccine efficacy (VE) in an open label, randomized Phase 1 trial against controlled human malaria infection (CHMI) than the two-antigen vaccine DNA/Human Adenovirus 5 (HuAd5) containing CSP and AMA1. The objective of this follow-up study was to determine whether responses to CSP, AMA1 or TRAP MHC Class I-restricted epitopes were associated with VE.
Methodology
Protected (n = 6) and non-protected participants (n = 26) were screened in FluoroSpot interferon gamma (IFN-γ) and Granzyme B (GzB) assays using antigen-specific 15mer peptide subpools spanning CSP (n = 9 subpools), AMA1 (n = 12 subpools), and TRAP (n = 11 subpools). Individual antigen-specific 15mers in the subpools with strong responses were then deconvoluted, evaluated for activities, and MHC Class I-restricted epitopes within the active 15mers were predicted using NetMHCpan algorithms. The predicted epitopes were synthesized and evaluated in the FluoroSpot IFN-γ and GzB assays.
Results
Protected and some non-protected participants had similar responses to individual antigen-specific peptide subpools, which did not distinguish only protected participants. However, deconvoluted antigen-specific positive subpools with high magnitudes of responses revealed individual 15mer peptides containing specific and/or predicted MHC Class I (HLA) epitopes. Responses to epitopes were either IFN-γ-only, IFN-γ and GzB, or GzB-only. Due to limitation of cells, most of the analysis concentrated on the identification of protection associated AMA1 epitopes, since most of the predominant pool specific responses were generated against AMA1 15mer subpools. Furthermore, we previously identified protection associated HLA class I-restricted epitopes in a previous gene-based vaccine trial. Seven predicted minimal epitopes in AMA1 were synthesized and upon testing, five recalled responses from protected participants confirming their possible contribution and association with protection, and two recalled responses from non-protected participants. Two protection-associated epitopes were promiscuous and may have also contributed to protection by recognition of different HLA alleles. In addition, strongly positive antigen-specific 15mers identified within active antigen-specific subpools contained 39 predicted but not tested epitopes were identified in CSP, AMA1 and TRAP. Finally, some non-protected individuals recognized HLA-matched protection-associated minimal epitopes and we discuss possible reasons. Other factors such as HLA allele fine specificity or interaction between other HLA alleles in same individual may also influence protective efficacy.
Conclusions
This integrated approach using immunoassays and bioinformatics identified and confirmed AMA1-MHC Class I-restricted epitopes and a list of predicted additional epitopes which could be evaluated in future studies to assess possible association with protection against CHMI in the Phase 1 trial participants. The results suggest that identification of protection-associated epitopes within malaria antigens is feasible and can help design potent next generation multi-antigen, multi-epitope malaria vaccines for a genetically diverse population and to develop robust assays to measure protective cellular immunity against pre-erythrocytic stages of malaria. This approach can be used to develop vaccines for other novel emerging infectious disease pathogens.
Objectives
Globally, the burden of sepsis is highest in malaria endemic areas of sub-Saharan Africa. The influence of malaria on biological heterogeneity inherent to sepsis in this setting is poorly understood. We sought to determine shared and distinct features of the host response in malarial and non-malarial sepsis in sub-Saharan Africa.
Design and Setting
Analysis of Olink proteomic data from prospective observational cohort studies of sepsis conducted at public hospitals in Uganda (discovery cohort [Entebbe, urban], n = 238; validation cohort [Tororo, rural], n = 253).
Patients
Adults (age ≥ 18 yr) hospitalized with sepsis.
Interventions
None.
Measurements and Main Results
The frequency of malaria-associated (malarial) sepsis was 20% in the discovery cohort and 28% in the validation cohort. In both cohorts, a shared host response was predominant, with less than or equal to 8% of proteins differentially expressed (Benjamini-Hochberg-adjusted p ≤ 0.05) between malarial and non-malarial sepsis, after adjustment for demographic variables and HIV and tuberculosis coinfection. In both cohorts, malarial sepsis was associated with increased expression of immunosuppressive proteins (interleukin-10, leukocyte immunoglobulin-like receptor B1, killer cell immunoglobulin-like receptor 3DL1), including those associated with Tcell exhaustion and apoptosis (lymphocyte activation gene 3, T cell immunoglobulin and mucin domain containing 4). A classifier model including these immunosuppressive proteins showed reasonable discrimination (area under the receiver operating characteristic curves, 0.73 [95% CI, 0.65–0.81] and 0.72 [0.65–0.79]) and calibration (Brier scores 0.14 and 0.18) for stratification of malarial sepsis in the discovery and validation cohorts, respectively.
Conclusions
Host responses are largely conserved in malarial and non-malarial sepsis but may be distinguished by a signature of relative immunosuppression in the former. Further investigations are needed to differentiate mechanisms of malarial and non-malarial sepsis, with the goal of informing pathogen-stratified and pathogen-agnostic treatment strategies.
Lymph node T follicular helper (Tfh) cells and germinal center (GC) B cells are critical to generate potent antibodies but are rarely possible to study in humans. To understand how Tfh/GC B-cell interactions during acute HIV-1 infection (AHI) impact the generation of HIV-specific antibodies, we performed a unique cross-sectional analysis of inguinal lymph node biopsies taken prior to antiretroviral therapy (ART) initiation in AHI. Although total Tfh and GC B cell frequencies did not change during AHI, increased frequencies of proliferating Th1-like CXCR3 ⁺ Tfh, CXCR3 ⁺ non-GC B cells, and total CXCR3 ⁺ GC B cells correlated with gp120-specific IgG antibody levels in AHI. Frequencies of proliferating CXCR3 ⁺ Tfh in AHI also correlated with gp120-specific IgG antibody levels after 48 weeks of ART, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and increased antibody binding to infected cells after ART. Importantly, while beneficial for antibody development, CXCR3 ⁺ Tfh cells were also infected by HIV-1 at higher frequencies than their CXCR3 ⁻ counterparts and may contribute to the initial dissemination of HIV-1 in follicles. Together, these data suggest that activation of CXCR3 ⁺ Tfh cells is associated with induction of the germinal center response and subsequent antibody development, making these cells an important target for future therapeutic interventions.
IMPORTANCE
Early initiation of antiretroviral therapy (ART) is important to limit the seeding of the long-lasting HIV-1 reservoir; however, it also precludes the development of HIV-specific antibodies that can help control the virus if ART is stopped. Antibody development occurs within germinal centers in the lymph node and requires activation of both antigen-specific B cells and T follicular helper cells (Tfh), a specialized CD4 ⁺ cell that provides B cell help. To understand how early ART initiation may prohibit antibody development, we analyzed the frequencies and activation status of Tfh and B cells in lymph node biopsies collected in the different stages of acute HIV-1 infection. Our data suggest that decreased antibody development after early ART initiation may be due to limited germinal center development at the time of treatment and that new interventions that target activation of CXCR3 ⁺ Tfh may be beneficial to increase long-term HIV-specific antibody levels.
Background
Cytotoxic T-lymphocyte-associated protein 4 deficiency (CTLA4-D) is an inborn error of immunity (IEI) caused by heterozygous mutations, and characterized by immune cell infiltration into the gut and other organs, leading to intestinal disease, immune dysregulation and autoimmunity. While regulatory T-cell dysfunction remains central to CTLA4-D immunopathogenesis, mechanisms driving disease severity and intestinal pathology are unknown but likely involve intestinal dysbiosis. We determined whether the intestinal microbiome and metabolome could distinguish individuals with severe CTLA4-D and identify biomarkers of disease severity.
Results
The genera Veillonella and Streptococcus emerged as biomarkers that distinguished CTLA4-D from healthy cohorts from both the National Institutes of Health (NIH) Clinical Center, USA (NIH; CTLA-D, n = 32; healthy controls, n = 16), and a geographically distinct cohort from the Center for Chronic Immunodeficiency (CCI) of the Medical Center - University of Freiburg, Germany (CCI; CTLA4-D, n = 25; healthy controls, n = 24). Since IEIs in general may be associated with perturbations of the microbiota, a disease control cohort of individuals with common variable immunodeficiency (CVID, n = 20) was included to evaluate for a CTLA4-D-specific microbial signature. Despite common IEI-associated microbiome changes, the two bacterial genera retained their specificity as biomarkers for CTLA4-D. We further identified intestinal microbiome and metabolomic signatures that distinguished patients with CTLA4-D having severe vs. mild disease. Microbiome changes were associated with distinct stool metabolomic profiles and predicted changes in metabolic pathways. These differences were impacted by the presence of gastrointestinal manifestations and were partially reversed by treatment with abatacept and/or sirolimus.
Conclusions
Loss of intestinal microbial diversity and dysbiosis causing metabolomic changes was observed in CTLA4-D. Albeit some of these features were shared with CVID, the distinct changes associated with CTLA4-D highlight the fact that IEI-associated microbiome changes likely reflect the underlying immune dysregulation. Identified candidate intestinal microbial and metabolic biomarkers distinguishing individuals with CTLA4-D based on severity should be studied prospectively to determine their predictive value, and investigated as potential therapeutic ta.
5D3rs3jgvo7MqmP_TFVE2KVideo Abstract
Heat-labile toxin (LT) from enterotoxigenic Escherichia coli (ETEC) is an important pathogenic protein. Anti-LT antibodies (Abs) induced by vaccination can neutralize the toxin and potentially prevent diarrheal secretion from ~ 60% of ETEC strains expressing LT. However, only superficial investigation of the anti-toxin response is usually conducted in clinical trials. Here, we utilized human serum samples from two clinical trials performed to assess safety, immunogenicity and protection in a controlled human infection model with a LT + ST + CFA/I + H10407 ETEC strain. These Phase 1 and Phase 2b clinical trials explored a prototype ETEC adhesin (CfaE) and a chimeric adhesin-toxoid protein (dscCfaE-CTA2/LTB5) delivered intradermally or transcutaneously with a mutated form of LT (mLT) as an adjuvant. Serum samples were tested for antigen-specific IgG or IgA Abs by immunoblot, enzyme-linked immunosorbent assay (ELISA), or functional neutralizing Abs using LT holotoxin, LTA or LTB subunits. Abs to both LT subunits were present, but the response to each was altered by vaccine formulation, dose, and delivery routes as well as subject. The anti-LT IgG response correlated best to neutralizing antibodies and protection from H10407 controlled challenge when compared to other measures including serum IgA or anti-fimbriae (CfaE) Abs. In addition, our results helped to explain cohort attack rate differences in naïve unvaccinated participants and we found higher anti-LTA IgG post-challenge significantly related to ETEC severity score. Thus, strategies generating and measuring immunity to the complete AB5 structure of LT and subunits are better determinant of assessing protective immunity against LT + or LT + ST + ETEC diarrheal secretion in humans.
Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and other synucleinopathies are characterized by the accumulation of abnormal, self-propagating aggregates of α-synuclein. RT-QuIC or seed amplification assays are currently showing unprecedented diagnostic sensitivities and specificities for synucleinopathies even in prodromal phases years in advance of the onset of Parkinsonian signs or dementia. However, commonly used α-synuclein seed amplification assays take ≥48 h to perform as applied to patients’ diagnostic biospecimens. Here, we report the development of a faster α-synuclein RT-QuIC assay that is as analytically sensitive as prior assays of this type, but can be completed in ≤12 h for brain, skin, and intestinal mucosa, with positive signals often arising in <5 h. CSF assays took a few hours longer. Our same-day α-synuclein RT-QuIC (sdRT-QuIC) assay should increase the practicality, cost-effectiveness, and throughput of measurements of pathological forms of α-synuclein for fundamental research, clinical diagnosis, and therapeutics development.
Background
CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) disease is a newly identified condition with an estimated worldwide prevalence of < 100 patients. Patient interviews can ensure that what is important to patients is assessed in a clinical trial program. Due to the rare and potentially fatal nature of CHAPLE disease, interviews were conducted as part of the pozelimab clinical trial, rather than in a separate study before the trial. The aim of the interviews was to identify the key disease-related signs, symptoms, and health-related quality-of-life (HRQoL) impacts that are important and relevant to patients with CHAPLE disease.
Methods
Interviews were conducted with patients and/or caregivers at two timepoints (screening and Week 24) during the pozelimab trial to document the signs/symptoms and HRQoL impacts of CHAPLE disease, and document the most bothersome sign/symptom at screening. At Week 24, interviews gathered additional information on the patient experience from caregivers and patients (note: the impact of pozelimab treatment was also collected, though these results are presented elsewhere).
Results
Ten patients, aged 3–19 years, were enrolled in the trial; caregivers contributed to nine interviews. Thirty-one signs/symptoms and 65 HRQoL impacts were reported during the interviews. Abdominal pain, diarrhea, facial and peripheral edema/swelling, nausea, and vomiting emerged as the core signs/symptoms of CHAPLE disease (i.e., experienced by ≥ 90% of patients prior to treatment). The remaining 25 signs/symptoms were experienced by four or fewer ( n ≤ 4, ≤ 40.0%) patients, and 15 were only reported by one patient each. Abdominal pain and facial edema were reported as the most bothersome signs/symptoms ( n = 9, 90.0% and n = 1, 10.0%, respectively). The most frequently reported (i.e., ≥ 80% of interviews) HRQoL impacts were restricted diet ( n = 10, 100.0%), sleep disruptions ( n = 10, 100.0%), missing school ( n = 9, 90.0%), ability to get dressed independently ( n = 8, 80.0%), and difficulty engaging in play activities ( n = 8, 80.0%).
Conclusions
The main finding from these patient interviews is the identification of six core signs/symptoms of CHAPLE disease: abdominal pain, diarrhea, facial edema/swelling, peripheral edema/swelling, nausea, and vomiting. The severity of the core signs/symptoms leads to substantial impacts on patients’ lives.
Trial registration
ClinicalTrials.gov, NCT04209634. Registered 20 December 2019 https://classic.clinicaltrials.gov/ct2/show/NCT04209634 .
Artemisinin-based combination therapies (ACTs) are vital for malaria treatment, but these are threatened by blood-stage persisters—dormant forms of Plasmodium parasites that can survive drug exposure and cause recrudescent infections. Here, we present improved protocols for efficient preparation of pure Plasmodium falciparum persister populations without the need for magnetically activated columns, sorbitol exposure, or prolonged manipulations. Our protocols transformed actively replicating parasites into persister populations by exposing mixed blood-stage parasites to three or four consecutive daily 6 h pulses of 700 nM or 200 nM dihydroartemisinin (DHA). In micrographs of Giemsa-stained cells, we observed different persister morphologies: Type I persisters containing a rounded magenta-stained nucleus accompanied by a local region of blue-stained cytoplasm; and the more-prevalent Type II persisters characterized by a dark round or irregular-appearing nucleus and faded or no detectable cytoplasm. We also observed cells with disorganized nuclear and cytoplasmic structure, suggesting possible autophagic processes of destruction and remodeling. Recrudescence of actively replicating parasites to starting parasitemia or higher occurred around 17–22 days after initial DHA exposure. Differential expression patterns of the acetyl CoA carboxylase ( acc ) and skeleton binding protein 1 ( sbp1 ) genes during DHA treatment, dormancy, and recrudescence highlighted the evolution of physiologic states and metabolic changes underlying persister formation and recovery. Our findings suggest hypotheses and questions for further research to understand the cellular pathways of dormancy and uncover strategies to thwart parasite survival after drug exposure.
This Viewpoint discusses microbiome restoration by vaginal seeding in infants born by cesarean delivery and the potential of vaginal seeding to mitigate diseases associated with cesarean birth.
Objectives
Janus kinase inhibition (JAKi) has been proposed as a treatment for idiopathic inflammatory myopathies to target increased interferon signalling. Predominantly retrospective reports have demonstrated effectiveness of JAKi in refractory juvenile dermatomyositis (JDM). However, JAKi remains an off-label treatment for JDM and there may be variation in use worldwide. An international survey was conducted to investigate approaches to JAKi for JDM.
Methods
The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Therapeutics workgroup and core members of the Paediatric Rheumatology European Society (PReS) JDM working party devised an electronic survey to assess the use of JAKi in JDM. CARRA and PReS members were invited by email to complete the survey.
Results
There were 229 respondents (18%), with 50% from the US and 29% from Europe. 150 had used JAKi for over 450 patients with JDM; among them, 77% noted clinical improvement in most or all patients and 17% reported side effects. The highest ranked perceived barriers to JAKi use were lack of clinical data and inability to obtain insurance approval. The highest ranked clinical indications for starting JAKi were refractory skin disease, refractory muscle disease, inability to wean steroids, and intolerance to other steroid-sparing agents.
Conclusion
Pediatric rheumatologists use JAKi off-label treatment for refractory JDM. Most providers noted clinical improvement in their patients. Barriers to JAKi use include lack of clinical data and insurance coverage. Clinical trials are needed to provide better data on the efficacy and safety of JAKi.
Enveloped viruses such as influenza A virus (IAV) often produce a mixture of virion shapes, ranging from 100 nm spheres to micron-long filaments. Spherical virions use fewer resources, while filamentous virions resist cell-entry pressures such as antibodies. While shape changes are believed to require genetic adaptation, the mechanisms of how viral mutations alter shape remain unclear. Here we find that IAV dynamically adjusts its shape distribution in response to environmental pressures. We developed a quantitative flow virometry assay to measure the shape of viral particles under various infection conditions (such as multiplicity, replication inhibition and antibody treatment) while using different combinations of IAV strains and cell lines. We show that IAV rapidly tunes its shape distribution towards spheres under optimal conditions but favours filaments under attenuation. Our work demonstrates that this phenotypic flexibility allows IAV to rapidly respond to environmental pressures in a way that provides dynamic adaptation potential in changing surroundings.
Observational studies are critical tools in clinical research and public health response, but challenges arise in ensuring the data produced by these studies are scientifically robust and socially valuable. Resolving these challenges requires careful attention to prioritising the most valuable research questions, ensuring robust study design, strong data management practices, expansive community engagement, and access and benefit sharing of results and research materials. This paper opens with a discussion of how well-designed observational studies contribute to biomedical evidence and provides examples from across the clinical literature of how these methods generate hypotheses for future research and uncover otherwise unattainable insights by providing examples from across the clinical literature. Then, we present obstacles that remain in ensuring observational studies are optimally designed, conducted and communicated.
Background
Platform trials typically feature a shared control arm and multiple experimental treatment arms. Staggered entry and exit of arms splits the control group into two cohorts: those randomized during the same period in which the experimental arm was open (concurrent controls) and those randomized outside that period (nonconcurrent controls). Combining these control groups may offer increased statistical power but can lead to bias if analyses do not account for time trends in the response variable. Proposed methods of adjustment for time may increase type I error rates when time trends impact arms unequally or when large, sudden changes to the response rate occur. However, there has been limited exploration of the degree of type I error inflation one can plausibly expect in real-world scenarios.
Methods
We use data from the Adaptive COVID-19 Treatment Trial (ACTT) to mimic a realistic platform trial with a remdesivir control arm. We compare four strategies for estimating the effect of interferon beta-1a (the ACTT-3 experimental arm) relative to remdesivir (data from ACTT-1, ACTT-2, and ACTT-3) on recovery and death by day 29: utilizing concurrent controls only (the prespecified analysis), pooling all remdesivir arm data without adjustment (the “unadjusted-pooled” analysis), adjusting for time as a categorical variable, and a Bayesian hierarchical model implementation which adjusts for time trends using smoothing techniques (the “Bayesian time machine”). We compare type I error rates and relative efficiency of each method in simulation settings based on observed ACTT remdesivir arm data.
Results
The unadjusted-pooled approach provided substantially different estimates of the effect of interferon beta-1a relative to remdesivir compared with the concurrent-only and model-based approaches, indicating that changes in recovery and death rates over time were not ignorable across different stages of ACTT. The model-based approaches rely on an assumption of constant treatment effects for each arm in the platform relative to control; error rates more than doubled in settings where this was not satisfied. Relative efficiency of the model-based approaches compared with the concurrent-only analysis was moderate.
Conclusions
In simulation settings where key model assumptions were not met, potential efficiency gains from incorporation of nonconcurrent controls were outweighed by the risk of substantial type I error rate inflation. This leads us to advise against these strategies for primary analyses in confirmatory clinical trials, aligning with current FDA guidance advising against comparisons to nonconcurrent controls in COVID-19 settings. The model-based adjustment methods may be useful in other settings, but we recommend performing the concurrent-only analysis as a reference for assessing the degree to which nonconcurrent controls drive results.
The history of clinical resistance to tetracycline antibiotics is characterized by cycles whereby the deployment of a new generation of drug molecules is quickly followed by the discovery of a new mechanism of resistance. This suggests mechanism-specific selection by each tetracycline generation; however, the evolutionary dynamics of this remain unclear. Here, we evaluate 24 recombinant Escherichia coli strains expressing tetracycline resistance genes from each mechanism (efflux pumps, ribosomal protection proteins, and enzymatic inactivation) in the context of each tetracycline generation. We employ a high-throughput barcode sequencing protocol that can discriminate between strains in mixed culture and quantify their relative abundances. We find that each mechanism is preferentially selected for by specific antibiotic generations, leading to their expansion. Remarkably, the minimum inhibitory concentration associated with individual genes is secondary to resistance mechanism for inter-mechanism relative fitness, but it does explain intra-mechanism relative fitness. These patterns match the history of clinical deployment of tetracycline drugs and resistance discovery in pathogens.
Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the BCG route and dose from 5 × 10⁵ CFUs ID to 5 × 10⁷ CFUs i.v. resulted in prevention of Mycobacterium tuberculosis (Mtb) infection and TB disease in highly susceptible nonhuman primates. Identifying immune mechanisms protection following i.v. BCG will facilitate development of more effective vaccines against TB. Here, we depleted lymphocyte subsets prior to and during Mtb challenge in i.v. BCG–vaccinated macaques to identify those necessary for protection. Depletion of adaptive CD4 T cells, but not adaptive CD8αβ T cells, resulted in loss of protection with increased Mtb burdens and dissemination, indicating that CD4 T cells are critical to i.v. BCG–mediated protection. Depletion of unconventional CD8α-expressing lymphocytes (NK cells, innate T cells, and CD4⁺CD8α⁺ double-positive T cells) abrogated protection in most i.v. BCG–immunized macaques, supporting further investigation into which of these cell subsets contribute to protection after vaccination.
The COVID-19 pandemic and increased demands for neurologists have inspired the creation of remote, digitalized tests of neurological functions. This study investigates two tests from the Neurological Functional Tests Suite (NeuFun-TS) smartphone application, the “Postural Sway” and “Pronator Drift” tests. These tests capture different domains of postural control and motoric dysfunction in healthy volunteers (n = 13) and people with neurological disorders (n = 68 relapsing–remitting multiple sclerosis [MS]; n = 21 secondary progressive MS; n = 23 primary progressive MS; n = 13 other inflammatory neurological diseases; n = 21 non-inflammatory neurological diseases; n = 4 clinically isolated syndrome; n = 1 radiologically isolated syndrome). Smartphone accelerometer data was transformed into digital biomarkers, which were filtered in the training cohort (~ 80% of subjects) for test–retest reproducibility and correlations with subdomains of neurological examinations and validated imaging biomarkers. The independent validation cohort (~ 20%) determined whether biomarker models outperformed the best single digital biomarkers. Postural sway acceleration magnitude in the eyes closed and feet together stance demonstrated the highest reliability (ICC = 0.706), strongest correlations with age (Pearson r <= 0.82) and clinical and imaging outcomes (r <= 0.65, p < 0.001) and stronger predictive value for sway-relevant neurological disability outcomes than models that aggregated multiple biomarkers (coefficient of determination R² = 0.46 vs 0.38). The pronator drift test only captured cerebellar dysfunction, had less reproducible biomarkers, but provided additive value when combined with postural sway biomarkers into models predicting global scales of neurological disability. In conclusion, a simple 1-min postural sway test accurately measures body oscillations that increase with natural aging and differentiates them from abnormally increased body oscillations in people with neurological disabilities.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12883-025-04038-2.
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