Showing papers by "Karolinska Institutet published in 2022"

From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures

Abstract: Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study

Abstract: The SARS-CoV-2 omicron (B.1.1.529) variant, which was first identified in November, 2021, spread rapidly in many countries, with a spike protein highly diverged from previously known variants, and raised concerns that this variant might evade neutralising antibody responses. We therefore aimed to characterise the sensitivity of the omicron variant to neutralisation.For this cross-sectional study, we cloned the sequence encoding the omicron spike protein from a diagnostic sample to establish an omicron pseudotyped virus neutralisation assay. We quantified the neutralising antibody ID50 (the reciprocal dilution that produces 50% inhibition) against the omicron spike protein, and the fold-change in ID50 relative to the spike of wild-type SARS-CoV-2 (ie, the pandemic founder variant), for one convalescent reference plasma pool (WHO International Standard for anti-SARS-CoV-2 immunoglobulin [20/136]), three reference serum pools from vaccinated individuals, and two cohorts from Stockholm, Sweden: one comprising previously infected hospital workers (17 sampled in November, 2021, after vaccine rollout and nine in June or July, 2020, before vaccination) and one comprising serum from 40 randomly sampled blood donors donated during week 48 (Nov 29-Dec 5) of 2021. Furthermore, we assessed the neutralisation of omicron by five clinically relevant monoclonal antibodies (mAbs).Neutralising antibody responses in reference sample pools sampled shortly after infection or vaccination were substantially less potent against the omicron variant than against wild-type SARS-CoV-2 (seven-fold to 42-fold reduction in ID50 titres). Similarly, for sera obtained before vaccination in 2020 from a cohort of convalescent hospital workers, neutralisation of the omicron variant was low to undetectable (all ID50 titres <20). However, in serum samples obtained in 2021 from two cohorts in Stockholm, substantial cross-neutralisation of the omicron variant was observed. Sera from 17 hospital workers after infection and subsequent vaccination had a reduction in average potency of only five-fold relative to wild-type SARS-CoV-2 (geometric mean ID50 titre 495 vs 105), and two donors had no reduction in potency. A similar pattern was observed in randomly sampled blood donors (n=40), who had an eight-fold reduction in average potency against the omicron variant compared with wild-type SARS-CoV-2 (geometric mean ID50 titre 369 vs 45). We found that the omicron variant was resistant to neutralisation (50% inhibitory concentration [IC50] >10 μg/mL) by mAbs casirivimab (REGN-10933), imdevimab (REGN-10987), etesevimab (Ly-CoV016), and bamlanivimab (Ly-CoV555), which form part of antibody combinations used in the clinic to treat COVID-19. However, S309, the parent of sotrovimab, retained most of its activity, with only an approximately two-fold reduction in potency against the omicron variant compared with ancestral D614G SARS-CoV-2 (IC50 0·1-0·2 μg/mL).These data highlight the extensive, but incomplete, evasion of neutralising antibody responses by the omicron variant, and suggest that boosting with licensed vaccines might be sufficient to raise neutralising antibody titres to protective levels.European Union Horizon 2020 research and innovation programme, European and Developing Countries Clinical Trials Partnership, SciLifeLab, and the Erling-Persson Foundation.

Clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics

Abstract: The mammalian brain contains many specialized cells that develop from a thin sheet of neuroepithelial progenitor cells. Single-cell transcriptomics revealed hundreds of molecularly diverse cell types in the nervous system, but the lineage relationships between mature cell types and progenitor cells are not well understood. Here we show in vivo barcoding of early progenitors to simultaneously profile cell phenotypes and clonal relations in the mouse brain using single-cell and spatial transcriptomics. By reconstructing thousands of clones, we discovered fate-restricted progenitor cells in the mouse hippocampal neuroepithelium and show that microglia are derived from few primitive myeloid precursors that massively expand to generate widely dispersed progeny. We combined spatial transcriptomics with clonal barcoding and disentangled migration patterns of clonally related cells in densely labeled tissue sections. Our approach enables high-throughput dense reconstruction of cell phenotypes and clonal relations at the single-cell and tissue level in individual animals and provides an integrated approach for understanding tissue architecture.

Metabolic determination of cell fate through selective inheritance of mitochondria

Abstract: Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions1–4. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron–sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria. Döhla et al. show that selectively and asymmetrically inherited mitochondria impose a metabolic bias on progeny in mammary stem-like cells that alters the balance between stem cell self-renewal and differentiation.

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation.

Abstract: Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

Transcriptional kinetics and molecular functions of long noncoding RNAs

Abstract: An increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene's transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.

SARS-CoV-2 induces a durable and antigen specific humoral immunity after asymptomatic to mild COVID-19 infection

Abstract: Current SARS-CoV-2 serological assays generate discrepant results, and the longitudinal characteristics of antibodies targeting various antigens after asymptomatic to mild COVID-19 are yet to be established. This longitudinal cohort study including 1965 healthcare workers, of which 381 participants exhibited antibodies against the SARS-CoV-2 spike antigen at study inclusion, reveal that these antibodies remain detectable in most participants, 96%, at least four months post infection, despite having had no or mild symptoms. Virus neutralization capacity was confirmed by microneutralization assay in 91% of study participants at least four months post infection. Contrary to antibodies targeting the spike protein, antibodies against the nucleocapsid protein were only detected in 80% of previously anti-nucleocapsid IgG positive healthcare workers. Both anti-spike and anti-nucleocapsid IgG levels were significantly higher in previously hospitalized COVID-19 patients four months post infection than in healthcare workers four months post infection (p = 2*10-23 and 2*10-13 respectively). Although the magnitude of humoral response was associated with disease severity, our findings support a durable and functional humoral response after SARS-CoV-2 infection even after no or mild symptoms. We further demonstrate differences in antibody kinetics depending on the antigen, arguing against the use of the nucleocapsid protein as target antigen in population-based SARS-CoV-2 serological surveys.

Immune responses after omicron infection in triple-vaccinated health-care workers with and without previous SARS-CoV-2 infection

Abstract: The SARS-CoV-2 omicron variant (B.1.1.529) is less sensitive to neutralising antibody responses induced by vaccination and prior infection than previous variants.1Dejnirattisai W Shaw RH Supasa P et al.Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum.Lancet. 2022; 399: 234-236Summary Full Text Full Text PDF PubMed Google Scholar, 2Pajon R Doria-Rose NA Shen X et al.SARS-CoV-2 omicron variant neutralization after mRNA-1273 booster vaccination.N Engl J Med. 2022; 386: 1088-1091Crossref PubMed Scopus (109) Google Scholar Less is known regarding omicron-induced serological and T-cell responses after breakthrough infection of vaccinated individuals with and without prior infection.In this prospective cohort study, we analysed serological and T-cell responses following omicron infection in 56 triple-vaccinated health-care workers in Sweden with and without prior SARS-CoV-2 infection. A surrogate virus neutralisation test (sVNT) was used to assess neutralisation of SARS-CoV-2 variants. Immune responses of all participants had been regularly assessed since April, 2020, in the ongoing Swedish COMMUNITY study.3Rudberg A-S Havervall S Månberg A et al.SARS-CoV-2 exposure, symptoms and seroprevalence in healthcare workers in Sweden.Nat Commun. 2020; 115064Crossref PubMed Scopus (155) Google Scholar, 4Havervall S Marking U Greilert-Norin N et al.Impact of SARS-CoV-2 infection on vaccine-induced immune responses over time.Clin Transl Immunology. 2022; 11e1388Crossref PubMed Scopus (6) Google Scholar For this sub-study, participants were screened with qPCR twice a week for 4 weeks,5Marking U Havervall S Norin NG et al.High rate of BA.1, BA.1.1 and BA.2 infection in triple vaccinated.medRxiv. 2022; (published online April 3.)https://doi.org/10.1101/2022.04.02.22273333Google Scholar with additional qPCR tests every other day for 14 days if positive. Blood samples were collected 1 week, 2 weeks, 3 weeks, 5 weeks, and 7 weeks after the first positive qPCR sample. For information on study design, demographic characteristics of the study population, and vaccination histories see appendix pp 4–5.Overall, we observed a two-fold increase in anti-spike IgG and sVNT titres against wildtype, delta (B.1.617.2), BA.1, and BA.2 variants 2–5 weeks after omicron breakthrough infection (appendix pp 6–7). Strikingly, however, post-omicron serological responses were significantly higher in previously non-infected (triple-vaccinated with no history of SARS-CoV-2 infection; n=40) than in previously SARS-CoV-2-infected (triple-vaccinated with a confirmed SARS-CoV-2 wildtype infection before primary vaccination; n=16) participants (figure A,C; appendix pp 8–9). The magnitude of serological responses correlated with nadir cycle threshold (Ct) values (appendix pp 8–9). Notably, nadir Ct value and symptomatology5Marking U Havervall S Norin NG et al.High rate of BA.1, BA.1.1 and BA.2 infection in triple vaccinated.medRxiv. 2022; (published online April 3.)https://doi.org/10.1101/2022.04.02.22273333Google Scholar were similar in participants with and without previous SARS-CoV-2 infection (appendix pp 8–9). The magnitude of serological responses correlated inversely with pre-infection titres in both previously non-infected and previously infected participants (appendix pp 10–11).There were no differences in spike-specific T-cell responses between participants 7 weeks after omicron breakthrough infection and participants without omicron infection, regardless of previous SARS-CoV-2 infection status (figure B,D). A significant increase in specific T-cells against nucleocapsid and membrane proteins was observed in omicron-infected individuals without past SARS-CoV-2 infection, showing that omicron breakthrough infection can prime specific T-cells (appendix p 11). Higher serological responses against both BA.1 and BA.2, but similar T-cell responses, were observed in BA.1-infected compared with BA.2-infected individuals (appendix p 12).This study is limited by the use of sVNT, which is based on the capacity of antibodies to block binding of variant-specific spike protein to ACE2. It is possible that other factors are also involved in neutralisation,6Lustig Y Gonen T Meltzer L et al.Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose.Nat Immunol. 2022; (published online May 9.)https://doi.org/10.1038/S41590-022-01212-3Crossref PubMed Scopus (9) Google Scholar which might be better reflected in live microneutralisation assays. However, when analysing a subset of samples we observed a strong correlation between live microneutralising titres and sVNT titres for both wildtype and BA.1 (appendix p 13), mirroring other reports4Havervall S Marking U Greilert-Norin N et al.Impact of SARS-CoV-2 infection on vaccine-induced immune responses over time.Clin Transl Immunology. 2022; 11e1388Crossref PubMed Scopus (6) Google Scholar, 7Tan CW Chia WN Qin X et al.A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction.Nat Biotechnol. 2020; 38: 1073-1078Crossref PubMed Scopus (546) Google Scholar suggesting that sVNT can be used as a surrogate method for live virus neutralisation.These findings suggest that previous SARS-CoV-2 infection, as well as high pre-infection antibody titres, might impact omicron-induced spike-specific serological responses in triple-vaccinated individuals. Close monitoring of immune responses following repeated antigenic exposures through infection or booster doses is needed. The SARS-CoV-2 omicron variant (B.1.1.529) is less sensitive to neutralising antibody responses induced by vaccination and prior infection than previous variants.1Dejnirattisai W Shaw RH Supasa P et al.Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum.Lancet. 2022; 399: 234-236Summary Full Text Full Text PDF PubMed Google Scholar, 2Pajon R Doria-Rose NA Shen X et al.SARS-CoV-2 omicron variant neutralization after mRNA-1273 booster vaccination.N Engl J Med. 2022; 386: 1088-1091Crossref PubMed Scopus (109) Google Scholar Less is known regarding omicron-induced serological and T-cell responses after breakthrough infection of vaccinated individuals with and without prior infection. In this prospective cohort study, we analysed serological and T-cell responses following omicron infection in 56 triple-vaccinated health-care workers in Sweden with and without prior SARS-CoV-2 infection. A surrogate virus neutralisation test (sVNT) was used to assess neutralisation of SARS-CoV-2 variants. Immune responses of all participants had been regularly assessed since April, 2020, in the ongoing Swedish COMMUNITY study.3Rudberg A-S Havervall S Månberg A et al.SARS-CoV-2 exposure, symptoms and seroprevalence in healthcare workers in Sweden.Nat Commun. 2020; 115064Crossref PubMed Scopus (155) Google Scholar, 4Havervall S Marking U Greilert-Norin N et al.Impact of SARS-CoV-2 infection on vaccine-induced immune responses over time.Clin Transl Immunology. 2022; 11e1388Crossref PubMed Scopus (6) Google Scholar For this sub-study, participants were screened with qPCR twice a week for 4 weeks,5Marking U Havervall S Norin NG et al.High rate of BA.1, BA.1.1 and BA.2 infection in triple vaccinated.medRxiv. 2022; (published online April 3.)https://doi.org/10.1101/2022.04.02.22273333Google Scholar with additional qPCR tests every other day for 14 days if positive. Blood samples were collected 1 week, 2 weeks, 3 weeks, 5 weeks, and 7 weeks after the first positive qPCR sample. For information on study design, demographic characteristics of the study population, and vaccination histories see appendix pp 4–5. Overall, we observed a two-fold increase in anti-spike IgG and sVNT titres against wildtype, delta (B.1.617.2), BA.1, and BA.2 variants 2–5 weeks after omicron breakthrough infection (appendix pp 6–7). Strikingly, however, post-omicron serological responses were significantly higher in previously non-infected (triple-vaccinated with no history of SARS-CoV-2 infection; n=40) than in previously SARS-CoV-2-infected (triple-vaccinated with a confirmed SARS-CoV-2 wildtype infection before primary vaccination; n=16) participants (figure A,C; appendix pp 8–9). The magnitude of serological responses correlated with nadir cycle threshold (Ct) values (appendix pp 8–9). Notably, nadir Ct value and symptomatology5Marking U Havervall S Norin NG et al.High rate of BA.1, BA.1.1 and BA.2 infection in triple vaccinated.medRxiv. 2022; (published online April 3.)https://doi.org/10.1101/2022.04.02.22273333Google Scholar were similar in participants with and without previous SARS-CoV-2 infection (appendix pp 8–9). The magnitude of serological responses correlated inversely with pre-infection titres in both previously non-infected and previously infected participants (appendix pp 10–11). There were no differences in spike-specific T-cell responses between participants 7 weeks after omicron breakthrough infection and participants without omicron infection, regardless of previous SARS-CoV-2 infection status (figure B,D). A significant increase in specific T-cells against nucleocapsid and membrane proteins was observed in omicron-infected individuals without past SARS-CoV-2 infection, showing that omicron breakthrough infection can prime specific T-cells (appendix p 11). Higher serological responses against both BA.1 and BA.2, but similar T-cell responses, were observed in BA.1-infected compared with BA.2-infected individuals (appendix p 12). This study is limited by the use of sVNT, which is based on the capacity of antibodies to block binding of variant-specific spike protein to ACE2. It is possible that other factors are also involved in neutralisation,6Lustig Y Gonen T Meltzer L et al.Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose.Nat Immunol. 2022; (published online May 9.)https://doi.org/10.1038/S41590-022-01212-3Crossref PubMed Scopus (9) Google Scholar which might be better reflected in live microneutralisation assays. However, when analysing a subset of samples we observed a strong correlation between live microneutralising titres and sVNT titres for both wildtype and BA.1 (appendix p 13), mirroring other reports4Havervall S Marking U Greilert-Norin N et al.Impact of SARS-CoV-2 infection on vaccine-induced immune responses over time.Clin Transl Immunology. 2022; 11e1388Crossref PubMed Scopus (6) Google Scholar, 7Tan CW Chia WN Qin X et al.A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction.Nat Biotechnol. 2020; 38: 1073-1078Crossref PubMed Scopus (546) Google Scholar suggesting that sVNT can be used as a surrogate method for live virus neutralisation. These findings suggest that previous SARS-CoV-2 infection, as well as high pre-infection antibody titres, might impact omicron-induced spike-specific serological responses in triple-vaccinated individuals. Close monitoring of immune responses following repeated antigenic exposures through infection or booster doses is needed. We declare no competing interests. KB, UM, SHa, JK, and CT contributed equally. This research was funded by grants from the Knut and Alice Wallenberg Foundation (to CT and JK), the Jonas and Kristina af Jochnick Foundation (to CT), the Leif Lundblad Family Foundation (to CT), Region Stockholm (to CT), and Center for Innovative Medicine (to KB and JK). Supplementary Material Download .pdf (.45 MB) Help with pdf files Supplementary appendix Download .pdf (.45 MB) Help with pdf files Supplementary appendix

Risk factors for COVID-19-related death, hospitalization and intensive care: a population-wide study of all inhabitants in Stockholm

Abstract: Since the beginning of the Covid-19 pandemic, the scientific community has explored determinants of Covid 19 disease severity. However, the majority of studies are based on in-hospital patients with high risk of collider- or selection bias. The present investigation details risk factors associated with overall mortality, hospitalization and intensive care unit (ICU) admission in Covid-19 infections, with complete population coverage and high-resolution data on patient characteristics and comorbid conditions This population-based observational study comprises all residents 18 years and older in Stockholm Region-1.8 million inhabitants-using the real-time Covid-19 monitoring framework. The observation period lasted between March 1 to December 31, 2020. Hazard ratios (HR) for risk factors of Covid-19 disease severity were assessed using Cox proportional hazard models. In total, 3322 deaths, 11,508 hospitalizations and 1423 ICU-admissions related to Covid-19 occurred during the study period. Kidney failure, diabetes and obesity increased risk of mortality and so did heart failure and ischemic heart disease. However, atrial fibrillation and hypertension did not. Risk of hospitalization follow a similar pattern, whereas admission to intensive care differs; triage processes where clearly present as certain co-morbid conditions were associated with lower ICU admission. Observed differences in risk of mortality and hospitalization among patients with Covid 19 raise important questions about potentially protective comedication which will be further addressed using the real-time Covid-19 monitoring framework.

The impact of digital media on children’s intelligence while controlling for genetic differences in cognition and socioeconomic background

Abstract: Digital media defines modern childhood, but its cognitive effects are unclear and hotly debated. We believe that studies with genetic data could clarify causal claims and correct for the typically unaccounted role of genetic predispositions. Here, we estimated the impact of different types of screen time (watching, socializing, or gaming) on children's intelligence while controlling for the confounding effects of genetic differences in cognition and socioeconomic status. We analyzed 9855 children from the USA who were part of the ABCD dataset with measures of intelligence at baseline (ages 9-10) and after two years. At baseline, time watching (r = - 0.12) and socializing (r = - 0.10) were negatively correlated with intelligence, while gaming did not correlate. After two years, gaming positively impacted intelligence (standardized β = + 0.17), but socializing had no effect. This is consistent with cognitive benefits documented in experimental studies on video gaming. Unexpectedly, watching videos also benefited intelligence (standardized β = + 0.12), contrary to prior research on the effect of watching TV. Although, in a posthoc analysis, this was not significant if parental education (instead of SES) was controlled for. Broadly, our results are in line with research on the malleability of cognitive abilities from environmental factors, such as cognitive training and the Flynn effect.

Structure of the vasopressin hormone–V2 receptor–β-arrestin1 ternary complex

Abstract: Arrestins interact with G protein-coupled receptors (GPCRs) to stop G protein activation and to initiate key signaling pathways. Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling, but whether this process is conserved among GPCRs is poorly understood. Here, we report the cryo-electron microscopy active structure of the wild-type arginine-vasopressin V2 receptor (V2R) in complex with β-arrestin1. It reveals an atypical position of β-arrestin1 compared to previously described GPCR-arrestin assemblies, associated with an original V2R/β-arrestin1 interface involving all receptor intracellular loops. Phosphorylated sites of the V2R carboxyl terminus are clearly identified and interact extensively with the β-arrestin1 N-lobe, in agreement with structural data obtained with chimeric or synthetic systems. Overall, these findings highlight a notable structural variability among GPCR-arrestin signaling complexes.

Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial

Abstract: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744.Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns.RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.Swedish Research Council.

Evasion of neutralizing antibodies by Omicron sublineage BA.2.75

Abstract: Abstract An emerging SARS-CoV-2 Omicron sublineage, BA.2.75, is increasing in frequency in India and has been detected in at least 15 countries as of 19 July 2022. Relative to BA.2, BA.2.75 carries nine additional mutations in spike. Here we report the sensitivity of the BA.2.75 spike to neutralization by a panel of clinically-relevant and pre-clinical monoclonal antibodies, as well as by serum from blood donated in Stockholm, Sweden, before and after the BA.1/BA.2 infection wave. BA.2.75 largely maintains sensitivity to bebtelovimab, despite a slight reduction in potency, and exhibits moderate susceptibility to tixagevimab and cilgavimab. For sera sampled both before and after the BA.1/BA.2 infection wave, BA.2.75 does not show significantly greater antibody evasion than the currently-dominating BA.5.

High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations

Abstract: Background: In amyloid-positive individuals at risk for Alzheimer’s disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. Objective: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer’s disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). Methods: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. Results: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19–0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68–0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. Conclusion: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.