Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023

Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study, 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May 2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. We found that the dominant sublineages changed over time, and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD.Acknowledgements: We would like to thank the personnel at Clinical Microbiology and Hospital Hygiene, Uppsala University Hospital for their help with handling samples, RNA extraction, PCR, and whole-genome sequencing.Funder: Regional Research Council Mid Sweden; Grant(s): RFR-98011

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage

Vos et al. compare the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage based on the IWG-1, IWG-2 and NIA-AA criteria. All three aid identification of early Alzheimer's disease, but combining amyloid and neuronal injury markers according to the NIA-AA criteria offers the most accurate prognosi

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ 4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo

Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia

A metabolite-based machine learning approach to diagnose Alzheimer’s-type dementia in blood: Results from the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort

INTRODUCTION: Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer’s Disease (AD). Here we set out to test the performance of metabolites in blood to categorise AD when compared to CSF biomarkers. METHODS: This study analysed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n=883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV). RESULTS: On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively. DISCUSSION: This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders

Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023

From Crossref journal articles via Jisc Publications RouterHistory: epub 2023-09-27, issued 2023-09-27Article version: VoRPublication status: PublishedFunder: Regional Research Council Mid Sweden; Grant(s): RFR-980115Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study, 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May 2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. We found that the dominant sublineages changed over time, and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD

Neuroticism-related personality traits are associated with posttraumatic stress after abortion : findings from a Swedish multi-center cohort study

Background: Most women who choose to terminate a pregnancy cope well following an abortion, although some women experience severe psychological distress. The general interpretation in the field is that the most consistent predictor of mental disorders after induced abortion is the mental health issues that women present with prior to the abortion. We have previously demonstrated that few women develop posttraumatic stress disorder (PTSD) or posttraumatic stress symptoms (PTSS) after induced abortion. Neuroticism is one predictor of importance for PTSD, and may thus be relevant as a risk factor for the development of PTSD or PTSS after abortion. We therefore compared Neuroticism-related personality trait scores of women who developed PTSD or PTSS after abortion to those of women with no evidence of PTSD or PTSS before or after the abortion. Methods: A Swedish multi-center cohort study including six Obstetrics and Gynecology Departments, where 1294 abortion-seeking women were included. The Screen Questionnaire-Posttraumatic Stress Disorder (SQ-PTSD) was used to evaluate PTSD and PTSS. Measurements were made at the first visit and at three and six month after the abortion. The Swedish universities Scales of Personality (SSP) was used for assessment of Neuroticism-related personality traits. Multiple logistic regression analyses were performed to investigate the risk factors for development of PTSD or PTSS post abortion. Results: Women who developed PTSD or PTSS after the abortion had higher scores than the comparison group on several of the personality traits associated with Neuroticism, specifically Somatic Trait Anxiety, Psychic Trait Anxiety, Stress Susceptibility and Embitterment. Women who reported high, or very high, scores on Neuroticism had adjusted odds ratios for PTSD/PTSS development of 2.6 (CI 95% 1.2-5.6) and 2.9 (CI 95% 1.3-6.6), respectively. Conclusion: High scores on Neuroticism-related personality traits influence the risk of PTSD or PTSS post abortion. This finding supports the argument that the most consistent predictor of mental disorders after abortion is pre-existing mental health status

Posttraumatic stress among women after induced abortion : a Swedish multi-centre cohort study

BACKGROUND: Induced abortion is a common medical intervention. Whether psychological sequelae might follow induced abortion has long been a subject of concern among researchers and little is known about the relationship between posttraumatic stress disorder (PTSD) and induced abortion. Thus, the aim of the study was to assess the prevalence of PTSD and posttraumatic stress symptoms (PTSS) before and at three and six months after induced abortion, and to describe the characteristics of the women who developed PTSD or PTSS after the abortion. METHODS: This multi-centre cohort study included six departments of Obstetrics and Gynaecology in Sweden. The study included 1457 women who requested an induced abortion, among whom 742 women responded at the three-month follow-up and 641 women at the six-month follow-up. The Screen Questionnaire-Posttraumatic Stress Disorder (SQ-PTSD) was used for research diagnoses of PTSD and PTSS, and anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Measurements were made at the first visit and at three and six months after the abortion. The 95% confidence intervals for the prevalence of lifetime or ongoing PTSD and PTSS were calculated using the normal approximation. The chi-square test and the Student's t-test were used to compare data between groups. RESULTS: The prevalence of ongoing PTSD and PTSS before the abortion was 4.3% and 23.5%, respectively, concomitant with high levels of anxiety and depression. At three months the corresponding rates were 2.0% and 4.6%, at six months 1.9% and 6.1%, respectively. Dropouts had higher rates of PTSD and PTSS. Fifty-one women developed PTSD or PTSS during the observation period. They were young, less well educated, needed counselling, and had high levels of anxiety and depressive symptoms. During the observation period 57 women had trauma experiences, among whom 11 developed PTSD or PTSS and reported a traumatic experience in relation to the abortion. CONCLUSION: Few women developed PTSD or PTSS after the abortion. The majority did so because of trauma experiences unrelated to the induced abortion. Concomitant symptoms of depression and anxiety call for clinical alertness and support

The prevalence of posttraumatic stress among women requesting induced abortion

Objectives To describe the prevalence and pattern of traumatic experiences, to assess the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS), to identify risk factors for PTSD and PTSS, and to analyse the association of PTSD and PTSS with concomitant anxiety and depressive symptoms in women requesting induced abortion. Methods A Swedish multi-centre study of women requesting an induced abortion. The Screen Questionnaire - Posttraumatic Stress Disorder was used for research diagnoses of PTSD and PTSS. Anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Results Of the 1514 respondents, almost half reported traumatic experiences. Lifetime- and point prevalence of PTSD were 7% (95% confidence interval [CI]: 5.8-8.5) and 4% (95% CI: 3.1-5.2), respectively. The prevalence of PTSS was 23% (95% CI: 21.1-25.4). Women who reported symptoms of anxiety or depression when requesting abortion were more likely to have ongoing PTSD or PTSS. Also single-living women and smokers displayed higher rates of ongoing PTSD. Conclusions Although PTSD is rare among women who request an induced abortion, a relatively high proportion suffers from PTSS. Abortion seeking women with trauma experiences and existing or preexisting mental disorders need more consideration and alertness when counselled for termination