Publications by authors named "R S Falk"

1,237 Publications

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The Oslo Ischaemia Study: cohort profile.

BMJ Open 2021 Oct 13;11(10):e049111. Epub 2021 Oct 13.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Purpose: The Oslo Ischaemia Study was designed to investigate the prevalence and predictors of silent coronary disease in Norwegian middle-aged men, specifically validating exercise electrocardiography (ECG) findings compared with angiography. The study has been important in investigating long-term predictors of cardiovascular morbidity and mortality, as well as investigating a broad spectrum of epidemiological and public health perspectives.

Participants: In 1972-1975, 2014 healthy men, 40-59 years old, were enrolled in the study. Comprehensive clinical examination included an ECG-monitored exercise test at baseline and follow-ups. The cohort has been re-examined four times during 20 years. Linkage to health records and national health registries has ensured complete endpoint registration of morbidity until the end of 2006, and cancer and mortality until the end of 2017.

Findings To Date: The early study results provided new evidence, as many participants with a positive exercise ECG, but no chest pain ('silent ischaemia'), did not have significant coronary artery stenosis after all. Still, they were over-represented with coronary disease after years of follow-up. Furthermore, participants with the highest physical fitness had lower risk of cardiovascular disease, and the magnitude of blood pressure responses to moderate exercise was shown to influence the risk of cardiovascular disease and mortality. With time, follow-up data allowed the scope of research to expand into other fields of medicine, with the aim of investigating predictors and the importance of lifestyle and risk factors.

Future Plans: Recently, the Oslo Ischaemia Study has been found worthy, as the first scientific study, to be preserved by The National Archives of Norway. All the study material will be digitised, free to use and accessible for all. In 2030, the Oslo Ischaemia Study will be linked to the Norwegian Cause of Death Registry to obtain complete follow-up to death. Thus, a broad spectrum of additional opportunities opens.
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http://dx.doi.org/10.1136/bmjopen-2021-049111DOI Listing
October 2021

Novel multivalent design of a monoclonal antibody improves binding strength to soluble aggregates of amyloid beta.

Transl Neurodegener 2021 Sep 28;10(1):38. Epub 2021 Sep 28.

Protein Drug Design, Faculty of Pharmacy, Uppsala University, 75124, Uppsala, Sweden.

Background: Amyloid-β (Aβ) immunotherapy is a promising therapeutic strategy in the fight against Alzheimer's disease (AD). A number of monoclonal antibodies have entered clinical trials for AD. Some of them have failed due to the lack of efficacy or side-effects, two antibodies are currently in phase 3, and one has been approved by FDA. The soluble intermediate aggregated species of Aβ, termed oligomers and protofibrils, are believed to be key pathogenic forms, responsible for synaptic and neuronal degeneration in AD. Therefore, antibodies that can strongly and selectively bind to these soluble intermediate aggregates are of great diagnostic and therapeutic interest.

Methods: We designed and recombinantly produced a hexavalent antibody based on mAb158, an Aβ protofibril-selective antibody. The humanized version of mAb158, lecanemab (BAN2401), is currently in phase 3 clinical trials for the treatment of AD. The new designs involved recombinantly fusing single-chain fragment variables to the N-terminal ends of mAb158 antibody. Real-time interaction analysis with LigandTracer and surface plasmon resonance were used to evaluate the kinetic binding properties of the generated antibodies to Aβ protofibrils. Different ELISA setups were applied to demonstrate the binding strength of the hexavalent antibody to Aβ aggregates of different sizes. Finally, the ability of the antibodies to protect cells from Aβ-induced effects was evaluated by MTT assay.

Results: Using real-time interaction analysis with LigandTracer, the hexavalent design promoted a 40-times enhanced binding with avidity to protofibrils, and most of the added binding strength was attributed to the reduced rate of dissociation. Furthermore, ELISA experiments demonstrated that the hexavalent design also had strong binding to small oligomers, while retaining weak and intermediate binding to monomers and insoluble fibrils. The hexavalent antibody also reduced cell death induced by a mixture of soluble Aβ aggregates.

Conclusion: We provide a new antibody design with increased valency to promote binding avidity to an enhanced range of sizes of Aβ aggregates. This approach should be general and work for any aggregated protein or repetitive target.
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http://dx.doi.org/10.1186/s40035-021-00258-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477473PMC
September 2021

Long-term quality of life among breast cancer survivors eligible for screening at diagnosis: a systematic review and meta-analysis.

Public Health 2021 Sep 21;199:65-76. Epub 2021 Sep 21.

Cancer Registry of Norway, Section of Cancer Screening, P.O. 5313, Majorstuen, Oslo, 0304, Norway; Department of Health and Care Sciences, UiT The Artic University of Norway, P.O. 6050, Tromsø, 9037, Norway. Electronic address:

Objectives: This study aimed to explore the long-term quality of life (QoL) among breast cancer survivors eligible for mammographic screening at diagnosis and compare that to QoL among women with no history of breast cancer.

Study Design: Systematic review and meta-analysis.

Methods: A systematic review of randomised controlled trials and observational studies published between January 2000 and July 2019 was performed. Eight studies were included in the review. Six studies with QoL measurement scales (0-100) were included in the meta-analysis. We used fixed and random effects models to obtain Cohen's d with 95% confidence interval (CI). Heterogeneity among studies was evaluated by the I statistics.

Results: Information about 6145 breast cancer survivors diagnosed between 1995 and 2012 and followed for >1-10 years was analysed. Four studies used SF-36/RAND-36, three studies used EORTC QLQ-C30, one study used FACT-G and one study used FACT-B. The mean score of QoL for breast cancer survivors varied from 63.0 (RAND SF-36, 0-100) to 110.5 (FACT-B, 0-123). Two studies showed better, three studies showed similar and two studies showed poorer mean scores for breast cancer survivors compared with women with no history of breast cancer. The meta-analysis showed no significant differences in QoL for breast cancer survivors compared with women with no history of breast cancer (Cohen's d = -0.07, 95% confidence interval [CI] -0.14 to 0.00 and I = 83.7% for the fixed effect model; Cohen's d = -0.00, 95% CI -0.18 to 0.17 and I = 82.4% for the random effects model).

Conclusion: QoL did not differ between breast cancer survivors eligible for mammographic screening at diagnosis and followed for >1-10 years and women with no history of breast cancer.
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http://dx.doi.org/10.1016/j.puhe.2021.08.008DOI Listing
September 2021

Platelet activation and reactivity in a large cohort of patients with Gaucher disease.

Thromb Haemost 2021 Sep 10. Epub 2021 Sep 10.

Gaucher Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data.

Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients.

Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r 0.17, p-value 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 SD of reference range) was found in 79 (53%, 95% CI 44%-61%) patients, of whom 10 (6.7%, 95% CI 3.3%-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (OR (95% CI), 1.05 (1.01-1.1)) and low P-selectin reactivity (OR (95% CI), 2.03 (1.25-3.35)) were associated with more than one bleeding manifestation.

Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.
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http://dx.doi.org/10.1055/a-1642-4206DOI Listing
September 2021

Longitudinal strain is an independent predictor of survival and response to therapy in patients with systemic AL amyloidosis.

Eur Heart J 2021 Sep 2. Epub 2021 Sep 2.

National Amyloidosis Centre, University College London, Rowland Hill Street, London NW3 2PF, UK.

Aims: Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients.

Methods And Results: A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean -21.1%, -17.1%, -12.9%, and -12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤-16.2%: 80 months, -16.1% to -12.2%: 36 [95% confidence interval (CI) 20.9-51.1] months, -12.1% to -9.1%: 22 (95% CI 9.1-34.9) months, and ≥-9.0%: 5 (95% CI 3.2-6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from -13.8% to -14.9% in those with CR and difference between involved and uninvolved light chain <10 mg/L). Strain improvement was associated with improved OS (median not reached at 53 months vs. 72 months in patients without strain improvement, P = 0.007). Patients achieving an LS% improvement and a standard N-terminal pro-brain natriuretic peptide-based cardiac response survived longer than those achieving a biomarker-based cardiac response alone (P < 0.0001).

Conclusion: Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.
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http://dx.doi.org/10.1093/eurheartj/ehab507DOI Listing
September 2021
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