dataesr/scientific-paragraphs-categorization huggingface dataset:
In a previous study using data from over one million COVID Symptom Study participants, we described the characteristics of illness following the primary COVID-19 vaccination course, compared to illness in unvaccinated individuals. 11  Vaccination was associated with a reduction in severe illness, and reduction in long-duration symptoms following the second vaccine dose. Almost all individual symptoms were less frequently reported in individuals infected post-vaccination, who were also more likely to be asymptomatic. The exception was sneezing, which was more common in infected individuals after the first vaccine dose. It remains unclear whether a third vaccine confers further protective effects against severe, symptomatic, and long duration disease. Furthermore, accumulating evidence suggests a waning of vaccine effectiveness against symptomatic and severe illness with time since vaccination.
Study design and participants This prospective, community-based, case-control study used data from UK-based, adult (≥18 years) participants of the COVID Symptom Study logged through a free smartphone app developed by Zoe (London, UK) and King's College London (London, UK). The app was launched in the UK on March 24, 2020. 20  At registration, each participant reported baseline demographic information (e. g. , age, sex, ethnicity, whether healthcare worker), geographic location, and information on health risk factors including comorbidities, lifestyle, frailty, and visits to hospital. Participants were encouraged to selfreport any pre-specified symptoms daily, providing prospective, longitudinal information on incident symptoms. All users were prompted to record any COVID-19 testing results (whether tests were provided via the app or from other sources), and any COVID-19 vaccine(s) and subsequent symptoms.
Each included participant was at least seven days post-vaccination and had at least 12 weeks of symptom reporting following the positive test. The data census for symptom reporting was June 24, 2022, to allow each user at least 12 weeks of reporting. To analyse the effect of booster vaccination on post-vaccination infection we compared disease severity, duration, and individual symptoms in users reporting a positive SARS-CoV-2 test at least seven days after a third vaccine dose (cases) to those reporting a positive test at least seven days after a second dose (controls). Controls were matched 1:1 with cases by a Euclidean-based algorithm based on age, sex, Body Mass Index (BMI), time elapsed between the first vaccination and the infection, and test week, a method used in our previously published study.
Discussion We present data on 155,967 and 56,236 community-based adults in the UK with reported test-confirmed SARS-CoV-2 infection after a third (booster) or second vaccination, respectively. During the period when Delta was the predominant COVID-19 variant in the UK, a third vaccination conferred reductions in disease severity and duration, and a higher proportion of infected individuals reporting asymptomatic illness. The observed protective effect of booster vaccination against long COVID is supported by findings from our previous study of over one million COVID Symptom Study participants, where long duration illness was reduced following a second vaccination dose, at a time when the Delta variant was predominant in the UK. 11  In the current study, protective effects of booster vaccination were also apparent during the Omicron period, with a significant reduction in acute, functionally limiting symptoms, although not in hospitalisation rate.
Access to testing is a potential source of bias, although this was mitigated by only including reported infections up until April 1st, 2022, after which free tests were no longer universally available in the UK. Our study has some limitations. We were unable to include an unvaccinated control group for comparison, as there were very few unvaccinated individuals enroled at the time of the study. Our findings might not apply at all timepoints post-vaccination, to countries with different recommended vaccination types and schedules, or settings with different proportions of SARS-CoV-2 variants. Additionally, the data were self-reported; recording of comorbidities, test results, and vaccination status might not have been completely accurate and there might have been temporal gaps in reporting.
Acknowledgements Zoe Global provided in-kind support for all aspects of building, running and supporting the app and service to all users worldwide. This work is supported by the  UK Department of Health  via the  National Institute for Health Research (NIHR)  comprehensive  Biomedical Research Centre award  to Guy's & St Thomas'  NHS Foundation  Trust in partnership with  King's College London  and  King's College Hospital NHS Foundation Trust , and a grant to  ZOE Globals , as well as by the  Wellcome EPSRC Centre for Medical Engineering at King's College London  ( WT 203148/Z/16/Z ). This work was further supported by the  UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value-Based Healthcare. Investigators also received support from the  Wellcome Trust, Medical Research Council (MRC) ,  British Heart Foundation (BHF) ,  Alzheimer's Society ,  European Union ,  NIHR ,  Chronic Disease Research Foundation (CDRF)  and the  NIHR-funded BioResource ,  Clinical Research Facility and Biomedical Research Centre (BRC)  based at  GSTT NHS Foundation Trust  in partnership with KCL.
SO was supported by the  French government , through the  3IA Côte d'Azur Investments  in the Future project managed by the  National Research Agency (ANR)  with the reference number  ANR-19-P3IA-0002. ATC was supported by a  Stuart and Suzanne Steele MGH Research Scholar Award  and by the  Massachusetts Consortium on Pathogen Readiness (MassCPR)  and  M. Schwartz  and  L. Schwartz. JM was partially supported by the  European Commission   Horizon 2020 programme  ( H2020-MSCA-IF-2015-703787 ). EM was supported by an  MRC Skills Development Fellowship  [ MR/R016372/1 ].
This was followed by incubation for 40 minutes in a dark room with Poly-HRP40 (Fitzgerald, Acton, MA, USA) diluted 1:20,000 in PBS with 1% BSA. Detection substrate was TMB-PLUS (Kem-En-TEC, Denmark), the reaction was stopped with 0. 5 M H2SO4 and absorbance was recorded at 450 nm (after subtraction of the background absorbance value measured at 620 nm). The IgG and IgA references were then used to establish a standard curve for the determination of titers in arbitrary ELISA Units/ml (AEU/ml) based on a five-parameter logistic curve using the package 'drc' in R (version 4. 3. 1)  [27]. For determination of total IgG and IgA in tears, the same ELISA protocol (MaxiSorp, Nunc) was used except that plates were coated with anti-human kappa and lambda light chain specific mouse antibodies (Southern Biotech) at 1:1 ratio diluted to 1 μg/ml in PBS overnight.
Statistical analysis Correlation between multiple parameters was assessed using the non-parametric Spearman correlation test, with a two-tailed p-value, performed using R software (version 4. 3. 1)  [27]. For each combination of two parameters, this analysis assigned a correlation factor (r) from -1, a maximum negative correlation to 1, a maximum positive correlation, and the p-value. For all other statistical analyses, particularly to confirm significant differences during longitudinal observation, the Wilcoxon test as well as the Friedman test (with a two-stage linear procedure correction) were conducted using Prism (GraphPad version 9. 5. 1).
; https://doi. org/10. 1101/2023. 12. 05. 570239 doi: bioRxiv preprint Fig S2. Gating strategy of pseudo-color plots windows performed using FlowJo software and applied to cells eluted from conjunctival imprints. This strategy was used to assess the following ocular surface cell immune populations: leukocytes (CD45 + ), neutrophils (CD66 + ), monocytes (CD14 + ), T cells (CD3 + ), CD4 T cells (CD3 + , then CD4 + /CD8 -), CD8 T cells (CD3 + , then CD4 -/CD8 + ), natural killer cells (CD3 -/CD8 + , then NKG2A + ), B cells (CD20 + and HLA-DR + ). This strategy is applied to conjunctival imprints' cells' flow cytometry data.
Acknowledgment This study was supported by the  European Commission  through the  TracVac  consortium contract (Grant agreement ID:  733373 ) and The  Innovation Fund Denmark  ( 069-2011-1 ). The  Infectious Disease Models and Innovative Therapies research infrastructure (IDMIT ) is supported by the  Domaine d'Intérêt Majeur ( DIM) "One Health" program , and the " Programme Investissements d'Avenir " (PIA) , managed by the  ANR  under references  ANR-11-INBS-0008  and  ANR-10-EQPX-02-01. We thank the  Thea foundation  and  Didier Renault  for their financial support. We also thank  Quentin Sconosciuti ,  Victor Magneron ,  Maxime Potier , and  Jean-Marie Robert  for the NHP experiments ;  Laetitia Bossevot ,  Laura Junges ,  Laurine Moenne-Loccoz  and  Loïc Pintore  for the RT-qPCR assays ;  Mario Gomez-Pacheco  and  Jérôme van Wassenhove  for the flow cytometry helps ;  Yann Gorin  for the logistics and safety management ;  Isabelle Mangeot  and  Camille Morice  for help with resources management ;  Brice Targat  and  Karl-Stefan Baczowski  who contributed to data management and  Oscar Haigh  for help during manuscript proofreading.
This phase IB/II trial evaluated safety and efficacy of cobimetinib alone and in novel combinations with venetoclax with/without atezolizumab in patients with relapsed/refractory multiple myeloma. Forty-nine patients were enrolled. Cobimetinib alone and in combination with venetoclax with/without atezolizumab was determined to be safe and tolerable; anti-tumor activity was moderate overall but higher in patients with translocation t(11;14). Introduction: Mitogen-activated protein kinase pathway mutations are present in > 50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combination with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab (atezo) in patients with R/R MM.
Study Design and Treatment This open-label, multicenter, phase Ib/II study evaluated cobi alone (Arm A), cobi-ven (Arm B), and cobi-ven-atezo (Arm C) in patients with R/R MM (ClinicalTrials. gov identifier: NCT03312530). The primary objectives were to evaluate preliminary safety, tolerability, and efficacy; secondary objectives were to further evaluate efficacy and pharmacokinetics; and exploratory objectives were to identify biomarkers predictive of response, and assess biomarkers associated with disease biology. This study was terminated early following the Sponsor's decision to discontinue the development of the drug combinations, due to modest anti-tumor activity in all-comers; the decision was not based on safety findings in the study. In the safety run-in (SRI) phase, two successive cohorts were evaluated: cobi-ven, and cobi-ven-atezo.
Results The data cut-off was July 7, 2021. In total, 49 patients were enrolled at 16 centers worldwide (Spain, Germany, Denmark, Norway, Czech Republic, France, Poland, and Sweden) between November 2017 and March 2019. All patients received ≥1 dose of study drug. Patient disposition is shown in ( Supplemental Figure  1 ). In the SRI phase, six patients received cobi-ven, and six patients received cobi-ven-atezo. Only partial enrollment into the RP was completed due to early study termination (following the Sponsor's decision to discontinue the development of the drug combinations, due to modest anti-tumor activity in all-comers and not based on safety findings), Clinical Lymphoma, Myeloma and Leukemia January 2023 e61 Cobimetinib, Venetoclax, Atezolizumab in R/R MM with patients assigned to receive each treatment as follows: cobi, n = 6; cobi-ven, n = 16; cobi-ven-atezo, n = 15.
Biomarker Analysis Key baseline biomarker data were evaluable for 49 patients, including t(11:14) status in 48 patients, mutations in Ras/MAPK pathway genes ( KRAS / NRAS / BRAF ) in 43 patients, and ratio of BCL2 : BCL2L1 gene expression in 32 patients ( Figure  4 A ). The t(11:14) translocation was detected in 10 of 48 patients (20. 8%), mutations in Ras/MAPK pathway genes were detected in 25 of 43 patients (58. 1%), and the BCL2 : BCL2L1 ratio was high in 11 of 32 (34. 4%) patients. Since atezo did not appear to contribute additional efficacy in the cobi-ven-atezo arm, patients in both the cobi-ven and ven-cobi-atezo arms were combined to assess correlative biomarkers associated with response. Twenty-seven patients of the combined arms were evaluable for t(11;14) status, NRAS / KRAS / BRAF mutation status, and BCL2 : BCL2L1 ratio.
Conclusion In summary, cobi alone, cobi-ven, and cobi-ven-atezo demonstrated manageable safety and tolerability in heavily pre-treated PI-, IMiD-, and anti-CD38 mAb-exposed patients with R/R MM. Despite incomplete evaluation due to early study termination, encouraging activity was seen for both the cobi-ven and cobi-venatezo combinations in patients harboring t (11;14). The translocation t (11;14) appeared to be the primary predictive biomarker for the ven-based combinations, supporting the current investigation of ven in t(11;14)-positive MM in the ongoing phase III CANOVA trial (NCT03539744). While evaluation of the combinations will not proceed in the current study, future efforts may be directed toward better understanding of how to optimize patient selection, and evaluation of combination strategies targeting the Ras/MAPK pathway and immunotherapy.
Acknowledgments The authors thank the patients and their families, and all study team members and investigators. Venetoclax is being developed in a collaboration between  Genentech  (a member of the  Roche group ) and  AbbVie. Genentech, Inc. provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Denise Cheung ,  B. Pharm  and  Aparna Raval, PhD , of  Genentech, Inc. , provided support in the analysis of the data. Third-party medical writing assistance, under the direction of  Maika Onishi , was provided by  Sinéad Holland, PhD , of  Ashfield MedComms, UK , an Inizio company, and was funded by  Genentech, Inc.
The introduction of well-oxygenated seawater, and subsequent gradual oxygen consumption through organic matter respiration results in widely ranging oxygenation cycles in deep waters (e. g. , Gullmar Fjord (GF) monitoring data by the Swedish Meteorological and Hydrological Institute, SMHI). Due to its redox-sensitivity, manganese (Mn) has received attention as a potential geochemical proxy for bottom-water (BW) oxygen concentrations (e. g. ,  Groeneveld & Filipsson, 2013; Limburg & Casini, 2018; Schöne et al. , 2021). Seasonal low-oxygen conditions, inherent in many fjords, facilitate steep redox gradients in surficial sediments. Sedimentary manganese oxides (MnOx) are a thermodynamically favorable electron acceptor in microbially mediated organic matter degradation after depletion of oxygen and nitrate (e.
5 cm sections for foraminiferal sampling (ca. 40 ml sediment each) in the same temperature-regulated room (6°C). The first core from the second cast was sampled to supplement sediment for foraminiferal sampling if specimen abundance was low. All sediment samples were treated with 36 μl of CellTracker™ Green (CTG) CMFDA dye (5-chloromethylfluorescein diacetate; with dime thyl sulfoxide (DMSO); both ThermoFisher Scientific), which allows the identification of foraminifera (and other organisms) living at the time of sampling by epifluorescence microscopy during later observations (e. g. ,  Bernhard et al. , 2003 Bernhard et al. , , 2006)). The second core from the primary cast was sampled for BW and PW trace-elemental (trace element (TE)) analyses. Data for GF 117 are published in  Brinkmann et al.
Hydrographic Data Bottom-water temperature, dissolved oxygen concentration and salinity data measured with a Seabird CTDO 2 at the times of sampling are published in  Brinkmann et al. (2022). Further hydrographic data of GF are publicly available from SMHI (SMHI, 2022) and its "SHARK" hydrographic database (https://sharkweb. smhi. se/hamtadata/; last access 01 February 2022). We used [O 2 ] across 2018 and 2019 from three fjord stations, Släggö (58°25. 980 N, 11°43. 570 E, 70 m water depth), Alsbäck (58°19. 400 N, 11°32. 800 E, 120 m water depth), and Björkholmen (58°23. 260 N, 11°37. 600 E, 50 m water depth) (Figure  1a ).
e. , first chamber; P) of B. marginata (749 ablation profiles), and n, n -1, and n -2 of N. labradorica specimens (531 ablation profiles) (Table  1 ). The P signal is considered to represent the juvenile chambers as well as subsequently added layers of calcite with each new chamber addition (e. g. ,  Erez, 2003) , thus a bulk signal of primary and secondary calcite layers over an extended growth period. Raw counts were converted to elemental concentrations using the software package Igor Pro 6. 37 with Iolite v. 3. 5  (Paton et al. , 2011). The element concentrations were calculated as averages over selections of the ablation profiles (>15 laser ablation data points per selection). These selections were made by manually screening the profiles for ablation intervals of constant 43 Ca counts, corresponding to the primary CaCO 3 material of the foraminifera test walls (e.
g. ,  Brinkmann et al. , 2022; Guo et al. , 2019; Petersen et al. , 2018). Ablation intervals enriched with elements such as aluminum (Al) or zinc (Zn) at the beginning and/or end of the profiles were deselected, as these represent contaminations. Trace elemental ratios (TE/Ca) were calculated with the assumption that the TEs were bound as carbonate (assuming 40% wt Ca in the CaCO 3 matrix) and normalized to Ca. The raw data were processed according to the following quality control criteria: (a) exclusion of data with [Mn] lower than the limit of detection (LOD = baseline signal +3. 3 × σ; σ = standard deviation of background signal) (63 selections removed), (b) exclusion of ablation selections with potential clay contamination (i. e. , Al/ Ca >0. 4 mmol/mol;  Wit et al. , 2010)  (76 selections removed), (c) application of a 95% confidence limit on Mn/ Ca, for each species, site and season, to remove outliers (i.
Synchrotron Scanning X-Ray Fluorescence Imaging For synchrotron scanning X-ray fluorescence (XRF) imaging, four specimens (I-IV) of B. marginata from the 0-0. 5 cm interval of the September 2018 sampling data in GF 117 were selected. The specimens were embedded in epoxy (EPO-TEK® 301) in a mold of 1 cm diameter and dried at room temperature for 48 hr. The mount Note. Median Mn/Ca with median average deviation (MAD) of n-chambers in mmol/mol per 0-1 and 1-2 cm interval. *indicates samples compiled from two duplicate cores; n. a. = not available. surface was ground down (Struers LaboSystem with a LaboPol-60 and LaboForce-Mi specimen mover head, DiaDuo diamond emulsion 9-μm grain size) at the Department of Geology to expose central test cross-sections. The backside of the mount was abraded until an overall thickness of less than 1 mm was reached.
2-keV X-ray energy) and the XRF spectra were collected by two SDD XRF detectors positioned at 20° to the reflecting sample surface. Elemental concentrations and distributions were mapped using the Flyscan continuous sample scanning technique  (Medjoubi et al. , 2013). Fast maps of entire specimens were acquired with 1-μm spatial resolution and 20-100 ms dwell time per pixel to guide the selection of regions of interest for higher resolution and longer dwell time zoom-in mapping (300-500 nm, 100 ms/pixel). The detection limit of [Mn] per pixel was ∼5-10 ppm for these high-resolution maps. The information depth was several tens of μm. PyMca software was used to fit the XRF sum-spectra to identify the elements present in the sample and possible spectral overlapping  (Solé et al. , 2007). The elemental distribution maps were reconstructed by a custom Matlabcode including dead-time correction, showing intensities above the detection limit (95% confidence limit).
Statistical Analyses All statistical analyses were performed using the software PAST 4. 05  (Hammer et al. , 2001) , considering a p value of <0. 05 as significant. Correlations between TE/Ca ratios were calculated using the Pearson correlation coefficient. Medians, median average deviations (MAD) and relative standard deviation (RSD, in %) were calculated for TE data of foraminiferal n-chambers (i. e. , final chambers) for the sediment intervals 0-1 and 1-2 cm. The non-normally distributed data sets (Shapiro-Wilk's test), and those comprising variable specimen or sample numbers (heteroscedastic data) were tested using the non-parametric Kruskal-Wallis and associated Mann-Whitney post-hoc tests or the Wilcoxon signed-rank test, for pairwise comparisons, to test for differences between different subsets of our data (e.
, 2018; Ernst et al. , 2005; Filipsson et al. , 2010). However, these observations are based on adult size-fractions, thus not necessarily reflecting on the ambient conditions during the growth of initial chambers. Indeed,  Alve and Bernhard (1995)  recorded a reproduction event of B. marginata under low-oxygen conditions. Accordingly, the last recorded period of extended low-oxygen conditions in the fjord at the end of 2017 (SMHI) may correspond to the time of precipitation of the juvenile chambers, particularly of those specimens sampled in September 2018. Specimens sampled at later dates during 2019, presumably calcified later and, indeed, show comparatively less elevated P chamber signals (Figure  S2  in Supporting Information S1). We do not have data on B. marginata reproduction events during 2017-2019 to confirm this hypothesis.
ED-XRF calibration method In order to attribute a mass fraction to each net counting, a calibration method has been set up, based on a numerical model. Indeed, it is complicated to conceive of physical standards representative of a LPBF fume. Therefore, to avoid transfer coefficients and biases potentially induced by a matrix effect, the choice was to elaborate a numerical calibration model. Then, by using the reference particle transport Monte-Carlo simulation code PENELOPE  [9]  , representative configurations for the X-ray spectrum, flux, geometry, detector and detector collimation have been modelled. For the two atmospheres chemistry (N and He) of the interaction chamber, a fixed number of ten mass fraction values of simulated Ni and Cr materials have been considered. The Ni and Cr materials are assumed homogeneously distributed in the simulated interaction chamber.
Data scoring Fragment sizes for each VNTR locus were estimated using GENEMAPER v 4. 0 (Applied Biosystems). When necessary, a truncated number of repeats was rounded up to the nearest integer  [12]. The discriminatory power of each VNTR locus was calculated based on the Hunter and Gaston discriminatory index (HGDI)  [42]. Numbers of alleles and Nei's unbiased estimates of diversity were estimated using ARLEQUIN software  [43]. Haplotype networks were represented by minimum spanning trees using the algorithm combining global optimal eBURST (goeBURST) and Euclidian distances in the software PHYLOViZ 2. 0  [44]. The minimum spanning trees display the relationships between clonal complexes defined as groups of single locus variants (SLVs). The population structure of Xpm was assessed by discriminant analysis of principal components (DAPC) of MLVA-12 data using the adegenet V.