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Palm wine fermentation is a complex microbial process that evolves with tapping times. The dynamics in microbiota and metabolites throughout palm wine tapping days is still not established, which are critical for the distinctive characteristics of palm wine taste and quality, and thus the mastery of the daily quality fluctuation during tapping. We analyzed the changes in microbial community structure by amplicon sequencing of bacterial 16S rRNA gene and fungal internal transcribed spacer (ITS) region, and metabolite profile changes using mass spectrometry in palm wine collected over 25–30 days tapping of ron (Borassus aethiopum) and oil palms (Elaeis guineensis) from Côte d’Ivoire. The stage-wise collected palm wine samples showed distinct changes in microbial diversity and pH, supporting microbial community dynamics during palm wine tapping. Results highlighted the dominance ofSaccharomyces cerevisiaein early stages and the emergence of non-Saccharomycesyeasts, particularlyHanseniasporaspp. in the later stages of oil palm wine tapping, vice versa in the case of ron palm wine tapping, with a unique presence ofSaccharomycodesin the later stages (15–30 days). Fructophilic lactic acid bacteria (FLAB), mainlyFructobacillusandLeuconostoc, encountered in both types of palm wine tapping showed a decline at later stages of oil palm wine tapping. In this type of palm wine, acetic acid bacteria with generaAcetobacterandGlucanoacetobacter, by surpassingLactobacillusin the last stage become dominant, whereasLactobacillusremained dominant in ron palm wine throughout tapping days. The decline in the relative abundance of gevotroline and essential amino acids during the later stages of palm wine tapping (15–25 days) supports the difference in the health benefits of the palm wine obtained from different days of tapping, indicating that early stages of tapping is more nutritional and healthy than the later stages. The microbial dynamics may be a potential indicator of metabolite changes during palm sap fermentation, thus contributing to establish particular features of palm wines in different stages of tapping. This understanding of microbial ecology and chemical composition changes during palm wine tapping can be used as biomarkers to assess palm wine’s quality and help to design an optimum starter culture.

The Cedars ultramafic block hosts alkaline springs (pH > 11) in which calcium carbonate forms upon uptake of atmospheric CO2 and at times via mixing with surface water. These processes lead to distinct carbonate morphologies with “floes” forming at the atmosphere-water interface, “snow” of fine particles accumulating at the bottom of pools and terraced constructions of travertine. Floe material is mainly composed of aragonite needles despite CaCO3 precipitation occurring in waters with low Mg/Ca ( The calcium carbonates exhibit an extreme range and approximately 1:1 covariation in δ13C (−9 to −28‰ VPDB) and δ18O (0 to −20‰ VPDB) that is characteristic of travertine formed in high pH waters. The large isotopic fractionations have previously been attributed to kinetic isotope effects accompanying CO2 hydroxylation but the controls on the δ13C-δ18O endmembers and slope have not been fully resolved, limiting the use of travertine as a paleoenvironmental archive. The limited areal extent of the springs (∼0.5 km2) and the limited range of water sources and temperatures, combined with our sampling strategy, allow us to place tight constraints on the processes involved in generating the systematic C and O isotope variations. We develop an isotopic reaction–diffusion model and an isotopic box model for a CO2-fed solution that tracks the isotopic composition of each dissolved inorganic carbon (DIC) species and CaCO3. The box model includes four sources or sinks of DIC (atmospheric CO2, high pH spring water, fresh creek water, and CaCO3 precipitation). Model parameters are informed by new floe Δ44Ca data (−0.75 ± 0.07‰), direct mineral growth rate measurements (4.8 to 8 × 10−7 mol/m2/s) and by previously published elemental and isotopic data of local water and DIC sources. Model results suggest two processes control the extremes of the array: (1) the isotopically light end member is controlled by the isotopic composition of atmospheric CO2 and the kinetic isotope fractionation factor (KFF (‰) = (α − 1) × 1000) accompanying CO2 hydroxylation, estimated here to be −17.1 ± 0.8‰ (vs. CO2(aq)) for carbon and −7.1 ± 1.1‰ (vs. ‘CO2(aq) + H2O’) for oxygen at 17.4 ± 1.0 °C. Combining our results with revised CO2 hydroxylation KFF values based on previous work suggests consistent KFF values of −17.0 ± 0.3‰ (vs. CO2(aq)) for carbon and −6.8 ± 0.8‰ for oxygen (vs. ‘CO2(aq) + H2O’) over the 17–28 °C temperature range. (2) The isotopically heavy endmember of calcium carbonates at The Cedars reflects the composition of isotopically equilibrated DIC from creek or surface water (mostly HC O 3 - , pH = 7.8–8.7) that occasionally mixes with the high-pH spring water. The bulk carbonate δ13C and δ18O values of modern and ancient travertines therefore reflect the proportion of calcium carbonate formed by processes (1) and (2), with process (2) dominating the carbonate precipitation budget at The Cedars. These results show that recent advances in understanding kinetic isotope effects allow us to model complicated but common natural processes, and suggest ancient travertine may be used to retrieve past meteoric water δ18O and atmospheric δ13C values. There is evidence that older travertine at The Cedars recorded atmospheric δ13C that predates large-scale combustion of fossil fuels.

The present study focuses on the rheological properties of polyethylene glycol (PEG) modified, positively charged, and negatively charged superparamagnetic iron oxide nanoparticles (SPIONs) at different temperatures. We hypothesized that the surface properties of these nanoparticles in the water did not affect their rheological properties. These nanoparticles had not the same surface properties as SPIONs-PEG had not to charge on their surface whereas positively charged and negatively charged ones with amine and carboxyl groups as their surfaces had positive and negative surface charges, respectively. However, their rheological behaviors were not different from each other. The comparative rheological study of SPIONs revealed their pseudo-Newtonian behavior. The viscosity of SPIONs decreased with the increase in temperature. At low shear rates, the shear stress of SPIONs was independent of rate and increased with the increase of rate. Moreover, at high shear rates, the shear stress for PEG-SPIONs was more than those for positively charged and negatively charged SPIONs. These measurements also revealed that at high shear rates, the shear stress of samples decreased with the increase of temperature. The shear stress of samples decreased with the increase of shear strain and the temperature. We also observed that all the samples had the same amount of shear strain at each shear stress, which indicated the exact resistance of SPIONs to deformation. Furthermore, the shear modulus decreased with time for these nanoparticles. These results suggest that these nanoparticles are promising candidates with appropriate properties for fluid processing applications and drug vectors in biomedical applications.

Background Reliable data on the adult SARS-CoV-2 infection fatality rate in Germany are still scarce. We performed a federal state-wide cross-sectional seroprevalence study named SaarCoPS, that is representative for the adult population including elderly individuals and nursing home residents in the Saarland. Methods Serum was collected from 2940 adults via stationary or mobile teams during the 1st pandemic wave steady state period. We selected an antibody test system with maximal specificity, also excluding seroreversion effects due to a high longitudinal test performance. For the calculations of infection and fatality rates, we accounted for the delays of seroconversion and death after infection. Results Using a highly specific total antibody test detecting anti-SARS-CoV-2 responses over more than 180 days, we estimate an adult infection rate of 1.02% (95% CI: [0.64; 1.44]), an underreporting rate of 2.68-fold (95% CI: [1.68; 3.79]) and infection fatality rates of 2.09% (95% CI: (1.48; 3.32]) or 0.36% (95% CI: [0.25; 0.59]) in all adults including elderly individuals, or adults younger than 70 years, respectively. Conclusion The study highlights the importance of study design and test performance for seroprevalence studies, particularly when seroprevalences are low. Our results provide a valuable baseline for evaluation of future pandemic dynamics and impact of public health measures on virus spread and human health in comparison to neighbouring countries such as Luxembourg or France.

Despite their high predictive performance, random forest and gradient boosting are often considered as black boxes or uninterpretable models which has raised concerns from practitioners and regulators. As an alternative, we propose in this paper to use partial linear models that are inherently interpretable. Specifically, this article introduces GAM-lasso (GAMLA) and GAM-autometrics (GAMA), denoted as GAM(L)A in short. GAM(L)A combines parametric and non-parametric functions to accurately capture linearities and non-linearities prevailing between dependent and explanatory variables, and a variable selection procedure to control for overfitting issues. Estimation relies on a two-step procedure building upon the double residual method. We illustrate the predictive performance and interpretability of GAM(L)A on a regression and a classification problem. The results show that GAM(L)A outperforms parametric models augmented by quadratic, cubic and interaction effects. Moreover, the results also suggest that the performance of GAM(L)A is not significantly different from that of random forest and gradient boosting., 47 pages, 12 tables and 7 figures

Palm wine, the most commonly consumed traditional alcoholic beverage in Western Africa, harbours a complex microbiota and metabolites, which plays a crucial role in the overall quality and value of the product. In the present study, a combined metagenomic and metabolomic approach was applied to describe the microbial community structure and metabolites profile of fermented saps from three palm species (Elaeis guineensis, Raphia hookeri, Borassus aethiopum) in Côte d’Ivoire. Lactobacillaceae (47%), Leuconostocaceae (16%) and Acetobacteriaceae (28%) were the most abundant bacteria and Saccharomyces cerevisiae (87%) the predominant yeasts in these beverages. The microbial community structure of Raphia wine was distinctly different from the others. Multivariate analysis based on the metabolites profile clearly separated the three palm wine types. The main differentiating metabolites were putatively identified as gevotroline hydrochloride, sesartemin and methylisocitrate in Elaeis wine; derivative of homoserine, mitoxantrone in Raphia wine; pyrimidine nucleotide sugars (UDP-D-galacturonate) and myo-Inositol derivatives in Borassus wine. The enriched presence of gevotroline (an antipsychotic agent) and mitoxantrone (an anticancer drug) in palm wine supports its therapeutic potential. This work provides a valuable insight into the microbiology and biochemistry of palm wines and a rationale for selecting functional microorganisms for potential biotechnology applications.

Additional file 5: Figure S2. Implementation in Fiji. (A) Graphical user interface for the plugin ���Template Matching Image��� with: (1) Dropdown menu to select the template image of the object of interest. The template must be smaller than the image specified in 2, (2) dropdown menu to select an image (or stack of images) in which to search for the template, (3) tick-boxes to optionally generate additional templates by horizontal/vertical flipping of the initial template, (4) input field for rotation angles to generate additional templates by rotations of the initial and, if selected, flipped templates. The angles are specified in degrees with clockwise orientation and must be separated by commas, (5) dropdown menu to choose the score used for the computation of the score map (normalised square-difference, normalised cross-correlation or 0-mean normalised cross-correlation), (6) input field to specify the number of objects expected in the image, (7) input field to enter a score-threshold in the range 0���1. If the normalised square-difference is selected, only local minima with values below the threshold are returned. While for cross-correlation scores, maxima above this value are returned, (8) input field to specify the maximum value in range 0���1 for the intersection over union (IoU) between a pair of overlapping bounding boxes (Non-Maxima Suppression), (9) tick-box to select if the detected Regions Of Interest (ROI) should be added to Fiji ROI Manager, (10) tick-box to specify if the result table should be displayed at the end of the execution. Parameters 7 and 8 are only required if several objects are expected in each image. (B) Outputs of the plugin with (1) result table with each row containing the names of the image and template, the prediction score and coordinates of the top left corner and centre of the predicted bounding box, and (2) the detected ROI appended to the ROI Manager and highlighted on the image (yellow).

Additional file 13. Supplementary information. Supplementary Material for Multi-Template Matching: a versatile tool for object-localization in microscopy images.

Additional file 8: Figure S5. Multi-template matching is robust to noise. (A) Original image (2048 �� 2048 pixels). (B) Image as in A corrupted with artificial noise (normally distributed random noise ��� mean:0, standard deviation:50). (C, D) Result of multi-template matching for respectively A and B. The template used is a crop of the specimen in the middle of image A (hence a correlation score of 1 for the first row of Table C). Parameters for the detection: rotation of the template: 90,180�� - score type: 0-mean normalised cross-correlation - N = 4 expected objects per image ��� score threshold: 0.3 ��� maximal overlap between bounding boxes: 0.3.

Additional file 12: Figure S9. Using multi-template matching for phenotypes classification. (A) Manually annotated templates used for the classification of phenotypes of embryonic zebrafish kidneys. (B) Example of image to classify and (C) resulting correlation-scores for the 3 classes. In this case, the image is correctly classified as cystic. (D) Confusion matrix depicting the results for the classification of 167 annotated images (50 normal, 52 cystic, 65 long). The class Cystic and Normal are particularly well predicted. A number of Long were classified as Cystic, this can be expected as those 2 morphologies show similar elongated regions.

Additional file 10: Figure S7. Multi-template matching for the localization of randomly oriented and positioned medaka embryos. (A) Initial template (410 �� 420 pixels) and one of the images in which the search is performed (2048 �� 2048 pixels, scale bar of 1 mm). The yellow bounding boxes indicate predicted locations when only the original template in A is used for the search, the green boxes indicate predicted locations when using a set of templates (original, horizontal and vertical flipping, rotation of the original and flipped templates by 90��,180�� and 270��). Parameters for the detection: score type: 0-mean normalized cross-correlation, N = 4 expected objects per image, score threshold:0.35, maximal overlap between bounding boxes:0.25. (B) Result of the detections for 10 images each containing 4 embryos (i.e. 40 embryos in total) See detected region in D. (C) Mean computation time per image (error bars show standard deviation) for the different conditions using the same hardware as in the main text. The computation time for each image scales with the number of templates. (D) Montage of the detected regions for 10 images similar to A, each containing 4 embryos (1 column/image). The montage corresponds to the benchmark ���1 Template + transformations��� as in B and C. Yellow bounding boxes indicate the 2 detections classified as Partial in B.

Additional file 9: Figure S6. Multi-template matching for eye-region detection in oriented zebrafish larvae. (A) Templates (108 �� 76 pixels) and image in which the search is performed (2048 �� 2048 pixels, scale bar: 1 mm). Orange rectangle indicates optional search region (1820 �� 452 pixels), and blue dotted rectangle the head-region template used for 2-step template matching (see B and D). Parameters for the detection: Vertical flipping of the templates (only if FlipV indicated), score type: 0-mean normalized cross-correlation, N = 2 expected objects per image, score threshold: 0.5, maximal overlap between bounding boxes: 0.25. For 2-step template matching the search region in orange is used for the 1st step (head-detection with a single head template, N = 1 expected object), then a single eye template is used with flipping for the detection of the eyes within the previously detected head region. (B) Result of the detections for N = 94 images. 2 eyes/1 eye/No eyes in figure legend refer to the outcome of eye-region detection in each larva. Vertical flipping of the templates readily increases the number of genuine matches. The 2-step template matching approach (search of template within a previously identified ROI) offers the best results and is recommended for more challenging template images (see Additional file 3). (C) Montage of the eye regions detections (yellow) for the 2-step matching approach as in B and D. Specimen in well B8 and F7 are excluded from the count in B as they are not dorsally oriented. (D) Mean computation time per image (error bars show standard deviation) for the different conditions (as in B) using the same hardware as in the main text.

Additional file 7: Figure S4. Template matching for head region detection in oriented zebrafish larvae. (A) Single template (188 �� 194 pixels, no additional transformation) and image (2048 �� 2048 pixels, scale bar: 1 mm) in which the search is performed. The orange rectangle shows the optionally used restricted search region (1820 �� 452 pixels). Parameters for the detection: score type: 0-mean normalised cross-correlation ��� N = 1 expected object per image. (B) Result of the detection for N = 96 images, with and without search region (both 100% detection rate). (C) Montage of detected zebrafish larval head regions within a 96 well plate (as in Fig. 1c). (D) Mean computation time per image (error bars show standard deviation) for the different conditions as in B using the same computing hardware as in the main text. Prior information about the position of the sample within the field of view (e.g. due to standardized sample mounting) can be used to specify a search region, drastically accelerating the computation and reducing the chance of incorrect predictions.

Additional file 11: Figure S8. Multi-template matching for simultaneous head and trunk region detection in oriented zebrafish larvae. (A) Head (188 �� 194 pixels) and trunk region (264 �� 192 pixels) templates. Image (2048 �� 2048 pixels, scale bar: 1 mm) in which the search is performed. The orange rectangle shows the optionally used restricted search region (1820 �� 452 pixels). Parameters for the detection: Vertical flipping of the templates - score type: 0-mean normalised cross-correlation ��� N = 2 expected objects per image ��� score threshold: 0.6 ��� maximal overlap between bounding boxes: 0.35. (B) Result of the detection for N = 96 images, with and without search region. (C) Montage of the detected head regions in 96 zebrafish larvae when the search region is used. The head region was not detected in 3 specimens, 2 of them were not properly dorsally aligned. (see. Additional file 7: Figure S4C). (D) Montage of the detected trunk regions in 96 zebrafish larvae when the search region is used. When 2 trunks were detected in one image (instead of one trunk and one head), the trunk with the best score was used for the montage. Prior information about the position of the sample within the field of view (e.g. due to standardized sample mounting) can be used to specify a search region, drastically accelerating the computation and reducing the chance of incorrect predictions. (E) Mean computation time per image (N = 96 - error bars show standard deviation) for the different conditions as in B using the same computing hardware as in the main text.

Additional file 4: Figure S1. Flowchart of the implemented multi-template matching. The chart illustrates the sequential execution of the tool, for correlation-based score. For difference-based score, the pipeline is identical except that a difference map is computed, minima are detected instead of maxima and the lowest minima are returned. (IoU: Intersection over Union).x

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community-based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima-media thickness, Young's elastic modulus, carotid-femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid-femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5 +/- 6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9 +/- 8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima-media thickness (beta=0.21; 0.17-0.26), Young's elastic modulus (beta=0.21; 0.17-0.25), carotid-femoral pulse wave velocity (beta=0.24; 0.14-0.34), carotid pulse wave velocity (beta=0.31; 0.26-0.35), and carotid diameter (beta=0.43; 0.38-0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

Of the 10 million people estimated to have fallen ill with tuberculosis (TB) in 2019, nearly half million developed TB resistant to rifampicin (RIF), and over one million developed TB susceptible to RIF but resistant to isoniazid (INH). Drug resistance must be detected rapidly and accurately to initiate appropriate and effective treatment. The detection of RIF resistance has improved significantly in the past decade with the introduction of rapid diagnostic tools based on DNA detection. The introduction of these tests has dramatically increased the number of TB patients tested for RIF resistance, leading to a 129% increase of individuals started on second-line TB treatment between 2012 and 2019. The majority of patients with RIF-resistant TB can be detected by analysing the 81-base pair fragment of the rpoB gene region. However, the situation is not that clear for other anti-TB drugs due to the lack of knowledge of how phenotypic resistance is associated with mutations in the Mycobacterium tuberculosis (Mtb) genome. In response to this issue the WHO has developed a catalogue of Mtb mutations in the and their association with phenotypic drug resistance. The catalogue provides a reference standard for the interpretation of mutations conferring resistance to all first-line and a variety of second-line drugs. The report summarises the analysis of over 38,000 isolates with matched data on whole genome sequencing and phenotypic drug susceptibility testing from over 40 countries for 13 anti-TB medicines. It lists over 17,000 mutations, their frequency and association with or not with resistance and includes methods used, mutations identified and summaries of important findings for each drug. Tuberculosis laboratories around the world can use the catalogue as a support in the interpretation of genome sequencing results. The catalogue can also guide the development of new molecular drug susceptibility tests, including next-generation sequencing.

Background: Head and neck cancer is particular due to its infiltrative nature and lymphatic extension, with multidisciplinary treatment. Immunotherapy may be a brand-new therapeutic approach.Case P...

Reliable data on the adult SARS-CoV-2 infection fatality rate in Germany are still scarce. We performed a federal state-wide cross-sectional seroprevalence study named SaarCoPS, that is representative for the adult population including elderly individuals and nursing home residents in the Saarland.Serum was collected from 2940 adults via stationary or mobile teams during the 1Using a highly specific total antibody test detecting anti-SARS-CoV-2 responses over more than 180 days, we estimate an adult infection rate of 1.02% (95% CI: [0.64; 1.44]), an underreporting rate of 2.68-fold (95% CI: [1.68; 3.79]) and infection fatality rates of 2.09% (95% CI: (1.48; 3.32]) or 0.36% (95% CI: [0.25; 0.59]) in all adults including elderly individuals, or adults younger than 70 years, respectively.The study highlights the importance of study design and test performance for seroprevalence studies, particularly when seroprevalences are low. Our results provide a valuable baseline for evaluation of future pandemic dynamics and impact of public health measures on virus spread and human health in comparison to neighbouring countries such as Luxembourg or France.

The Cedars ultramafic block hosts alkaline springs (pH > 11) in which calcium carbonate forms upon uptake of atmospheric CO2 and at times via mixing with surface water. These processes lead to distinct carbonate morphologies with “floes” forming at the atmosphere-water interface, “snow” of fine particles accumulating at the bottom of pools and terraced constructions of travertine. Floe material is mainly composed of aragonite needles despite CaCO3 precipitation occurring in waters with low Mg/Ca (

Quantitative measurements and qualitative description of scientific images are both important to describe the complexity of digital image data. While various software solutions for quantitative measurements in images exist, there is a lack of simple tools for the qualitative description of images in common user-oriented image analysis software. To address this issue, we developed a set of Fiji plugins that facilitate the systematic manual annotation of images or image-regions. From a list of user-defined keywords, these plugins generate an easy-to-use graphical interface with buttons or checkboxes for the assignment of single or multiple pre-defined categories to full images or individual regions of interest. In addition to qualitative annotations, any quantitative measurement from the standard Fiji options can also be automatically reported. Besides the interactive user interface, keyboard shortcuts are available to speed-up the annotation process for larger datasets. The annotations are reported in a Fiji result table that can be exported as a pre-formatted csv file, for further analysis with common spreadsheet software or custom automated pipelines. To illustrate possible use case of the annotations, and facilitate the analysis of the generated annotations, we provide examples of such pipelines, including data-visualization solutions in Fiji and KNIME, as well as a complete workflow for training and application of a deep learning model for image classification in KNIME. Ultimately, the plugins enable standardized routine sample evaluation, classification, or ground-truth category annotation of any digital image data compatible with Fiji.

Quantitative measurements and qualitative description of scientific images are both important to describe the complexity of digital image data. While various software solutions for quantitative measurements in images exist, there is a lack of simple tools for the qualitative description of images in common user-oriented image analysis software. To address this issue, we developed a set of Fiji plugins that facilitate the systematic manual annotation of images or image-regions. From a list of user-defined keywords, these plugins generate an easy-to-use graphical interface with buttons or checkboxes for the assignment of single or multiple pre-defined categories to full images or individual regions of interest. In addition to qualitative annotations, any quantitative measurement from the standard Fiji options can also be automatically reported. Besides the interactive user interface, keyboard shortcuts are available to speed-up the annotation process for larger datasets. The annotations are reported in a Fiji result table that can be exported as a pre-formatted csv file, for further analysis with common spreadsheet software or custom automated pipelines. To illustrate possible use case of the annotations, and facilitate the analysis of the generated annotations, we provide examples of such pipelines, including data-visualization solutions in Fiji and KNIME, as well as a complete workflow for training and application of a deep learning model for image classification in KNIME. Ultimately, the plugins enable standardized routine sample evaluation, classification, or ground-truth category annotation of any digital image data compatible with Fiji.

A combination of targeted molecular methods and phenotypic drug-susceptibility testing is the most widely used approach to detect drug resistance in Mycobacterium tuberculosis isolates. We report the delay in the introduction of an efficient anti-tuberculous drug regimen because of a M. tuberculosis strain displaying a high level of resistance to isoniazid, in the absence of the common mutations associated with isoniazid-resistance, including katG mutations and inhA promoter mutations. Whole-genome sequencing (WGS) identified a large loss-of-function insertion (>1000 pb) at the end of katG in the isolate together with a -57C>T ahpC mutation, a resistance mechanism that would have remained undetected by a conventional molecular targeted approach. A retrospective search using publicly available WGS data of more than 1200 isoniazid-resistant isolates and a similar sized control dataset of isoniazid-susceptible isolates revealed that most (22/31) isoniazid-resistant, KatG loss-of-function mutants had an associated rare ahpC promoter mutation. In contrast, only 7 of 1411 isoniazid-susceptible strains carried a rare ahpC promoter mutation, including shared mutations with the 31 isoniazid-resistant KatG loss-of-function mutants. These results indicate that rare ahpC promoter mutations could be used as a proxy for investigating simultaneous KatG loss-of-function or missense mutations. In addition, WGS in routine diagnosis would improve drug susceptibility testing in M. tuberculosis clinical isolates and is an efficient tool for detecting resistance mechanisms undetected by conventional molecular methods.

Despite widespread drug exposure, for example during gestation or in prematurely born children, organ-specific developmental toxicity of most drugs is poorly understood. Developmental and functional abnormalities are a major cause of kidney diseases during childhood; however, the potential causal relationship to exposure with nephrotoxic drugs during nephrogenesis is widely unknown. To identify developmental nephrotoxic drugs in a large scale, we established and performed an automated high-content screen to score for phenotypic renal alterations in the Tg(wt1b:EGFP) zebrafish line. During early nephrogenesis, embryos were exposed to a compound library of approved drugs. After treatment, embryos were aligned within microtiter plates using 3D-printed orientation tools enabling the robust acquisition of consistent dorsal views of pronephric kidneys by automated microscopy. To qualitatively and quantitatively score and visualize phenotypes, we developed software tools for the semi-automated analysis, processing and visualization of this large image-based dataset. Using this scoring scheme, we were able to categorize compounds based on their potential developmental nephrotoxic effects. About 10% of tested drugs induced pronephric phenotypes including glomerular and tubular malformations, or overall changes in kidney morphology. Major chemical compound groups identified to cause glomerular and tubular alterations included dihydropyridine derivatives, HMG CoA reductase inhibitors, fibrates, imidazole, benzimidazole and triazole derivatives, corticosteroids, glucocorticoids, acetic acid derivatives and propionic acid derivatives. In conclusion, the presented study demonstrates the large-scale screening of kidney-specific toxicity of approved drugs in a live vertebrate embryo. The associated technology and tool-sets can be easily adapted for other organ systems providing a unique platform for in vivo large-scale assessment of organ-specific developmental toxicity or other biomedical applications. Ultimately, the presented data and associated visualization and browsing tools provide a resource for potentially nephrotoxic drugs and for further investigations.

Despite widespread drug exposure, for example during gestation or in prematurely born children, organ-specific developmental toxicity of most drugs is poorly understood. Developmental and functional abnormalities are a major cause of kidney diseases during childhood; however, the potential causal relationship to exposure with nephrotoxic drugs during nephrogenesis is widely unknown. To identify developmental nephrotoxic drugs in a large scale, we established and performed an automated high-content screen to score for phenotypic renal alterations in theTg(wt1b:EGFP)zebrafish line. During early nephrogenesis, embryos were exposed to a compound library of approved drugs. After treatment, embryos were aligned within microtiter plates using 3D-printed orientation tools enabling the robust acquisition of consistent dorsal views of pronephric kidneys by automated microscopy. To qualitatively and quantitatively score and visualize phenotypes, we developed software tools for the semi-automated analysis, processing and visualization of this large image-based dataset. Using this scoring scheme, we were able to categorize compounds based on their potential developmental nephrotoxic effects. About 10% of tested drugs induced pronephric phenotypes including glomerular and tubular malformations, or overall changes in kidney morphology. Major chemical compound groups identified to cause glomerular and tubular alterations included dihydropyridine derivatives, HMG CoA reductase inhibitors, fibrates, imidazole, benzimidazole and triazole derivatives, corticosteroids, glucocorticoids, acetic acid derivatives and propionic acid derivatives. In conclusion, the presented study demonstrates the large-scale screening of kidney-specific toxicity of approved drugs in a live vertebrate embryo. The associated technology and tool-sets can be easily adapted for other organ systems providing a unique platform forin vivolarge-scale assessment of organ-specific developmental toxicity or other biomedical applications. Ultimately, the presented data and associated visualization and browsing tools provide a resource for potentially nephrotoxic drugs and for further investigations.

La Comisión Lancet de Hipertensión determinó que una medida clave para responder a la carga mundial que representa la hipertensión arterial era mejorar la calidad de las mediciones de la presión arterial, mediante la utilización de dispositivos cuya exactitud haya sido validada. En la actualidad existen 3000 dispositivos comercializados, pero muchos no tienen datos publicados sobre pruebas de exactitud conformes a las normas científicas establecidas. La falta de regulación o su ineficiencia, que permiten la autorización de dispositivos para uso comercial sin una validación oficial, posibilitan este problema. Además, han surgido tecnologías nuevas de medición de la presión arterial (por ejemplo, los sensores sin brazalete) sobre las cuales no existe unanimidad en la comunidad científica con respecto a las normas de exactitud de la medición. En conjunto, estos aspectos contribuyen a la disponibilidad generalizada de tensiómetros de consultorio o domiciliarios que ofrecen una exactitud limitada o incierta, que llevan a diagnósticos, manejo y farmacoterapia inapropiados de la hipertensión a escala mundial. Los problemas más importantes relacionados con la exactitud de los dispositivos de medición de la presión arterial se pueden resolver mediante el requisito regulatorio de una validación independiente obligatoria de los dispositivos, en consonancia con la norma ISO universalmente aceptada. Esta es una recomendación básica y constituye una necesidad internacional acuciante. Otras recomendaciones clave son la elaboración de normas de validación específicas para las tecnologías nuevas de medición de la presión arterial y la publicación en línea de listas de los dispositivos nuevos exactos que están a la disposición de los usuarios y los profesionales de salud. Las recomendaciones están en consonancia con las políticas de la Organización Mundial de la Salud sobre los dispositivos médicos y la atención universal de la salud. El cumplimiento de las recomendaciones aumentará la disponibilidad mundial de dispositivos de medición de la presión arterial que sean exactos y tendrá como efecto un mejor diagnóstico y tratamiento, reduciendo así la carga mundial de la hipertensión. The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP. A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas on-line de aparelhos com acurácia adequada que sejam acessíveis aos consumidores e profissionais de saúde. As recomendações estão alinhadas com as políticas da Organização Mundial da Saúde (OMS) sobre dispositivos médicos e atenção universal à saúde. A adesão às recomendações aumentaria a oferta global de dispositivos de pressão arterial com acurácia adequada e resultaria em melhor diagnóstico e tratamento da hipertensão arterial, diminuindo assim a carga mundial dessa doença.

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organisation for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Background: Orthostatic hypotension, blood pressure (BP) variability, and arterial stiffness are three markers of cardiovascular risk beyond the average BP. However, the relationships between these three parameters are not well known. Aim: To examine the relationships between orthostatic hypotension, BP variability, and arterial stiffness. Methods and results: In the Three-City study, a sample of 1151 elderly participants (mean age = 80 ± 3 years) was screened for orthostatic hypotension, undertook home BP and pulse wave velocity (PWV) measurements. We performed logistic regression analyses to look at the associations between orthostatic hypotension and both day-to-day (D-to-D) BP variability quartiles and PWV quartiles. Orthostatic hypotension was detected in 210 participants who were more likely to be hypertensive, exhibit higher BP variability and have increased arterial stiffness. In the multivariate logistic regression analysis, the frequency of orthostatic hypotension increased by 20% with every quartile of D-to-D SBP variability and by 20% with every quartile of PWV. PWV and D-to-D BP variability were not associated. In stratified analysis, the use of beta-blocker changes these relationships: orthostatic hypotension was not associated to PWV anymore but its association with D-to-D SBP variability was apparently stronger. Conclusion: In this large sample of elderly individuals, orthostatic hypotension was independently associated with both BP variability and PWV. BP variability being more indicative of a baroreflex dysfunction and PWV being a marker of vascular ageing, these two components would participate to the orthostatic hypotension mechanisms.

The kepler and TESS missions have generated over 100,000 potential transit signals that must be processed in order to create a catalog of planet candidates. During the last few years, there has been a growing interest in using machine learning to analyze these data in search of new exoplanets. Different from the existing machine learning works, ExoMiner, the proposed deep learning classifier in this work, mimics how domain experts examine diagnostic tests to vet a transit signal. ExoMiner is a highly accurate, explainable, and robust classifier that 1) allows us to validate 301 new exoplanets from the MAST Kepler Archive and 2) is general enough to be applied across missions such as the on-going TESS mission. We perform an extensive experimental study to verify that ExoMiner is more reliable and accurate than the existing transit signal classifiers in terms of different classification and ranking metrics. For example, for a fixed precision value of 99%, ExoMiner retrieves 93.6% of all exoplanets in the test set (i.e., recall=0.936) while this rate is 76.3% for the best existing classifier. Furthermore, the modular design of ExoMiner favors its explainability. We introduce a simple explainability framework that provides experts with feedback on why ExoMiner classifies a transit signal into a specific class label (e.g., planet candidate or not planet candidate)., Comment: Accepted for Publication in Astrophysical Journals, November 12, 2021

Erwan Treillet,1 Sophie Laurent,2 Yacine Hadjiat3 1AP-HP, Médecine de la Douleur et Médecine Palliative, Hôpital Lariboisière, Paris, France; 2Institut de Cancérologie, Institut Gustave Roussy, Villejuif, France; 3Mundipharma France, Paris, France Purpose: To review the recent literature on opioid rotation (ie, switching from one opioid drug to another or changing an opioid’s administration route) in cancer patients experiencing severe pain and to develop a novel equianalgesia table for use in routine clinical practice. Methods: The MEDLINE database was searched with terms “cancer pain,” “opioid rotation,” “opioid switching,” “opioid ratio,” “opioid conversion ratio,” and “opioid equianalgesia” for the major opioids (morphine, oxycodone, fentanyl, and hydromorphone) and the intravenous, subcutaneous, oral, and transdermal administration routes. Selected articles were assessed for the calculated or cited opioid dose ratio, bidirectionality, and use of the oral morphine equivalent daily dose or a direct drug-to-drug ratio. Results: Twenty publications met our selection criteria and were analyzed in detail. We did not find any large-scale, prospective, double-blind randomized controlled trial with robust design, and most of the studies assessed relatively small numbers of patients. Bidirectionality was investigated in seven studies only. Conclusion: The updated equianalgesic table presented here incorporates the latest data and provides information on bidirectionality. Despite the daily use of equianalgesic tables, they are not based on high-level scientific evidence. More clinical research is needed on this topic. Keywords: opioid rotation, opioid switching, equianalgesic dose, morphine, hydromorphone, oxycodone, fentanyl

International audience; We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi- platform and language-agnostic package manager Conda. Currently, Bioconda o ers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bio- conda improves analysis reproducibility by allowing users to de ne isolated environments with de ned software versions, all of which are easily installed and managed without administrative privileges.

Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus.

The δ18O of ostracod valves is widely used to infer water δ18O and temperature. However, ostracod δ18O appears sensitive to other environmental variables. In addition, there is species-dependent ostracod calcite 18O enrichment, relative to slowly precipitated inorganic calcite under the same conditions. Together these uncertainties complicate ostracod paleoclimate reconstructions. This study presents a new understanding of the causes of ostracod δ18O variations based on a global database of published ostracod δ18O values in lake, marine and coastal environments, and from culture experiments. The database includes associated field/experiment host water parameters including temperature (−1 to 32 °C), water δ18O (−13.2‰ to 4.3‰ VSMOW), pH (6.9–10.4), salinity (0–72 g/kg), calcite saturation states (0.6–26), and dissolved inorganic carbon concentration [DIC] (0.9–54.3 mmol/kg). The data show that: (1) the δ18O of marine and non-marine ostracods reflects the 18O/16O of the sum of host water CO32− and HCO3− ions. For example, at a given temperature, the δ18O of non-marine ostracods decreases by 4‰ to 6‰ as [CO32−]/[DIC] reaches 70%, depending on the ostracod species. In low [CO32−]/[DIC] settings (i.e. high HCO3−/CO32−), ostracod 18O/16O is close to the 18O/16O of HCO3− ions, which explains why on average ostracod δ18O is higher than the δ18O of inorganic calcite precipitated slowly under the same conditions. (2) Taxonomic offsets in ostracod δ18O vary with the host water [CO32−]/[DIC]. In environments where HCO3− ≫ CO32− (i.e. most freshwater lakes), the 18O/16O of Candonids is indistinguishable from the 18O/16O of HCO3− ions (difference of 0.10 ± 0.16‰) while the 18O/16O of Cyprids is lower than the 18O/16O of HCO3− ions by −0.77‰ to −0.32‰, Cytherids by −0.88 ± 0.29‰, and Limnocytherids by −1.12 ± 0.05‰. (3) The sensitivity of ostracod δ18O to [CO32−]/[DIC] also varies with taxonomy. For each percent increase in [CO32−]/[DIC], Candonids δ18O decreases by −0.098 ± 0.024‰, Cyprids by −0.075 ± 0.004‰, Cytherids by −0.057 ± 0.012‰, and Limnocytherids by −0.058 ± 0.005‰. (4) The similarity in 18O/16O between ostracod calcite and the sum of host water ‘HCO3− and CO32−’ (despite species-specific offsets) suggests rapid precipitation of a finite DIC pool in the ostracod calcifying fluid. We propose an ostracod δ18O model whereby the more negative the 18O/16O of a given species relative to the sum of CO32− and HCO3−, the greater the isotopic equilibrium between the DIC pool and H2O in the ostracod calcifying fluid. (5) Higher host water salinities and pH induce higher [CO32−]/[DIC], resulting in lower ostracod δ18O, which explains the variable salinity and pH effects on ostracod δ18O. Our database and ostracod δ18O model shows that ostracod δ18O records from closed basin environments likely reflect high or variable [CO32−]/[DIC], rather than water temperature and δ18O alone. Our study reconciles contradictory observations of controls on ostracod δ18O and paves the way for improved paleo-environmental interpretations and reconstructions of past water [CO32−]/[DIC].

The cohabitation of Drosophila melanogaster with humans is nearly ubiquitous. Though it has been well established that this fly species originated in sub-Saharan Africa, and only recently has spread globally, many details of its swift expansion remain unclear. Elucidating the demographic history of D. melanogaster provides a unique opportunity to investigate how human movement might have impacted patterns of genetic diversity in a commensal species, as well as providing neutral null models for studies aimed at identifying genomic signatures of local adaptation. Here, we use whole-genome data from five populations (Africa, North America, Europe, Central Asia, and the South Pacific) to carry out demographic inferences, with particular attention to the inclusion of migration and admixture. We demonstrate the importance of these parameters for model fitting and show that how previous estimates of divergence times are likely to be significantly underestimated as a result of not including them. Finally, we discuss how human movement along early shipping routes might have shaped the present-day population structure of D. melanogaster.

Background: Belimumab is a monoclonal antibody against BAFF/BLyS and has been approved for patients with active systemic lupus erythematosus (SLE) despite standard of care immunosuppressive treatment (ST). Nevertheless, the interference of belimumab with pathogenetic pathways of SLE is not fully[for full text, please go to the a.m. URL], 46. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 32. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), Wissenschaftliche Herbsttagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. In the present case report, two patients with advanced and metastatic uterine leiomyosarcomas (ULMS) with significant progression-free survival (PFS) and overall survival (OS) administered Trabectedin as second and third line treatment are reported. The first case received third line Trabectedin with a PFS of 24 months and an OS of 35 months. The second case received second line Trabectedin with a PFS of 24 months and an OS of 30 months. In addition, a good safety record was obtained in the long-term administration of Trabectedin (more so in case 1 than case 2), with a good quality of life.

Proceedings of the ICA 2019 and EAA Euroregio : 23rd International Congress on Acoustics, integrating 4th EAA Euroregio 2019 : 9-13 September 2019, Aachen, Germany / proceedings editor: Martin Ochmann, Michael Vorländer, Janina Fels 23rd International Congress on Acoustics, integrating 4th EAA Euroregio 2019, ICA 2019, Aachen, Germany, 9 Sep 2019 - 13 Sep 2019; Aachen (2019)., Published by Aachen

Proceedings of the ICA 2019 and EAA Euroregio : 23rd International Congress on Acoustics, integrating 4th EAA Euroregio 2019 : 9-13 September 2019, Aachen, Germany / proceedings editor: Martin Ochmann, Michael Vorländer, Janina Fels 23rd International Congress on Acoustics, integrating 4th EAA Euroregio 2019, ICA 2019, Aachen, Germany, 9 Sep 2019 - 13 Sep 2019; Aachen (2019)., Published by Aachen

CD33 is an immunomodulatory receptor linked to Alzheimer’s disease (AD) susceptibility via regulation of phagocytosis in microglia. Divergent features between human CD33 (hCD33) and murine CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new αmCD33 monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. Notably, cell surface expression of mCD33 is entirely dependent on Dap12 due to an interaction with the transmembrane lysine in mCD33. In RAW264.7 cultured macrophages, BV-2 cultured microglia, primary neonatal and adult microglia, uptake of cargo — including aggregated Aβ1–42 — is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis, highlighting the importance of studying hCD33 in AD susceptibility., Abhishek Bhattacherjee et al. investigate the functional differences between human and mouse CD33, an immunomodulatory receptor linked to Alzheimer’s disease. They find that loss of mouse CD33 does not affect cargo uptake in macrophages in contrast to human CD33, which represses phagocytosis when expressed in cells or mice.

Following recent experiments on ultracold dual superflows, we model in this work the dynamics of two harmonically trapped counterflowing superfluids. Using complementary analytical and numerical approaches, we study the shedding of elementary excitations triggered by the relative motion of the two species. We exhibit two different excitation mechanisms leading to distinct threshold velocities for the onset of dissipation: in addition to the parametric pair production present in homogeneous , galilean-invariant systems, we show that non-uniform motion and density inhomogeneities allow for a Landau-like decay mechanism where single excitations are produced.