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Despite evidence that the microbiome extends host genetic and phenotypic traits, information on how the microbiome is transmitted and maintained across generations remains fragmented. For seed-bearing plants, seeds harbor a distinct microbiome and play a unique role by linking one generation to the next. Studies on microbial inheritance, a process we suggest including both vertical transmission and the subsequent migration of seed microorganisms to the new plant, thus become essential for our understanding of host evolutionary potential and host-microbiome coevolution. We propose dividing the inheritance process into three stages: (i) plant to seed, (ii) seed dormancy, and (iii) seed to seedling. We discuss the factors affecting the assembly of the microbiome during the three stages, highlight future research directions, and emphasize the implications of microbial inheritance for fundamental science and society.

Cystic echinococcosis (CE) is endemic in humans and domestic animals in eastern Africa. All the species of the Echinococcus granulosus sensu lato complex have been reported in this region except for E. equinus, possibly due to the small number of studies involving equids. This study reports the frequency of different Echinococcus species in donkeys from eastern Africa. A total of 5961 donkeys were examined during meat inspection in 3 slaughterhouses in Kenya. Identification of Echinococcus spp. was achieved through polymerase chain reaction-restriction fragment-length polymorphism and sequencing of the mitochondrial nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 1 gene. The prevalence of CE was 5.7% (337/5961). The 263 genotyped cysts belonged to E. equinus (n = 163), E. granulosus sensu stricto (n = 70), E. canadensis (G6/7) (n = 26) and E. ortleppi (n = 4). One donkey harboured a metacestode of Spirometra theileri. All E. equinus cases, except 2, originated from southern Ethiopia, whereas the other species were more evenly distributed across the study area. Most of the cysts belonging to E. equinus were fertile (111/163), while those of the other species were non-fertile. This is the first report of Echinococcus spp. in donkeys from sub-Saharan Africa and the first confirmation of E. equinus in East Africa. The frequent fertility of E. equinus cysts in donkeys affirms their suitability as intermediate hosts of this species, while low frequency and cyst fertility suggest a marginal role of donkeys in the transmission of E. granulosus s. s., E. canadensis (G6/7) and E. ortleppi.

Plant diversification and co-evolution shaped the plant microbiome and vice versa. This resulted in a specific composition of the plant microbiome and a strong connection with the host in terms of functional interplay. Symbionts are part of the microbiota, and important for the plant’s germination and growth, nutrition, as well as stress protection. However, human activities in the Anthropocene are linked to a significant shift of diversity, evenness and specificity of the plant microbiota. In addition, and very importantly, many plant symbionts are missing or no longer functional. It will require targeted microbiome management to support and reintroduce them. In future agriculture, we should aim at replacing harmful chemicals in the field, as well as post-harvest, by using precision microbiome engineering. This is because the plant microbiome is connected across systems and crucial for human and planetary health. This commentary aims to inspire holistic studies for the development of solutions for sustainable agriculture in framework of the One Health and the Planetary Health concepts.

Collaborators : AP-HP / Université de Paris / INSERM COVID-19 research collaboration, AP-HP COVID CDR Initiative, “Entrepôt de Données de Santé” AP-HP Consortium: Pierre-Yves Ancel, Alain Bauchet, Nathanaël Beeker, Vincent Benoit, Mélodie Bernaux, Ali Bellamine, Romain Bey, Aurélie Bourmaud, Stéphane Breant, Anita Burgun, Fabrice Carrat, Charlotte Caucheteux, Julien Champ, Sylvie Cormont, Christel Daniel, Julien Dubiel, Catherine Ducloas, Loic Esteve, Marie Frank, Nicolas Garcelon, Alexandre Gramfort, Nicolas Griffon, Olivier Grisel, Martin Guilbaud, Claire Hassen-Khodja, François Hemery, Martin Hilka, Anne Sophie Jannot, Jerome Lambert, Richard Layese, Judith Leblanc, Léo Lebouter, Guillaume Lemaitre, Damien Leprovost, Ivan Lerner, Kankoe Levi Sallah, Aurélien Maire, Marie-France Mamzer, Patricia Martel, Arthur Mensch, Thomas Moreau, Antoine Neuraz, Nina Orlova, Nicolas Paris, Bastien Rance, Hélène Ravera, Antoine Rozes, Elisa Salamanca, Arnaud Sandrin, Patricia Serre, Xavier Tannier, Jean-Marc Treluyer, Damien Van Gysel, Gaël Varoquaux, Jill Jen Vie, Maxime Wack, Perceval Wajsburt, Demian Wassermann, Eric Zapletal; International audience; Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) receiving a FIASMA medication, and 1,060 patients (41.4%) who did not. Despite being significantly and substantially associated with older age and greater medical severity, FIASMA medication use was significantly associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p

Strongly walk regular graphs (SWRGs or $s$-SWRGs) form a natural generalization of strongly regular graphs (SRGs) where paths of length~2 are replaced by paths of length~$s$. They can be constructed as coset graphs of the duals of projective three-weight codes whose weights satisfy a certain equation. We provide classifications of the feasible parameters of these codes in the binary and ternary case for medium size code lengths. For the binary case, the divisibility of the weights of these codes is investigated and several general results are shown. It is known that an $s$-SWRG has at most 4 distinct eigenvalues $k > \theta_1 > \theta_2 > \theta_3$, and that the triple $(\theta_1, \theta_2, \theta_3)$ satisfies a certain homogeneous polynomial equation of degree $s - 2$ (Van Dam, Omidi, 2013). This equation defines a plane algebraic curve; we use methods from algorithmic arithmetic geometry to show that for $s = 5$ and $s = 7$, there are only the obvious solutions, and we conjecture this to remain true for all (odd) $s \ge 9$., Comment: 42 pages

Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable.This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non-function (PNF), delayed graft function (DGF), 3- and 12-month graft function and 1- and 3-year patient- and death-censored graft survival.In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771-0.993], 0.818 [95% CI: 0.726-0.922] and 0.793 [0.689-0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817-1.106]), the highest eGFR was the best predictor of 3-month graft function (adjusted b coefficient 1.161 [95% CI: 0.355-1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667-0.968] and 0.750 [0.611-0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient- and graft survival.The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3- and 12-month graft function. Regarding short-term patient- and graft survival, there appears to be impacted by recipient factors rather than donor kidney function.

BackgroundWe assessed the prevalence of self-reported perceived discrimination in the workplace after the end of treatment among breast cancer (BC) survivors and studied its association with social, health-related and work-related factors.MethodsWe used data from a French prospective cohort (CANcer TOxicities) including women diagnosed with stage I–III BC. Our analysis included 2130 women who were employed, ResultsOverall, 26% of women reported perceived discrimination in the workplace after the end of treatment. Women working for a small company, in the public sector or with better overall health status were less likely to report perceived discrimination. Women who benefited from easing dispositions at their workplace, who did not feel supported by their colleagues and those who returned to work because of fear of job loss were more likely to report perceived discrimination.ConclusionsOne in four BC survivors perceives discrimination in the workplace. Health and work-related factors are associated with increased likelihood of reporting perceived discrimination.Trial registration numberNCT01993498.

Recent studies used functional magnetic resonance imaging (fMRI) population receptive field (pRF) mapping to demonstrate that retinotopic organization extends from the primary visual cortex to ventral and dorsal visual pathways, by quantifying visual field maps, receptive field size, and laterality throughout multiple areas. Visuospatial representation in the posterior parietal cortex (PPC) is modulated by attentional deployment, raising the question of whether spatial representation in the PPC is dynamic and flexible, and whether this flexibility contributes to visuospatial learning. To answer this question, changes in spatial representation within the PPC and early visual cortex were recorded with pRF mapping before and after prism adaptation (PA)—a well-established visuomotor technique that modulates visuospatial attention according to the direction of the visual displacement. As predicted, results showed that adaptation to left-shifting prisms increases pRF size in left PPC, while leaving space representation in the early visual cortex unchanged. This is the first evidence that PA drives a dynamic reorganization of response profiles in the PPC. These findings show that spatial representations in the PPC not only reflect changes driven by attentional deployment but dynamically change in response to modulation of external factors such as manipulation of the visuospatial input during visuomotor adaptation.

In this Voicing, Ute Wassermann describes how sympoietic vocal practice brings her into resonance with the world in different ways, creating a complex network of relationships within her body between various vocal identities. Stories are told about how her many voices and the environment exist in a mutually stimulating feedback relationship. She gives examples of how her sympoietic voice collaborates with the polyphonies of other-than-human voices. She communicates with voices sounding from objects, and at the same time is influenced by them. Does her voice remain human, or will it become the other?

SUMMARY The essential goal of seismic microzonation is the estimation of the shallow velocity structure in order to characterize the local earthquake shaking characteristics. This is of special importance in densely inhabited areas with unfavourable soil conditions. The common approach is the analysis of ambient noise array data using frequency–wavenumber (FK) or spatial autocorrelation (SPAC) techniques. However, the installation of arrays is difficult, especially within urban environments, making single-station approaches more desirable. In this study, we directly compare the recently developed approach of velocity estimation using single-station six-component (6C) measurements, combining three translational and three rotational motions, with the established methods of FK and SPAC analysis. We conduct measurements in Munich’s inner city using a geophone array and an iXblue blueSeis-3A rotational motion sensor together with a Nanometrics Trillium Compact Seismometer, respectively. From the array data, as well as from the 6C data, Love and Rayleigh dispersion curves are estimated and further inverted for 1-D P- and S-wave velocity profiles. We find that all methods give similar results, indicating the potential of the novel 6C approach. Furthermore, adding horizontal-to-vertical spectral ratios enables the inversion for structures at greater depth and increases the resolution of the velocity structure. In addition, we test different array geometries to evaluate the influence of the sensor configuration on the results. As a last step, we compare the estimated velocity models to lithologic profiles and find an overall positive correlation, which supports our inversion results.

Background Deceased donor kidneys with acute kidney injury (AKI) are often discarded because of concerns about inferior transplant outcomes. A means of grading the quality of such kidneys is the performance of procurement biopsies. Methods This is a retrospective study of 221 brain death donors with marginal kidneys transplanted in 223 recipients in Germany. Marginal kidneys were defined as kidneys with procurement biopsies done exceptionally to assess suitability for transplantation in otherwise potentially discarded organs. The impact of deceased donor AKI on patient survival and death-censored graft survival at 1, 3 and 5 years and graft function at 1 and 3 years after transplantation was investigated. Results Recipients of kidneys with stage 3 AKI had a greater incidence of delayed graft function [DGF; ORStage 1: 1.435 (95% CI 0.438–0.702), ORStage 2: 2.463 (95% CI 0.656–9.245), ORStage 3: 4.784 (95% CI 1.421–16.101)] but a similar graft and patient survival compared to recipients of donors without AKI and with AKI stage 1 and 2 as well. The coexistence of recipient DGF and donor AKI was associated with the lowest graft survival and function rates. Conclusion The transplantation of deceased donor marginal kidneys with AKI confers a higher risk for DGF but is associated with acceptable graft and patient outcomes, which do not differ in comparison with marginal donor kidneys without AKI. Graft prognosis is especially poor if donor AKI and recipient DGF concur. Donor AKI was a risk factor independent of the histological lesions of procurement biopsies.

Observing motion within a building in six degrees of freedom (three components of translational motion plus three components of rotational motion) opens completely new approaches to structural health monitoring. Inspired by inertial navigation, we can monitor the absolute motion of a building or parts of it without the need for an external reference. Rotational motion sensors can directly measure harmful torsional modes of a building, which has always been challenging and prone to errors when using translation sensors only. Currently, we are developing methodologies including rotational motion observations for monitoring of material parameters in order to locate and characterize structural damage. Within the framework of the GIOTTO project (funded by the German Federal Ministry for Education and Research, BMBF) we explore these approaches.Here, we introduce a newly developed 6C sensor network for structural health monitoring. It consists of 14 inertial measurement units (IMU50 from exail, former iXblue, France) that were adapted to the needs of seismology and structural health monitoring. We performed experiments at the BLEIB test structure of the Bundesanstalt für Materialforschung und -prüfung (BAM), a 24 m long concrete beam serving as a large scale bridge model. We present results on detecting changes in material properties (seismic wave speed) of the beam with varying pre-stress and load, as derived from a novel approach by comparing amplitudes of translational to rotational motions at a single measurement point. We compare our findings to results obtained with coda wave interferometry using rotational as well as translational motions.

Piton de la Fournaise is a shield volcano located on La Réunion island in the Indian Ocean and most recently tends to erupt once - twice annually. Besides volcanic tremor during eruptions and rockfall, long-period (LP) and volcano-tectonic (VT) earthquakes are dominating signals on the island.In October 2022, a rotational sensor and an array of seven seismometers were installed within the Enclos Fouqué, the youngest caldera of volcano Piton de la Fournaise. We record volcano-seismic signals that were also detected by the seismic network of the Observatoire Volcanologique du Piton de la Fournaise (OVPF). Our aim is to test the performance of the rotational sensor and the conventional seismic array with respect to these events.Local VT and rockfall events have been detected on all instruments and could be compared by calculations of backazimuth (BAZ) and signal-to-noise ratio (SNR). We derive the rotational rate using three array stations for array derived rotation (ADR). First results indicate an agreement between the BAZ obtained from the rotational sensor, the array and the location using the OVPF network for strong rockfall events. Summit VT and weak local earthquakes could furthermore be located by the array BAZ. Preliminary SNR results from all considered events indicate higher values for the array stations. Since the instruments could not be buried on site and the rotational sensor is likely affected by wind noise, it is assumed that comparison between the instruments will work best for strong and/ or close events.

In September 2022, a three-component rotational rate sensor (blueSeis-3A) provided by IRIS has been deployed at the underground vault of the Piñon Flat Observatory (PFO) near San Diego in California. A three-component broadband seismometer (Trillium 240s) is co-located on the granite pier, creating a 6C station for permanent observations of local and regional seismicity and wavefield studies. The permanent record is streamed online via IRIS and freely available with all required metadata (station: BlueSeis at Pinon Flat = BSPF). Additionally, the site offers observations of strain by optical fiber and vacuum laser strainmeters at PFO, allowing to study 7 components of the seismic wavefield in a quiet area with regard to seismic noise, but high seismicity (e.g. San Andreas fault zone, San Jacinto fault zone). Such a setup enables advanced studies of the seismic wavefield. Dense, large-N nodal experiments, temporarily deployed around PFO could provide dense sampling of the seismic wavefield for comparison studies. The seismic array of borehole sensors at PFO is well designed to compute array derived rotations with enables a direct comparison with the rotational record and applied methods. Moreover, the array is employed to compare array analysis with 6C methods (e.g. backazimuth estimation, wavefield separation, source tracking, local subsurface velocity changes). We present characteristics on the 6C station and preliminary analysis results.

In the past decade, significant progress has been made in the acquisition and processing of seismic wavefield gradient data (e.g., recordings of ground strain and rotation). When combined with conventional multicomponent seismic data, wavefield gradients enable the estimation of local wavefield properties (e.g., the local wave speed, the propagation direction, and the wave type) and the reconstruction of spatially under-sampled seismic wavefields. However, the seismological community has yet to embrace wavefield gradient data as a new observable.We present TwistPy (Toolbox for Wavefield Inertial Sensing Techniques), an open-source software package for seismic data processing written in Python. It includes routines for single-station polarization analysis and filtering, as well as array processing tools. A special focus lies on innovative techniques to process spatial wavefield gradient data and, in particular, rotational seismic data obtained from dedicated rotational seismometers or small-aperture arrays of three-component sensors. Routines currently included in the package comprise polarization analysis and filtering in both the time domain and the time-frequency domain (for three-component and six-component data), dynamic tilt corrections, and beamforming (Bartlett, Capon, and MUSIC beamformers). With TwistPy, we attempt to lower the barrier of entry for the seismological community to use state-of-the art multicomponent and wavefield gradient analysis techniques by providing a user-friendly software interface.Extensive documentation of the software and examples in the form of Jupyter notebooks can be found at https://twistpy.org.

One major objective of Geodesy is the observation of the Earth, its gravity field and climate. To study subtle but impactful changes in the gravitational field, novel paradigms and high-precision measurement schemes are emerging.According to Einstein’s Theory of General Relativity, the proper time of a clock is the four-dimensional length of its worldline through curved spacetime. Thus, the comparison of clocks always is a comparison of local spacetime geometries. Thereupon, clock comparison could be used as a new method, termed chronometry, for gravity field recovery (GFR) via high-precision timing and redshift measurements. With the fast development of new, better, and smaller time measurement devices, optical clocks are a promising tool for GFR. Such clocks can be compared using, e.g., a light signal propagating in free space. For the determination of all gravitational degrees of freedom, it is necessary to relocate at least one clock around the planet. This can be done via moving clocks on satellites. To interpret these precise measurements correctly, it is essential to consider all influences on the laser signal used.For this purpose, DLR and ZARM developed a simulation platform called XHPS in the scope of the DFG Collaborative Research Center 1464 TerraQ to model the environmental effects on satellites. It is used to study the influences on the laser signal between a ground station and satellites (or between two satellites). In particular, we want to simulate the signal loss caused by the Earth’s atmosphere, as well as other influences such as the relativistic redshift. It might also be interesting to compare the magnitude of redshift and atmospheric perturbations. This work will present the current state of our research.

As observed elsewhere on a global scale, mountain permafrost at the Zugspitze (German/Austrian Alps) is degrading in response to climate change, which affects the rock slope stability and thus the hazard potential. Recent studies suggest that passive seismology is a promising and emerging tool to monitor permafrost changes as the seismic velocity of rocks strongly decreases/increases upon thawing/freezing. Compared to other, more classical methods like borehole temperature logging or electrical resistivity tomography (ERT), seismology is less laborious and costly, non-invasive and allows continuous monitoring. At Mt. Zugspitze, we exploit these advantages using a permanent seismic station (installed in 2006) as well as three small seismic arrays and Distributed Acoustic Sensing (DAS; both available since summer/fall 2021), to infer permafrost dynamics with high spatio-temporal resolution. The seismic data show repeating diurnal noise generated by the operation of cable cars, which we leverage for cross-correlation analysis. Our results suggest that the dominant signal in the retrieved seismic velocity change time series is caused by the seasonal freeze-thaw cycles associated with permafrost bodies on the northern side of the mountain ridge. On the long-term, the time series show a gradual velocity decrease associated with permafrost degradation due to atmospheric warming and compare well with modeled velocity change time series using rock temperature data from a nearby borehole, which intersects the mountain ridge. We discuss differences in our seismic analysis results obtained from direct and coda waves as well as from single station to station pairs and DAS and interpret the results in the light of other measurements including ERT, rock temperature logging and meteorological parameters.

The prospect for the sustainability of the Gallo-Roman archeological site located in Genainville (France), where relics and artifacts dated to the 2rd century CE have been excavated is threaten by groundwater ingression. The in-situ building heritage materials and structures comprising a two cellea temple and an amphitheater made of limestones, are submitted all days to rising and changing groundwater levels; water being the main agent or vector of damage processes (salt weathering or freeze-thaw cycles). As part of a multi-disciplinary effort to support archeological expeditions and conserve the site structures. We report the results of groundwater monitoring and hydrogeological studies as well as tidal subsurface analysis executed to quantitatively evaluate hydraulic and geo-mechanical characteristics of the subsurface sequences toward a nondestructive approach. Continuous groundwater level data recorded in three wells in the archeological site were decomposed into constituent events that impact the observed fluctuations. The groundwater levels and barometric pressure data were acquired at 60 seconds intervals to study the response of the aquifer to strain and stress prevalence at the site. Using the method of regression deconvolution, the response to barometric pressure was disentangled from the measured water levels. Theoretical Earth tides parameters were computed using the PyGtide code, based on the ETERNA PREDICT program, at intervals of 1 minute. Harmonic analysis of the raw and filtered data using the classical Fast Fourier transform (FFT), and Singular Spectral Analysis (SSA) identify M2, S2, K1 and O1 tidal constituents as the dominant amplitudes. The SSA technique has the advantage of resolving the events into individual strands compare to the spectra of the composite data produced by the FFT. Hence, an event decomposed in the data is isolated in terms of it frequency and amplitude, and visualized. The K1 and S2 harmonic constituents were present in the filtered and raw data sets with different amplitudes. The amplitude response method was used to compute the poroelastic properties of the aquifer and characterize the subsurface heterogeneity. The model identified a semi-confined aquifer as the main groundwater storage system in the site.Keyword: Heritage site, groundwater ingress, harmonic constituents, hydraulic properties

Salt weathering is a main cause of damage in building heritage materials. Despite the large amount of research on this topic, the mechanism of damaging processes remains not fully understood in particular at the pore scale where the salt crystallization and dissolution occur. For this reason, we propose an innovative approach combining damage proxy measurements at pore-scale using Atomic Force Microscopy (AFM), Raman spectrometry and multi-scale numerical modelling, performed during weathering cycles. Imbibition-evaporation cycles are performed on carbonate stones (Savonnières and Saint Maximin limestones) with a 0.1 mol/L sodium sulfate solution at controlled room temperature and relative humidity. The stone samples are especially designed for the measurements at the pore-scale. Cylinder of 1.6 cm diameter and 1.5 cm thickness have been coated with very viscous epoxy resin. Then the two sides of the cylinder have been polished to obtained two free surfaces that allow the fluid circulation in the sample and the measurements. After each weathering cycle, nanoindentation experiments are performed on representative areas of several hundreds of square micrometers in order to monitor the mechanical properties evolution. A force of the µN order is applied in order to stay in the elastic deformation regime. Young modulus values can be then deduced from the slope of the force curves that occurs during the cantilever deflection. With this method, the effect of salt weathering on the mechanical properties of stone minerals is investigated at the pore scale and with no impact of the measurement on the phases structure (reversible indentations). The AFM results are then coupled with chemical Raman mapping to identify the present phases and assign them their mechanical properties. The obtained experimental data are then used in numerical modeling, to generate a numerical Young modulus field with the same properties than the experimental field. Finally, a new medium with higher dimensions will be generated to compare the results with the macro-scale observations on building heritage stones. AFM characterization shows that changes occurred on the topography of the samples between the first and the third alteration cycles. They are of the order of several tens of nanometers and correspond either to salt crystals deposits or in some cases to the loss of material that took place between the second and the third cycle. A decrease of the Young modulus is observed after each cycle that is of the order of 2 GPa between the first and the second cycles. More significant changes are observed after the third cycle especially in some areas where a decrease up to 3 to 4 GPa is estimated.

PDF file - 274K, Additional information for Figure 3 and 6 and full length blots for Figure 2K and Figure 4C

Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy and in combination with capecitabine for HER2+ metastatic breast cancer. Diarrhea is the most frequently reported on-target side effect associated with neratinib; in the ExteNET adjuvant trial, where no mandatory anti-diarrheal prophylaxis was used, 39.8% of patients reported grade 3 diarrhea and 16.8% of patients discontinued neratinib due to diarrhea. The CONTROL trial (Clinicaltrials.gov: NCT02400476) was designed to investigate pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or neratinib dose escalation (DE) for the prevention of neratinib-associated diarrhea. Data for the loperamide, budesonide and colestipol cohorts have been reported previously [Barcenas et al. Ann Oncol 2020]. The final findings for the two DE regimen cohorts are reported here. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer received oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) neratinib DE + loperamide PRN (two cohorts). DE1 schedule: neratinib 120 mg/day for week 1, 160 mg/day for week 2, then 240 mg/day from week 3 onwards to complete 12 months of treatment. DE2 schedule: neratinib 160 mg/day for weeks 1&2, 200 mg/day for weeks 3&4, then 240 mg/day from week 5 onwards up to 12 months. Both DE cohorts included loperamide PRN. Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Results: A total of 563 patients were enrolled in CONTROL. All preventive strategies reduced the incidence of grade 3 diarrhea compared with that seen in ExteNET (historical control: 39.8%). Median cumulative duration of grade 3 diarrhea ranged from 2-3.5 days across the CONTROL study cohorts for the entire 12-month treatment period (compared with 5.0 days for ExteNET). The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for loperamide alone. Adoption of neratinib DE, particularly the 2-week DE schedule (DE1), most markedly reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET (see Table). Conclusions: Neratinib DE + loperamide PRN during the first 2 weeks of treatment (DE1 cohort) was associated with the lowest rates of grade 3 diarrhea (13.3%) and diarrhea-related discontinuations (3.3%) compared with all other anti-diarrheal strategies investigated in CONTROL. These final findings from the study show improved tolerability of neratinib with all diarrhea prophylaxis strategies and suggest that neratinib DE1 with loperamide PRN allows patients to stay on treatment longer and receive the full benefit of neratinib therapy. Table. Patient disposition and diarrhea characteristics: ExteNET vs CONTROL DE cohortsExteNET(n=1408)CONTROL DE1 (n=60)CONTROL DE2 (n=62)Patients completing 1 year of neratinib treatment, %617874Median duration of treatment, months (range)11.6 (2.5–11.9)12.0 (0.2–12.4)11.9 (0.3–14.5)Diarrhea, %Grade 339.813.327.4Grade 4 Citation Format: Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, Adam Brufsky, Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A Cheong, Christian F Singer, Daniel Hunt, Navid Foruzan, Leanne McCulloch, Carlos H Barcenas. Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-02.

Diffusion MRI (dMRI) is the only noninvasive method for mapping white matter connections in the brain. We describe SlicerDMRI, a software suite that enables visualization and analysis of dMRI for neuroscientific studies and patient-specific anatomic assessment. SlicerDMRI has been successfully applied in multiple studies of the human brain in health and disease, and here, we especially focus on its cancer research applications. As an extension module of the 3D Slicer medical image computing platform, the SlicerDMRI suite enables dMRI analysis in a clinically relevant multimodal imaging workflow. Core SlicerDMRI functionality includes diffusion tensor estimation, white matter tractography with single and multi-fiber models, and dMRI quantification. SlicerDMRI supports clinical DICOM and research file formats, is open-source and cross-platform, and can be installed as an extension to 3D Slicer (www.slicer.org). More information, videos, tutorials, and sample data are available at dmri.slicer.org. Cancer Res; 77(21); e101–3. ©2017 AACR.

Expression of the urokinase plasminogen activator (uPA) increases during the progression of colorectal tumors from adenomas to carcinomas. The highest amounts of uPA are found at the invasion front of carcinomas, which also displays a strong expression of nuclear β-catenin and is therefore a region expressing β-catenin target genes at high levels. Here we show that β-catenin contributes to the transactivation of uPA. Therefore, β-catenin might have an impact on the capacity of colorectal tumors for invasion and metastasis, as well as dormancy, which are hallmarks of cancer.

Video 2. This video shows visualization of multi-fiber diffusion MRI tractography for a neurosurgical patient with a left insular glioblastoma.

Materials and Methods, 6 Tables, and 1 Figure

Video 1. This video demonstrates the installation, one-click download of sample data, and basic usage of SlicerDMRI.

Most MWD systems use Mud Pulse (MP) or Electro Magnetic (EM) telemetry. Each telemetry system has very specific applications and limitations due to the governing physics. The Hybrid-Mode Telemetry of MP and EM in one system widens the operational envelope and increases drilling performance covered by a single BHA. This paper discusses the applications and benefits of Hybrid-Mode Telemetry with proven field deployments for both conventional and unconventional drilling.The Hybrid-Mode Telemetry system is designed to operate with either the EM or MP channel, or to use both channels simultaneously and independently. The latter case also supports the parallel transmission of two different data streams. With this flexibility, Hybrid-Mode Telemetry can increase drilling performance significantly through reducing survey time, reducing downlinking time, and increase reliability by having two telemetry channels serving as back up for each other. Furthermore, with a maximum system bandwidth capability of up to 20 bits per second and zero downtime on transmission, the Hybrid-Mode Telemetry technology also enhances data rate for Formation Evaluation, Geosteering, and Automation drilling.Hybrid-Mode Telemetry allows for the EM channel to transmit up to 16 bps, and the Mud Pulser channel up to 3.6 bps. With high data rates of 20 bps, high signal strength, and advanced algorithms capable of reliably decoding signals as low as 0.01 mV (10 times more sensitive than typical industry capabilities of 0.1-0.2mV), the Hybrid-mode Telemetry provides superior data and decoding capabilities for today's land-based drilling markets.Hybrid-Mode Telemetry has been successfully used in conventional wells for more than 10 million feet drilled, mainly in onshore North America and Canada. In comparison with legacy Mud Pulse in the same areas, Hybrid-Mode Telemetry showed on average a 37% reduction in drilling time with Motor BHAs. The drilling time reduction is mainly driven by higher data rate, reduction in stationary survey time, and higher reliability of the entire system – up to 99% operating efficiency. This allowed for optimization of drilling parameters and improved decision-making processes.Field testing of Hybrid-Mode Telemetry with Rotary Steerable BHAs is currently ongoing for unconventional drilling applications at deeper drilling depths, involving more complex well profiles and faster drilling rates compared to Motor drilling wells. While sufficient data for evaluation and conclusion is still to be gathered, the Hybrid-Mode Telemetry is expected to contribute to a gross ROP increase by 15-30%.This paper will present, in detail, techniques observed from field data on how to maximize drilling efficiencies through survey time reduction, flow independent downlinking, and optimized telemetry configurations that increase data rate while drilling. In addition, the paper will also describe drilling applications using Hybrid-Mode Telemetry.

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies.MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L.Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol+loperamide [CL] 21%, DE2 27%; budesonide+loperamide [BL] 28%; loperamide [L] 31%; colestipol+loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed.ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective.ClinicaltrialsGov registration numberNCT02400476.

Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer and is associated with poor prognosis. In platinum-refractory or -resistant SCLC patients, few treatment options are available. Topotecan is one of the standards of care for these patients, however, due to its high toxicity, several different approaches are employed. FOLFIRI (folinate, 5-fluorouracil and irinotecan) is a chemotherapy regimen used in digestive neuroendocrine carcinoma, which shares pathological similarities with SCLC. In this retrospective study, we evaluated the efficacy and safety of FOLFIRI in patients with platinum-resistant/refractory SCLC. Medical records from all consecutive SCLC patients treated with FOLFIRI in a French University Hospital from 2013 to 2021 were analyzed retrospectively. The primary endpoint was the objective response rate according to RECIST v1.1 or EORTC criteria (ORR); secondary endpoints included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS) and safety profile. Thirty-four patients with metastatic platinum-resistant (n = 14) or -refractory (n = 20) SCLC were included. Twenty-eight were evaluable for response, with a partial response observed in 5 patients for an overall ORR in the evaluable population of 17.9% (5/28) and 14.7% (5/34) in the overall population. The disease control rate was 50% (14/28) in the evaluable population. The median PFS and OS were 2.8 months (95%CI, 2.0–5.2 months) and 5.3 months (95%CI, 3.5–8.9 months), respectively. All patients were included in the safety analysis. Grade 3 or 4 adverse events occurred in 13 (38.2%) patients. The most common grade 3 or 4 adverse events were asthenia, neutropenia, thrombopenia and diarrhea. There was no adverse event leading to discontinuation or death. FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response and had an acceptable safety profile. However, caution is needed in interpreting this result. FOLFIRI could represent a potential new treatment for platinum-resistant/refractory SCLC patients. Further prospective studies are needed to assess the benefits of this chemotherapy regimen.HIGHLIGHTSFOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response.FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients.FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed. FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response. FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients. FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed.

The large ring laser array ROMY (ROtational Motions in seismologY) consists of four Sagnac inferferometers, each representingan individual, high-sensitive rotation rate sensor, joined as a tetrahedral, heterolithic structure,due to its triangular rings of 12 meter side length.This size and the heterolithic construction introduces new challenges in the operation and monitoring of a large ring laser. Currently high performing ring lasers, such as G-ring, are individual, monolithic large ring lasers, that are less affected by mechanical instability, however, suffer from orientation changes that contribute to the variation in Sagnac frequency. Exploiting the full potential of a large ring laser such as ROMY would enable to observe rotational ground motions close to the rotational low noise model. We discuss required steps towards a stable and enhanced performance of the hetherolicitc ring laser array ROMY, especially for seismology and present implemented tilt and environmental monitoring as well as the influence of the signal processing chain on the obtained signals., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

In this article, the variety of experiences of Natal Afrikaner women as British subjects who were related by blood and culture to the Boers of the Republics of the Transvaal and the Orange Free State, with which the British Empire was at war with, are analysed. This is done in a blended, thematic, and chronological manner. Drawing on primary and secondary sources, the encounters of Natal Afrikaner women with the Boer commandos, the British Army, the Natal colonial authorities as well as other wartime encounters are scrutinised. For the period of the South African War from 1899-1902, as per social history, this paper attempts to give an authentic voice to Natal Afrikaner women in what is a gendered history. In so doing, the article contributes to the neglected historiography of the unique war experiences of Afrikaner women. More specifically, the difficult relationships of Natal Afrikaner women with both the invading Boer commandos and the British Army as well as the Natal colonial authorities are laid bare. At the same time, economic and other hardships, removals, imprisonment in concentration camps, and general physiological and physical hardships are investigated. The end result was an alienation of Natal Afrikaner women from the Natal authorities and a drift towards an emerging post-war Afrikaner Nationalism.

Introduction Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methods The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. Results RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2–43.6) best response rate and 89.4% (83.5–93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3–17.4; CP:11.9, 95% CI 7.5–15.6) months (HR 0.79, 0.49–1.27). 6m-SuT rates were similar (IP:80% 66.0–88.7%; CP:78% 63.8–87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8–7.8; CP: 9.2 7.3–11.1) months (HR 1.36, 0.88–2.12). Pazopanib-related adverse events grade 3–4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. Conclusions Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov , number NCT01813136 .

DNA nanotechnology allows for the fabrication of nano-meter-sized objects with high precision and selective addressability as a result of the programmable hybridization of complementary DNA strands. Such structures can template the formation of other materials, including metals and complex silica nanostructures, where the silica shell simultaneously acts to protect the DNA from external detrimental factors. However, the formation of silica nanostructures with site-specific addressability has thus far not been explored. Here we show that silica nanostructures templated by DNA origami remain addressable for post silicification modification with guest molecules even if the silica shell measures several nm in thickness. We used the conjugation of fluorescently labelled oligonucleotides to different silicified DNA origami structures carrying a complementary ssDNA handle as well as DNA PAINT super-resolution imaging to show that ssDNA handles remain unsilicified and thus ensure retained addressability. We also demonstrate that not only handles, but also ssDNA scaffold segments within a DNA origami nanostructure remain accessible, allowing for the formation of dynamic silica nanostructures. Finally we demonstrate the power of this approach by forming 3D DNA origami crystals from silicified monomers. Our results thus present a fully site-specifically addressable silica nanostructure with complete control over size and shape.

Background Women carrying BRCA1/2 pathogenic variants are exposed to elevated risks of developing breast cancer (BC) and are faced by a complex decision-making process on preventative measures, i.e., risk-reducing mastectomy (RRM), and intensified breast surveillance (IBS). In this prospective cohort study we investigated the effect of anxiety, personality factors and coping styles on the decision-making process on risk management options in women with pathogenic variants in BRCA1/2. Methods Breast cancer unaffected and affected women with a pathogenic variant in the BRCA1 or BRCA2 gene were psychologically evaluated immediately before (T0), 6 to 8 weeks (T1) and 6 to 8 months (T2) after the disclosure of their genetic test results. Uptake of RRM and IBS was assessed at T2. Psychological data were gathered using questionnaires on risk perception, personality factors, coping styles, decisional conflict, depression and anxiety, including the Hospital Anxiety and Depression Scale (HADS). We performed tests on statistical significance and fitted a logistic regression based on significance level. Results A total of 98 women were included in the analysis. Baseline anxiety levels in women opting for RRM were high but decreased over time, while they increased in women opting for intensified breast surveillance (IBS). Elevated levels of anxiety after genetic test result disclosure (T1) were associated with the decision to undergo RRM (p Conclusions Considering psychosocial factors influencing the decision-making process of women with pathogenic variants in BRCA1/2 may help improving their genetic and psychological counselling. When opting for IBS they may profit from additional medical and psychological counselling. Trial registration Retrospectively registered at the German Clinical Trials Register under DRKS00027566 on January 13, 2022.