Search

Abstract Tackling climate change requires both systemic changes and individual lifestyle changes. Are those best placed to understand the risks and solutions to climate change acting on their knowledge? In a large-scale study of N = 9220 researchers across 115 countries, we found that climate researchers reported engaging in considerably more advocacy and activism on climate change and, to a lesser extent, high-impact lifestyle changes than non-climate researchers.

Abstract Background The intestinal microbiota plays a significant role in maintaining systemic and intestinal homeostasis, but can also influence diseases such as inflammatory bowel disease (IBD) and cancer. Certain bacterial species within the intestinal tract can chronically activate the immune system, leading to low-grade intestinal inflammation. As a result, plasma cells produce high levels of secretory antigen-specific immunoglobulin A (IgA), which coats the immunostimulatory bacteria. This IgA immune response against intestinal bacteria may be associated with the maintenance of homeostasis and health, as well as disease. Unraveling this dichotomy and identifying the immunostimulatory bacteria is crucial for understanding the relationship between the intestinal microbiota and the immune system, and their role in health and disease. IgA-SEQ technology has successfully identified immunostimulatory, IgA-coated bacteria from fecal material. However, the original technology is time-consuming and has limited downstream applications. In this study, we aimed to develop a next-generation, high-throughput, magnet-based sorting approach (ng-IgA-SEQ) to overcome the limitations of the original IgA-SEQ protocol. Results We show, in various settings of complexity ranging from simple bacterial mixtures to human fecal samples, that our magnetic 96-well plate-based ng-IgA-SEQ protocol is highly efficient at sorting and identifying IgA-coated bacteria in a high-throughput and time efficient manner. Furthermore, we performed a comparative analysis between different IgA-SEQ protocols, highlighting that the original FACS-based IgA-SEQ approach overlooks certain nuances of IgA-coated bacteria, due to the low yield of sorted bacteria. Additionally, magnetic-based ng-IgA-SEQ allows for novel downstream applications. Firstly, as a proof-of-concept, we performed metagenomic shotgun sequencing on 10 human fecal samples to identify IgA-coated bacterial strains and associated pathways and CAZymes. Secondly, we successfully isolated and cultured IgA-coated bacteria by performing the isolation protocol under anaerobic conditions. Conclusions Our magnetic 96-well plate-based high-throughput next-generation IgA-SEQ technology efficiently identifies a great number of IgA-coated bacteria from fecal samples. This paves the way for analyzing large cohorts as well as novel downstream applications, including shotgun metagenomic sequencing, culturomics, and various functional assays. These downstream applications are essential to unravel the role of immunostimulatory bacteria in health and disease. Video Abstract

Abstract We present a next-to-leading-order (NLO) study of the process pp (→ {h 1, h 2}) → t t ¯ $$ t\overline{t} $$ + X in the 1-Higgs-singlet extension of the Standard Model with an additional heavy Higgs boson h 2 that mixes with the light Higgs boson h 1. This process is subject to large interference effects between loop-induced Higgs-mediated amplitudes and the QCD continuum background which tend to overcompensate any resonance contributions. A reliable modelling of the resulting top-pair invariant mass shapes requires the inclusion of higher-order QCD corrections, which are presented here. The computation of these NLO corrections is exact in all contributions but in the class of non-factorisable two-loop diagrams which are included in an approximate way such that all infrared singular limits are preserved. We present numerical results for several benchmark points with heavy Higgs masses in the range 700–3000 GeV considering the production of stable top quarks. We find that the interference effects dominate the BSM signal yielding sharp dip structures instead of resonance peaks. The significance and excludability of the BSM effect is explored for the LHC Run 2, Run 3 and HL-LHC.

Abstract Objectives To generate pseudo-CT (pCT) images of the pelvis from zero echo time (ZTE) MR sequences and compare them to conventional CT. Methods Ninety-one patients were prospectively scanned with CT and MRI including ZTE sequences of the pelvis. Eleven ZTE image volumes were excluded due to implants and severe B1 field inhomogeneity. Out of the 80 data sets, 60 were used to train and update a deep learning (DL) model for pCT image synthesis from ZTE sequences while the remaining 20 cases were selected as an evaluation cohort. CT and pCT images were assessed qualitatively and quantitatively by two readers. Results Mean pCT ratings of qualitative parameters were good to perfect (2–3 on a 4-point scale). Overall intermodality agreement between CT and pCT was good (ICC = 0.88 (95% CI: 0.85–0.90); p 0.05) with the exception of transverse pelvic diameter measurements and lateral center-edge angle measurements (p = 0.001 and p = 0.002, respectively). Image quality and tissue differentiation in CT and pCT were similar without significant differences between CT and pCT CNRs (all p > 0.05). Conclusions Using a DL-based algorithm, it is possible to synthesize pCT images of the pelvis from ZTE sequences. The pCT images showed high bone depiction quality and accurate geometrical measurements compared to conventional CT. Critical relevance statement pCT images generated from MR sequences allow for high accuracy in evaluating bone without the need for radiation exposure. Radiological applications are broad and include assessment of inflammatory and degenerative bone disease or preoperative planning studies. Key Points pCT, based on DL-reconstructed ZTE MR images, may be comparable with true CT images. Overall, the intermodality agreement between CT and pCT was good with excellent interreader agreements for pCT. Geometrical measurements and tissue differentiation were similar in CT and pCT images. Graphical Abstract

ABSTRACT Legionella pneumophila serogroup 1 sequence types (ST) 213 and 222, a single-locus variant of ST213, were first detected in the early 1990s in the Midwest United States (U.S.) and the late 1990s in the Northeast U.S. and Canada. Since 1992, these STs have increasingly been implicated in community-acquired sporadic and outbreak-associated Legionnaires’ disease (LD) cases. We were interested in understanding the change in LD frequency due to these STs and identifying genetic features that differentiate these STs from one another. For the geographic area examined here (Mountain West to Northeast) and over the study period (1992–2020), ST213/222-associated LD cases identified by the Centers for Disease Control and Prevention increased by 0.15 cases per year, with ST213/222-associated LD cases concentrated in four states: Michigan (26%), New York (18%), Minnesota (16%), and Ohio (10%). Additionally, between 2002 and 2021, ST222 caused at least five LD outbreaks in the U.S.; no known outbreaks due to ST213 occurred in the U.S. during this time. We compared the genomes of 230 ST213/222 isolates and found that the mean of the average nucleotide identity (ANI) within each ST was high (99.92% for ST222 and 99.92% for ST213), with a minimum between ST ANI of 99.50% and a maximum of 99.87%, indicating low genetic diversity within and between these STs. While genomic features were identified (e.g., plasmids and CRISPR-Cas systems), no association explained the increasing geographic distribution and prevalence of ST213 and ST222. Yet, we provide evidence of the expanded geographical distribution of ST213 and ST222 in the U.S.IMPORTANCESince the 1990s, cases of Legionnaires’ disease (LD) attributed to a pair of closely related Legionella pneumophila variants, ST213 and ST222, have increased in the U.S. Furthermore, between 2002 and 2021, ST222 caused at least five outbreaks of LD in the U.S., while ST213 has not been linked to any U.S. outbreak. We wanted to understand how the rate of LD cases attributed to these variants has changed over time and compare the genetic features of the two variants. Between 1992 and 2020, we determined an increase of 0.15 LD cases ascribed to ST213/222 per year in the geographic region studied. Our research shows that these STs are spreading within the U.S., yet most of the cases occurred in four states: Michigan, New York, Minnesota, and Ohio. Additionally, we found little genetic diversity within and between these STs nor could specific genetic features explain their geographic spread.

Prostate cancer with a cribriform pattern, including invasive cribriform carcinoma (ICC) and/or intraductal carcinoma (IDC) is associated with a poor prognosis, and the underlying mechanisms are unclear. Therefore, we aimed to identify biomarkers for this feature. Using a radical prostatectomy cohort, we performed within-patient differential expression analyses with RNA sequencing data to compare samples with a cribriform pattern to those with non-cribriform Gleason pattern 4 (NcGP4; n=13). ACSM1, GRIN3A, PCDHB2, and REG4 were identified as differentially expressed, and validation was performed using real-time reverse transcription polymerase chain reaction (n=99; 321 RNA samples) and RNA in situ hybridization on tissue microarrays (n=479; 2047 tissue cores). GRIN3A was significantly higher expressed in cribriform pattern vs. NcGP4, when assessed within the same patient (n=27; p=0.005) and between different patients (n=83; p=0.001). Tissue cores with IDC more often expressed GRIN3A compared to ICC, NcGP4, and benign tissue (52 % vs. ≤ 32 %). When IDC and NcGP4 was compared within the same patient (173 pairs of tissue cores; 54 patients), 38 (22 %) of the tissue microarray core pairs had GRIN3A expression in only IDC, 33 (19 %) had expression in both IDC and NcGP4, 14 (8 %) in only NcGP4 and 88 (51 %) were negative in both entities (p=0.001). GRIN3A was as well associated with biochemical recurrence (log-rank, p=0.002). In conclusion, ectopic GRIN3A expression is an RNA-based biomarker for the presence of cribriform prostate cancer, particularly for IDC.

Summary: Neutrophil-derived bactericidal/permeability-increasing protein (BPI) is known for its bactericidal activity against gram-negative bacteria and neutralization of lipopolysaccharide. Here, we define BPI as a potent activator of murine dendritic cells (DCs). As shown in GM-CSF-cultured, bone-marrow-derived cells (BMDCs), BPI induces a distinct stimulation profile including IL-2, IL-6, and tumor necrosis factor expression. Conventional DCs also respond to BPI, while M-CSF-cultivated or peritoneal lavage macrophages do not. Subsequent to BPI stimulation of BMDCs, CD4+ T cells predominantly secrete IL-22 and, when naive, preferentially differentiate into T helper 22 (Th22) cells. Congruent with the tissue-protective properties of IL-22 and along with impaired IL-22 induction, disease severity is significantly increased during dextran sodium sulfate-induced colitis in BPI-deficient mice. Importantly, physiological diversification of intestinal microbiota fosters BPI-dependent IL-22 induction in CD4+ T cells derived from mesenteric lymph nodes. In conclusion, BPI is a potent activator of DCs and consecutive Th22 cell differentiation with substantial relevance in intestinal homeostasis.

Abstract The increasingly high accuracy of top-quark studies at the LHC calls for a theoretical description of t t ¯ $$ t\overline{t} $$ production and decay in terms of exact matrix elements for the full 2 → 6 process that includes the off-shell production and the chain decays of t t ¯ $$ t\overline{t} $$ and tW intermediate states, together with their quantum interference. Corresponding NLO QCD calculations matched to parton showers are available for the case of dileptonic channels and are implemented in the bb4l Monte Carlo generator, which is based on the resonance-aware POWHEG method. In this paper, we present the first NLOPS predictions of this kind for the case of semileptonic channels. In this context, the interplay of off-shell t t ¯ $$ t\overline{t} $$ + tW production with various other QCD and electroweak subprocesses that yield the same semileptonic final state is discussed in detail. On the technical side, we improve the resonance-aware POWHEG procedure by means of new resonance histories based on matrix elements, which enable a realistic separation of t t ¯ $$ t\overline{t} $$ and tW contributions. Moreover, we introduce a general approach which makes it possible to avoid certain spurious terms that arise from the perturbative expansion of decay widths in any off-shell higher-order calculation, and which are large enough to jeopardise physical finite-width effects. These methods are implemented in a new version of the bb4l Monte Carlo generator, which is applicable to all dileptonic and semileptonic channels, and can be extended to fully hadronic channels. The presented results include a NLOPS comparison of off-shell against on-shell t t ¯ $$ t\overline{t} $$ + tW production and decay, where we highlight various non-trivial aspects related to NLO and parton-shower radiation in leptonic and hadronic top decays.

Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation.

E-mental health interventions may offer innovative means to increase access to psychological support and improve the mental health of refugees. However, there is limited knowledge about how these innovations can be scaled up and integrated sustainably into routine services. This study examined the scalability of a digital psychological intervention called Step-by-Step (SbS) for refugees in Egypt, Germany, and Sweden. We conducted semi-structured interviews (n = 88) with Syrian refugees, and experts in SbS or refugee' mental health systems in the three countries. Data collection and analysis were guided by a system innovation perspective. Interviewees identified three contextual factors that influenced scalability of SbS in each country: increasing use of e-health, the COVID-19 pandemic, and political instability. Nine factors lay at the interface between the innovation and potential delivery systems, and these were categorised by culture (ways of thinking), structure (ways of organising), and practice (ways of doing). Factors related to culture included: perceived need and acceptability of the innovation. Acceptability was influenced by mental health stigma and awareness, digital trust, perceived novelty of self-help interventions, and attitudes towards non-specialist (e-helper) support. Factors related to structure included financing, regulations, accessibility, competencies of e-helpers, and quality control. Factors related to practice were barriers in the initial and continued engagement of end-users. Many actors with a potential stake in the integration of SbS across the three countries were identified, with nineteen stakeholders deemed most powerful. Several context-specific integration scenarios were developed, which need to be tested. We conclude that integrating novel e-mental health interventions for refugees into routine services will be a complex task due to the many interrelated factors and actors involved. Multi-stakeholder collaboration, including the involvement of end-users, will be essential.

The effective reproductive number Rt has taken a central role in the scientific, political, and public discussion during the COVID-19 pandemic, with numerous real-time estimates of this quantity routinely published. Disagreement between estimates can be substantial and may lead to confusion among decision-makers and the general public. In this work, we compare different estimates of the national-level effective reproductive number of COVID-19 in Germany in 2020 and 2021. We consider the agreement between estimates from the same method but published at different time points (within-method agreement) as well as retrospective agreement across eight different approaches (between-method agreement). Concerning the former, estimates from some methods are very stable over time and hardly subject to revisions, while others display considerable fluctuations. To evaluate between-method agreement, we reproduce the estimates generated by different groups using a variety of statistical approaches, standardizing analytical choices to assess how they contribute to the observed disagreement. These analytical choices include the data source, data pre-processing, assumed generation time distribution, statistical tuning parameters, and various delay distributions. We find that in practice, these auxiliary choices in the estimation of Rt may affect results at least as strongly as the selection of the statistical approach. They should thus be communicated transparently along with the estimates.

Abstract In the present study, an epoxy compound, 1,2‐epoxy‐6‐methyl‐triglycidyl‐3,4,5‐cyclohexanetricarboxylate (EGCHC) synthesized from sorbic acid, maleic anhydride, and allyl alcohol is proposed. Using commodity chemicals, a bio‐based carbon content of 68.4 % for the EGCHC resin is achieved. When cured with amine hardeners, the high oxirane content of EGCHC forms stiff cross‐linked networks with strong mechanical and thermal properties. The characterization of the epoxy specimens showed that EGCHC can compete with conventional epoxy resins such as DGEBA. A maximum stiffness of 3965 MPa, tensile strength of 76 MPa, and Tg of 130 °C can be obtained by curing EGCHC with isophorone diamine (IPD). The cured resin showed to be decomposable under mild conditions due to the ester bonds. The solid material properties of EGCHC expose its potential as a promising bisphenol A, and epichlorohydrine free alternative to conventional petroleum‐based epoxies with an overall high bio‐based carbon content.

Comparing the capabilities of different quantum machine learning protocols is difficult. Here, the authors show that different learning models based on parametrized quantum circuits can all be seen as quantum linear models, thus driving general conclusions on their resource requirements and capabilities.

Abstract We consider W ± Z production in hadronic collisions and present high-precision predictions in QCD and electroweak (EW) perturbation theory matched to parton showers. To this end, we match next-to-next-to-leading order QCD corrections to parton showers using the MiNNLOPS method and consistently combine them with next-to-leading order EW corrections matched to parton showers. This is the first time such accuracy in the event generation is achieved for any collider process, and we study in detail the impact of different choices in the combination of QCD and EW corrections as well as QCD and QED showers. Spin correlations, interferences and off-shell effects are retained by considering the full leptonic processes pp → ℓ + ℓ − ℓ ′ ± ν ℓ ′ $$ pp\to {\ell}^{+}{\ell}^{-}{\ell}^{\prime \pm }{\nu}_{\ell}^{\prime } $$ with ℓ ′ ≠ ℓ and ℓ ′ = ℓ without approximations, and the matching to QED radiation is performed preserving the resonance structure of the process. We find that NNLO QCD predictions including QCD and QED shower effects provide a very good approximation in the bulk-region of the phase space, while EW effects become increasingly important in the high-energy tails of kinematic distributions. Our default predictions are in excellent agreement with recent ATLAS data.

This paper presents a new approach to monitoring ultrasonic systems using structurally integrated piezoceramics. These are integrated into the sonotrode at different points and with different orientations. The procedure for integrating the piezoceramics into the sonotrode and their performance is experimentally investigated. We examine whether the measured signal can be used to determine the optimal operating frequency of the ultrasonic system, if integrating several piezoceramics enables discernment of the current vibration shape, and if the piezoceramics can withstand the high strains caused by the vibrations in a frequency range of approximately 20–25 kHz. The signals from the piezoceramic sensors are compared to the real-time displacement at different points of the sonotrode using a 3D laser scanning vibrometer. To evaluate the performance of the sensors, different kinds of excitation of the ultrasonic system are chosen.

The supercurrent diode effect was recently observed in a Nb/V/Ta superlattice thin film with Rashba-type spin-orbit coupling. Here, the authors observe this effect in few-layer NbSe2 crystals driven by valley-Zeeman-type spin-orbit coupling and find that the effect is proportional to out-of-plane magnetic field.

Abstract Background For effective prevention of nosocomial transmissions continuous training and motivation of health care workers (HCW) are essential to maintain and increase compliance with high rates of hand hygiene. The use of Virtual Reality (VR) seems to be a contemporary and interesting approach for hand hygiene training in HCW. Nevertheless, HCW should be asked for their preferences as intrinsic motivation is essential for compliance with hand hygiene and training success should be evaluated. Methods A prospective, cross-controlled trial was conducted at two wards in a tertiary care hospital comparing a conventional lecture for hand hygiene to the use of VR. Both interventions were assigned at ward level. Primary outcome was HCW acceptance, which was verified in a third ward, secondary outcomes were hand rub consumption and compliance to indications for hand hygiene as proposed by WHO. Results In summary, 81 trainings were conducted, 48 VR trainings and 33 trainings by lecture. VR training was well accepted by HCW with a mean score in all items from 3.9 to 4.3 (out of 5). While most HCW (69%) would prefer VR teaching rather than a lecture for hand hygiene education, only 4% preferred the traditional lecture. 400 observations of hand hygiene indications were made, 50 before intervention and 50 after each intervention at the three wards. Mean proportion of correct and indication-appropriate performances was 81% before intervention, 87% after VR training (p = 0.12), and 95% after lecture (p = 0.04). Hand rub consumption did not change significantly in any group. Conclusions Due to the high acceptance of VR technology among healthcare workers, it can be considered an interesting addition to conventional lectures for teaching hand hygiene. However, the hypothesis that VR teaching has a higher impact on hand rub use and hand hygiene compliance than a conventional lecture cannot be confirmed.

Abstract Background To examine the pathological effect of a mesial temporal seizure onset zone (SOZ) on local and inter-regional response to faces in the amygdala and other structures of the temporal lobe. Methods Intracranial EEG data was obtained from the amygdala, hippocampus, fusiform gyrus and parahippocampal gyrus of nine patients with drug-refractory epilepsy during visual stimulation with faces and mosaics. We analyzed event-related potentials (ERP), gamma frequency power, phase-amplitude coupling and phase-slope-index and compared the results between patients with versus without a mesial temporal SOZ. Results In the amygdala and fusiform gyrus, faces triggered higher ERP amplitudes compared to mosaics in both patient groups and higher gamma power in patients without a mesial temporal SOZ. In the hippocampus, famous faces triggered higher gamma power for both groups combined but did not affect ERPs in either group. The differentiated ERP response to famous faces in the parahippocampal gyrus was more pronounced in patients without a mesial temporal SOZ. Phase-amplitude coupling and phase-slope-index results yielded bidirectional modulation between amygdala and fusiform gyrus, and predominately unidirectional modulation between parahippocampal gyrus and hippocampus. Conclusions A mesial temporal SOZ was associated with an impaired response to faces in the amygdala, fusiform gyrus and parahippocampal gyrus in our patients. Compared to this, the response to faces in the hippocampus was impaired in patients with, as well as without, a mesial temporal SOZ. Our results support existing evidence for face processing deficits in patients with a mesial temporal SOZ and suggest the pathological effect of a mesial temporal SOZ on the amygdala to play a pivotal role in this matter in particular.

Ceramides (CERs) are key intermediate sphingolipids implicated in contributing to mitochondrial dysfunction and the development of multiple metabolic conditions. Despite the growing evidence of CER role in disease risk, kinetic methods to measure CER turnover are lacking, particularly using in vivo models. The utility of orally administered 13C3, 15N l-serine, dissolved in drinking water, was tested to quantify CER 18:1/16:0 synthesis in 10-week-old male and female C57Bl/6 mice. To generate isotopic labeling curves, animals consumed either a control diet or high-fat diet (HFD; n = 24/diet) for 2 weeks and varied in the duration of the consumption of serine-labeled water (0, 1, 2, 4, 7, or 12 days; n = 4 animals/day/diet). Unlabeled and labeled hepatic and mitochondrial CERs were quantified using liquid chromatography tandem MS. Total hepatic CER content did not differ between the two diet groups, whereas total mitochondrial CERs increased with HFD feeding (60%, P < 0.001). Within hepatic and mitochondrial pools, HFD induced greater saturated CER concentrations (P < 0.05) and significantly elevated absolute turnover of 16:0 mitochondrial CER (mitochondria: 59%, P < 0.001 vs. liver: 15%, P = 0.256). The data suggest cellular redistribution of CERs because of the HFD. These data demonstrate that a 2-week HFD alters the turnover and content of mitochondrial CERs. Given the growing data on CERs contributing to hepatic mitochondrial dysfunction and the progression of multiple metabolic diseases, this method may now be used to investigate how CER turnover is altered in these conditions.

Abstract Controlling the wettability using microstructures has been studied because of many applications. In particular, bio‐mimetic microstructures modeled after the self‐cleaning properties of the lotus leaf have been extensively studied. Despite many studies successfully achieving the fabrication of superhydrophobic to superhydrophilic surfaces through the manipulation of microstructures, the effect of rough surfaces on contact angle remains an area of inquiry. In this study, conical microstructures with well‐defined geometric parameters are fabricated over a silicon wafer. They are replicated into soft matter that has transparent and flexible characteristics. From the measurement of the contact angle for fabricated surfaces, the prediction of the criteria for transitioning from the Cassie‐Baxter state to the Wenzel state can be suggested. Furthermore, the fabrication of an inexpensive, transparent, elastic, and superhydrophobic surface based on truncated micro‐conical structures in PDMS can be suggested.

Nucleosynthetic isotope anomalies in meteorites allow distinguishing between the noncarbonaceous (NC) and carbonaceous (CC) meteorite reservoirs and show that correlated isotope anomalies exist in both reservoirs. It is debated, however, whether these anomalies reflect thermal processing of presolar dust in the disk or are primordial heterogeneities inherited from the solar system’s parental molecular cloud. Here, using new high-precision ^84 Sr isotope data, we show that NC meteorites, Mars, and the Earth and Moon are characterized by the same ^84 Sr isotopic composition. This ^84 Sr homogeneity of the inner solar system contrasts with the well-resolved and correlated isotope anomalies among NC meteorites observed for other elements, and most likely reflects correlated s - and ( r , p )-process heterogeneities leading to ^84 Sr excesses and deficits of similar magnitude, which cancel each other out. For the same reason there is no clearly resolved ^84 Sr difference between NC and CC meteorites, because in some carbonaceous chondrites the characteristic ^84 Sr excess of the CC reservoir is counterbalanced by an ^84 Sr deficit resulting from s -process variations. Nevertheless, most carbonaceous chondrites exhibit ^84 Sr excesses, which reflect admixture of refractory inclusions and more pronounced s -process heterogeneities in these samples. Together, the correlated variation of s - and ( r , p )-process nuclides revealed by the ^84 Sr data of this study refute an origin of these isotope anomalies solely by processing of presolar dust grains, but points to primordial mixing of isotopically distinct dust reservoirs as the dominant process producing the isotopic heterogeneity of the solar system.

Carbonaceous chondrites are some of the most primitive meteorites and derive from planetesimals that formed a few million years after the beginning of the solar system. Here, using new and previously published Cr, Ti, and Te isotopic data, we show that carbonaceous chondrites exhibit correlated isotopic variations that can be accounted for by mixing among three major constituents having distinct isotopic compositions, namely refractory inclusions, chondrules, and CI chondrite-like matrix. The abundances of refractory inclusions and chondrules are coupled and systematically decrease with increasing amount of matrix. We propose that these correlated abundance variations reflect trapping of chondrule precursors, including refractory inclusions, in a pressure maximum in the disk, which is likely related to the water ice line and the ultimate formation location of Jupiter. The variable abundance of refractory inclusions/chondrules relative to matrix is the result of their distinct aerodynamical properties resulting in differential delivery rates and their preferential incorporation into chondrite parent bodies during the streaming instability, consistent with the early formation of matrix-poor and the later accretion of matrix-rich carbonaceous chondrites. Our results suggest that chondrules formed locally from isotopically heterogeneous dust aggregates, which themselves derive from a wide area of the disk, implying that dust enrichment in a pressure trap was an important step to facilitate the accretion of carbonaceous chondrite parent bodies or, more generally, planetesimals in the outer solar system.

IntroductionRecent advances hold promise of making personalized medicine a step closer to implementation in clinical settings. However, traditional sample preparation methods are not robust and reproducible. In this study, the TissueGrinder, a novel mechanical semi-automated benchtop device, which can isolate cells from tissue in a very fast and enzyme-free way is tested for cell isolation from surgically resected tumor tissues.MethodsThirty-three surgically resected tumor tissues from various but mainly pancreatic, liver or colorectal origins were processed by both novel TissueGrinder and explant method. An optimized processing program for tumors from pancreatic, liver or colorectal cancer was developed. The viability and morphological characteristics of the isolated cells were evaluated microscopically. Expression of pancreatic cancer markers was evaluated in cells isolated from pancreatic tumors. Finally, the effect of mechanical stress on the cells was evaluated by assessing apoptosis markers via western blotting.ResultsTissueGinder was more efficient in isolating cells from tumor tissue with a success rate of 75% when compared to explant method 45% in terms of cell outgrowth six weeks after processing. Cells isolated with TissueGinder had a higher abundance and were more heterogeneous in composition as compared to explant method. Mechanical processing of the cells with TissueGrinder does not lead to apoptosis but causes slight stress to the cells.DiscussionOur results show that TissueGrinder can process solid tumor tissues more rapidly and efficiently and with higher success rate compared to the conventionally used explant method. The results of the study suggest that the TissueGrinder might be a suitable method for obtaining cells, which is important for its application in individualized therapy. Due to the great variance in different tumor entities and the associated individual tissue characteristics, a further development of the dissociation protocol for other types of tumors and normal tissue will be targeted.

Objective Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship.Methods Five sites in Bangladesh, India and Pakistan enrolled mother–child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0–59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant’s infection in the ANISA study. The collected risk factors from all mother–child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection.Results Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99).Conclusion Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

Abstract We present a calculation of the next-to-leading order (NLO) QCD corrections to gluon-induced electroweak gauge boson pair production, $$gg \rightarrow ZZ$$ g g → Z Z and $$gg \rightarrow W^+W^-$$ g g → W + W - , matched to the PYTHIA 8 parton shower in the POWHEG approach. The calculation consistently incorporates the continuum background, the Higgs-mediated $$gg\rightarrow H^* \rightarrow VV$$ g g → H ∗ → V V process, and their interference. We consider leptonic decay modes of the vector bosons and retain offshell and non-resonant contributions. The processes considered are loop-induced at leading order and thus contain two-loop virtual contributions as well as loop-squared real contributions. Parton-shower effects are found to be marginal in inclusive observables and quite sizeable in observables that are exclusive in additional jet radiation. The Monte Carlo generator presented here allows for realistic experimental effects to be incorporated in state-of-the-art precision analyses of diboson production and of the Higgs boson in the offshell regime.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and the outbreak rapidly evolved into the current coronavirus disease pandemic. SARS-CoV-2 is a respiratory virus that causes symptoms similar to those caused by influenza A and B viruses. On July 2, 2020, the US Food and Drug Administration granted emergency use authorization for in vitro diagnostic use of the Influenza SARS-CoV-2 Multiplex Assay. This assay detects influenza A virus at 102.0, influenza B virus at 102.2, and SARS-CoV-2 at 100.3 50% tissue culture or egg infectious dose, or as few as 5 RNA copies/reaction. The simultaneous detection and differentiation of these 3 major pathogens increases overall testing capacity, conserves resources, identifies co-infections, and enables efficient surveillance of influenza viruses and SARS-CoV-2.

Background/Aims The recommendations on the time interval between pre-cleaning and reprocessing of endoscopes differ in international guidelines, with a low level of evidence. The aim of this study was to investigate the influence of postponing reprocessing on the reprocessing quality after pre-cleaning the flexible endoscopes. Methods We reprocessed 124 standardized test tubes simulating endoscope channels after soiling and contamination and determined the reprocessing performance. In addition, we examined contaminated gastroscopes, colonoscopes, and bronchoscopes. The duration of interim storage after pre-cleaning was 16 h for 100 test tubes and up to 24 h for 18 endoscopes. We determined the residual protein content and germ load as markers for cleaning and disinfection performance. In addition, we determined biofilm formation by photometry of crystal violet staining. Results All test tubes and flexible endoscopes showed residual protein content and germ load significantly below legally prescribed threshold values, independent of the interval between pre-cleaning and reprocessing. Conclusions Our findings indicate that flexible endoscopes could be stored overnight after pre-cleaning without any influence on the quality of reprocessing. While ensuring patient safety, this could simplify logistical processes and enable cost savings.

Here, the authors report on the large twist-angle susceptibility of excitons involving upper conduction bands in transition metal dichalcogenide bilayers. These high-lying excitons couple with band-edge excitons, and give rise to nonlinear quantum-optical processes that become tuneable by twisting.

Abstract Background Lack of sustainable access to clean drinking water continues to be an issue of paramount global importance, leading to millions of preventable deaths annually. Best practices for providing sustainable access to clean drinking water, however, remain unclear. Widespread installation of low-cost, in-home, point of use water filtration systems is a promising strategy. Methods We conducted a prospective, randomized, controlled trial whereby 16 villages were selected and randomly assigned to one of four treatment arms based on the installation location of Sawyer® PointONE™ filters (filter in both home and school; filter in home only; filter in school only; control group). Water samples and self-reported information on diarrhea were collected at multiple times throughout the study. Results Self-reported household prevalence of diarrhea decreased from 25.6 to 9.76% from installation to follow-up (at least 7 days, and up to 200 days post-filter installation). These declines were also observed in diarrhea with economic or educational consequences (diarrhea which led to medical treatment and/or missing school or work) with baseline prevalence of 9.64% declining to 1.57%. Decreases in diarrhea prevalence were observed across age groups. There was no evidence of a loss of efficacy of filters up to 200 days post-filter installation. Installation of filters in schools was not associated with decreases in diarrhea prevalence in school-aged children or family members. Unfiltered water samples both at schools and homes contained potential waterborne bacterial pathogens, dissolved heavy metals and metals associated with particulates. All dissolved metals were detected at levels below World Health Organization action guidelines. Conclusions This controlled trial provides strong evidence of the effectiveness of point-of-use, hollow fiber membrane filters at reducing diarrhea from bacterial sources up to 200 days post-installation when installed in homes. No statistically significant reduction in diarrhea was found when filters were installed in schools. Further research is needed in order to explore filter efficacy and utilization after 200 days post-installation. Trial registration ClinicalTrials.gov, NCT03972618 . Registered 3 June 2019—retrospectively registered.

Abstract A variant in the GBA1 gene is one of the most common genetic risk factors to develop Parkinson’s disease (PD). Here the serendipitous finding is reported of a polymerase dependent allelic imbalance when using next generation sequencing, potentially resulting in false-negative results when the allele frequency falls below the variant calling threshold (by default commonly at 30%). The full GBA1 gene was sequenced using next generation sequencing on saliva derived DNA from PD patients. Four polymerase chain reaction conditions were varied in twelve samples, to investigate the effect on allelic imbalance: (1) the primers (n = 4); (2) the polymerase enzymes (n = 2); (3) the primer annealing temperature (Ta) specified for the used polymerase; and (4) the amount of DNA input. Initially, 1295 samples were sequenced using Q5 High-Fidelity DNA Polymerase. 112 samples (8.6%) had an exonic variant and an additional 104 samples (8.0%) had an exonic variant that did not pass the variant frequency calling threshold of 30%. After changing the polymerase to TaKaRa LA Taq DNA Polymerase Hot-Start Version: RR042B, all samples had an allele frequency passing the calling threshold. Allele frequency was unaffected by a change in primer, annealing temperature or amount of DNA input. Sequencing of the GBA1 gene using next generation sequencing might be susceptible to a polymerase specific allelic imbalance, which can result in a large amount of flase-negative results. This was resolved in our case by changing the polymerase. Regions displaying low variant calling frequencies in GBA1 sequencing output in previous and future studies might warrant additional scrutiny.

Introduction The World Health Organization’s (WHO) scalable psychological interventions, such as Problem Management Plus (PM+) and Step-by-Step (SbS) are designed to be cost-effective non-specialist delivered interventions to reduce symptoms of common mental disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD). The STRENGTHS consortium aims to evaluate the effectiveness, cost-effectiveness and implementation of the individual format of PM+ and its group version (gPM+), as well as of the digital SbS intervention among Syrian refugees in seven countries in Europe and the Middle East. This is a study protocol for a prospective individual participant data (IPD) meta-analysis to evaluate (1) overall effectiveness and cost-effectiveness and (2) treatment moderators of PM+, gPM+ and SbS with Syrian refugees.Methods and analysis Five pilot randomised controlled trials (RCTs) and seven fully powered RCTs conducted within STRENGTHS will be combined into one IPD meta-analytic dataset. The RCTs include Syrian refugees of 18 years and above with elevated psychological distress (Kessler Psychological Distress Scale (K10>15)) and impaired daily functioning (WHO Disability Assessment Schedule 2.0 (WHODAS 2.0>16)). Participants are randomised into the intervention or care as usual control group, and complete follow-up assessments at 1-week, 3-month and 12-month follow-up. Primary outcomes are symptoms of depression and anxiety (25-item Hopkins Symptom Checklist). Secondary outcomes include daily functioning (WHODAS 2.0), PTSD symptoms (PTSD Checklist for DSM-5) and self-identified problems (PSYCHLOPS). We will conduct a one-stage IPD meta-analysis using linear mixed models. Quality of evidence will be assessed using the GRADE approach, and the economic evaluation approach will be assessed using the CHEC-list.Ethics and dissemination Local ethical approval has been obtained for each RCT. This IPD meta-analysis does not require ethical approval. The results of this study will be published in international peer-reviewed journals.

Objectives: This study investigated causes of fever in the primary levels of care in Southeast Asia, and evaluated whether C-reactive protein (CRP) could distinguish bacterial from viral pathogens. Methods: Blood and nasopharyngeal swab specimens were taken from children and adults with fever (>37.5 °C) or history of fever (

We present the R package mgm for the estimation of k-order mixed graphical models (MGMs) and mixed vector autoregressive (mVAR) models in high-dimensional data. These are a useful extensions of graphical models for only one variable type, since data sets consisting of mixed types of variables (continuous, count, categorical) are ubiquitous. In addition, we allow to relax the stationarity assumption of both models by introducing time-varying versions of MGMs and mVAR models based on a kernel weighting approach. Time-varying models offer a rich description of temporally evolving systems and allow to identify external influences on the model structure such as the impact of interventions. We provide the background of all implemented methods and provide fully reproducible examples that illustrate how to use the package.

IntroductionSodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs. Emerging findings from laboratory studies indicate that SGLT2 inhibitors can improve liver function and suppress the proliferation of hepatocellular carcinoma (HCC) cells. The aim of this study was to test the hypothesis that initiation of SGLT2 inhibitors improves HCC prognosis in a human population.MethodsWe used National Surveillance, Epidemiology and End Results (SEER)-Medicare linked data in the United States to evaluate the role of SGLT2 inhibitor initiation on the survival of HCC patients. 3,185 HCC patients newly diagnosed between 2014 and 2017 aged 66 years or older with pre-existing type 2 diabetes were included and followed to the end of 2019. Information on SGLT2 inhibitor initiation was extracted from the Medicare Part D file.ResultsSGLT2 inhibitor initiation was associated with significantly lower mortality risk after adjusting for potential confounders (HR = 0.68, 95% CI = 0.54-0.86) with stronger association for longer duration of use (HR = 0.60, 95% CI = 0.41-0.88). Further, we found that SGLT2 inhibitor initiation was associated with a lower risk mortality risk ranging from 14% to 60% regardless of patient demographic variables, tumor characteristics, and cancer treatments.ConclusionOur large SEER-Medicare linked data study indicates that SGLT2 inhibitor initiation was associated with improved overall survival of HCC patients with pre-existing type 2 diabetes compared with no SGLT2 inhibitor use. Further studies are needed to confirm our findings and elucidate the possible mechanisms behind the association.

Objectives: To assess the impact on bone depiction quality by decreasing number of radial acquisitions (RA) of a UTE MR bone imaging sequence in MRONJ. Material and methods: UTE MR bone imaging sequences using pointwise encoding time reduction with RA (PETRA) with 60’000, 30’000 and 10’000 RA were acquired in 16 patients with MRONJ and 16 healthy volunteers. Blinded readout sessions were performed by two radiologists. Qualitative analysis compared the detection of osteolytic lesions and productive bony changes in the PETRA sequences of the patients with MRONJ. Quantitative analysis assessed the differences in image artifacts, contrast-to-noise ratio (CNR) and image noise. Results: Acquisition times were reduced from 315 to 165 and 65 s (60’000, 30’000, 10’000 RA, respectively), resulting in a fewer number of severe motion artifacts. Bone delineation was increasingly blurred when reducing the number of RA but without any trade-off in terms of diagnostic performance. Interreader agreement for the detection of pathognomonic osteolysis was moderate (κ = 0.538) for 60’000 RA and decreased to fair (κ = 0.227 and κ = 0.390) when comparing 30’000 and 10’000 RA, respectively. Image quality between sequences was comparable regarding CNR, image noise and artifact dimensions without significant differences (all P > 0.05). Conclusions: UTE MR bone imaging sequences with a lower number of RA provide sufficient image quality for detecting osteolytic lesions and productive bony changes in MRONJ subjects at faster acquisition times compared to the respective standard UTE MR bone imaging sequence.

Category: Trauma; Ankle Introduction/Purpose: Several studies discuss the relation between prolonged time to surgery and postoperative complications in ankle fractures, but little is known about how a longer wait affects clinical outcomes. The present study, therefore, aims to assess the association between time from injury to surgery and patient-reported outcomes after operative treatment of severe ankle fractures. Methods: Patients treated operatively for low-energy ankle fractures which also involve the posterior malleolus from 2014 to 2016 were included. Patient charts were reviewed for patient demographics, type of trauma, fracture characteristics, treatment given, and complications. Ankle function was evaluated on a follow-up visit by clinical examination, radiographs and patient- reported outcome measures (SEFAS, RAND-36, VAS of Pain, VAS of Satisfaction). For analyses, patients were stratified based on time from injury to definitive surgery; Group 1: within the same day, Group 2: 1 to 7 days after injury, and Group 3: later than 7 days after injury. Results: Follow-up visits of 130 patients were performed at median 25 (Interquartile range (IQR), 19-34) months after surgery. Patient demographics and fracture characteristics were similar between groups. Median SEFAS was 40 in Group 1 (IQR 33-43), 41 (IQR 33-44) in Group 2, and 33 (IQR 27-42) in Group 3. The difference between Group 1 and 3 (p =.03), and between Group 2 and 3 (p =.04) was statistically significant. Group 1 had the highest rate of mechanical irritation and secondary surgery following malreduced fractures or missing syndesmotic fixation. Patients operated later than seven days from injury reported more pain than those treated earlier (p =.03). Conclusion: Time from injury to final surgery influenced clinical outcomes after these severe ankle fractures. Patients who waited more than seven days until definitive surgery had poorer clinical outcomes and more pain compared to those who had surgery within a week.

The brain has a never-ending internal activity, whose spatiotemporal evolution interacts with external inputs to constrain their impact on brain activity and thereby how we perceive them. We used reproducible touch-related spatiotemporal sensory inputs and recorded intracellularly from rat (Sprague-Dawley, male) neocortical neurons to characterize this interaction. The synaptic responses, or the summed input of the networks connected to the neuron, varied greatly to repeated presentations of the same tactile input pattern delivered to the tip of digit 2. Surprisingly, however, these responses tended to sort into a set of specific time-evolving response types, unique for each neuron. Further, using a set of eight such tactile input patterns, we found each neuron to exhibit a set of specific response types for each input provided. Response types were not determined by the global cortical state, but instead likely depended on the time-varying state of the specific subnetworks connected to each neuron. The fact that some types of responses recurred indicates that the cortical network had a non-continuous landscape of solutions for these tactile inputs. Therefore, our data suggest that sensory inputs combine with the internal dynamics of the brain networks, thereby causing them to fall into one of the multiple possible perceptual attractor states. The neuron-specific instantiations of response types we observed suggest that the subnetworks connected to each neuron represent different components of those attractor states. Our results indicate that the impact of cortical internal states on external inputs is substantially more richly resolvable than previously shown.

Abstract We present the new version of OpenLoops, an automated generator of tree and one-loop scattering amplitudes based on the open-loop recursion. One main novelty of OpenLoops 2 is the extension of the original algorithm from NLO QCD to the full Standard Model, including electroweak (EW) corrections from gauge, Higgs and Yukawa interactions. In this context, among several new features, we discuss the systematic bookkeeping of QCD–EW interferences, a flexible implementation of the complex-mass scheme for processes with on-shell and off-shell unstable particles, a special treatment of on-shell and off-shell external photons, and efficient scale variations. The other main novelty is the implementation of the recently proposed on-the-fly reduction algorithm, which supersedes the usage of external reduction libraries for the calculation of tree–loop interferences. This new algorithm is equipped with an automated system that avoids Gram-determinant instabilities through analytic methods in combination with a new hybrid-precision approach based on a highly targeted usage of quadruple precision with minimal CPU overhead. The resulting significant speed and stability improvements are especially relevant for challenging NLO multi-leg calculations and for NNLO applications.

Abstract We discuss the inclusion of next-to–next-to leading order electromagnetic and of next-to leading order electroweak corrections to the leptonic decays of weak gauge and Higgs bosons in the Sherpa event generator. To this end, we modify the Yennie– Frautschi–Suura scheme for the resummation of soft photon corrections and its systematic improvement with fixed-order calculations, to also include the effect of virtual corrections due to the exchange of weak gauge bosons. We detail relevant technical aspects of our implementation and present numerical results for observables relevant for high-precision Drell–Yan and Higgs boson production and decay simulations at the LHC.

Insulin resistance in skeletal muscle in type 2 diabetes (T2D) is characterized by more pronounced metabolic and molecular defects than in obesity per se. There is increasing evidence that adipose tissue dysfunction contributes to obesity-induced insulin resistance in skeletal muscle. Here, we used an unbiased approach to examine if adipose tissue dysfunction is exaggerated in T2D and linked to diabetes-related mechanisms of insulin resistance in skeletal muscle. Transcriptional profiling and biological pathways analysis were performed in subcutaneous adipose tissue (SAT) and skeletal muscle biopsies from 17 patients with T2D and 19 glucose-tolerant, age and weight-matched obese controls. Findings were validated by qRT-PCR and western blotting of selected genes and proteins. Patients with T2D were more insulin resistant and had lower plasma adiponectin than obese controls. Transcriptional profiling showed downregulation of genes involved in mitochondrial oxidative phosphorylation and the tricarboxylic-acid cycle and increased expression of extracellular matrix (ECM) genes in SAT in T2D, whereas genes involved in proteasomal degradation were upregulated in the skeletal muscle in T2D. qRT-PCR confirmed most of these findings and showed lower expression of adiponectin in SAT and higher expression of myostatin in muscle in T2D. Interestingly, muscle expression of proteasomal genes correlated positively with SAT expression of ECM genes but inversely with the expression of ADIPOQ in SAT and plasma adiponectin. Protein content of proteasomal subunits and major ubiquitin ligases were unaltered in the skeletal muscle of patients with T2D. A transcriptional signature of exaggerated adipose tissue dysfunction in T2D, compared with obesity alone, is linked to low plasma adiponectin and increased transcriptional activation of proteasomal degradation in skeletal muscle.

Recurrent circuitry components are distributed widely within the brain, including both excitatory and inhibitory synaptic connections. Recurrent neuronal networks have potential stability problems, perhaps a predisposition to epilepsy. More generally, instability risks making internal representations of information unreliable. To assess the inherent stability properties of such recurrent networks, we tested a linear summation, non-spiking neuron model with and without a “dynamic leak”, corresponding to the low-pass filtering of synaptic input current by the RC circuit of the biological membrane. We first show that the output of this neuron model, in either of its two forms, follows its input at a higher fidelity than a wide range of spiking neuron models across a range of input frequencies. Then we constructed fully connected recurrent networks with equal numbers of excitatory and inhibitory neurons and randomly distributed weights across all synapses. When the networks were driven by pseudorandom sensory inputs with varying frequency, the recurrent network activity tended to induce high frequency self-amplifying components, sometimes evident as distinct transients, which were not present in the input data. The addition of a dynamic leak based on known membrane properties consistently removed such spurious high frequency noise across all networks. Furthermore, we found that the neuron model with dynamic leak imparts a network stability that seamlessly scales with the size of the network, conduction delays, the input density of the sensory signal and a wide range of synaptic weight distributions. Our findings suggest that neuronal dynamic leak serves the beneficial function of protecting recurrent neuronal circuitry from the self-induction of spurious high frequency signals, thereby permitting the brain to utilize this architectural circuitry component regardless of network size or recurrency.

Inspired by modeling approaches from the ecosystems literature, in this paper, we expand the network approach to psychopathology with risk and protective factors to arrive at an integrated analysis of resilience. We take a complexity approach to investigate the multifactorial nature of resilience and present a system in which a network of interacting psychiatric symptoms is targeted by risk and protective factors. These risk and protective factors influence symptom development patterns and thereby increase or decrease the probability that the symptom network is pulled toward a healthy or disorder state. In this way, risk and protective factors influence the resilience of the network. We take a step forward in formalizing the proposed system by implementing it in a statistical model and translating different influences from risk and protective factors to specific targets on the node and edge parameters of the symptom network. To analyze the behavior of the system under different targets, we present two novel network resilience metrics: Expected Symptom Activity (ESA, which indicates how many symptoms are active or inactive) and Symptom Activity Stability (SAS, which indicates how stable the symptom activity patterns are). These metrics follow standard practices in the resilience literature, combined with ideas from ecology and physics, and characterize resilience in terms of the stability of the system's healthy state. By discussing the advantages and limitations of our proposed system and metrics, we provide concrete suggestions for the further development of a comprehensive modeling approach to study the complex relationship between risk and protective factors and resilience.

Whereas, there is data to support that cuneothalamic projections predominantly reach a topographically confined volume of the rat thalamus, the ventroposterior lateral (VPL) nucleus, recent findings show that cortical neurons that process tactile inputs are widely distributed across the neocortex. Since cortical neurons project back to the thalamus, the latter observation would suggest that thalamic neurons could contain information about tactile inputs, in principle regardless of where in the thalamus they are located. Here we use a previously introduced electrotactile interface for producing sets of highly reproducible tactile afferent spatiotemporal activation patterns from the tip of digit 2 and record neurons throughout widespread parts of the thalamus of the anesthetized rat. We find that a majority of thalamic neurons, regardless of location, respond to single pulse tactile inputs and generate spike responses to such tactile stimulation patterns that can be used to identify which of the inputs that was provided, at above-chance decoding performance levels. Thalamic neurons with short response latency times, compatible with a direct tactile afferent input via the cuneate nucleus, were typically among the best decoders. Thalamic neurons with longer response latency times as a rule were also found to be able to decode the digit 2 inputs, though typically at a lower decoding performance than the thalamic neurons with presumed direct cuneate inputs. These findings provide support for that tactile information arising from any specific skin area is widely available in the thalamocortical circuitry.