Coherent correlation imaging for resolving fluctuating states of matter.

Fluctuations and stochastic transitions are ubiquitous in nanometre-scale systems, especially in the presence of disorder. However, their direct observation has so far been impeded by a seemingly fundamental, signal-limited compromise between spatial and temporal resolution. Here we develop coherent correlation imaging (CCI) to overcome this dilemma. Our method begins by classifying recorded camera frames in Fourier space. Contrast and spatial resolution emerge by averaging selectively over same-state frames. Temporal resolution down to the acquisition time of a single frame arises independently from an exceptionally low misclassification rate, which we achieve by combining a correlation-based similarity metric1,2 with a modified, iterative hierarchical clustering algorithm3,4. We apply CCI to study previously inaccessible magnetic fluctuations in a highly degenerate magnetic stripe domain state with nanometre-scale resolution. We uncover an intricate network of transitions between more than 30 discrete states. Our spatiotemporal data enable us to reconstruct the pinning energy landscape and to thereby explain the dynamics observed on a microscopic level. CCI massively expands the potential of emerging high-coherence X-ray sources and paves the way for addressing large fundamental questions such as the contribution of pinning5-8 and topology9-12 in phase transitions and the role of spin and charge order fluctuations in high-temperature superconductivity13,14.

NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain.

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.

A pan-cancer compendium of chromosomal instability.

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA1. The broad genomic complexity caused by CIN is a hallmark of cancer2; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.

Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling.

There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell-cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.

Genome-wide association study revealed significant SNPs for anthracnose resistance, seed alkaloids and protein content in white lupin.

White lupin (Lupinus albus L.) is a high-protein grain legume alternative to soybean in Central Europe, but its cultivation is risky due to the fungal disease anthracnose that can cause severe yield damage. In addition, management of seed alkaloids is critical for human nutrition and animal feed. We report on a white lupin collection of genebank accessions, advanced breeding lines and cultivars that was genotyped and phenotypically characterized for anthracnose resistance and seed alkaloids and protein levels. Using genotyping by sequencing (GBS), SeqSNP-targeted GBS, BiomarkX genotyping and Sanger sequencing, a genetic resource of genome-wide SNPs for white lupin was established. We determined anthracnose resistance in two years field trials at four locations with infection rows and measured seed alkaloids and protein levels by near-infrared spectroscopy (NIRS). Few white lupin breeding lines showed anthracnose resistance comparable or better than Celina and Frieda, currently the best commercial cultivars in Germany. NIRS estimates for seed alkaloids and protein levels revealed variation in the white lupin collection. Using genome-wide association studies (GWAS), we identified SNPs significantly associated with anthracnose resistance in the field representing known and new genomic regions. We confirmed the pauper locus and detected new SNP markers significantly associated with seed alkaloids. For the first time, we present loci associated with total grain protein content. Finally, we tested the potential of genomic prediction (GP) in predicting the phenotype of these three quantitative traits. Application of results and resources are discussed in the context of fostering breeding programs for white lupin.

Edema related to treatment with psychotropic drugs.

Edema as an adverse drug reaction is a commonly underestimated yet potentially debilitating condition. This study analyzes the incidence of severe psychotropic drug-induced edema (e.g., edema affecting the face, legs, or multiple body parts and lasting for more than 1 week, or in any case necessitating subsequent diuretic use) among psychiatric inpatients. The cases under examination are derived from an observational pharmacovigilance program conducted in German-speaking countries ("Arzneimittelsicherheit in der Psychiatrie", AMSP) from 1993 to 2016. Among the 462,661 inpatients monitored, severe edema was reported in 231 cases, resulting in an incidence of 0.05%. Edema occurred more frequently in women (80% of all cases) and older patients (mean age 51.8 years). Pregabalin had the highest incidence of severe edema, affecting 1.46‰ of patients treated with pregabalin, followed by mirtazapine (0.8‰). The majority of edema cases showed a positive response to appropriate countermeasures, such as dose reduction and drug discontinuation, and resolved by the end of the observation period. While most instances of drug-induced edema are reversible, they can have a significant impact on patient well-being and potentially result in decreased treatment adherence. It is, therefore, crucial to remain vigilant regarding risk-increasing circumstances during treatment with psychotropic drugs.

Histoplasmosis peritonitis in an immunocompetent patient: case report.

Histoplasmosis is a fungal infection most frequently seen in immunocompromised patients. It is endemic in Central and South America and in Africa. The infection is usually asymptomatic in a healthy individual. Extrapulmonary dissemination can be seen in immunocompromised hosts. Gastrointestinal manifestations frequently involve the terminal ileum and cecum, mimicking Crohn's disease or malignancy. We describe the case of a 36-year-old healthy man from Cameroon, living in Switzerland for 13 years and without any medical nor surgical history, who presented peritonitis not responding to antibiotics. CT-scan showed bowel obstruction and signs of peritonitis. We opted for an explorative laparoscopy, which was converted to laparotomy with extensive adhesiolysis. Diagnostic of histoplasmosis was confirmed by histology and PCR analysis on biopsy. To our knowledge, this is the first described case of peritonitis as main outcome of a disseminated histoplasmosis involving the peritoneum in an immunocompetent patient.

Psychiatrists' perceptions of conditions and consequences associated with the implementation of open notes: qualitative investigation.

OBJECTIVE: In a growing list of countries, patients are granted access to their clinical notes ("open notes") as part of their online record access. Especially in the field of mental health, open notes remain controversial with some clinicians perceiving open notes as a tool for improving therapeutic outcomes by increasing patient involvement, while others fear that patients might experience psychological distress and perceived stigmatization, particularly when reading clinicians' notes. More research is needed to optimize the benefits and mitigate the risks. METHODS: Using a qualitative research design, we conducted semi-structured interviews with psychiatrists practicing in Germany, to explore what conditions they believe need to be in place to ensure successful implementation of open notes in psychiatric practice as well as expected subsequent changes to their workload and treatment outcomes. Data were analyzed using thematic analysis. RESULTS: We interviewed 18 psychiatrists; interviewees believed four key conditions needed to be in place prior to implementation of open notes including careful consideration of (1) diagnoses and symptom severity, (2) the availability of additional time for writing clinical notes and discussing them with patients, (3) available resources and system compatibility, and (4) legal and data protection aspects. As a result of introducing open notes, interviewees expected changes in documentation, treatment processes, and doctor-physician interaction. While open notes were expected to improve transparency and trust, participants anticipated negative unintended consequences including the risk of deteriorating therapeutic relationships due to note access-related misunderstandings and conflicts. CONCLUSION: Psychiatrists practiced in Germany where open notes have not yet been established as part of the healthcare data infrastructure. Interviewees were supportive of open notes but had some reservations. They found open notes to be generally beneficial but anticipated effects to vary depending on patient characteristics. Clear guidelines for managing access, time constraints, usability, and privacy are crucial. Open notes were perceived to increase transparency and patient involvement but were also believed to raise issues of stigmatization and conflicts.

Young children intuitively organize numbers on straight, horizontal lines from left to right before the onset of formal instruction.

The number line estimation task is frequently used to measure children's numerical magnitude understanding. It is unclear whether the resulting straight, horizontal, left-to-right-oriented estimate patterns indicate task constraints or children's intuitive number-space mapping. Three- to six-year-old children (N = 72, Mage = 4.89, 56% girls, 94% German citizenship) were asked to explain the meaning of numbers to a teddy by laying out a rope and attaching cards showing non-symbolic numerosities (dots) to it. Most children intuitively created straight, horizontal, and left-to-right-oriented representations. Characteristics of the line correlated with age, mathematical competencies, and home numeracy. This demonstrates the usefulness of the number line estimation task for assessing how children intuitively map numbers onto space.

A Germany-wide survey of caregiving professionals on climate change and mental health of children and adolescents - factors influencing their relevance rating of extreme weather event associated mental health impairments.

INTRODUCTION: Climate change presents a significant risk for the mental and physical health of young people. In order to identify and properly care for potential mental health impairments from extreme weather events, the relevance of these impairments must be assessed as high by the professional groups providing care for children and adolescents. This raises the question of which factors influence the individual relevance assessment of caretaking professionals? METHODS: Data was collected creating and conducting a Germany-wide online questionnaire via LimeSurvey. The questionnaire was addressed to professionals providing care for children and adolescents, in this case medical and therapeutic personnel as well as school and pedagogical personnel. Professional associations, chief physicians and school principals were contacted as multipliers and asked to forward the questionnaire to their members and staff. The data was analyzed using the R statistical software, and multiple linear regressions were performed to test the hypotheses. RESULTS: Overall, 648 questionnaires were taken into analysis. Approximately 70% of the participants considered climate change-induced impacts on the mental health of children and adolescents due to extreme weather events as relevant. Experiencing heat, storm, heavy precipitation, flood/flooding, and/or avalanches/mudflows made a modest yet significant contribution to explaining higher relevance assessments. In contrast, there was no evidence to suggest that an urban working environment increases the relevance assessment. CONCLUSION: The described influence of experiencing extreme weather events should not be regarded as the sole factor leading to higher relevance ratings. A more comprehensive understanding of the factors influencing relevance assessments is necessary to address key aspects of risk communication and increase risk awareness.

Pain-related single nucleotide polymorphisms: association with lumbar spinal stenosis patient experience and non-surgical treatment outcomes.

PURPOSE: Lumbar spinal stenosis (LSS) is common in our aging population resulting in pain and functional impairment. Recent advances in pain research have identified several single nucleotide polymorphisms (SNP) associated with inter-individual symptom and treatment response. The goal of the current study was to investigate the association of SNPs in Neuropeptide Y (NPY) and Catechol-O-methyltransferase (COMT) with pain, function, and treatment outcomes in Lumbar spinal stenosis (LSS) patients receiving non-surgical treatments. METHODS: An exploratory observational biomarker study was performed ancillary to a previously published clinical trial evaluating three different non-surgical treatments for LSS. Saliva samples were obtained for single nucleotide polymorphism genotyping and blood samples were collected for NPY protein. Data on pain and function collected as part of the clinical trial at baseline, 2 and 6 months were examined for association with known polymorphisms in NPY and COMT. RESULTS: Subjects with the NPY rs16147 TT genotype exhibited higher baseline symptom severity but also a higher likelihood of responding to non-surgical treatments. Subjects with the COMT rs4680 GG genotype also exhibited higher baseline symptom severity but did not demonstrate greater response to treatment. CONCLUSIONS: NPY rs16147 and COMT rs4680 are important potential biomarkers associated with pain and function. NPY genotype may be useful in predicting response to non-surgical treatments in older adults with LSS.

[Evidence-based interventions to treat chronic low back pain: treatment selection for a personalized medicine approach : German version]. / Evidenzbasierte Interventionen zur Behandlung von chronischem Schmerz im unteren Rücken ­ Therapieauswahl für einen personalisierten Behandlungsansatz : Deutsche Fassung.

INTRODUCTION: Chronic low back pain (cLBP) is highly prevalent in the United States and globally, resulting in functional impairment and lowered quality of life. While many treatments are available for cLBP, clinicians have little information about which specific treatment(s) will work best for individual patients or subgroups of patients. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-termSM (HEAL) Initiative, will conduct a collaborative clinical trial, which seeks to develop a personalized medicine algorithm to optimize patient and provider treatment selection for patients with cLBP. OBJECTIVE: The primary objective of this article is to provide an update on evidence-based cLBP interventions and describe the process of reviewing and selecting interventions for inclusion in the clinical trial. METHODS: A working group of cLBP experts reviewed and selected interventions for inclusion in the clinical trial. The primary evaluation measures were strength of evidence and magnitude of treatment effect. When available in the literature, duration of effect, onset time, carryover effect, multimodal efficacy, responder subgroups, and evidence for the mechanism of treatment effect or biomarkers were considered. CONCLUSION: The working group selected 4 leading, evidence-based treatments for cLBP to be tested in the clinical trial and for use in routine clinical treatment. These treatments include (1) duloxetine, (2) acceptance and commitment therapy, (3) a classification-based exercise and manual therapy intervention, and (4) a self-management approach. These interventions each had a moderate to high level of evidence to support a therapeutic effect and were from different therapeutic classes.

Calcar-guided short-stem total hip arthroplasty in fractures of the femoral neck: a prospective observational study of 68 hips.

INTRODUCTION: The indications for cementless short-stem total hip arthroplasty (THA) have been expanded due to encouraging results. However, no evidence in cases of femoral neck fractures (FNFs) is available. We aimed to prospectively obtain data on the safety and the clinical outcomes of a cementless calcar-guided short stem in patients with FNFs. MATERIALS AND METHODS: We conducted a prospective observational study of 68 patients diagnosed with FNFs who underwent short-stem THA between 2016 and 2019 with a calcar-guided stem. Complications during follow-up leading to revision were documented, and patient reported outcome measurements recorded. Stem migration was analyzed using the Einzel-Bild-Röntgen-Analysis Femoral Component Analysis software. RESULTS: The mean follow-up was 33.8 ± 14.8 months. The patient mortality at last follow-up was 10.6%. Two patients required stem revision, due to periprosthetic fracture and late aseptic loosening, respectively, corresponding to 96.2% stem survival. Survivorship for the endpoint of revision for any reason was 91.1% at 6 years. All revisions occurred in females. The mean Harris Hip Score at the last follow-up was 93.0 ± 8.9. The mean axial migration at last follow-up was 1.90 ± 1.81 mm. No significant influence on migration was found regarding gender, age, weight, and body mass index. CONCLUSIONS: The clinical and radiological findings were satisfying and most patients benefited from the minimally invasive procedure. However, as for conventional THA as well, implant survivorship and mortality were markedly worse compared to results regarding osteoarthritis. Especially in elderly female patients with FNF, cementless short-stem THA is a concern and a cemented THA should be the first choice.

Longitudinal Relationship Between Anemia and Statural Growth Impairment in Children and Adolescents With Nonglomerular CKD: Findings From the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Anemia and statural growth impairment are both prevalent in children with nonglomerular chronic kidney disease (CKD) and are associated with poor quality of life and increased morbidity and mortality. However, to date no longitudinal studies have demonstrated a relationship between anemia and statural growth in this population. STUDY DESIGN: The CKD in Children (CKiD) study is a multicenter prospective cohort study with over 15 years of follow-up observation. SETTING & PARTICIPANTS: CKiD participants younger than 22 years with nonglomerular CKD who had not reached final adult height. EXPOSURE: Age-, sex-, and race-specific hemoglobin z score. OUTCOME: Age- and sex-specific height z score. ANALYTICAL APPROACH: The relationship between hemoglobin and height was quantified using (1) multivariable repeated measures paired person-visit analysis, and (2) multivariable repeated measures linear mixed model analysis. Both models were adjusted for age, sex, body mass index, estimated glomerular filtration rate, acidosis, and medication use. RESULTS: Overall, 67% of the 510 participants studied had declining hemoglobin z score trajectories over the follow-up period, which included 1,763 person-visits. Compared with average hemoglobin z scores of≥0, average hemoglobin z scores of less than -1.0 were independently associated with significant growth impairment at the subsequent study visit, with height z score decline ranging from 0.24 to 0.35. Importantly, in 50% of cases hemoglobin z scores of less than -1.0 corresponded to hemoglobin values higher than those used as cutoffs defining anemia in the KDIGO clinical practice guideline for anemia in CKD. When stratified by age, the magnitude of the association peaked in participants aged 9 years. In line with paired-visit analyses, our mixed model analysis demonstrated that in participants with baseline hemoglobin z score less than -1.0, a hemoglobin z score decline over the follow-up period was associated with a statistically significant concurrent decrease in height z score. LIMITATIONS: Limited ability to infer causality. CONCLUSIONS: Hemoglobin decline is associated with growth impairment over time in children with mild to moderate nonglomerular CKD, even before hemoglobin levels reach the cutoffs that are currently used to define anemia in this population.

Convergently selected NPF2.12 coordinates root growth and nitrogen use efficiency in wheat and barley.

Understanding the genetic and molecular function of nitrate sensing and acquisition across crop species will accelerate breeding of cultivars with improved nitrogen use efficiency (NUE). Here, we performed a genome-wide scan using wheat and barley accessions characterized under low and high N inputs that uncovered the NPF2.12 gene, encoding a homolog of the Arabidopsis nitrate transceptor NRT1.6 and other low-affinity nitrate transporters that belong to the MAJOR FACILITATOR SUPERFAMILY. Next, it is shown that variations in the NPF2.12 promoter correlated with altered NPF2.12 transcript levels where decreased gene expression was measured under low nitrate availability. Multiple field trials revealed a significantly enhanced N content in leaves and grains and NUE in the presence of the elite allele TaNPF2.12TT grown under low N conditions. Furthermore, the nitrate reductase encoding gene NIA1 was up-regulated in npf2.12 mutant upon low nitrate concentrations, thereby resulting in elevated levels of nitric oxide (NO) production. This increase in NO correlated with the higher root growth, nitrate uptake, and N translocation observed in the mutant when compared to wild-type. The presented data indicate that the elite haplotype alleles of NPF2.12 are convergently selected in wheat and barley that by inactivation indirectly contribute to root growth and NUE by activating NO signaling under low nitrate conditions.

Boosting distributional copula regression.

Capturing complex dependence structures between outcome variables (e.g., study endpoints) is of high relevance in contemporary biomedical data problems and medical research. Distributional copula regression provides a flexible tool to model the joint distribution of multiple outcome variables by disentangling the marginal response distributions and their dependence structure. In a regression setup, each parameter of the copula model, that is, the marginal distribution parameters and the copula dependence parameters, can be related to covariates via structured additive predictors. We propose a framework to fit distributional copula regression via model-based boosting, which is a modern estimation technique that incorporates useful features like an intrinsic variable selection mechanism, parameter shrinkage and the capability to fit regression models in high-dimensional data setting, that is, situations with more covariates than observations. Thus, model-based boosting does not only complement existing Bayesian and maximum-likelihood based estimation frameworks for this model class but rather enables unique intrinsic mechanisms that can be helpful in many applied problems. The performance of our boosting algorithm for copula regression models with continuous margins is evaluated in simulation studies that cover low- and high-dimensional data settings and situations with and without dependence between the responses. Moreover, distributional copula boosting is used to jointly analyze and predict the length and the weight of newborns conditional on sonographic measurements of the fetus before delivery together with other clinical variables.

Longitudinal changes in uric acid concentration and their relationship with chronic kidney disease progression in children and adolescents.

BACKGROUND: Elevated serum uric acid concentration is a risk factor for CKD progression. Its change over time and association with CKD etiology and concomitant changes in estimated glomerular filtration rate (eGFR) in children and adolescents are unknown. METHODS: Longitudinal study of 153 children/adolescents with glomerular (G) and 540 with non-glomerular (NG) etiology from the CKD in Children (CKiD) study. Baseline serum uric acid, change in uric acid and eGFR over time, CKD etiology, and comorbidities were monitored. Adjusted linear mixed-effects regression models quantified the relationship between within-person changes in uric acid and concurrent within-person changes in eGFR. RESULTS: Participants with stable uric acid over follow-up had CKD progression which became worse for increased baseline uric acid (average annual percentage changes in eGFR were - 1.4%, - 7.7%, and - 14.7% in those with G CKD with baseline uric acid < 5.5 mg/dL, 5.5 - 7.5 mg/dL, and > 7.5 mg/dL, respectively; these changes were - 1.4%, - 4.1%, and - 8.6% in NG CKD). Each 1 mg/dL increase in uric acid over follow-up was independently associated with significant concomitant eGFR decreases of - 5.7% (95%CI - 8.4 to - 3.0%) (G) and - 5.1% (95%CI - 6.3 to - 4.0%) (NG) for those with baseline uric acid < 5.5 mg/dL and - 4.3% (95%CI - 6.8 to - 1.6%) (G) and - 3.3% (95%CI - 4.1 to - 2.6%) (NG) with baseline uric acid between 5.5 and 7.5 mg/dL. CONCLUSIONS: Higher uric acid levels and increases in uric acid over time are risk factors for more severe progression of CKD in children and adolescents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Associations of body mass index (BMI) and BMI change with progression of chronic kidney disease in children.

BACKGROUND: Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD progression has not been described. METHODS: We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan-Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change. RESULTS: Participants had median age of 10.9 years [IQR: 6.5, 14.6], median eGFR of 50 ml/1.73 m2 [IQR: 37, 64] and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years [IQR: 2, 8]. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change. CONCLUSION: Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.