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Abstract Background Parkinson's disease (PD) is the most common movement disorder. Extrapyramidal motor symptoms stem from the degeneration of the dopaminergic pathways in patient brain. Current treatments for PD are symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Although the cause of PD remains unknown, several pathogenic factors have been identified, which cause dopaminergic neuron (DN) death in the substantia nigra (SN). These include oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity. Manipulation of these factors may allow the development of disease-modifying treatment strategies to slow neuronal death. Inhibition of DJ-1A, the Drosophila homologue of the familial PD gene DJ-1, leads to oxidative stress, mitochondrial dysfunction, and DN loss, making fly DJ-1A model an excellent in vivo system to test for compounds with therapeutic potential. Results In the present study, a Drosophila DJ-1A model of PD was used to test potential neuroprotective drugs. The drugs applied are the Chinese herb celastrol, the antibiotic minocycline, the bioenergetic amine coenzyme Q10 (coQ10), and the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo[f]-quinoxaline (NBQX). All of these drugs target pathogenic processes implicated in PD, thus constitute mechanism-based treatment strategies. We show that celastrol and minocycline, both having antioxidant and anti-inflammatory properties, confer potent dopaminergic neuroprotection in Drosophila DJ-1A model, while coQ10 shows no protective effect. NBQX exerts differential effects on cell survival and brain dopamine content: it protects against DN loss but fails to restore brain dopamine level. Conclusion The present study further validates Drosophila as a valuable model for preclinical testing of drugs with therapeutic potential for neurodegenerative diseases. The lower cost and amenability to high throughput testing make Drosophila PD models effective in vivo tools for screening novel therapeutic compounds. If our findings can be further validated in mammalian PD models, they would implicate drugs combining antioxidant and anti-inflammatory properties as strong therapeutic candidates for mechanism-based PD treatment.

Background: Subjective reports can reveal relevant information regarding the nature of the impairment of brain tumor patients, unveiling potential gaps in current assessment practices. The co-occurrence of language and memory impairments has been previously reported, albeit scarcely. The aim of this study is therefore to understand the co-occurrence of subjective language and memory complaints in the preoperative state of brain tumor patients and its impact on Quality of Life (QoL)., Methods: 31 brain tumor patients (12 LGG, 19 HGG) underwent a semi-structured interview to assess subjective complaints of language deficits, co-occurrences between language and memory dysfunction, and changes in QoL. Group and subgroup analyses were conducted to provide general and tumor grade specific data., Results: 48.4% of patients mentioned co-occurrence of language and memory impairments in reading, writing, and conversation. The HGG group reported co-occurrences in all three of these (reading: 31.6%; writing: 21.1%; conversation: 26.3%), while the LGG only described co-occurrences in reading (25%) and conversation (8.3%), although these were not statistically significant. All patients with co-occurring language and memory deficits reported these to be linked to reduced QoL (48.4%). In patients with an HGG, this number was slightly higher (52.6%) than in patients with an LGG (41.7%)., Conclusion: Language impairments co-occur with memory dysfunction as perceived in patients' daily life. Patients see these impairments as affecting their quality of life. Further attention to dedicated language and memory tasks seems necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rybka, Jonkers, Burzlaff, Rosenstock, Vajkoczy, Picht, Faust and Rofes.)

Background: One of the challenges in surgery of tumors in motor eloquent areas is the individual risk assessment for postoperative motor disorder. Previously a regression model was developed that permits estimation of the risk prior to surgery based on topographical and neurophysiological data derived from investigation with nTMS (navigated Transcranial Magnetic Stimulation). This study aims to analyze the impact of including additional neurophysiological TMS parameters into the established risk stratification model for motor outcome after brain tumor surgery., Methods: Biometric and clinical data of 170 patients with glioma in motor eloquent areas were collected prospectively. In addition, the following nTMS parameters were collected bihemispherically prior to surgery: resting motor threshold (RMT), recruitment curve (RC), cortical silent period (CSP) and a nTMS based fibertracking to measure the tumor tract distance (TTD). Motor function was quantified by Medical Research Council Scale (MRCS) preoperatively, seven days and three months postoperatively. Association between nTMS parameters and postoperative motor outcome was investigated in bivariate and multivariable analyses., Results: The bivariate analysis confirmed the association of RMT ratio with the postoperative motor outcome after seven days with higher rates of worsening in patients with RMT ratio > 1.1 compared to patients with RMT ratio ≤ 1.1 (31.6% vs. 15.1%, p = 0.009). Similarly, an association between a pathological CSP ratio and a higher risk of new postoperative motor deficits after seven days was observed (35.3% vs. 16.7% worsening, p = 0.025). A pathological RC Ratio was associated postoperative deterioration of motor function after three months (42.9% vs. 16.2% worsening, p = 0.004). In multiple regression analysis, none of these associations were statistically robust., Conclusions: The current results suggest that the RC ratio, CSP ratio and RMT ratio individually are sensitive markers associated with the motor outcome 7 days and 3 months after tumor resection in a presumed motor eloquent location. They can therefore supply valuable information during preoperative risk-benefit-balancing. However, underlying neurophysiological mechanisms might be too similar to make the parameters meaningful in a combined model., (© 2024. The Author(s).)

The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinson's disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography and subthalamic local field potential recordings were performed OFF therapy (n = 22), ON dopaminergic medication (n = 18) and on subthalamic deep brain stimulation (n = 8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography. In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinson's disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its' therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes that allow for parallel recordings of several basal ganglia nuclei, namely the striatum, external and internal pallidum, that all displayed activity in the low frequency band (3-12 Hz). In addition to a correlation with low-frequency activity in the internal pallidum (R = 0.88, P = 0.001), we demonstrate that dystonic symptoms correlate specifically with low-frequency coupling between striatum and internal pallidum (R = 0.75, P = 0.009). This points towards a pathophysiological role of the direct striato-pallidal pathway in dystonia that is conveyed via coupling in the enhanced low-frequency band. Our study provides a mechanistic insight into the pathophysiology of dystonia by revealing a link between symptom severity and frequency-specific coupling of distinct basal ganglia pathways., (© 2024. The Author(s).)

Purpose: Very low birth weight (VLBW) infants are at a risk of spontaneous focal intestinal perforation (FIP). Treatment includes supportive care, antibiotics, and drainage with/without surgery. Broad-spectrum antibiotic agents like carbapenems are applied frequently, although their use is not well-supported by the limited evidence of causal pathogens. We hypothesize that the use of carbapenems may not be necessary in VLBW infants with FIP. Our primary objective was to evaluate the antimicrobial use in VLBW infants with FIP in a cohort of the German Neonatal Network (GNN). The secondary objective was to characterize a subset in detail as a benchmark for future targets of stewardship., Methods: Data on VLBW infants with FIP was collected prospectively within the GNN, a collaboration of 68 neonatal intensive care units (NICU). With regards to the primary objective, patient characteristics and antimicrobial treatment were extracted from the predefined GNN database. To address our secondary objective, an additional on-site assessment of laboratory and microbiological culture results were performed., Results: In the GNN cohort, 613/21,646 enrolled infants (2.8%) developed FIP requiring surgery. They were frequently treated with carbapenems (500/613 (81.6%)) and vancomycin (497/613 (81.1%)). In a subset of 124 VLBW infants, 77 (72.6%) had proof of gram-positive bacteria in the abdominal cavity, coagulase-negative staphylococci (CoNS) predominantly. Despite the low prevalence of gram-negative bacteria (n = 6 (4.8%)), the combination of meropenem and vancomycin was prescribed most frequently (n = 96 (78.0%))., Conclusion: The use of carbapenems as broad-spectrum antimicrobials agents might not be justified in most VLBW infants with FIP. Knowledge on the development of the neonatal gut microbiota, local resistance patterns and individual microbiological findings should be taken into consideration when implementing antimicrobial stewardship programs (ASPs)., (© 2024. The Author(s).)

The neurosurgical management of traumatic brain injury (TBI) plays a critical role in ensuring acute survival and mitigating secondary brain damage, which significantly impacts patients' quality of life. TBI is defined as an external force impacting the skull, leading to brain injuries and subsequent functional impairments. It is a leading cause of mortality and morbidity, particularly among young individuals. The initial clinical examination is crucial, with external signs like scalp injuries, hematomas, nasal fluid leakage, skull deformities, and neurological deficits providing important clues to injury patterns. Pupil examination is particularly critical, as mydriasis coupled with reduced consciousness may indicate an acute life-threatening increase in intracranial pressure (ICP), necessitating immediate neurosurgical intervention. TBI assessment often utilizes the Glasgow Coma Scale (GCS), classifying injuries as mild (GCS 13-15), moderate (GCS 9-12), or severe (GCS < 9). Even mild TBI can lead to long-term complications. TBI should be viewed as a disease process rather than a singular event. Primary brain damage results from shearing forces on the parenchyma, manifesting as contusions, hematomas, or diffuse axonal injury. Secondary brain damage is driven by mechanisms such as inflammation and spreading depolarizations. Treatment aims not only to secure immediate survival but also to reduce secondary injuries, with ICP management being crucial. Neurosurgical interventions are guided by cranial pathologies, with options including ICP monitoring, burr hole trepanation, craniotomy. In severe TBI cases with refractory ICP elevation, decompressive craniectomy may be performed as a last resort, significantly reducing mortality but often resulting in high morbidity and vegetative states, necessitating careful consideration of indications., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht‐Sponsor der Veranstaltung): ja; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Antimicrobial peptides (AMPs) are crucial components of the innate immune system in various organisms, including humans. Beyond their direct antimicrobial effects, AMPs play essential roles in various physiological processes. They induce angiogenesis, promote wound healing, modulate immune responses, and serve as chemoattractants for immune cells. AMPs regulate the microbiome and combat microbial infections on the skin, lungs, and gastrointestinal tract. Produced in response to microbial signals, AMPs help maintain a balanced microbial community and provide a first line of defense against infection. In preterm infants, alterations in microbiome composition have been linked to various health outcomes, including sepsis, necrotizing enterocolitis, atopic dermatitis, and respiratory infections. Dysbiosis, or an imbalance in the microbiome, can alter AMP profiles and potentially lead to inflammation-mediated diseases such as chronic lung disease and obesity. In the following review, we summarize what is known about the vital role of AMPs as multifunctional peptides in protecting newborn infants against infections and modulating the microbiome and immune response. Understanding their roles in preterm infants and high-risk populations offers the potential for innovative approaches to disease prevention and treatment.

The computational capabilities of neuronal networks are fundamentally constrained by their specific connectivity. Previous studies of cortical connectivity have mostly been carried out in rodents; whether the principles established therein also apply to the evolutionarily expanded human cortex is unclear. We studied network properties within the human temporal cortex using samples obtained from brain surgery. We analyzed multineuron patch-clamp recordings in layer 2-3 pyramidal neurons and identified substantial differences compared with rodents. Reciprocity showed random distribution, synaptic strength was independent from connection probability, and connectivity of the supragranular temporal cortex followed a directed and mostly acyclic graph topology. Application of these principles in neuronal models increased dimensionality of network dynamics, suggesting a critical role for cortical computation.

Subthalamic beta band activity (13-35 Hz) is known as a real-time correlate of motor symptom severity in Parkinson's disease (PD) and is currently explored as a feedback signal for closed-loop deep brain stimulation (DBS). Here, we investigate the interaction of movement, dopaminergic medication, and deep brain stimulation on subthalamic beta activity in PD patients implanted with sensing-enabled, implantable pulse generators. We recorded subthalamic activity from seven PD patients at rest and during repetitive movements in four conditions: after withdrawal of dopaminergic medication and DBS, with medication only, with DBS only, and with simultaneous medication and DBS. Medication and DBS showed additive effects in improving motor performance. Distinct effects of each therapy were seen in subthalamic recordings, with medication primarily suppressing low beta activity (13-20 Hz) and DBS being associated with a broad decrease in beta band activity (13-35 Hz). Movement suppressed beta band activity compared to rest. This suppression was most prominent when combining medication with DBS and correlated with motor improvement within patients. We conclude that DBS and medication have distinct effects on subthalamic beta activity during both rest and movement, which might explain their additive clinical effects as well as their difference in side-effect profiles. Importantly, subthalamic beta activity significantly correlated with motor symptoms across all conditions, highlighting its validity as a feedback signal for closed-loop DBS., (© 2024. The Author(s).)

In estimated 10-15% of neurosurgical interventions employing a conventional three-pin head fixation device (HFD) the patient's head loses position due to slippage. At present no scientifically based stability criterion exists to potentially prevent the intraoperative loss of head position or skull fractures. Here, data on the skull penetration depth both on the single and two-pin side of a three-pin HFD are presented, providing scientific evidence for a stability criterion for the invasive three-pin head fixation. Eight fresh, chemically untreated human cadaveric heads were sequentially pinned 90 times in total in a noncommercially calibrated clamp screw applying a predefined force of 270 N (approximately 60 lbf) throughout. Three head positions were pinned each in standardized manner for the following approaches: prone, middle fossa, pterional. Titanium-aluminum alloy pins were used, varying the pin-cone angle on the single-pin side from 36° to 55° and on the two-pin side from 25° to 36°. The bone-penetration depths were directly measured by a dial gauge on neurocranium. The penetration depths on the single-pin side ranged from 0.00 mm (i.e., no penetration) to 6.17 mm. The penetration depths on the two-pin side ranged from 0.00 mm (no penetration) to 4.48 mm. We measured a significantly higher penetration depth for the anterior pin in comparison to the posterior pin on the two-pin side in prone position. One pin configuration (50°/25°) resulted in a quasi-homogenous pin depth distribution between the single- and the two-pin side. Emanating from the physical principle that pin depths behave proportionate to pin pressure distribution, a quasi-homogenous pin penetration depth may result in higher resilience against external shear forces or torque, thus reducing potential complications such as slippage and depressed skull fractures. The authors propose that the pin configuration of 50°/25° may be superior to the currently used uniform pin-cone angle distribution in common clinical practice (36°/36°). However, future research may identify additional influencing factors to improve head fixation stability., (© 2024. The Author(s).)

Background: Given a genome-scale metabolic model (GEM) of a microorganism and criteria for optimization, flux balance analysis (FBA) predicts the optimal growth rate and its corresponding flux distribution for a specific medium. FBA has been extended to microbial consortia and thus can be used to predict interactions by comparing in-silico growth rates for co- and monocultures. Although FBA-based methods for microbial interaction prediction are becoming popular, a systematic evaluation of their accuracy has not yet been performed., Results: Here, we evaluate the accuracy of FBA-based predictions of human and mouse gut bacterial interactions using growth data from the literature. For this, we collected 26 GEMs from the semi-curated AGORA database as well as four previously published curated GEMs. We tested the accuracy of three tools (COMETS, Microbiome Modeling Toolbox and MICOM) by comparing growth rates predicted in mono- and co-culture to growth rates extracted from the literature and also investigated the impact of different tool settings and media. We found that except for curated GEMs, predicted growth rates and their ratios (i.e. interaction strengths) do not correlate with growth rates and interaction strengths obtained from in vitro data., Conclusions: Prediction of growth rates with FBA using semi-curated GEMs is currently not sufficiently accurate to predict interaction strengths reliably., (© 2024. The Author(s).)

Background: Deep brain stimulation (DBS) is an invasive treatment option for patients with Parkinson's disease. Recently, adaptive DBS (aDBS) systems have been developed, which adjust stimulation timing and amplitude in real-time. However, it is unknown how changes in parameters, movement states and the controllability of subthalamic beta activity affect aDBS performance., Objective: To characterize how parameter choice, movement state and controllability interactively affect the electrophysiological and behavioral response to single threshold aDBS., Methods: We recorded subthalamic local field potentials in 12 patients with Parkinson's disease receiving single threshold aDBS in the acute post-operative state. We investigated changes in two aDBS parameters: the onset time and the smoothing of real-time beta power. Electrophysiological patterns and motor performance were assessed while patients were at rest and during a simple motor task. We further studied the impact of controllability on aDBS performance by comparing patients with and without beta power modulation during continuous stimulation., Results: Our findings reveal that changes in the onset time control the extent of beta power suppression achievable with single threshold adaptive stimulation during rest. Behavioral data indicate that only specific parameter combinations yield a beneficial effect of single threshold aDBS. During movement, action induced beta power suppression reduces the responsivity of the closed loop algorithm. We further demonstrate that controllability of beta power is a prerequisite for effective parameter dependent modulation of subthalamic beta activity., Conclusion: Our results highlight the interaction between single threshold aDBS parameter selection, movement state and controllability in driving subthalamic beta activity and motor performance. By this means, we identify directions for the further development of closed-loop DBS algorithms., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JR has received speaker honoraria from Medtronic outside of this work. GHS has received honoraria from Medtronic and Boston Scientific outside of this work. WJN has received speaker honoraria from Medtronic outside of this work. AAK has served on advisory boards of Medtronic and has received honoraria and travel support from Medtronic and Boston Scientific outside of this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) is an effective treatment option for patients with Parkinson's disease (PD). However, clinical programming remains challenging with segmented electrodes., Objective: Using novel sensing-enabled neurostimulators, we investigated local field potentials (LFPs) and their modulation by DBS to assess whether electrophysiological biomarkers may facilitate clinical programming in chronically implanted patients., Methods: Sixteen patients (31 hemispheres) with PD implanted with segmented electrodes in the subthalamic nucleus and a sensing-enabled neurostimulator were included in this study. Recordings were conducted 3 months after DBS surgery following overnight withdrawal of dopaminergic medication. LFPs were acquired while stimulation was turned OFF and during a monopolar review of both directional and ring contacts. Directional beta power and stimulation-induced beta power suppression were computed. Motor performance, as assessed by a pronation-supination task, clinical programming and electrode placement were correlated to directional beta power and stimulation-induced beta power suppression., Results: Better motor performance was associated with stronger beta power suppression at higher stimulation amplitudes. Across directional contacts, differences in directional beta power and the extent of stimulation-induced beta power suppression predicted motor performance. However, within individual hemispheres, beta power suppression was superior to directional beta power in selecting the contact with the best motor performance. Contacts clinically activated for chronic stimulation were associated with stronger beta power suppression than non-activated contacts., Conclusions: Our results suggest that stimulation-induced β power suppression is superior to directional β power in selecting the clinically most effective contact. In sum, electrophysiological biomarkers may guide programming of directional DBS systems in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Bacterial growth often alters the environment, which in turn can impact interspecies interactions among bacteria. Here, we used an in vitro batch system containing mucin beads to emulate the dynamic host environment and to study its impact on the interactions between two abundant and prevalent human gut bacteria, the primary fermenter Bacteroides thetaiotaomicron and the butyrate producer Roseburia intestinalis. By combining machine learning and flow cytometry, we found that the number of viable B. thetaiotaomicron cells decreases with glucose consumption due to acid production, while R. intestinalis survives post-glucose depletion by entering a slow growth mode. Both species attach to mucin beads, but only viable cell counts of B. thetaiotaomicron increase significantly. The number of viable co-culture cells varies significantly over time compared to those of monocultures. A combination of targeted metabolomics and RNA-seq showed that the slow growth mode of R. intestinalis represents a diauxic shift towards acetate and lactate consumption, whereas B. thetaiotaomicron survives glucose depletion and low pH by foraging on mucin sugars. In addition, most of the mucin monosaccharides we tested inhibited the growth of R. intestinalis but not B. thetaiotaomicron. We encoded these causal relationships in a kinetic model, which reproduced the observed dynamics. In summary, we explored how R. intestinalis and B. thetaiotaomicron respond to nutrient scarcity and how this affects their dynamics. We highlight the importance of understanding bacterial metabolic strategies to effectively modulate microbial dynamics in changing conditions., (© 2023. The Author(s).)

Background: Crashes involving farm equipment (FE) are a major safety concern for farmers as well as all other users of the public road system in both rural and urban areas. These crashes often involve passenger vehicle drivers striking the farm equipment from behind or attempting to pass, but little is known about drivers' perceived norms and self-reported passing behaviors. The objective of this study is to examine factors influencing drivers' farm equipment passing frequencies and their perceptions about the passing behaviors of other drivers., Methods: Data were collected via intercept surveys with adult drivers at local gas stations in two small rural towns in Iowa. The survey asked drivers about their demographic information, frequency of passing farm equipment, and perceptions of other drivers' passing behavior in their community and state when approaching farm equipment (proximal and distal descriptive norms). A multinomial logistic regression model was used to estimate the relationship between descriptive norms and self-reported passing behavior., Results: Survey data from 201 adult drivers showed that only 10% of respondents considered farm equipment crashes to be a top road safety concern. Respondents who perceived others passing farm equipment frequently in their community were more likely to report that they also frequently pass farm equipment. The results also showed interactions between gender and experience operating farm equipment in terms of self-reported passing behavior., Conclusions/implications: Results from this study suggest local and state-level norms and perceptions of those norms may be important targets for intervention to improve individual driving behaviors around farm equipment., Competing Interests: Declaration of competing interest The authors do not have any competing interests to declare.

Staphylococcus capitis is a frequent cause of late-onset sepsis in neonates admitted to Neonatal Intensive Care Units (NICU). One clone of S. capitis , NRCS-A has been isolated from NICUs globally although the reasons for the global success of this clone are not well understood.We analysed a collection of S. capitis colonising babies admitted to two NICUs, one in the UK and one in Germany as well as corresponding pathological clinical isolates. Genome analysis identified a population structure of three groups; non-NRCS-A isolates, NRCS-A isolates, and a group of 'proto NRCS-A' - isolates closely related to NRCS-A but not associated with neonatal infection. All bloodstream isolates belonged to the NRCS-A group and were indistinguishable from strains carried on the skin or in the gut. NRCS-A isolates showed increased tolerance to chlorhexidine and antibiotics relative to the other S. capitis as well as enhanced ability to grow at higher pH values. Analysis of the pangenome of 138 isolates identified characteristic nsr and tarJ genes in both the NRCS-A and proto groups. A CRISPR-cas system was only seen in NRCS-A isolates which also showed enrichment of genes for metal acquisition and transport.We found evidence for transmission of S. capitis NRCS-A within NICU, with related isolates shared between babies and multiple acquisitions by some babies. Our data show NRCS-A strains commonly colonise uninfected babies in NICU representing a potential reservoir for potential infection. This work provides more evidence that adaptation to survive in the gut and on skin facilitates spread of NRCS-A, and that metal acquisition and tolerance may be important to the biology of NRCS-A. Understanding how NRCS-A survives in NICUs can help develop infection control procedures against this clone.

Intratumoral heterogeneity can wreak havoc on current precision medicine strategies because of challenges in sufficient sampling of geographically separated areas of biodiversity distributed across centimeter-scale tumor distances. To address this gap, we developed a deep learning pipeline that leverages histomorphologic fingerprints of tissue to create "Histomic Atlases of Variation Of Cancers" (HAVOC). Using a number of objective molecular readouts, we demonstrate that HAVOC can define regional cancer boundaries with distinct biology. Using larger tumor specimens, we show that HAVOC can map biodiversity even across multiple tissue sections. By guiding profiling of 19 partitions across six high-grade gliomas, HAVOC revealed that distinct differentiation states can often coexist and be regionally distributed within these tumors. Last, to highlight generalizability, we benchmark HAVOC on additional tumor types. Together, we establish HAVOC as a versatile tool to generate small-scale maps of tissue heterogeneity and guide regional deployment of molecular resources to relevant biodiverse niches.

Many malignant cancers like glioblastoma are highly adaptive diseases that dynamically change their regional biology to survive and thrive under diverse microenvironmental and therapeutic pressures. While the concept of intra-tumoral heterogeneity has become a major paradigm in cancer research and care, systematic approaches to assess and document bio-variation in cancer are still in their infancy. Here we discuss existing approaches and challenges to documenting intra-tumoral heterogeneity and emerging computational approaches that leverage artificial intelligence to begin to overcome these limitations. We propose how these emerging techniques can be coupled with a diversity of molecular tools to address intra-tumoral heterogeneity more systematically in research and in practice, especially across larger specimens and longitudinal analyses. Systematic documentation and characterization of heterogeneity across entire tumor specimens and their longitudinal evolution has the potential to improve our understanding and treatment of cancer., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Aims: Immunohistochemistry (IHC) assessment of tissue is a central component of the modern pathology workflow, but quantification is challenged by subjective estimates by pathologists or manual steps in semi-automated digital tools. This study integrates various computer vision tools to develop a fully automated workflow for quantifying Ki-67, a standard IHC test used to assess cell proliferation on digital whole slide images (WSIs)., Methods: We create an automated nuclear segmentation strategy by deploying a Mask R-CNN classifier to recognise and count 3,3'-diaminobenzidine positive and negative nuclei. To further improve automation, we replaced manual selection of regions of interest (ROIs) by aligning Ki-67 WSIs with corresponding H&E-stained sections, using scale-invariant feature transform (SIFT) and a conventional histomorphological convolutional neural networks to define tumour-rich areas for quantification., Results: The Mask R-CNN was tested on 147 images generated from 34 brain tumour Ki-67 WSIs and showed a high concordance with aggregate pathologists' estimates ([Formula: see text] assessors; [Formula: see text] r=0.9750). Concordance of each assessor's Ki-67 estimates was higher when compared with the Mask R-CNN than between individual assessors (r avg =0.9322 vs 0.8703; p=0.0213). Coupling the Mask R-CNN with SIFT-CNN workflow demonstrated ROIs can be automatically chosen and partially sampled to improve automation and dramatically decrease computational time (average: 88.55-19.28 min; p<0.0001)., Conclusions: We show how innovations in computer vision can be serially compounded to automate and improve implementation in clinical workflows. Generalisation of this approach to other ancillary studies has significant implications for computational pathology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The dynamics of a community of four planktonic bacterial strains isolated from river water was followed in R2 broth for 72 h in batch experiments. These strains were identified as Janthinobacterium sp., Brevundimonas sp., Flavobacterium sp. and Variovorax sp. 16S rRNA gene sequencing and flow cytometry analyses were combined to monitor the change in abundance of each individual strain in bi-cultures and quadri-culture. Two interaction networks were constructed that summarize the impact of the strains on each other's growth rate in exponential phase and carrying capacity in stationary phase. The networks agree on the absence of positive interactions but also show differences, implying that ecological interactions can be specific to particular growth phases. Janthinobacterium sp. was the fastest growing strain and dominated the co-cultures. However, its growth rate was negatively affected by the presence of other strains 10 to 100 times less abundant than Janthinobacterium sp. In general, we saw a positive correlation between growth rate and carrying capacity in this system. In addition, growth rate in monoculture was predictive of carrying capacity in co-culture. Taken together, our results highlight the necessity to take growth phases into account when measuring interactions within a microbial community. In addition, evidence that a minor strain can greatly influence the dynamics of a dominant one underlines the necessity to choose population models that do not assume a linear dependency of interaction strength to abundance of other species for accurate parameterization from such empirical data., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)