Tackle Risk Factors for Head Injury Assessments (HIAs) in Sub-Elite Rugby League and Recommendations for Prevention: Head Contacts from Upright Tackles Increase the HIA Risk to Both Ball Carrier and Tackler.

BACKGROUND: The rugby league tackle has been identified as the game event with the greatest propensity for a clinically diagnosed concussion. This study aims to replicate the work conducted in professional rugby league and rugby union by examining Head Injury Assessment (HIA) events to determine the associated tackle characteristics that increase concussion risk in sub-elite rugby league players. This comparison between competition levels is important due to the less developed physiological and tackle proficiency characteristics of sub-elite rugby league players and the fewer resources available for an on-field diagnosis, compared to the elite level of the sport. RESULTS: Tackles resulting in Head Injury Assessments (HIAs, n = 131) and 2,088 tackles that did not result in a head injury were identified and coded from one season of the 2019 Queensland Cup. The body position of both ball carrier and tackler, tackle height, and body contact areas were evaluated. The propensity for tacklers to undergo a head injury assessment was 1.49 HIAs per 1,000 tackles, equating to a 2.5-fold higher risk than that of the ball carrier (0.59 HIAs per 1,000 tackles). The risk for an HIA was 2.75-fold greater when the tackler was upright (2.89 HIAs per 1,000 tackles) compared to a bent-at-the-waist tackler (1.05 HIAs per 1,000 tackles). The greatest risk for the tackler and ball carrier sustaining an HIA occurred when the tackle height was high, with head-to-head contact having the greatest propensity for an HIA (44.37 HIAs per 1,000 tackles). HIA risk was also greater for both players when the ball carrier did not employ an evasion strategy (3.73 HIAs per 1,000 tackles). CONCLUSIONS: The study replicates results from research in elite rugby league and rugby union. A combination of higher head contact/proximity and upright body position significantly increase an HIA risk. Tackler head position and ball carrier evasion behaviours also affect risk, suggesting that injury prevention strategies designed to reduce tackle height and improve tackle technique by focusing on head position, body position, and in a novel finding, ball carrier evasion, may reduce head injury risk in sub-elite rugby league players.

Dopamine­iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

Controlling stable Bloch points with electric currents.

The Bloch point is a point singularity in the magnetisation configuration, where the magnetisation vanishes. It can exist as an equilibrium configuration and plays an important role in many magnetisation reversal processes. In the present work, we focus on manipulating Bloch points in a system that can host stable Bloch points-a two-layer FeGe nanostrip with opposite chirality of the two layers. We drive Bloch points using spin-transfer torques and find that Bloch points can move collectively without any Hall effect and report that Bloch points are repelled from the sample boundaries and each other. We study pinning of Bloch points at wedge-shaped constrictions (notches) in the nanostrip and demonstrate that arrays of Bloch points can be moved past a series of notches in a controlled manner by applying consecutive current pulses of different strength. Finally, we simulate a T-shaped geometry and demonstrate that a Bloch point can be moved along different paths by applying current between suitable strip ends.

Impact of a pediatric primary care health-coaching program on change in health-related quality of life in children with mental health problems: results of the PrimA-QuO cohort study.

Mental health problems (MHP) have a considerable negative impact on health-related quality of life (HRQoL) in children and their families. A low threshold Health Coaching (HC) program has been introduced to bring MH services to primary care and strengthen the role of pediatricians. It comprised training concepts as a hands-on approach for pediatricians, standardization of diagnosis and treatment, and extended consultations. The aim of this study was to evaluate the potential effects of the HC on HRQoL in children with MHP and their parents.We used data from the PrimA-QuO cohort study conducted in Bavaria, Germany from November 2018 until November 2019, with two assessments one year apart. We included children aged 17 years or younger with developmental disorder of speech and language, non-organic enuresis, head and abdominal pain, and conduct disorder. All included children were already part of the Starke Kids (SK) program, a more general preventive care program, which includes additional developmental check-ups for children enrolled in the program. In addition,  treatment according to the HC guidelines can be offered to children and adolescents with mental health problems, who are already enrolled in the SK program. These children form the intervention group; while all others (members of BKK and SK but not HC) served as controls. HRQoL in children was assessed using the KINDL questionnaire. Parental HRQoL was measured by the visual analogue scale. To analyze the effects of the intervention on children´s HRQoL over the 1-year follow-up period, we used linear mixed effects models.We compared 342 children receiving HC with 767 control patients. We could not detect any effects of the HC on HRQoL in children and their parents. This may be attributed to the relatively high levels of children´s HRQoL at baseline, or because of highly motivated pediatricians for the controls because of the selection of only participant within the Starke Kids program. Generally, HRQoL was lower in older children (-0.42 points; 95% CI [-0.73; -0.11]) and in boys (-1.73 points; 95% CI [-3.11; -0.36]) when reported by proxy. Parental HRQoL improved significantly over time (2.59 points; 95% CI [1.29; 3.88]).Although this study was not able to quantitatively verify the positive impact of this HC that had been reported by a qualitative study with parents and other stakeholders, and a cost-effectiveness study, the approach of the HC may still be valid and improve health care of children with MHP and should be evaluated in a more general population.

Gods are watching and so what? Moralistic supernatural punishment across 15 cultures.

Psychological and cultural evolutionary accounts of human sociality propose that beliefs in punitive and monitoring gods that care about moral norms facilitate cooperation. While there is some evidence to suggest that belief in supernatural punishment and monitoring generally induce cooperative behaviour, the effect of a deity's explicitly postulated moral concerns on cooperation remains unclear. Here, we report a pre-registered set of analyses to assess whether perceiving a locally relevant deity as moralistic predicts cooperative play in two permutations of two economic games using data from up to 15 diverse field sites. Across games, results suggest that gods' moral concerns do not play a direct, cross-culturally reliable role in motivating cooperative behaviour. The study contributes substantially to the current literature by testing a central hypothesis in the evolutionary and cognitive science of religion with a large and culturally diverse dataset using behavioural and ethnographically rich methods.

Bloch points in nanostrips.

Complex magnetic materials hosting topologically non-trivial particle-like objects such as skyrmions are under intensive research and could fundamentally change the way we store and process data. One important class of materials are helimagnetic materials with Dzyaloshinskii-Moriya interaction. Recently, it was demonstrated that thin nanodisks consisting of two layers with opposite chirality can host a single stable Bloch point of two different types at the interface between the layers. Using micromagnetic simulations we show that FeGe nanostrips consisting of two layers with opposite chirality can host multiple coexisting Bloch points in an arbitrary combination of the two different types. We show that the number of Bloch points that can simultaneously coexist depends on the strip geometry and the type of the individual Bloch points. Our simulation results allow us to predict strip geometries suitable for an arbitrary number of Bloch points. We show an example of an 80-Bloch-point configuration verifying the prediction.

High-throughput and targeted drug screens identify pharmacological candidates against MiT-translocation renal cell carcinoma.

BACKGROUND: MiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3, TFEB, or MITF. MiT-RCC represents a specific subtype of sporadic RCC that is predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology of this aggressive cancer is poorly understood and there is no accepted standard of care therapy for patients with advanced disease. Tumor-derived cell lines have been established from human TFE3-RCC providing useful models for preclinical studies. METHODS: TFE3-RCC tumor derived cell lines and their tissues of origin were characterized by IHC and gene expression analyses. An unbiased high-throughput drug screen was performed to identify novel therapeutic agents for treatment of MiT-RCC. Potential therapeutic candidates were validated in in vitro and in vivo preclinical studies. Mechanistic assays were conducted to confirm the on-target effects of drugs. RESULTS: The results of a high-throughput small molecule drug screen utilizing three TFE3-RCC tumor-derived cell lines identified five classes of agents with potential pharmacological efficacy, including inhibitors of phosphoinositide-3-kinase (PI3K) and mechanistic target of rapamycin (mTOR), and several additional agents, including the transcription inhibitor Mithramycin A. Upregulation of the cell surface marker GPNMB, a specific MiT transcriptional target, was confirmed in TFE3-RCC and evaluated as a therapeutic target using the GPNMB-targeted antibody-drug conjugate CDX-011. In vitro and in vivo preclinical studies demonstrated efficacy of the PI3K/mTOR inhibitor NVP-BGT226, Mithramycin A, and CDX-011 as potential therapeutic options for treating advanced MiT-RCC as single agents or in combination. CONCLUSIONS: The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC.

Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank.

Genome-wide association studies have discovered hundreds of associations between common genotypes and kidney function but cannot comprehensively investigate rare coding variants. Here, we apply a genotype imputation approach to whole exome sequencing data from the UK Biobank to increase sample size from 166,891 to 408,511. We detect 158 rare variants and 105 genes significantly associated with one or more of five kidney function traits, including genes not previously linked to kidney disease in humans. The imputation-powered findings derive support from clinical record-based kidney disease information, such as for a previously unreported splice allele in PKD2, and from functional studies of a previously unreported frameshift allele in CLDN10. This cost-efficient approach boosts statistical power to detect and characterize both known and novel disease susceptibility variants and genes, can be generalized to larger future studies, and generates a comprehensive resource ( https://ckdgen-ukbb.gm.eurac.edu/ ) to direct experimental and clinical studies of kidney disease.

TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.

Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.

Effects of predictable behavioral patterns on anxiety dynamics.

People face stressors that are beyond their control and that maladaptively perpetuate anxiety. In these contexts, rituals emerge as a natural coping strategy helping decrease excessive anxiety. However, mechanisms facilitating these purported effects have rarely been studied. We hypothesized that repetitive and rigid ritual sequences help the human cognitive-behavioral system to return to low-entropy states and assuage anxiety. This study reports a pre-registered test of this hypothesis using a Czech student sample (n = 268). Participants were exposed to an anxiety induction and then randomly assigned to perform one of three actions: ritualized, control, and neutral (no-activity). We assessed the effects of this manipulation on cognitive and physiological anxiety, finding that ritualized action positively affected anxiety decrease, but this decrease was only slightly larger than in the other two conditions. Nevertheless, the between-condition differences in the reduction of physiological anxiety were well-estimated in participants more susceptible to anxiety induction.

Megahertz-rate ultrafast X-ray scattering and holographic imaging at the European XFEL.

The advent of X-ray free-electron lasers (XFELs) has revolutionized fundamental science, from atomic to condensed matter physics, from chemistry to biology, giving researchers access to X-rays with unprecedented brightness, coherence and pulse duration. All XFEL facilities built until recently provided X-ray pulses at a relatively low repetition rate, with limited data statistics. Here, results from the first megahertz-repetition-rate X-ray scattering experiments at the Spectroscopy and Coherent Scattering (SCS) instrument of the European XFEL are presented. The experimental capabilities that the SCS instrument offers, resulting from the operation at megahertz repetition rates and the availability of the novel DSSC 2D imaging detector, are illustrated. Time-resolved magnetic X-ray scattering and holographic imaging experiments in solid state samples were chosen as representative, providing an ideal test-bed for operation at megahertz rates. Our results are relevant and applicable to any other non-destructive XFEL experiments in the soft X-ray range.

Longitudinal changes of mental health problems in children and adolescents treated in a primary care-based health-coaching programme - results of the PrimA-QuO cohort study.

BACKGROUND: In Germany, 19.1% of boys and 14.5% of girls are affected by mental health problems (MHP). Paediatricians are usually the first in line to be contacted but they often do not feel adequately trained to diagnose and treat MHP in primary care. A major statutory health insurance fund introduced a health coaching (HC) programme to strengthen primary care consultation for MHP. The HC includes a training concept for paediatricians, standardised guidelines for actions and additional payments. The aim of this study was to investigate the potential effects of the HC programme on the change of MHP in children and adolescents. METHODS: A prospective cohort study was conducted in Bavaria, Germany, in 2018 and 2019. Data were collected at 2 points 1 year apart using an online questionnaire. Parents of patients with developmental disorder of speech and language, head/abdominal pain, conduct disorder or non-organic enuresis were approached by their health insurance. Families treated according to the HC programme form the intervention group while all others serve as controls. MHP was assessed using the Strengths and Difficulties Questionnaire (SDQ) as a child self-assessment (SDQ-S)/or external assessment by parents (SDQ-P). Determinants of SDQ total score were analysed using linear mixed effects models. RESULTS: Cross-sectional (n = 1090) and longitudinal analyses (n = 599) were performed. At baseline, a total of 23.5% had an SDQ total score "at risk" (SDQ-S > 15/SDQ-P > 13). There were no significant differences between intervention and controls. After full adjustment for all potential confounders, higher SDQ scores indicating more problems were significantly associated with male sex (2.000, p < 0.001) whereas a high parental education level was significantly associated with decreased SDQ scores (-2.127, p =0.034). There was a significant improvement in the control group over time (-0.814, p = 0.001) while the SDQ scores in the intervention group remained stable (-0.012, p = 0.020). CONCLUSION: This evaluation of the HC programme could not prove a clinically relevant intervention's effect on the MHP developmental course. Nevertheless, (HC) paediatricians have crucial potential to improve the care of MHP patients. Targeting families with less access to support measures might help reduce the burden of MHP and be a step towards continuous improvement of care.

Crosstalk of organelles in Parkinson's disease - MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes.

Living organisms constantly need to adapt to their surrounding environment and have evolved sophisticated mechanisms to deal with stress. Mitochondria and lysosomes are central organelles in the response to energy and nutrient availability within a cell and act through interconnected mechanisms. However, when such processes become overwhelmed, it can lead to pathologies. Parkinson's disease (PD) is a common neurodegenerative disorder (NDD) characterized by proteinaceous intracellular inclusions and progressive loss of dopaminergic neurons, which causes motor and non-motor symptoms. Genetic and environmental factors may contribute to the disease etiology. Mitochondrial dysfunction has long been recognized as a hallmark of PD pathogenesis, and several aspects of mitochondrial biology are impaired in PD patients and models. In addition, defects of the autophagy-lysosomal pathway have extensively been observed in cell and animal models as well as PD patients' brains, where constitutive autophagy is indispensable for adaptation to stress and energy deficiency. Genetic and molecular studies have shown that the functions of mitochondria and lysosomal compartments are tightly linked and influence each other. Connections between these organelles are constituted among others by mitophagy, organellar dynamics and cellular signaling cascades, such as calcium (Ca2+) and mTOR (mammalian target of rapamycin) signaling and the activation of transcription factors. Members of the Microphthalmia-associated transcription factor family (MiT), including MITF, TFE3 and TFEB, play a central role in regulating cellular homeostasis in response to metabolic pressure and are considered master regulators of lysosomal biogenesis. As such, they are part of the interconnection between mitochondria and lysosome functions and therefore represent attractive targets for therapeutic approaches against NDD, including PD. The activation of MiT transcription factors through genetic and pharmacological approaches have shown encouraging results at ameliorating PD-related phenotypes in in vitro and in vivo models. In this review, we summarize the relationship between mitochondrial and autophagy-lysosomal functions in the context of PD etiology and focus on the role of the MiT pathway and its potential as pharmacological target against PD.

A genome on shaky ground: exploring the impact of mitochondrial DNA integrity on Parkinson's disease by highlighting the use of cybrid models.

Mitochondria play important roles in the regulation of key cellular processes, including energy metabolism, oxidative stress response, and signaling towards cell death or survival, and are distinguished by carrying their own genome (mtDNA). Mitochondrial dysfunction has emerged as a prominent cellular mechanism involved in neurodegeneration, including Parkinson's disease (PD), a neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons and the occurrence of proteinaceous Lewy body inclusions. The contribution of mtDNA variants to PD pathogenesis has long been debated and is still not clearly answered. Cytoplasmic hybrid (cybrid) cell models provided evidence for a contribution of mtDNA variants to the PD phenotype. However, conclusive evidence of mtDNA mutations as genetic cause of PD is still lacking. Several models have shown a role of somatic, rather than inherited mtDNA variants in the impairment of mitochondrial function and neurodegeneration. Accordingly, several nuclear genes driving inherited forms of PD are linked to mtDNA quality control mechanisms, and idiopathic as well as familial PD tissues present increased mtDNA damage. In this review, we highlight the use of cybrids in this PD research field and summarize various aspects of how and to what extent mtDNA variants may contribute to the etiology of PD.

Advertising cooperative phenotype through costly signals facilitates collective action.

Around the world, people engage in practices that involve self-inflicted pain and apparently wasted resources. Researchers theorized that these practices help stabilize within-group cooperation by assorting individuals committed to collective action. While this proposition was previously studied using existing religious practices, we provide a controlled framework for an experimental investigation of various predictions derived from this theory. We recruited 372 university students in the Czech Republic who were randomly assigned into either a high-cost or low-cost condition and then chose to play a public goods game (PGG) either in a group that wastes money to signal commitment to high contributions in the game or to play in the group without such signals. We predicted that cooperators would assort in the high-cost revealed group and that, despite these costs, they would contribute more to the common pool and earn larger individual rewards over five iterations of PGG compared with the concealed group and participants in the low-cost condition. The results showed that the assortment of cooperators was more effective in the high-cost condition and translated into larger contributions of the remaining endowment to the common pool, but participants in the low-cost revealed group earned the most. We conclude that costly signals can serve as an imperfect assorting mechanism, but the size of the costs needs to be carefully balanced with potential benefits to be profitable.

A germline 1;3 translocation disrupting the VHL gene: a novel genetic cause for von Hippel-Lindau.

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumour susceptibility disease caused by germline pathogenic variation of the VHL tumour suppressor gene. Affected individuals are at risk of developing multiple malignant and benign tumours in a number of organs.In this report, a male patient in his 20s who presented to the Urologic Oncology Branch at the National Cancer Institute with a clinical diagnosis of VHL was found to have multiple cerebellar haemangioblastomas, bilateral epididymal cysts, multiple pancreatic cysts, and multiple, bilateral renal tumours and cysts. The patient had no family history of VHL and was negative for germline VHL mutation by standard genetic testing. Further genetic analysis demonstrated a germline balanced translocation between chromosomes 1 and 3, t(1;3)(p36.3;p25) with a breakpoint on chromosome 3 within the second intron of the VHL gene. This created a pathogenic germline alteration in VHL by a novel mechanism that was not detectable by standard genetic testing.Karyotype analysis is not commonly performed in existing genetic screening protocols for patients with VHL. Based on this case, protocols should be updated to include karyotype analysis in patients who are clinically diagnosed with VHL but demonstrate no detectable mutation by existing genetic testing.

Cost Effects of a Health Coaching in Children and Adolescents With Mental Health and Developmental Disorders.

OBJECTIVE: Health coaching (HC) aims to strengthen the role of primary care pediatricians in the treatment of children and adolescents with mental health and developmental disorders by extending consultation time and using disease-specific manuals. We evaluated the effect of HC on costs of specialized, pediatrician, and overall care. METHODS: In a retrospective cohort study based on German health insurance claims data, we identified children aged up to 17 years with a newly diagnosed mental health and/or developmental disorder between 2013 and 2015. Patients getting HC were matched to patients receiving usual care. Costs were calculated for 1 year following the start of the treatment and compared by 2-part and gamma models. Absolute costs and cost differences were calculated with bootstrapped 95% confidence intervals (CI). RESULTS: We compared 5597 patients receiving HC with 5597 control patients. The probability of incurring specialized care costs was similar between the groups (0.96, 95% CI: 0.88; 1.05). However, for those who did incur costs, specialized care costs were significantly lower for HC-treated patients (0.77, 95% CI: 0.63; 0.93). Accordingly, specialized care costs were lower by €-94 (95% CI: €-175; €-18), while pediatrician care costs were higher for HC-treated patients by €57 (95% CI: €49; €64). Hence, overall costs did not differ between the groups (€-59, 95% CI: €-191; €71). CONCLUSION: Provision of HC has the potential to lower the costs of specialized care, while increasing the costs of pediatrician care. Overall costs did not differ, suggesting that the additional costs incurred by the HC were offset.

A comparison of self-report, systematic observation and third-party judgments of church attendance in a rural Fijian Village.

Social desirability reporting leads to over estimations of church attendance. To date, researchers have treated over-reporting of church attendance as a general phenomenon, and have been unable to determine the demographic correlates of inaccuracy in these self-reports. By comparing over eight months of observational data on church attendance (n = 48 services) to self-report in a rural Fijian village, we find that 1) self-report does not reliably predict observed attendance, 2) women with two or more children (≥ 2) are more likely to over-report their attendance than women with fewer children (≤ 1), and 3) self-report of religiosity more reliably predicts observed church attendance than does self-report of church attendance. Further, we find that third-party judgements of church attendance by fellow villagers are more reliably associated with observed church attendance than self-report. Our findings suggest that researchers interested in estimating behavioral variation, particularly in domains susceptible to social desirability effects, should consider developing and employing third-party methods to mitigate biases inherent to self-report.